Value through Innovation30 September 2014

Scientific Publications

Boehringer Ingelheim offers an overview of scientific publications on the following pages. This overview represents all publications of the last three years (YTD) where employees of Boehringer Ingelheim worldwide were involved.

185 publications regarding Metabolism
  • Author:
    Korzekwa K; Tweedie D; Argikar UA; Whitcher-Johnstone A; Bell L; Bickford S; Nagar S
    Title:
    A numerical method for analysis of in vitro time-dependent inhibition data. Part 2. Application to experimental data
    Source:
    Drug Metab Dispos 42 (9), 1587-1595 (2014)
    Abstract:
    Time-dependent inhibition (TDI) of cytochrome P450 enzymes is an important cause of drug-drug interactions. The standard approach to characterize the kinetics of TDI is to determine the rate of enzyme loss, kobs, at various inhibitor concentrations, [I], and replot the kobs versus [I] to obtain the key kinetic parameters, KI and kinact. In our companion manuscript (Part 1; Nagar et al., 2014) in this issue of Drug Metabolism and Disposition, we used simulated datasets to develop and test a new numerical method to analyze in vitro TDI data. Here, we have applied this numerical method to five TDI datasets. Experimental datasets include the inactivation of CYP2B6, CYP2C8, and CYP3A4. None of the datasets exhibited Michaelis-Menten-only kinetics, and the numerical method allowed use of more complex models to fit each dataset. Quasi-irreversible as well as partial inhibition kinetics were observed and parameterized. Three datasets required the use of a multiple-inhibitor binding model. The mechanistic and clinical implications provided by these analyses are discussed. Together with the results in Part 1, we have developed and applied a new numerical method for analysis of in vitro TDI data. This method appears to be generally applicable to model in vitro TDI data with atypical and complex kinetic schemes. Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics.
  • Author:
    Lehrke M; Marx N; Patel S; Seck T; Crowe S; Cheng K; Von Eynatten M; Johansen O.E
    Title:
    Safety and tolerability of linagliptin in patients with type 2 diabetes: A comprehensive pooled analysis of 22 placebo-controlled studies
    Source:
    Clin Ther 36 (8), 1130-1146 (2014)
    Abstract:
    Purpose Dipeptidyl peptidase (DPP)-4 inhibitors are an increasingly used antihyperglycemic therapy for patients with type 2 diabetes mellitus (T2DM). Linagliptin, an orally administered DPP-4 inhibitor, has demonstrated favorable efficacy/safety in clinical trials. The aim of this post hoc pooled analysis was to expand current knowledge of the safety of linagliptin. Methods Safety data for once-daily linagliptin 5 mg (1 study of linagliptin 2.5 mg twice daily) were analyzed from 22 randomized, double-blind, Phase I-III, placebo-controlled clinical trials of .102 weeks' duration. Assessments of pooled data included incidence of patient-reported adverse events (AEs). Findings Data from 7400 patients (linagliptin, 4810; placebo, 2590) were pooled. Most patients (58.4%) had T2DM diagnosis for 5 years; approximately 75% were receiving .1 type of background therapy in addition to linagliptin/placebo. Overall exposure to the study drug was 2412.8 years for linagliptin and 1481.4 years for placebo (mean [SD], 183 [120] days and 209 [150] days, respectively). Overall frequencies of AEs were similar for linagliptin- and placebo-treated patients (57.3% and 61.8%, respectively). The incidence of neoplastic AEs was low (0.6% and 0.9%, respectively); there were no reports of pancreatic neoplasia. Pancreatitis was observed in 2 linagliptin-treated patients (<0.1%) and 1 placebo-treated patient (<0.1%). The occurrence of cardiac disorder AEs was similar in linagliptin- and placebo-treated patients (3.2% [n = 153] and 3.3% [n = 83], respectively); the incidence of heart failure AEs for linagliptin- and placebo-treated patients was 0.2% (n = 11) and 0.3% (n = 7), respectively. Overall, linagliptin was weight neutral. Occurrence of investigator-defined hypoglycemic AEs was low for both linagliptin and placebo (11.5% vs 14.0%). In patients receiving concomitant sulfonylurea therapy, investigator-defined hypoglycemic AEs were more frequent with linagliptin versus placebo (22.1% [238/1079] vs 14.5% [61/421], respectively). Subgroup analyses showed similar frequencies of AEs for linagliptin- and placebo-treated patients across different age groups and renal function levels. Implications This updated and expanded pooled, post hoc analysis of 22 placebo-controlled trials of linagliptin 5 mg daily supports previous findings of the acceptable overall safety/tolerability profile of linagliptin when administered to a broad range of patients with T2DM. Linagliptin-treated patients demonstrated a low overall risk of hypoglycemia (risk increased by concomitant sulfonylurea therapy). As with all pooled analyses, this study is limited by the use of data from different studies, and the relatively short duration of some included studies, although use of individual patient data from consistently designed trials should minimize methodological differences between trials. Results from ongoing clinical trials will provide additional insight into the long-term safety/tolerability of linagliptin. © 2014 The Authors.
  • Author:
    Vazvaei F; Duggan JX
    Title:
    Validation of LC-MS/MS bioanalytical methods for protein therapeutics
    Source:
    Bioanalysis 6 (13), 1739-1742 (2014)
    Abstract:
    no abstract available
  • Author:
    Sarashina A; Ueki K; Sasaki T; Tanaka Y; Koiwai K; Sakamoto W; Woerle HJ; Salsali A; Broedl UC; Macha S
    Title:
    Effect of Renal Impairment on the Pharmacokinetics, Pharmacodynamics, and Safety of Empagliflozin, a Sodium Glucose Cotransporter 2 Inhibitor, in Japanese Patients With Type 2 Diabetes Mellitus
    Source:
    Clin Ther Article in Press (2014)
    Abstract:
    Purpose: The purpose of this study was to assess the effect of renal impairment on the pharmacokinetic, pharmacodynamic, and safety profiles of empagliflozin, a sodium glucose cotransporter 2 (SGLT2) inhibitor, in Japanese patients with type 2 diabetes mellitus (T2DM). Methods: In an open-label, parallel-group study, 32 Japanese patients with T2DM and different degrees of renal function (n = 8 per renal function category: normal renal function, estimated glomerular filtration rate [eGFR; Japanese equation] .90 mL/min/1.73 m2; mild renal impairment, eGFR of 60-&lt;90 mL/min/1.73 m2; moderate renal impairment, eGFR of 30-&lt;60 mL/min/1.73 m2; and severe renal impairment, eGFR of 15-&lt;30 mL/min/1.73 m2) received a single 25 mg dose of empagliflozin. Findings: Empagliflozin exposure increased with increasing renal impairment. Maximum empagliflozin plasma concentrations were similar among all renal function groups. Adjusted geometric mean ratios for extent of exposure (AUC0-.) to empagliflozin versus normal renal function were 128.8% (95% CI, 106.0-156.6%), 143.8% (95% CI, 118.3-174.8%), and 152.3% (95% CI, 125.3-185.2%) for patients with mild, moderate, and severe renal impairment, respectively. Decreases in renal clearance of empagliflozin correlated with eGFR. Urinary glucose excretion decreased with increasing renal impairment and correlated with eGFR (adjusted mean [SE] change from baseline: 75.0 [4.84] g, 62.6 [5.75] g, 57.9 [4.86] g, and 23.7 [5.24] g for patients with normal renal function and mild, moderate, and severe renal impairment, respectively). Only 2 patients (6%) had adverse events; both were mild. Implications: Pharmacokinetic data suggest that no dose adjustment of empagliflozin is necessary in Japanese patients with T2DM and renal impairment because increases in exposure were &lt;2-fold. Urinary glucose excretion decreased with increasing renal impairment. ClinicalTrials.gov identifier: NCT01581658. © 2014 Elsevier HS Journals, Inc. All rights reserved.
  • Author:
    Darsalia V; Nathanson D; Nyström T; Klein T; Sjöholm Å; Patrone C
    Title:
    GLP-1R activation for the treatment of stroke: Updating and future perspectives
    Source:
    Rev Endocr Metab Disord 15 (3), 233-242 (2014)
    Abstract:
    Stroke is the leading cause of adult disability in Westernized societies with increased incidence along ageing and it represents a major health and economical threat. Inactive lifestyle, smoking, hypertension, atherosclerosis, obesity and diabetes all dramatically increase the risk of stroke. While preventive strategies based on lifestyle changes and risk factor management can delay or decrease the likelihood of having a stroke, post stroke pharmacological strategies aimed at minimizing stroke-induced brain damage are highly needed. Unfortunately, several candidate drugs that have shown significant preclinical neuroprotective efficacy, have failed in clinical trials and no treatment for stroke based on neuroprotection is available today. Glucagon-like peptide 1 (GLP-1) is a peptide originating in the enteroendocrine L-cells of the intestine and secreted upon nutrient ingestion. The activation of the GLP-1R by GLP-1 enhances glucose-dependent insulin secretion, suppresses glucagon secretion and exerts multifarious extrapancreatic effects. Stable GLP-1 analogues and inhibitors of the proteolytic enzyme dipeptidyl peptidase 4 (DPP-4) (which counteract endogenous GLP-1 degradation) have been developed clinically for the treatment of type 2 diabetes. Besides their antidiabetic properties, experimental evidence has shown neurotrophic and neuroprotective effects of GLP-1R agonists and DPP-4 inhibitors in animal models of neurological disorders. Herein, we review recent experimental data on the neuroprotective effects mediated by GLP-1R activation in stroke. Due to the good safety profile of the drugs targeting the GLP-1R, we also discuss the high potential of GLP-1R stimulation in view of developing a safe clinical treatment against stroke based on neuroprotection in both diabetic and non-diabetic patients. © 2014 Springer Science+Business Media.
  • Author:
    Zimdahl H; Ittrich C; Graefe-Mody U; Boehm BO; Mark M; Woerle H-J; Dugi KA
    Title:
    Influence of TCF7L2 gene variants on the therapeutic response to the dipeptidylpeptidase-4 inhibitor linagliptin
    Source:
    Diabetologia 57 (9), 1869-1875 (2014)
    Abstract:
    Aims/hypothesis: Individuals carrying variants of the transcription factor 7-like 2 gene (TCF7L2) are at increased risk for type 2 diabetes. These metabolic genetic risk factors have been linked to diminished pancreatic islet-cell responsiveness to incretins, thus pharmacological interventions aimed at amplifying endogenous incretin biology may be affected. However, clinical evidence from randomised controlled trials so far is lacking. We investigated the influence of TCF7L2 risk alleles on the response to treatment with the dipeptidylpeptidase-4 (DPP-4) inhibitor linagliptin from four 24 week, phase III, placebo-controlled trials. Methods: Pharmacogenomic samples and clinical data were available from 961 patients with type 2 diabetes. Whole-blood DNA samples were genotyped for TCF7L2 single-nucleotide polymorphisms in conjunction with assessments of 24 week changes in HbA1c. Results: Linagliptin lowered HbA1c meaningfully in all three genotypes of rs7903146 (non-risk variant carriers CC [n = 356]: -0.82% [-9.0 mmol/mol], p &lt; 0.0001; heterozygous CT [n = 264]: -0.77% [-8.4 mmol/mol], p &lt; 0.0001; homozygous risk variant carriers TT [n = 73]: -0.57% [-6.2 mmol/mol], p &lt; 0.0006). No significant treatment differences were seen between CC and CT patients, although HbA1c response was reduced in TT compared with CC patients (~0.26% [~2.8 mmol/mol], p = 0.0182). Conclusions/interpretation: Linagliptin significantly improved hyperglycaemia in patients with type 2 diabetes both with and without the TCF7L2 gene diabetes risk alleles. However, differences in treatment response were observed, indicating that diabetes susceptibility genes may be an important contributor to the inter-individual variability of treatment response. © 2014 The Author(s).
  • Author:
    Metsärinne K; Bröijersen A; Kantola I; Niskanen L; Rissanen A; Appelroth Tina; Pöntynen Nora; Poussa T; Koivisto V; Virkamäki; Antti
    Title:
    High prevalence of chronic kidney disease in Finnish patients with type 2 diabetes treated in primary care
    Source:
    Prim Care Diabetes Article in Press (2014)
    Abstract:
    Objective: To examine the prevalence of chronic kidney disease (CKD) and related cardiovascular morbidity in a cross-sectional population in patients with type 2 diabetes (T2D) treated in a primary care setting in Finland. Research design and methods: Data were collected and recorded from 42 primary care centres, which recruited 629 patients diagnosed with type 2 diabetes (T2D) to this non-interventional study. Data including patient characteristics, kidney function and albuminuria, blood pressure, HbA1c, lipid and lipoprotein levels, and diabetes duration as well as current medication was collected in each patient. Results: In the final study population of 625 patients, the mean age was 67 years (range 29-92 years), BMI 32.8 kg/m2 (95% CI 32-33), blood pressure 142/80 mmHg (140-143/80-81) and HbA1c 7.1% (7.0-7.2) (53.8 mmol/mol, 53-55) and the median duration of diabetes was 9.2 years ranging from newly diagnosed to 43 years. History of dyslipidemia had in 73.3% of patients, 27.8% had cardiovascular disease and 82.7% had hypertension. The primary endpoint, prevalence of CKD of any grade (1-5) or albuminuria, was 68.6%. Regarding declined renal function, 16.2% of patients had an estimated glomerular filtration rate (eGFR) &lt;60 ml/min/1.72 m2, classifying as CKD 3-5. Only one patient was within CKD5. Regarding renal damage, albuminuria was present in 24.3% of patients, with microalbuminuria in 17.1% and macroalbuminuria in 7.2%, respectively. Combining the patients with CKD 3-5 and/or the presence of albuminuria, 34.7% seemed to suffer from significant CKD. The proportion of patients with albuminuria increased with a decrease in glomerular filtration rate. Historically, diabetic nephropathy had been diagnosed in 24.3% of the patients. Conclusions: Nearly 70% of patients with T2D treated in primary care in Finland have some sign of CKD and nearly half of all T2D patients have a significant CKD. However, only half of the latter had it diagnosed and documented in their patient charts, thus highlighting the importance of performing routine screening of nephropathy by measuring both albuminuria and eGFR in patients with T2D. Prevention of this complication with active therapy for risk factors, such as hypertension and dyslipidemia is warranted. © 2014 Primary Care Diabetes Europe.
  • Author:
    Friedrich C; Emser A; Woerle HJ; Graefe-Mody UN
    Title:
    Renal impairment has no clinically relevant effect on the long-term exposure of linagliptin in patients with type 2 diabetes.
    Source:
    Am J Ther 20 (6), 618-621 (2013)
    Abstract:
    Linagliptin is a dipeptidyl peptidase-4 (DPP-4) inhibitor with a primarily nonrenal route of excretion. Consequently, renal impairment should not substantially affect drug exposure. This analysis was undertaken to compare steady-state trough concentrations of linagliptin among patients with type-2 diabetes receiving linagliptin 5 mg in phase 3 studies. Data were pooled from 3 randomized studies from the global phase 3 program of linagliptin (5 mg daily in each) in patients with type-2 diabetes. These studies were selected for their inclusion of pharmacokinetic data. Linagliptin plasma concentrations were available for 969 patients who were determined by estimated glomerular filtration rate to have normal renal function (n = 438), mild renal impairment (RI) (n = 429), moderate RI (n = 44), or severe RI (n = 58). In patients with normal renal function, the geometric mean linagliptin trough concentration (coefficient of variation) was 5.93 nmol/L (56.3%); in patients with mild, moderate, or severe RI, geometric mean concentrations were 6.07 nmol/L (62.9%), 7.34 nmol/L (58.6%), and 8.13 nmol/L (49.8%), respectively. In patients with type-2 diabetes, RI had a minor effect on linagliptin exposure. Therefore, neither dose-adjustment nor drug-related monitoring of estimated glomerular filtration rate is necessary for patients with RI.
  • Author:
    Bajaj M; Gilman R; Patel S; Kempthorne-Rawson J; Lewis-D'Agostino D; Woerle H-J
    Title:
    Linagliptin improved glycaemic control without weight gain or hypoglycaemia in patients with Type 2 diabetes inadequately controlled by a combination of metformin and pioglitazone: A 24-week randomized, double-blind study
    Source:
    Diabetic Med Article in Press (2014)
    Abstract:
    Aims: To investigate the efficacy and safety of the dipeptidyl peptidase-4 inhibitor linagliptin in patients with Type 2 diabetes mellitus inadequately controlled by a combination of metformin and pioglitazone. Methods: This was a multi-centre, phase 3, randomized, double-blind, placebo-controlled study comparing linagliptin 5 mg once daily (n = 183) and placebo (n = 89) as add-on to metformin and pioglitazone. The primary endpoint was the change from baseline in glycated haemoglobin (HbA1c) after 24 weeks. Results: The placebo-corrected adjusted mean (se) change in HbA1c from baseline to 24 weeks was -6 (1) mmol/mol [-0.57 (0.13)%] (P &lt; 0.0001). In patients with baseline HbA1c . 53 mmol/mol (7.0%), 32.4% of patients in the linagliptin group and 13.8% in the placebo group achieved HbA1c &lt; 53 mmol/mol (7.0%) (odds ratio 2.94; P = 0.0033). The placebo-corrected adjusted mean (se) change from baseline in fasting plasma glucose at week 24 was -0.57 (0.26) mmol/l [-10.4 (4.7) mg/dl] (P = 0.0280). The incidence of serious adverse events was 2.2% with linagliptin and 3.4% with placebo. Investigator-defined hypoglycaemia occurred in 5.5% of the linagliptin group and 5.6% of the placebo group. No meaningful changes in mean body weight were noted for either group. Conclusions: Linagliptin as add-on therapy to metformin and pioglitazone produced significant and clinically meaningful improvements in glycaemic control, without an additional risk of hypoglycaemia or weight gain (Clinical Trials Registry No: NCT 00996658). © 2014 The Authors.
  • Author:
    Vickers SP; Cheetham SC; Headland KR; Dickinson K; Grempler R; Mayoux E; Mark M; Klein T
    Title:
    Combination of the sodium-glucose cotransporter-2 inhibitor empagliflozin with orlistat or sibutramine further improves the body-weight reduction and glucose homeostasis of obese rats fed a cafeteria diet
    Source:
    Diabetes Metab Syndr Obes Targets Ther 7, 265-275 (2014)
    Abstract:
    The present study assessed the potential of the sodium glucose-linked transporter (SGLT)-2 inhibitor empagliflozin to decrease body weight when administered alone or in combination with the clinically effective weight-loss agents orlistat and sibutramine in obese rats fed a cafeteria diet. Female Wistar rats were exposed to a cafeteria diet to induce obesity. Empagliflozin was dosed once daily (10, 30, and 60 mg/kg) for 28 days. Combination studies were subsequently performed using a submaximal empagliflozin dose (10 mg/kg) with either sibutramine or orlistat. Body weight, food, and water intake were recorded daily. The effect of drug treatment on glucose tolerance, relevant plasma parameters, and carcass composition was determined. Empagliflozin dose-dependently reduced body weight, plasma leptin, and body fat though increased urinary glucose excretion. The combination of empagliflozin and orlistat significantly reduced body weight compared to animals treated with either drug alone, and significantly improved glucose tolerance, plasma insulin, and leptin compared to vehicle-treated controls. The effect of sibutramine to improve glycemic control in an oral glucose-tolerance test was also significantly increased, with empagliflozin and combination treatment leading to a reduction in carcass fat greater than that observed with either drug alone. These data demonstrate that empagliflozin reduces body weight in cafeteria-fed obese rats. In combination studies, empagliflozin further improved the body-weight or body-fat loss of animals in comparison to orlistat or sibutramine alone. Such studies may indicate improved strategies for the treatment of obese patients with prediabetes or type 2 diabetes. © 2014 Vickers et al.
  • Author:
    Lehrke M; Marx N; Patel S; Seck T; Crowe S; Cheng K; von Eynatten; M Johansen OE
    Title:
    Safety and Tolerability of Linagliptin in Patients With Type 2 Diabetes: A Comprehensive Pooled Analysis of 22 Placebo-Controlled Studies
    Source:
    Clin Ther Article in Press (2014)
    Abstract:
    Purpose: Dipeptidyl peptidase (DPP)-4 inhibitors are an increasingly used antihyperglycemic therapy for patients with type 2 diabetes mellitus (T2DM). Linagliptin, an orally administered DPP-4 inhibitor, has demonstrated favorable efficacy/safety in clinical trials. The aim of this post hoc pooled analysis was to expand current knowledge of the safety of linagliptin. Methods: Safety data for once-daily linagliptin 5 mg (1 study of linagliptin 2.5 mg twice daily) were analyzed from 22 randomized, double-blind, Phase I-III, placebo-controlled clinical trials of .102 weeks' duration. Assessments of pooled data included incidence of patient-reported adverse events (AEs). Findings: Data from 7400 patients (linagliptin, 4810; placebo, 2590) were pooled. Most patients (58.4%) had T2DM diagnosis for >5 years; approximately 75% were receiving .1 type of background therapy in addition to linagliptin/placebo. Overall exposure to the study drug was 2412.8 years for linagliptin and 1481.4 years for placebo (mean [SD], 183 [120] days and 209 [150] days, respectively). Overall frequencies of AEs were similar for linagliptin- and placebo-treated patients (57.3% and 61.8%, respectively). The incidence of neoplastic AEs was low (0.6% and 0.9%, respectively); there were no reports of pancreatic neoplasia. Pancreatitis was observed in 2 linagliptin-treated patients (<0.1%) and 1 placebo-treated patient (<0.1%). The occurrence of cardiac disorder AEs was similar in linagliptin- and placebo-treated patients (3.2% [n = 153] and 3.3% [n = 83], respectively); the incidence of heart failure AEs for linagliptin- and placebo-treated patients was 0.2% (n = 11) and 0.3% (n = 7), respectively. Overall, linagliptin was weight neutral. Occurrence of investigator-defined hypoglycemic AEs was low for both linagliptin and placebo (11.5% vs 14.0%). In patients receiving concomitant sulfonylurea therapy, investigator-defined hypoglycemic AEs were more frequent with linagliptin versus placebo (22.1% [238/1079] vs 14.5% [61/421], respectively). Subgroup analyses showed similar frequencies of AEs for linagliptin- and placebo-treated patients across different age groups and renal function levels. Implications: This updated and expanded pooled, post hoc analysis of 22 placebo-controlled trials of linagliptin 5 mg daily supports previous findings of the acceptable overall safety/tolerability profile of linagliptin when administered to a broad range of patients with T2DM. Linagliptin-treated patients demonstrated a low overall risk of hypoglycemia (risk increased by concomitant sulfonylurea therapy). As with all pooled analyses, this study is limited by the use of data from different studies, and the relatively short duration of some included studies, although use of individual patient data from consistently designed trials should minimize methodological differences between trials. Results from ongoing clinical trials will provide additional insight into the long-term safety/tolerability of linagliptin. © 2014 The Authors.
  • Author:
    Rosenstock J; Jelaska A; Frappin G; Salsali A; Kim G; Woerle HJ; Broedl UC
    Title:
    Improved glucose control with weight loss, lower insulin doses, and no increased hypoglycemia with empagliflozin added to titrated multiple daily injections of insulin in obese inadequately controlled type 2 diabetes
    Source:
    Diabetes Care 37 (7), 1815-1823 (2014)
    Abstract:
    OBJECTIVE: We investigated the efficacy and safety of the sodium glucose cotransporter 2 inhibitor, empagliflozin, added to multiple daily injections of insulin (MDI insulin) in obese patients with type 2 diabetes mellitus (T2DM). RESEARCH DESIGN AND METHODS: Patients inadequately controlled on MDI insulin ± metformin (mean HbA1c 8.3% [67 mmol/mol]; BMI 34.8 kg/m 2; insulin dose 92 international units/day) were randomized and treated with once-daily empagliflozin 10 mg (n = 186), empagliflozin 25mg (n = 189), or placebo ( n = 188) for 52 weeks. Insulin dosewas to remain stable in weeks 1-18, adjusted to meet glucose targets in weeks 19- 40, then stable in weeks 41- 52. The primary end point was change from baseline in HbA1c at week 18. Secondary end points were changes from baseline in insulin dose, weight, and HbA1c at week 52. RESULTS: Adjusted mean ± SE changes frombaseline in HbA1c were -0.50 ± 0.05% (-5.5 ± 0.5 mmol/mol) for placebo versus -0.94 ± 0.05% (-10.3 ± 0.5 mmol/mol) and -1.02 ± 0.05% (-11.1 ± 0.5 mmol/mol) for empagliflozin 10 mg and empagliflozin 25 mg, respectively, at week 18 (both P &lt; 0.001). At week 52, further reductions with insulin titration resulted in changes from baseline in HbA1c of -0.81 ± 0.08% (-8.9 ± 0.9 mmol/mol), -1.18 ± 0.08% (-12.9 ± 0.9 mmol/ mol), and -1.27 ± 0.08% (-13.9 ± 0.9 mmol/mol) with placebo,empagliflozin 10 mg, and empagliflozin 25 mg, respectively, and final HbA1c of 7.5% (58 mmol/mol), 7.2% (55 mmol/mol), and 7.1% (54 mmol/mol), respectively. More patients attained HbA1c &lt;7% (&lt;53 mmol/mol) with empagliflozin (31-42%) versus placebo (21%; both P &lt; 0.01). Empagliflozin 10 mg and empagliflozin 25 mg reduced insulin doses (-9 to -11 international units/day) and weight (-2.4 to -2.5 kg) versus placebo (all P &lt; 0.01) at week 52. CONCLUSIONS: In obese, difficult-to-treat patients with T2DM inadequately controlled on high MDI insulin doses, empagliflozin improved glycemic control and reduced weight without increasing the risk of hypoglycemia and with lower insulin requirements. © 2014 by the American Diabetes Association.
  • Author:
    Brennan VK; Colosia AD; Copley-Merriman C; Mauskopf J; Hass B; Palencia R
    Title:
    Incremental costs associated with myocardial infarction and stroke in patients with type 2 diabetes mellitus: An overview for economic modeling
    Source:
    J Med Econ 17 (7), 469-480 (2014)
    Abstract:
    Objective: To identify cost estimates related to myocardial infarction (MI) or stroke in patients with type 2 diabetes mellitus (T2DM) for use in economic models. Methods: A systematic literature review was conducted. Electronic databases and conference abstracts were screened against inclusion criteria, which included studies performed in patients who had T2DM before experiencing an MI or stroke. Primary cost studies and economic models were included. Costs were converted to 2012 pounds sterling. Results: Fifty-four studies were identified: 13 primary cost studies and 41 economic evaluations using secondary sources for complication costs. Primary studies provided costs from 10 countries. Estimates for a fatal event ranged from £2482-£5222 for MI and from £4900-£6694 for stroke. Costs for the year a non-fatal event occurred ranged from £5071-£29,249 for MI and from £5171-£38,732 for stroke. Annual follow-up costs ranged from £945-£1616 for an MI and from £4704-£12,926 for a stroke. Economic evaluations from 12 countries were identified, and costs of complications showed similar variability to the primary studies. Discussion: The costs identified within primary studies varied between and within countries. Many studies used costs estimated in studies not specific to patients with T2DM. Data gaps included a detailed breakdown of resource use, which affected the ability to compare data across countries. Conclusions: In the development of economic models for patients with T2DM, the use of accurate estimates of costs associated with MI and stroke is important. When country-specific costs are not available, clear justification for the choice of estimates should be provided. © 2014 All rights reserved: reproduction in whole or part not permitted.
  • Author:
    Lewis ND; Patnaude LA; Pelletier J; Souza DJ; Lukas SM; King FJ; Hill JD; Stefanopoulos DE; Ryan K; Desai S; Skow D; Kauschke SG; Broermann A; Kuzmich D; Harcken C; Hickey ER; Modis LK
    Title:
    A GPBAR1 (TGR5) small molecule agonist shows specific inhibitory effects on myeloid cell activation in vitro and reduces Experimental Autoimmune Encephalitis (EAE) in vivo
    Source:
    PloS ONE 9 (6) art.no.e100883 (2014)
    Abstract:
    GPBAR1 is a G protein-coupled receptor that is activated by certain bile acids and plays an important role in the regulation of bile acid synthesis, lipid metabolism, and energy homeostasis. Recent evidence suggests that GPBAR1 may also have important effects in reducing the inflammatory response through its expression on monocytes and macrophages. To further understand the role of GPBAR1 in inflammation, we generated a novel, selective, proprietary GPBAR1 agonist and tested its effectiveness at reducing monocyte and macrophage activation in vitro and in vivo. We have used this agonist, together with previously described agonists to study agonism of GPBAR1, and shown that they can all induce cAMP and reduce TLR activation-induced cytokine production in human monocytes and monocyte-derived macrophages in vitro. Additionally, through the usage of RNA sequencing (RNA-Seq), we identified a select set of genes that are regulated by GPBAR1 agonism during LPS activation. To further define the in vivo role of GPBAR1 in inflammation, we assessed GPBAR1 expression and found high levels on circulating mouse monocytes. Agonism of GPBAR1 reduced LPS-induced cytokine production in mouse monocytes ex vivo and serum cytokine levels in vivo. Agonism of GPBAR1 also had profound effects in the experimental autoimmune encephalomyelitis (EAE) mouse model of multiple sclerosis, where monocytes play an important role. Mice treated with the GPBAR1 agonist exhibited a significant reduction in the EAE clinical score which correlated with reduced monocyte and microglial activation and reduced trafficking of monocytes and T cells into the CNS. These data confirm the importance of GPBAR1 in controlling monocyte and macrophage activation in vivo and support the rationale for selective agonists of GPBAR1 in the treatment of inflammatory diseases. © 2014 Lewis et al. This.
  • Author:
    Schuetz JD; Swaan PW; Tweedie DJ
    Title:
    The role of transporters in toxicity and disease
    Source:
    Drug Metab Dispos 42 (4), 541-545 (2014)
    Abstract:
    The significance of transporters in the disposition, metabolism, and elimination of drugs is well recognized. One gap in our knowledge is a comprehensive understanding of how drug transporters change functionality (their amount and activity) in response to disease and how disease and its inevitable pathology change transporter expression. In this issue of Drug Metabolism and Disposition a series of review and primary research articles are presented to highlight the importance of transporters in toxicity and disease. Because of the central role of the liver in drug metabolism, many of the articles in this theme issue focus on transporters in the liver and how pathology or alterations in physiology affects transporter expression. The contributing authors have also considered the role of transporters in drug interactions as well as drug-induced liver injury. Noninvasive approaches to assessing transporter function in vivo are also described. Several articles highlight important issues in oncology where toxicity must be balanced against efficacy. In total, this theme issue will provide a stepping-stone to future studies that will establish a more comprehensive understanding of transporters in disease. Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics.
  • Author:
    Kadowaki T; Haneda M; Inagaki N; Terauchi Y; Taniguchi A; Koiwai K; Rattunde H; Woerle HJ; Broedl UC
    Title:
    Empagliflozin Monotherapy in Japanese Patients with Type 2 Diabetes Mellitus: a Randomized, 12-Week, Double-Blind, Placebo-Controlled, Phase II Trial
    Source:
    Adv Ther Article in Press (2014)
    Abstract:
    Introduction This study was designed to determine the efficacy and tolerability of empagliflozin monotherapy in Japanese patients with type 2 diabetes mellitus (T2DM). Methods Patients with glycosylated hemoglobin (HbA1c) .7.0-.10% were randomized via an interactive web response system, and treated double-blind with empagliflozin 5, 10, 25, 50 mg, or placebo once daily for 12 weeks. The primary endpoint was change from baseline in HbA1c at week 12. Other endpoints included percentage of patients with HbA1c <7.0% and changes from baseline in fasting plasma glucose (FPG), body weight, and systolic blood pressure (SBP) at week 12. Results A total of 547 patients were randomized and treated with empagliflozin 5 mg (n = 110), 10 mg (n = 109), 25 mg (n = 109), 50 mg (n = 110), or placebo (n = 109) for 12 weeks. Adjusted mean [95% confidence interval (CI)] differences vs. placebo in changes from baseline in HbA1c were -0.72% (-0.87, -0.57) with empagliflozin 5 mg, -0.70% (-0.85, -0.55) with 10 mg, -0.95% (-1.10, -0.80) with 25 mg, and -0.91 (-1.06, -0.76) with 50 mg (all p < 0.001). More patients with HbA1c .7.0% at baseline reached HbA1c <7.0% with empagliflozin (19-33%) than placebo (3%). Compared with placebo, empagliflozin reduced FPG, body weight (p < 0.001 for all doses for both endpoints) and SBP (p = 0.001, p = 0.014 and p = 0.003 for empagliflozin 10, 25, and 50 mg, respectively). Adverse events were reported by 42% of patients receiving placebo and 33-38% of patients receiving empagliflozin. There were few reports of confirmed hypoglycemic adverse events or events consistent with urinary tract infection or genital infection in any treatment group. Conclusions Empagliflozin monotherapy for 12 weeks in Japanese patients with T2DM reduced HbA1c, FPG, body weight and SBP, and was well tolerated. © 2014 Springer Healthcare
  • Author:
    Hall TS; Herrscher TE; Jarolim P; Fagerland MW; Jensen T; Agewall S; Atar D; Hallén J
    Title:
    Myeloid-related protein-8/14 and C-reactive protein in individuals evaluated for obstructive sleep apnea
    Source:
    Sleep Med 15 (7), 762-768 (2014)
    Abstract:
    Background: Obstructive sleep apnea (OSA) and obesity are often present concomitantly. Their potential contribution to inflammation remains an ongoing debate. The objectives of this study were to investigate whether variables of sleep-disordered breathing are associated with levels of myeloid-related protein-8/14 (MRP-8/14) or C-reactive protein (CRP), and to characterize how adiposity interacts with these associations in individuals evaluated for possible OSA. Methods: Consecutive individuals referred to Lovisenberg Diakonale Hospital's sleep laboratory between 1st October 2009 and 1st March 2010 were included. We characterized the biomarker distribution sampled the morning after sleep and related these to clinical characteristics and variables recorded during polygraphy or polysomnography. Results: Of the total study population of 222 individuals, 161 (72.5%) were diagnosed with OSA (apnea-hypopnea index (AHI) .5/h). In baseline models (multiple median regression adjusted for age and sex), AHI was independently associated with MRP-8/14 (P= 0.025) and CRP (P<. 0.001). The associations were attenuated after the addition of body mass index (BMI), but remained statistically significant for CRP (P= 0.025). However, in final models adjusted for additional factors (systolic blood pressure, cholesterol:high-density lipoprotein ratio, glycosylated haemoglobin, smoking, and cardiovascular disease), only average oxygen saturation for MRP-8/14 (P= 0.028) and oxygen desaturation index (ODI) for CRP (P= 0.037) remained independent predictors of inflammation, whereas AHI lost its predictive value (MRP-8/14; P= 0.30 and CRP; P= 0.092). The association between several variables of sleep-disordered breathing and inflammation were stronger in individuals with a higher BMI (P for interaction <0.05 for AHI, nadir oxygen saturation, and time <90% oxygen saturation). Conclusions: No definitive indication of independent immunological activity resulting from apneas and hypopneas was found in final models adjusted for other factors associated with inflammation, whereas average oxygen saturation for MRP-8/14 and ODI for CRP remained statistically significant predictors. Interactions were observed between BMI and several variables of sleep-disordered breathing on MRP-8/14 and CRP levels. © 2014 Elsevier B.V.
  • Author:
    Heise T; Larbig M; Patel S; Seck T; Hehnke U; Woerle H-J; Dugi K
    Title:
    The dipeptidyl peptidase-4 inhibitor linagliptin lowers postprandial glucose and improves measures of .-cell function in type 2 diabetes
    Source:
    Diabetes Obes Metab Article in Press (2014)
    Abstract:
    Progressive deterioration of pancreatic .-cell function in patients with type 2 diabetes mellitus (T2DM) contributes to worsening of hyperglycaemia. To investigate the effects of the dipeptidyl peptidase-4 inhibitor linagliptin on .-cell function parameters, a pooled analysis of six randomized, 24-week, placebo-controlled, phase 3 trials of 5mg of linagliptin daily was performed in 2701 patients with T2DM (linagliptin, n=1905; placebo, n=796). At week 24, observed improvements in HbA1c, fasting plasma glucose, and 2-h postprandial glucose were significantly greater for linagliptin than placebo (all p<0.0001). Homeostasis model assessment (HOMA)-%., as a surrogate marker of fasting .-cell function, was significantly improved with linagliptin, and did not change with placebo (placebo-adjusted mean±s.e. change for linagliptin: 16.5±4.6 (mU/l)/(mmol/l); p=0.0003). Further study is required to determine if the significant improvement in HOMA-%. with linagliptin will translate into long-term improvements in .-cell function. © 2014 John Wiley & Sons Ltd.
  • Author:
    Ridderstråle M; Andersen KR; Zeller C; Kim G; Woerle HJ; Broedl UC
    Title:
    Comparison of empagliflozin and glimepiride as add-on to metformin in patients with type 2 diabetes: a 104-week randomised, active-controlled, double-blind, phase 3 trial
    Source:
    Lancet Diabetes Endocrinol Article in Press (2014)
    Abstract:
    Background: Metformin is the recommended first-line pharmacotherapy for patients with type 2 diabetes. There is no consensus on the optimum second-line pharmacotherapy. We compared the efficacy and safety of the sodium glucose cotransporter 2 inhibitor empagliflozin and the sulfonylurea glimepiride as add-on to metformin in patients with type 2 diabetes. Methods: In this double-blind phase 3 trial, patients (aged .18 years) with type 2 diabetes and HbA1c concentrations of 7-10%, despite metformin treatment and diet and exercise counselling, were randomly assigned in a 1:1 ratio with a computer-generated random sequence, stratified by HbA1c, estimated glomerular filtration rate (eGFR), and region, to empagliflozin (25 mg once daily, orally) or glimepiride (1-4 mg once daily, orally) as add-on to metformin for 104 weeks. Patients and investigators were masked to treatment assignment. The primary endpoint was change from baseline in HbA1c levels at weeks 52 and 104. Differences in the primary endpoint were first tested for non-inferiority (based on a margin of 0.3%). If non-inferiority was shown, differences in the primary endpoint at week 104 were then tested for superiority. Analysis was done on the full-analysis set-ie, patients who were treated with at least one dose of study drug and had a baseline HbA1c value. This study is registered with ClinicalTrials.gov, number NCT01167881. A 104-week extension is ongoing. Findings: Between August, 2010, and June, 2011, 1549 patients were randomly assigned to receive empagliflozin (n=769) or glimepiride (n=780); four patients in the empagliflozin group did not receive the assigned treatment. Empagliflozin was non-inferior to glimepiride at both timepoints. At week 104, adjusted mean difference in change from baseline in HbA1c with empagliflozin versus glimepiride was -0.11% (95% CI -0.19 to -0.02; p=0.0153 for superiority). Adverse events were reported in 661 (86%) patients treated with empagliflozin and 673 (86%) patients treated with glimepiride. Severe adverse events were reported in 72 (9%) patients in the empagliflozin group and 68 (9%) in the glimepiride group. Serious adverse events were reported in 119 (16%) patients in the empagliflozin group and 89 (11%) in the glimepiride group. Confirmed hypoglycaemic adverse events (plasma glucose .3.9 mmol/L or requiring assistance) at week 104 were reported in 19 (2%) patients treated with empagliflozin and 189 (24%) patients treated with glimepiride. Interpretation: Empagliflozin might be an effective and a well tolerated second-line treatment option for patients with type 2 diabetes who have not achieved good glycaemic control on metformin. Funding: Boehringer Ingelheim and Eli Lilly. © 2014 Elsevier Ltd. All rights reserved.
  • Author:
    Zimdahl H; Ittrich C; Graefe-Mody U; Boehm BO; Mark M; Woerle H-J; Dugi KA
    Title:
    Influence of TCF7L2 gene variants on the therapeutic response to the dipeptidylpeptidase-4 inhibitor linagliptin
    Source:
    Diabetologia Article in Press (2014)
    Abstract:
    Aims/hypothesis Individuals carrying variants of the transcription factor 7-like 2 gene (TCF7L2) are at increased risk for type 2 diabetes. These metabolic genetic risk factors have been linked to diminished pancreatic islet-cell responsiveness to incretins, thus pharmacological interventions aimed at amplifying endogenous incretin biology may be affected. However, clinical evidence from randomised controlled trials so far is lacking. We investigated the influence of TCF7L2 risk alleles on the response to treatment with the dipeptidylpeptidase-4 (DPP-4) inhibitor linagliptin from four 24 week, phase III, placebo-controlled trials. Methods Pharmacogenomic samples and clinical data were available from 961 patients with type 2 diabetes. Whole-blood DNA samples were genotyped for TCF7L2 single-nucleotide polymorphisms in conjunction with assessments of 24 week changes in HbA1c. Results Linagliptin lowered HbA1c meaningfully in all three genotypes of rs7903146 (non-risk variant carriers CC [n = 356]: -0.82% [-9.0 mmol/mol], p &lt; 0.0001; heterozygous CT [n = 264]: -0.77% [-8.4 mmol/mol], p &lt; 0.0001; homozygous risk variant carriers TT [n = 73]: -0.57% [-6.2 mmol/mol], p &lt; 0.0006). No significant treatment differences were seen between CC and CT patients, although HbA1c response was reduced in TT compared with CC patients (~0.26% [~2.8 mmol/mol], p = 0.0182). Conclusions/interpretation Linagliptin significantly improved hyperglycaemia in patients with type 2 diabetes both with and without the TCF7L2 gene diabetes risk alleles. However, differences in treatment response were observed, indicating that diabetes susceptibility genes may be an important contributor to the inter-individual variability of treatment response. © 2014 The Author(s).
  • Author:
    Häring H-U; Merker L; Seewaldt-Becker E; Weimer M; Meinicke T; Broedl UC; Woerle HJ
    Title:
    Empaglif lozin as add-on to metformin in patients with type 2 diabetes: A 24-week, randomized, double-blind, placebo-controlled trial
    Source:
    Diabetes Care 37 (6), 1650-1659 (2014)
    Abstract:
    OBJECTIVE To investigate the efficacy and tolerability of empagliflozin as an add-on to metformin therapy in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS Patientswith HbA1c levels of .7% to . 10%(.53 to .86mmol/mol)while receiving metformin (.1,500 mg/day) were randomized and treated with once-daily treatment with empagliflozin 10mg (n = 217), empagliflozin 25 mg (n = 213), or placebo (n = 207) for 24 weeks. The primary end point was the change in HbA1c level from baseline at week 24. Key secondary end points were changes from baseline in weight and mean daily glucose (MDG) at week 24. RESULTS At week 24, adjusted mean (SE) changes from baseline in HbA1c were 20.13% (0.05)% (21.4 [0.5] mmol/mol) with placebo, 20.70% (0.05)% (27.7 [0.5] mmol/mol) with empagliflozin 10 mg, and20.77% (0.05)% (28.4 [0.5] mmol/mol) with empagliflozin 25 mg (both P &lt; 0.001). Empagliflozin significantly reduced MDG level and systolic and diastolic blood pressure (BP) versus placebo. Adjusted mean (SE) changes from baseline in weight were 20.45 kg (0.17 kg) with placebo, 22.08 kg (0.17 kg) with empagliflozin 10 mg, and 22.46 kg (0.17 kg) with empagliflozin 25 mg (both P &lt; 0.001). Adverse events (AEs) were similar across groups (placebo 58.7%; empagliflozin 49.5-57.1%). Confirmed hypoglycemic AEs were reported in 0.5%, 1.8%, and 1.4% of patients receiving placebo, empagliflozin 10 mg, and empagliflozin 25 mg, respectively. Events consistent with urinary tract infections were reported in 4.9%, 5.1%, and 5.6% of patients, and events consistent with genital infections were reported in 0%, 3.7%, and 4.7% of patients, respectively. CONCLUSIONS Empagliflozin 10 and 25 mg for 24 weeks as add-on to metformin therapy significantly improved glycemic control, weight, and BP, and were well-tolerated. © 2014 by the American Diabetes Association
  • Author:
    Fenwick C; Amad M; Bailey MD; Bethell R; Bös M; Bonneau P; Cordingley M; Coulombe R; Duan J; Edwards P; Fader LD; Faucher A-M; Garneau M; Jakalian A; Kawai S; Lamorte L; LaPlante S; Luo L; Mason S; Poupart M-A; Rioux N; Schroeder P; Simoneau B; Tremblay S; Tsantrizos Y; Witvrouw M; Yoakim C
    Title:
    Preclinical profile of BI 224436, a novel hiv-1 non-catalytic-site integrase inhibitor
    Source:
    Antimicrob Agents Chemother 58 (6), 3233-3244 (2014)
    Abstract:
    BI 224436 is an HIV-1 integrase inhibitor with effective antiviral activity that acts through a mechanism that is distinct from that of integrase strand transfer inhibitors (INSTIs). This 3-quinolineacetic acid derivative series was identified using an enzymatic integrase long terminal repeat (LTR) DNA 3'-processing assay. A combination of medicinal chemistry, parallel synthesis, and structure-guided drug design led to the identification of BI 224436 as a candidate for preclinical profiling. It has antiviral 50% effective concentrations (EC50s) of&lt;15 nM against different HIV-1 laboratory strains and cellular cytotoxicity of&gt;90 .M. BI 224436 also has a low,.2.1-fold decrease in antiviral potency in the presence of 50% human serum and, by virtue of a steep dose-response curve slope, exhibits serum-shifted EC95 values ranging between 22 and 75 nM. Passage of virus in the presence of inhibitor selected for either A128T, A128N, or L102F primary resistance substitutions, all mapping to a conserved allosteric pocket on the catalytic core of integrase. BI 224436 also retains full antiviral activity against recombinant viruses encoding INSTI resistance substitutions N155S, Q148H, and E92Q. In drug combination studies performed in cellular antiviral assays, BI 224436 displays an additive effect in combination with most approved antiretrovirals, including INSTIs. BI 224436 has drug-like in vitro absorption, distribution, metabolism, and excretion (ADME) properties, including Caco-2 cell permeability, solubility, and low cytochrome P450 inhibition. It exhibited excellent pharmacokinetic profiles in rat (clearance as a percentage of hepatic flow [CL], 0.7%; bioavailability [F], 54%), monkey (CL, 23%; F, 82%), and dog (CL, 8%; F, 81%). Based on the excellent biological and pharmacokinetic profile, BI 224436 was advanced into phase 1 clinical trials. © 2014, American Society for Microbiology.
  • Author:
    Schaefer JH; Leung W; Wu L; Van Cott EM; Lok J; Whalen M; Van Leyen K; Lauer A; Van Ryn J; Lo EH; Foerch C
    Title:
    Translational insights into traumatic brain injury occurring during dabigatran or warfarin anticoagulation
    Source:
    J Cereb Blood Flow Metab 34 (5), 870-875 (2014)
    Abstract:
    To date, only limited data are available on the effects of pretreatment with novel oral anticoagulants in the event of traumatic brain injury (TBI). We determined intracerebral hemorrhage volume and functional outcome in a standardized TBI model in mice treated with warfarin or dabigatran. Additionally, we investigated whether excess concentrations of dabigatran could increase bleeding and whether this was preventable by using prothrombin complex concentrate (PCC). C57 mice were treated orally with warfarin or dabigatran; sham-treated mice served as controls. Effective anticoagulation was verified by measurement of international normalized ratio and diluted thrombin time, and TBI was induced by controlled cortical impact (CCI). Twenty-four hours after CCI, intracerebral hemorrhage volume was larger in warfarin-pretreated mice than in controls (10.1±4.9 vs 4.1±1.7 .L; analysis of variance post hoc P=0.001), but no difference was found between controls and dabigatran- pretreated mice (5.3±1.5 .L). PCC applied 30 minutes after CCI did not reliably reduce intracerebral hemorrhage induced by excess dabigatran concentration compared with saline (10.4±11.2 vs 8.7±7.1 .L). Our data suggest pathophysiological differences in TBI occurring during warfarin and dabigatran anticoagulation. The reduced hemorrhage formation under dabigatran therapy could present a safety advantage compared with warfarin. An excess dabigatran concentration, however, can increase hemorrhage. © 2014 ISCBFM.
  • Author:
    Thrasher J; Daniels K; Patel S; Whetteckey J; Woerle H-J
    Title:
    Efficacy and safety of linagliptin in black/African American patients with type 2 diabetes: A 6-month, randomized, double-blind, placebo-controlled study
    Source:
    Endocr Pract 20 (5), 412-420 (2014)
    Abstract:
    Objective: Although black/African American individuals are disproportionately affected by type 2 diabetes, there is scant clinical trial information available on antidiabetes therapies in this group. We compared linagliptin with placebo in black/African American adults who were treatment-naïve or receiving one oral antidiabetes drug.Methods: Of 226 patients randomized to 24 weeks' linagliptin 5 mg/day or placebo, 208 had baseline and at least one on-treatment glycated hemoglobin (HbA&lt;1c&lt;) measurement. Mean baseline HbA&lt;1c&lt; was 8.6% in the linagliptin group (n = 98) and 8.68% in the placebo group (n = 110). The primary outcome was change in HbA&lt;1c&lt; from baseline to week 24.Results: By week 24, mean HbA&lt;1c&lt; changes were-0.84% with linagliptin and-0.25% with placebo (treatment difference,-0.58%; P&lt;.001), and more patients in the linagliptin group achieved HbA1 &lt;7.0% (26.8% vs. 8.3%; P = .001) or an Hb A1 reduction .0.5% (54.1% vs. 30.0%; P&lt;.001). Mean weight loss was-1.1 kg in both groups. During the treatment period, 8 of 98 linagliptin-group patients and 17 of 110 placebo-group patients required rescue therapy (odds ratio, 0.5; P = .14). For postprandial glucose, values were available for few patients (11 placebo, 10 linagliptin), and thus the between-group difference was associated with wide confidence intervals (CIs) (difference,-1.97 mg/dL; 95% CI,-53.80 to 49.86; P = .94). In the overall study population, a similar proportion of patients in both groups had adverse events (58.5% vs. 61.7%); most events were mild or moderate and considered unrelated to study drug. Investigator-defined hypoglycemia was rare (3 linagliptin-group patients and 1 placebo-group patient), with no severe events (requiring external assistance).Conclusion: This study confirms that linagliptin is efficacious and well tolerated in black/African American patients with type 2 diabetes. © 2014 AACE.
  • Author:
    Hutzler JM; Yang Y-S; Brown C; Heyward S; Moeller T
    Title:
    Aldehyde oxidase activity in donor-matched fresh and cryopreserved human hepatocytes and assessment of variability in 75 donors
    Source:
    Drug Metab Dispos 42 (6), 1090-1097 (2014)
    Abstract:
    Studies were conducted to evaluate the impact of time and cryopreservation on aldehyde oxidase (AO) activity in human hepatocytes isolated from 10 donor livers, using O6-benzylguanine as a probe substrate. In addition, variability in activity was assessed using cryopreserved hepatocytes from 75 donors. Substantial donor-dependent loss in AO activity within 24 hours after isolation of hepatocytes was observed (average loss of 42%, range 15%-81%). Meanwhile, AO activity in cryopreserved hepatocytes more closely represented the activity observed in fresh hepatocytes that were incubated immediately after isolation for the same donors (within 81% of fresh, range 48%-100%). Activity of AO in cryopreserved hepatocytes from 75 donors varied by at least 17-fold (. 5.4 to 90 ml/minute per kilogram of body weight), with 63% of the donors having higher activity than a pooled 19-donor lot (34.2 ml/minute per kilogram). Comparison of demographics such as gender, body mass index, age, and ethnicity showed no statistically significant correlations with activity. Evaluation of medical histories revealed that three of the five donors with no measurable activity had immediate histories of extensive alcohol abuse. Meanwhile, two single nucleotide polymorphisms (SNPs) for AOX1 (rs3731772 and rs55754655) were detected in our donor pool and showed allelic frequencies similar to those reported from other cohort studies. However, these SNPs did not correlate with a statistically significant difference in intrinsic clearance compared with wild-type donors. With a general lack of clarity about what causes highly variable AO activity, prescreening donors for AO activity and creating a custom high-activity pooled lot of cryopreserved hepatocytes are advised to minimize underpredictions of clearance. Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics.
  • Author:
    Krug AK; Gutbier S; Zhao L; Pöltl D; Kullmann C; Ivanova V; Förster S; Jagtap S; Meiser J; Leparc G; Schildknecht S; Adam M; Hiller K; Farhan H; Brunner T; Hartung T; Sachinidis A; Leist M
    Title:
    Transcriptional and metabolic adaptation of human neurons to the mitochondrial toxicant MPP +
    Source:
    Cell Death Dis 5 (5) art. no.e1222 (2014)
    Abstract:
    Assessment of the network of toxicity pathways by Omics technologies and bioinformatic data processing paves the road toward a new toxicology for the twenty-first century. Especially, the upstream network of responses, taking place in toxicant-treated cells before a point of no return is reached, is still little explored. We studied the effects of the model neurotoxicant 1-methyl-4-phenylpyridinium (MPP +) by a combined metabolomics (mass spectrometry) and transcriptomics (microarrays and deep sequencing) approach to provide unbiased data on earliest cellular adaptations to stress. Neural precursor cells (LUHMES) were differentiated to homogeneous cultures of fully postmitotic human dopaminergic neurons, and then exposed to the mitochondrial respiratory chain inhibitor MPP + (5 .M). At 18-24 h after treatment, intracellular ATP and mitochondrial integrity were still close to control levels, but pronounced transcriptome and metabolome changes were seen. Data on altered glucose flux, depletion of phosphocreatine and oxidative stress (e.g., methionine sulfoxide formation) confirmed the validity of the approach. New findings were related to nuclear paraspeckle depletion, as well as an early activation of branches of the transsulfuration pathway to increase glutathione. Bioinformatic analysis of our data identified the transcription factor ATF-4 as an upstream regulator of early responses. Findings on this signaling pathway and on adaptive increases of glutathione production were confirmed biochemically. Metabolic and transcriptional profiling contributed complementary information on multiple primary and secondary changes that contribute to the cellular response to MPP +. Thus, combined 'Omics' analysis is a new unbiased approach to unravel earliest metabolic changes, whose balance decides on the final cell fate. © 2014 Macmillan Publishers Limited All rights reserved 2041-4889/14.
  • Author:
    Naidoo P; Rambiritch V; Butkow N; Saman S
    Title:
    Optimal utilisation of sulphonylureas in resource-constrained settings
    Source:
    Cardiovas J Afri 25 (2), 83-85 (2014)
    Abstract:
    Sulphonylureas (SUs) are oral anti-diabetic drugs (OADs) that were introduced more than 60 years ago. Clinicians are familiar with their use and they remain extensively used. However, the SU class is associated with adverse effects of weight gain and hypoglycaemia. In addition, their effects on cardiovascular events remain contentious. Newer classes of anti-diabetic agents have been developed and these agents are weight neutral (di-peptidyl peptidase IV inhibitors), while others reduce weight (glucagon-like peptide analogues and sodium glucose co-transporter inhibitors). Furthermore, the newer agents are less likely to cause hypoglycaemia and have a potentially better cardiovascular safety profile. However, the newer agents are more costly than SUs and their long-term safety is unknown. It is therefore likely that SUs will continue to be used, and more so in resource-limited settings. One may mitigate the adverse effects of weight gain and hypoglycaemia associated with the SU class by using members within this class that are less probable to cause these adverse effects. Furthermore, the specific SU must be used at the lowest effective therapeutic dose. In patients at high risk of SU-induced hypoglycaemic episodes (frail, clinically significant renal impairment), or patients in whom hypoglycaemic episodes may have devastating effects (bus drivers), newer anti-diabetic agents may be a justifiable alternative option.
  • Author:
    Thrasher J; Daniels K; Patel S; Whetteckey J; Woerle H-J
    Title:
    Efficacy and safety of linagliptin in black/African American patients with type 2 diabetes: A 6-month, randomized, double-blind, placebo-controlled study
    Source:
    Endocr Pract 20 (5), 412-420 (2014)
    Abstract:
    Objective: Although black/African American individuals are disproportionately affected by type 2 diabetes, there is scant clinical trial information available on antidiabetes therapies in this group. We compared linagliptin with placebo in black/African American adults who were treatment-naïve or receiving one oral antidiabetes drug.Methods: Of 226 patients randomized to 24 weeks' linagliptin 5 mg/day or placebo, 208 had baseline and at least one on-treatment glycated hemoglobin (HbA&lt;1c&lt;) measurement. Mean baseline HbA&lt;1c&lt; was 8.6% in the linagliptin group (n = 98) and 8.68% in the placebo group (n = 110). The primary outcome was change in HbA&lt;1c&lt; from baseline to week 24.Results: By week 24, mean HbA&lt;1c&lt; changes were-0.84% with linagliptin and-0.25% with placebo (treatment difference,-0.58%; P&lt;.001), and more patients in the linagliptin group achieved HbA1 &lt;7.0% (26.8% vs. 8.3%; P = .001) or an Hb A1 reduction .0.5% (54.1% vs. 30.0%; P&lt;.001). Mean weight loss was-1.1 kg in both groups. During the treatment period, 8 of 98 linagliptin-group patients and 17 of 110 placebo-group patients required rescue therapy (odds ratio, 0.5; P = .14). For postprandial glucose, values were available for few patients (11 placebo, 10 linagliptin), and thus the between-group difference was associated with wide confidence intervals (CIs) (difference,-1.97 mg/dL; 95% CI,-53.80 to 49.86; P = .94). In the overall study population, a similar proportion of patients in both groups had adverse events (58.5% vs. 61.7%); most events were mild or moderate and considered unrelated to study drug. Investigator-defined hypoglycemia was rare (3 linagliptin-group patients and 1 placebo-group patient), with no severe events (requiring external assistance).Conclusion: This study confirms that linagliptin is efficacious and well tolerated in black/African American patients with type 2 diabetes. © 2014 AACE.
  • Author:
    Friedrich C; Jungnik A; Retlich S; Ring A; Meinicke T
    Title:
    Bioequivalence of linagliptin 5 mg once daily and 25 mg twice daily: Pharmacokinetics and pharmacodynamics in an open-label crossover trial
    Source:
    Drug Res (Stuttg) 64 (5), 269-275 (2014)
    Abstract:
    Purpose: Linagliptin is an oral antihyperglycemic drug that acts by inhibiting the dipeptidyl peptidase-4 enzyme. A 5-mg once-daily regimen is available, but an alternative regimen was needed for twice-daily fixed-dose combinations. Although linagliptin has non-linear pharmacokinetics, simulation suggested 2.5 mg twice-daily would provide bioequivalent exposure and comparable plasma dipeptidyl peptidase-4 inhibition to 5 mg once-daily. Methods: This crossover study compared steady-state pharmacokinetics and pharmacodynamics of linagliptin 5 mg once-daily and 2.5 mg twice-daily, both administered for 7 days. Results: In total, 16 healthy volunteers entered the study, and 15 completed both treatment periods. Exposure over 24-h at steady state (AUC 0-24,ss) was similar for linagliptin 5 mg once-daily and 2.5 mg twice-daily (132 vs. 124 nmol . h/L), and the 90% confidence interval of the adjusted geometric mean ratio of AUC0-24,ss was well within the acceptance range for bioequivalence (ratio 93.9%; 90% confidence interval 89.5, 98.5). Median dipeptidyl peptidase-4 inhibition over a 24-h interval at steady state was 85.9% with linagliptin 5 mg once-daily and 86.5% with 2.5 mg twice-daily, and median dipeptidyl peptidase-4 inhibition values were approximately 80.0% at trough. Most subjects had no adverse events and there were no serious adverse events. Conclusions: Linagliptin 5 mg once-daily and 2.5 mg twice-daily provided bioequivalent exposure and similar inhibition of dipeptidyl peptidase-4 over the whole dosing interval. © Georg Thieme Verlag KG Stuttgart.
  • Author:
    Gottschling Dr D
    Title:
    Discovery of BI 1356 (Linagliptin)
    Source:
    Symposium "Forschung der Chemischen Industrie" at the University of Münster, Germany, May 22, 2014
  • Author:
    Rambiritch V; Maharaj B; Naidoo P
    Title:
    Glibenclamide in patients with poorly controlled type 2 diabetes: A 12-week, prospective, single-center, open-label, dose-escalation study
    Source:
    Clin Pharmacol Adv Appl 6 (1), 63-69 (2014)
    Abstract:
    Background: The purpose of this study was to investigate the effect of glibenclamide dose escalation on blood glucose and insulin in patients with poorly controlled type 2 diabetes. Methods: Twenty-two subjects with type 2 diabetes were administered increasing doses (0, 2.5, 5, 10, and 20 mg/day) of glibenclamide at 2-week intervals. Glibenclamide, glucose, and insulin determinations were performed. Results: The decrease in mean blood glucose from zero dose was 20%, 22%, 26%, and 28% for doses of 2.5, 5, 10, and 20 mg/day, respectively, which was significant from zero dose to 2.5 mg/day (P.0.001). There were no significant decreases in glucose concentration beyond 2.5 mg/day. The percentage increase in mean insulin from zero dose was 51%, 58%, 44%, and 33% for 2.5, 5, 10, and 20 mg/day respectively. Mean blood insulin increased significantly from zero dose to 2.5 mg/day (P.0.001). There were no significant increases in mean insulin concentration beyond 2.5 mg/day. Conclusion: The results of this study suggest that increasing doses of glibenclamide do not produce a proportional increase in insulin secretion or a proportional decrease in blood glucose concentration. © 2014 Rambiritch et al.
  • Author:
    Groop P-H; Del Prato S; Taskinen M-R; Owens DR; Gong Y; Crowe S; Patel S; von Eynatten M; Woerle H-J
    Title:
    Linagliptin treatment in subjects with type 2 diabetes with and without mild-to-moderate renal impairment
    Source:
    Diabetes Obes Metab 16 (6), 560-568 (2014)
    Abstract:
    Aims: Renal disease is a frequent comorbidity of type 2 diabetes mellitus (T2DM) and an important factor complicating the choice of glucose-lowering drugs. The aim of this analysis was to evaluate the efficacy and safety of the dipeptidyl peptidase (DPP)-4 inhibitor linagliptin (5mg/day) in mono, dual or triple oral glucose-lowering regimens in subjects with T2DM and mild or moderate renal impairment (RI). Methods: In this pooled analysis of three 24-week, placebo-controlled, phase 3 trials, subjects with mild (estimated glomerular filtration rate (eGFR) 60-&lt;90ml/min/1.73m2, n=838) or moderate RI (30-&lt;60ml/min/1.73m2, n=93) were compared with subjects with normal renal function (.90ml/min/1.73m2, n=1212). Results: Subjects with RI were older, had longer duration of diabetes, and increased prevalence of diabetes-related comorbidities. After 24weeks, linagliptin achieved consistent placebo-corrected mean glycated haemoglobin (HbA1c) changes across the three renal function categories: normal (-0.63%; p&lt;0.0001), mild RI (-0.67%; p&lt;0.0001) and moderate RI (-0.53%; p&lt;0.01), with no inter-group difference (p=0.74). Renal function with linagliptin remained stable across all categories. In linagliptin-treated subjects, overall adverse event (AE) rates and serious AE rates were similar to placebo. The incidence of hypoglycaemia with linagliptin and placebo was 11.1 versus 6.9%, 11.9 versus 9.0% and 15.9 versus 12.0% in the normal, mild RI and moderate RI categories, respectively. Conclusions: This pooled analysis provides evidence that linagliptin is an effective, well-tolerated and convenient treatment in subjects with T2DM and mild or moderate RI. © 2014 The Authors. Diabetes, Obesity and Metabolism published by John Wiley &amp; Sons Ltd.
  • Author:
    Blech S; Laux R
    Title:
    Resolving the microcosmos of complex samples: UPLC/TWIMS/high res. MSE for the analysis of in vivo drug metabolism studies, Proceedings
    Source:
    20th International Symposium on Microsomes and Drug Oxidations, Stuttgart, Germany, May 18- 22, 2014
  • Author:
    Perkins BA; Cherney DZI; Partridge H; Soleymanlou N; Tschirhart H; Zinman B; Fagan NM; Kaspers S; Woerle H-J; Broedl UC; Johansen O-E
    Title:
    Sodium-glucose cotransporter 2 inhibition and glycemic control in type 1 diabetes: Results of an 8-week open-label proof-of-concept trial
    Source:
    Diabetes Care 37 (5), 1480-1483 (2014)
    Abstract:
    OBJECTIVE: Adjunctive-to-insulin therapy with sodium-glucose cotransporter 2 (SGLT2) inhibition may improve glycemic control in type 1 diabetes (T1D). RESEARCH DESIGN AND METHODS: We evaluated the glycemic efficacy and safety of empagliflozin 25 mg daily in 40 patients treated for 8 weeks in a single-arm open-label proof-of-concept trial (NCT01392560). RESULTS: Mean A1C decreased from 8.0 ± 0.9% (64 ± 10 mmol/mol) to 7.6 ± 0.9% (60 ± 10 mmol/mol) (P < 0.0001), fasting glucose from 9.0 ± 4.3 to 7.0 ± 3.2 mmol/L (P = 0.008), symptomatic hypoglycemia (<3.0 mmol/L) from 0.12 to 0.04 events per patient per day (P = 0.0004), and daily insulin dose from 54.7 ± 20.4 to 45.8 ± 18.8 units/day (P < 0.0001). Mean urinary excretion of glucose increased from 19 ± 19 to 134 ± 61 g/day (P < 0.0001). Weight decreased from 72.6 ± 12.7 to 70.0 ± 12.3 kg (P < 0.0001), and waist circumference decreased from 82.9 ± 8.7 to 79.1 6 8.0 cm (P < 0.0001). CONCLUSIONS: This proof-of-concept study strongly supports a randomized clinical trial of adjunctive-to-insulin empagliflozin in patients with T1D. © 2014 by the American Diabetes Association.
  • Author:
    Philipp Welschof; Matthias Oelze; Swenja Kröller-Schön; Thomas Jansen; Michael Hausding; Yuliya Mikhed; Paul Stamm; Michael Mader; Elena Zinßius; Saule Agdauletova; Philip Wenzel; Eberhard Schulz; Serge Bottari; Eric Mayoux; Thomas Münzel; Andreas Daiber
    Title:
    The sodium-glucose co-transporter 2 inhibitor empagliflozin improves diabetic complications in the streptozotocin T1DM model by interfering with glucotoxicity and rescue of beta-cell function
    Source:
    ATVB Toronto, CA, May 1-3, 2014
  • Author:
    Wu N; Yu X; Greene M; Oderda G
    Title:
    Evaluation of the prevalence of chronic kidney disease and rates of oral antidiabetic prescribing in accordance with guidelines and manufacturer recommendations in type 2 diabetic patients within a long-term care setting
    Source:
    Int J Nephrol art.no. 151706 (2014)
    Abstract:
    This retrospective study assessed the prevalence of moderate to severe chronic kidney disease (CKD) among nursing home (NH) residents with type 2 diabetes. The pattern of oral antidiabetic drug (OAD) use and their concordance with the National Kidney Foundation (NKF) guideline and prescribing information (PI) was also assessed. About half (47%) of diabetic residents had moderate to severe CKD. A little over a quarter of the 186 residents using OADs received at least one NKF-discordant OAD prescription. Metformin was the most commonly misused OAD. PI nonconcordance was observed in 58.6% of residents and was highest in glipizide and metformin users. With the high prevalence of moderate to severe CKD in NH residents with diabetes, physicians should consider residents' renal function when choosing treatment plans and review treatments regularly to check compliance with the NKF guidelines or PIs. © 2014 Ning Wu et al.
  • Author:
    Chen S-Y; Lee Y-C; Alas V; Greene M; Brixner D
    Title:
    Outcomes associated with nonconcordance to national kidney foundation guideline recommendations for oral antidiabetic drug treatments in patients with concomitant type 2 diabetes and chronic kidney disease
    Source:
    Endocr Pract 20 (3), 221-231 (2014)
    Abstract:
    Objective: To assess the association between oral antidiabetic drug (OAD) treatment concordance with National Kidney Foundation (NKF) guidelines and related economic and clinical outcomes in patients with type 2 diabetes mellitus (T2DM) and stage 3 to 5 chronic kidney disease (CKD). Methods: Analysis of nationwide health administrative claims and laboratory findings for the years 2005 to 2010 for a commercially insured U.S. population. T2DM patients age 18 to 64 years were selected if they had stage 3 to 5 CKD as identified using medical claims (International Classification of Diseases-9-CM codes 585.3-585.6), evidence of dialysis procedures, or laboratory findings showing an estimated glomerular filtration rate &lt;60 mL/min/1.73 m2(date of first CKD as the index date). OADs prescribed during the 6 months following the index date were evaluated to determine guideline concordance. Outcomes examined included glycemic control, healthcare costs and resource utilization, and severe hypoglycemic events. Regression models were used to assess the association between guideline nonconcordance and outcomes. Results: Of the final study sample (N = 3,300), 58.3% were nonconcordant with guidelines. After adjusting for patient characteristics, the nonconcordant patients were more likely to have severe hypoglycemic events (hazard ratio, 1.24; 95% confidence interval [CI], 1.03-1.49) and less likely to have glycemic control (odds ratio [OR], 0.70; 95% CI, 0.57-0.85) than guideline-concordant patients. Likelihood of hospital admission (OR, 0.95; 95% CI, 0.79-1.15) and annual total healthcare costs (adjusted difference, -$2,227; P = .051) were similar between cohorts. Conclusion: In T2DM patients with moderate to severe CKD, OAD treatment not concordant with guidelines is associated with a higher risk of severe hypoglycemic events and uncontrolled glycemic levels. Copyright © 2014 AACE.
  • Author:
    Zhou J; Li F
    Title:
    Potential pharmacokinetic interactions of therapeutic cytokines or cytokine modulators on small-molecule drugs: Mechanistic understanding via studies using in vitro systems
    Source:
    Drug Metab Drug Interact 29 (1), 17-28 (2014)
    Abstract:
    The potential pharmacokinetic interactions between macromolecules and small-molecule drugs have received more and more attention with the increasing development of macromolecule therapeutics. Studies have shown that cytokines can differentially modulate drug-metabolizing enzymes and transporters, which raises concerns on the potential interactions of therapeutic cytokines and cytokine modulators on the disposition of small-molecule drugs. Although many in vitro studies have been conducted to characterize the effects of cytokines on drug-metabolizing enzymes and transporters, these studies were limited to only a handful of cytokines, such as interleukin-1 (IL-1), IL-6, tumor necrosis factor-., and interferon. It is also challenging to translate these in vitro results to in vivo. In addition, information on the impact of cytokine modulators on drug-metabolizing enzymes and transporters is rather limited. More research is needed in this area. The present review is to provide a summary of the in vitro findings on the pharmacokinetic interactions of therapeutic cytokines and cytokine modulators on small-molecule drugs. Discussion on current challenges in assessing these interactions is also included. © 2014 by Walter de Gruyter Berlin Boston 2014.
  • Author:
    Groop P-H; Del Prato S; Taskinen M-R; Owens DR; Gong Y; Crowe S; Patel S; von Eynatten M; Woerle H-J
    Title:
    Linagliptin treatment in subjects with type 2 diabetes with and without mild-to-moderate renal impairment
    Source:
    Diabetes Obes Metab Article in Press (2014)
    Abstract:
    Aims: Renal disease is a frequent comorbidity of type 2 diabetes mellitus (T2DM) and an important factor complicating the choice of glucose-lowering drugs. The aim of this analysis was to evaluate the efficacy and safety of the dipeptidyl peptidase (DPP)-4 inhibitor linagliptin (5mg/day) in mono, dual or triple oral glucose-lowering regimens in subjects with T2DM and mild or moderate renal impairment (RI). Methods: In this pooled analysis of three 24-week, placebo-controlled, phase 3 trials, subjects with mild (estimated glomerular filtration rate (eGFR) 60-&lt;90ml/min/1.73m2, n=838) or moderate RI (30-&lt;60ml/min/1.73m2, n=93) were compared with subjects with normal renal function (.90ml/min/1.73m2, n=1212). Results: Subjects with RI were older, had longer duration of diabetes, and increased prevalence of diabetes-related comorbidities. After 24weeks, linagliptin achieved consistent placebo-corrected mean glycated haemoglobin (HbA1c) changes across the three renal function categories: normal (-0.63%; p&lt;0.0001), mild RI (-0.67%; p&lt;0.0001) and moderate RI (-0.53%; p&lt;0.01), with no inter-group difference (p=0.74). Renal function with linagliptin remained stable across all categories. In linagliptin-treated subjects, overall adverse event (AE) rates and serious AE rates were similar to placebo. The incidence of hypoglycaemia with linagliptin and placebo was 11.1 versus 6.9%, 11.9 versus 9.0% and 15.9 versus 12.0% in the normal, mild RI and moderate RI categories, respectively. Conclusions: This pooled analysis provides evidence that linagliptin is an effective, well-tolerated and convenient treatment in subjects with T2DM and mild or moderate RI. © 2014 The Authors.
  • Author:
    Jones RB; Vickers SP; Cheetham SC; Headland KR; Mark M; Klein T
    Title:
    Effect of linagliptin, alone and in combination with voglibose or exendin-4, on glucose control in male ZDF rats
    Source:
    Eur J Pharmacol 729, 59-66 Article in Press (2014)
    Abstract:
    no Abstract available
  • Author:
    Ferrannini E; Muscelli E; Frascerra S; Baldi S; Mari A; Heise T; Broedl UC; Woerle H-J
    Title:
    Metabolic response to sodium-glucose cotransporter 2 inhibition in type 2 diabetic patients
    Source:
    J Clin Invest 124 (2), 499-508 (2014)
    Abstract:
    Background. Sodium-glucose cotransporter 2 (SGLT2) inhibitors lower glycemia by enhancing urinary glucose excretion. The physiologic response to pharmacologically induced acute or chronic glycosuria has not been investigated in human diabetes. Methods. We evaluated 66 patients with type 2 diabetes (62 ± 7 years, BMI = 31.6 ± 4.6 kg/m2, HbA1c = 55 ± 8 mmol/mol, mean ± SD) at baseline, after a single dose, and following 4-week treatment with empagliflozin (25 mg). At each time point, patients received a mixed meal coupled with dual-tracer glucose administration and indirect calorimetry. Results. Both single-dose and chronic empagliflozin treatment caused glycosuria during fasting (median, 7.8 [interquartile range {IQR}, 4.4] g/3 hours and 9.2 [IQR, 5.2] g/3 hours) and after meal ingestion (median, 29.0 [IQR, 12.5] g/5 hours and 28.2 [IQR, 15.4] g/5 hours). After 3 hours of fasting, endogenous glucose production (EGP) was increased 25%, while glycemia was 0.9 ± 0.7 mmol/l lower (P < 0.0001 vs. baseline). After meal ingestion, glucose and insulin AUC decreased, whereas the glucagon response increased (all P < 0.001). While oral glucose appearance was unchanged, EGP was increased (median, 40 [IQR, 14] g and 37 [IQR, 11] g vs. 34 [IQR, 11] g, both P < 0.01). Tissue glucose disposal was reduced (median, 75 [IQR, 16] g and 70 [IQR, 21] g vs. 93 [IQR, 18] g, P < 0.0001), due to a decrease in both glucose oxidation and nonoxidative glucose disposal, with a concomitant rise in lipid oxidation after chronic administration (all P < 0.01). . Cell glucose sensitivity increased (median, 55 [IQR, 35] pmol.min-1.m- 2.mM-1 and 55 [IQR, 39] pmol.min-1.m-2.mM-1 vs. 44 [IQR, 32] pmol.min-1.m-2.mM-1, P < 0.0001), and insulin sensitivity was improved. Resting energy expenditure rates and those after meal ingestion were unchanged. Conclusions. In patients with type 2 diabetes, empagliflozin-induced glycosuria improved . cell function and insulin sensitivity, despite the fall in insulin secretion and tissue glucose disposal and the rise in EGP after one dose, thereby lowering fasting and postprandial glycemia. Chronic dosing shifted substrate utilization from carbohydrate to lipid. Trial registration. ClinicalTrials.Gov NCT01248364 (EudraCT no. 2010-018708-99). Funding. This study was funded by Boehringer Ingelheim. © Copyright 2014 American Society for Clinical Investigation.
  • Author:
    Schaefer JH; Leung W; Wu L; Van Cott EM; Lok J; Whalen M; van Leyen K; Lauer A; van Ryn J; Lo EH; Foerch C
    Title:
    Translational insights into traumatic brain injury occurring during dabigatran or warfarin anticoagulation
    Source:
    J Cereb Blood Flow Metab Article in Press (2014)
    Abstract:
    To date, only limited data are available on the effects of pretreatment with novel oral anticoagulants in the event of traumatic brain injury (TBI). We determined intracerebral hemorrhage volume and functional outcome in a standardized TBI model in mice treated with warfarin or dabigatran. Additionally, we investigated whether excess concentrations of dabigatran could increase bleeding and whether this was preventable by using prothrombin complex concentrate (PCC). C57 mice were treated orally with warfarin or dabigatran; sham-treated mice served as controls. Effective anticoagulation was verified by measurement of international normalized ratio and diluted thrombin time, and TBI was induced by controlled cortical impact (CCI). Twenty-four hours after CCI, intracerebral hemorrhage volume was larger in warfarin-pretreated mice than in controls (10.1±4.9 vs 4.1±1.7 .L; analysis of variance post hoc P=0.001), but no difference was found between controls and dabigatran-pretreated mice (5.3±1.5 .L). PCC applied 30 minutes after CCI did not reliably reduce intracerebral hemorrhage induced by excess dabigatran concentration compared with saline (10.4±11.2 vs 8.7±7.1 .L). Our data suggest pathophysiological differences in TBI occurring during warfarin and dabigatran anticoagulation. The reduced hemorrhage formation under dabigatran therapy could present a safety advantage compared with warfarin. An excess dabigatran concentration, however, can increase hemorrhage.Journal of Cerebral Blood Flow & Metabolism advance online publication, 19 February 2014; doi:10.1038/jcbfm.2014.31.
  • Author:
    Li Y; Zhou J; Ramsden D; Taub ME; O'Brien D; Xu J; Busacca CA; Gonnella N; Tweedie DJ
    Title:
    Enzyme-transporter interplay in the formation and clearance of abundant metabolites of faldaprevir found in excreta but not in circulations
    Source:
    Drug Metab Dispos, 384-393 (2014)
    Abstract:
    Faldaprevir is a hepatitis C virus protease inhibitor that effectively reduces viral load in patients. Since faldaprevir exhibits slow metabolism in vitro and low clearance in vivo, metabolism was expected to be a minor clearance pathway. The human [14C] absorption, distribution, metabolism, and excretion study revealed that two monohydroxylated metabolites (M2a and M2b) were the most abundant excretory metabolites in feces, constituting 41% of the total administered dose. To deconvolute the formation and disposition of M2a and M2b in humans and determine why the minor change in structure [the addition of 16 atomic mass units (amu)] produced chemical entities that were excreted and were not present in the circulation, multiple in vitro test systems were used. The results from these in vitro studies clarified the formation and clearance of M2a and M2b. Faldaprevir is metabolized primarily in the liver by CYP3A4/5 to form M2a and M2b, which are also substrates of efflux transporters (P-glycoprotein and breast cancer resistance protein). The role of transporters is considered important for M2a and M2b as they demonstrate low permeability. It is proposed that both metabolites are efficiently excreted via bile into feces and do not enter the systemic circulation to an appreciable extent. If these metabolites permeate to blood, they can be readily taken up into hepatocytes from the circulation by uptake transporters (likely organic anion transporting polypeptides). These results highlight the critical role of drug-metabolizing enzymes and multiple transporters in the process of the formation and clearance of faldaprevir metabolites. Faldaprevir metabolism also provides an interesting case study for metabolites that are exclusively excreted in feces but are of clinical relevance. Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics.
  • Author:
    Macha S; Mattheus M; Halabi A; Pinnetti S; Woerle HJ; Broedl UC
    Title:
    Pharmacokinetics, pharmacodynamics and safety of empagliflozin, a sodium glucose cotransporter 2 (SGLT2) inhibitor, in subjects with renal impairment
    Source:
    Diabetes Obes Metab 16 (3), 215-222 (2014)
    Abstract:
    Aims: Empagliflozin is a selective sodium glucose cotransporter 2 (SGLT2) inhibitor that inhibits renal glucose reabsorption and is being investigated for the treatment of type 2 diabetes mellitus (T2DM). Methods: In this open-label study, the effect of renal impairment on the pharmacokinetics, pharmacodynamics and safety of a 50mg dose of empagliflozin was investigated in 40 subjects, grouped according to estimated glomerular filtration rate (eGFR). Results: Maximum empagliflozin plasma concentrations were similar in subjects with normal renal function and renal impairment. Area under the empagliflozin concentration-time curve (AUC0-.) values increased by approximately 18, 20, 66 and 48% in subjects with mild, moderate, severe renal impairment and renal failure/end stage renal disease (ESRD), respectively, in comparison to healthy subjects. This was attributed to decreased renal clearance (CLR). Urinary glucose excretion (UGE) decreased with increasing renal impairment and correlated with decreased eGFR and CLR. Empagliflozin was well tolerated, with no increase in adverse events associated with renal impairment. Conclusions: Renal insufficiency resulted in decreased CLR of empagliflozin, moderately increased systemic exposure and decreased UGE. A single 50mg dose of empagliflozin was well tolerated in subjects with normal renal function and any degree of renal impairment. The pharmacokinetic results of this study indicate that no dose adjustment of empagliflozin is required in patients with renal impairment. © 2013 John Wiley &amp; Sons Ltd.
  • Author:
    Ramsden D; Tweedie DJ; St George R; Chen L-Z; Li Y
    Title:
    Generating an in vitro-in vivo correlation for metabolism and liver enrichment of a hepatitis C virus drug, faldaprevir, using a rat hepatocyte model (hepatopac)
    Source:
    Drug Metab Dispos 42 (3), 407-414 (2014)
    Abstract:
    Hepatocytes provide an integrated model to study drug metabolism and disposition. As a result of a loss of polarity or a significant decrease in the expression of enzymes and transporters, suspended and sandwich-cultured hepatocytes have limitations in determining hepatocellular drug concentrations. Underprediction of the extent of glucuronidation is also a concern for these hepatocyte models. Faldaprevir is a hepatitis C virus protease inhibitor in late-stage development that has demonstrated significant liver enrichment in in vivo rat models based on quantitative whole-body autoradiography (QWBA) and liver-to-plasma area under-the-curve ratio. In bile duct cannulated rats, the primary biliary metabolite was a glucuronide. Owing to ethical concerns, it is difficult to assess liver enrichment in humans, and a lack of in vitro and in vivo correlation of glucuronidation has been reported. The current study was conducted to verify whether a hepatocyte model, rat HepatoPac, could overcome some of these limitations and provide validity for follow-up studies with human HepatoPac. With rat HepatoPac, liver enrichment values averaged 34-fold and were consistent with rat QWBA (26.8-fold) and in vivo data (42-fold). In contrast, liver enrichment in suspended hepatocytes was only 2.8-fold. Furthermore, the extent of faldaprevir glucuronidation in HepatoPac studies was in agreement with in vivo results, with glucuronidation as the major pathway (96%). Suspended rat hepatocytes did not generate the glucuronide or two key hydroxylated metabolites that were observed in vivo. Overall, our studies suggest that HepatoPac is a promising in vitro model to predict in vivo liver enrichment and metabolism, especially for glucuronidation, and has demonstrated superiority over suspended hepatocytes. Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics.
  • Author:
    Ramsden D; Tweedie DJ; Chan TS; Taub ME; Li Y
    Title:
    Bridging in vitro and in vivo metabolism and transport of faldaprevir in human using a novel cocultured human hepatocyte system, hepatopac
    Source:
    Drug Metab Dispos 42 (3), 394-406 (2014)
    Abstract:
    An increased appreciation of the importance of transporter and enzyme interplay in drug clearance and a desire to delineate these mechanisms necessitates the utilization of models that contain a full complement of enzymes and transporters at physiologically relevant activities. Additionally, the development of drugs with longer half-lives requires in vitro systems with extended incubation times that allow characterization of metabolic pathways for lowclearance drugs. A recently developed coculture hepatocyte model, HepatoPac, has been applied to meet these challenges. Faldaprevir is a drug in late-stage development for the treatment of hepatitis C. Faldaprevir is a low-clearance drug with the somewhat unique characteristic of being slowly metabolized, producing two abundant hydroxylated metabolites (M2a and M2b) in feces (40% of the dose) without exhibiting significant levels of circulating metabolites in humans. The human HepatoPac model was investigated to characterize the metabolism and transport of faldaprevir. In human HepatoPac cultures, M2a and M2b were the predominant metabolites formed, with extents of formation comparable to in vivo. Direct glucuronidation of faldaprevir was shown to be a minor metabolic pathway. HepatoPac studies also demonstrated that faldaprevir is concentrated in liver with active uptake by multiple transporters (including OATP1B1 and Na+-dependent transporters). Overall, human HepatoPac cultures provided valuable insights into the metabolism and disposition of faldaprevir in humans and demonstrated the importance of enzyme and transporter interplay in the clearance of the drug. Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics.
  • Author:
    Cherney DZI; Perkins BA; Soleymanlou N; Maione M; Lai V; Lee A; Fagan NM; Woerle HJ; Johansen OE; Broedl UC; Von Eynatten M
    Title:
    Renal hemodynamic effect of sodium-glucose cotransporter 2 inhibition in patients with type 1 diabetes mellitus
    Source:
    Circulation 129 (5), 587-597 (2014)
    Abstract:
    BACKGROUND -: The primary objective of this mechanistic open-label, stratified clinical trial was to determine the effect of 8 weeks' sodium glucose cotransporter 2 inhibition with empagliflozin 25 mg QD on renal hyperfiltration in subjects with type 1 diabetes mellitus (T1D). METHODS AND RESULTS -: Inulin (glomerular filtration rate; GFR) and paraaminohippurate (effective renal plasma flow) clearances were measured in individuals stratified based on having hyperfiltration (T1D-H, GFR . 135 mL/min/1.73m, n=27) or normal GFR (T1D-N, GFR 90-134 mL/min/1.73m, n=13) at baseline. Renal function and circulating levels of renin-angiotensin-aldosterone system mediators and NO were measured under clamped euglycemic (4-6 mmol/L) and hyperglycemic (9-11 mmol/L) conditions at baseline and end of treatment. During clamped euglycemia, hyperfiltration was attenuated by -33 mL/min/1.73m with empagliflozin in T1D-H, (GFR 172±23-139±25 mL/min/1.73 m, P<0.01). This effect was accompanied by declines in plasma NO and effective renal plasma flow and an increase in renal vascular resistance (all P<0.01). Similar significant effects on GFR and renal function parameters were observed during clamped hyperglycemia. In T1D-N, GFR, other renal function parameters, and plasma NO were not altered by empagliflozin. Empagliflozin reduced hemoglobin A1c significantly in both groups, despite lower insulin doses in each group (P.0.04). CONCLUSIONS -: In conclusion, short-term treatment with the sodium glucose cotransporter 2 inhibitor empagliflozin attenuated renal hyperfiltration in subjects with T1D, likely by affecting tubular-glomerular feedback mechanisms. © 2013 American Heart Association, Inc.
  • Author:
    Barnett AH; Mithal A; Manassie J; Jones R; Rattunde H; Woerle HJ; Broedl UC
    Title:
    Efficacy and safety of empagliflozin added to existing antidiabetes treatment in patients with type 2 diabetes and chronic kidney disease: a randomised, double-blind, placebo-controlled trial
    Source:
    Lancet Diabetes Endocrinol article in press (2014)
    Abstract:
    Background: Diabetes is a leading cause of chronic kidney disease (CKD) worldwide. Optimum glycaemic control in patients with type 2 diabetes is important to minimise the risk of microvascular and macrovascular complications and to slow the progression of CKD. We assessed the efficacy and safety of empagliflozin as an add-on treatment in patients with type 2 diabetes and CKD. Methods: We did a phase 3, randomised, double-blind, parallel-group, placebo-controlled trial at 127 centres in 15 countries. Patients with HbA1c of 7% or greater to 10% or less were eligible for inclusion. Patients with stage 2 CKD (estimated glomerular filtration rate [eGFR] .60 to &lt;90 mL/min per 1.73 m2; n=290) were randomly assigned (1:1:1) to receive empagliflozin 10 mg or 25 mg or placebo once daily for 52 weeks. Patients with stage 3 CKD (eGFR .30 to &lt;60 mL/min per 1.73 m2; n=374) were randomly assigned (1:1) to receive empagliflozin 25 mg or placebo for 52 weeks. Randomisation was done with a computer-generated random sequence and stratified by renal impairment, HbA1c, and background antidiabetes medication. Treatment assignment was masked from patients and investigators. The primary endpoint was change from baseline in HbA1c at week 24 by ANCOVA in the full analysis set. This study is registered with ClinicalTrials.gov, number NCT01164501. Findings: In patients with stage 2 CKD, adjusted mean treatment differences versus placebo in changes from baseline in HbA1c at week 24 were -0.52% (95% CI -0.72 to -0.32) for empagliflozin 10 mg and -0.68% (-0.88 to -0.49) for empagliflozin 25 mg (both p&lt;0.0001). In patients with stage 3 CKD, adjusted mean treatment difference versus placebo in change from baseline in HbA1c at week 24 was -0.42% (-0.56 to -0.28) for empagliflozin 25 mg (p&lt;0.0001). In patients with stage 2 CKD, adverse events were reported over 52 weeks by 83 patients (87%) on placebo (15 severe [16%] and 11 serious [12%]), 86 (88%) on empagliflozin 10 mg (six severe [6%] and six serious [6%]) and 78 (80%) on empagliflozin 25 mg (eight severe [8%] and seven serious [7%]). In patients with stage 3 CKD, adverse events were reported over 52 weeks by 156 patients (83%) on placebo (15 severe [8%] and 23 serious [12%]) and 156 (83%) on empagliflozin 25 mg (18 severe [10%] and 22 serious [12%]). Interpretation: In patients with type 2 diabetes and stage 2 or 3 CKD, empagliflozin reduced HbA1c and was well tolerated. However, our findings might not be applicable to the general population of patients with type 2 diabetes and renal impairment. Funding: Boehringer Ingelheim, Eli Lilly. © 2014 Elsevier Ltd. All rights reserved.
  • Author:
    Johansen OE; Boehm BO; Grill V; Torjesen PA; Bhattacharya S; Patel S; Wetzel K; Woerle H-J
    Title:
    C-peptide levels in latent autoimmune diabetes in adults treated with linagliptin versus glimepiride: Exploratory results from a 2-year double-blind, randomized, controlled study
    Source:
    Diabetes Care 37 (1), e11-e12 (2014)
    Abstract:
    no abstract available
  • Author:
    Vallon V; Gerasimova M; Rose MA; Masuda T; Satriano J; Mayoux E; Koepsell H; Thomson SC; Rieg T
    Title:
    SGLT2 inhibitor empagliflozin reduces renal growth and albuminuria in proportion to hyperglycemia and prevents glomerular hyperfiltration in diabetic Akita mice
    Source:
    Am J Physiol 306 (2), F194-F204 (2014)
    Abstract:
    Our previous work has shown that gene knockout of the sodium-glucose cotransporter SGLT2 modestly lowered blood glucose in streptozotocin-diabetic mice (BG; from 470 to 300 mg/dl) and prevented glomerular hyperfiltration but did not attenuate albuminuria or renal growth and inflammation. Here we determined effects of the SGLT2 inhibitor empagliflozin (300 mg/kg of diet for 15 wk; corresponding to 60-80 mg.kg-1.day-1) in type 1 diabetic Akita mice that, opposite to streptozotocin-diabetes, upregulate renal SGLT2 expression. Akita diabetes, empagliflozin, and Akita + empagliflozin similarly increased renal membrane SGLT2 expression (by 38-56%) and reduced the expression of SGLT1 (by 33-37%) vs. vehicle-treated wild-type controls (WT). The diabetes-induced changes in SGLT2/ SGLT1 protein expression are expected to enhance the BG-lowering potential of SGLT2 inhibition, and empagliflozin strongly lowered BG in Akita (means of 187-237 vs. 517-535 mg/dl in vehicle group; 100-140 mg/dl in WT). Empagliflozin modestly reduced GFR in WT (250 vs. 306 (xl/min) and completely prevented the diabetes-induced increase in glomerular filtration rate (GFR) (255 vs. 397 (xl/min). Empagliflozin attenuated increases in kidney weight and urinary albumin/creatinine ratio in Akita in proportion to hyperglycemia. Empagliflozin did not increase urinary glucose/creatinine ratios in Akita, indicating the reduction in filtered glucose balanced the inhibition of glucose reabsorption. Empagliflozin attenuated/prevented the increase in systolic blood pressure, glomerular size, and molecular markers of kidney growth, inflammation, and gluconeogenesis in Akita. We propose that SGLT2 inhibition can lower GFR independent of reducing BG (consistent with the tubular hypothesis of diabetic glomerular hyperfiltration), while attenuation of albuminuria, kidney growth, and inflammation in the early diabetic kidney may mostly be secondary to lower BG.
  • Author:
    Rieg T; Masuda T; Gerasimova M; Mayoux E; Platt K; Powell DR; Thomson SC; Koepsell H; Vallon V
    Title:
    Increase in SGLT1-mediated transport explains renal glucose reabsorption during genetic and pharmacological SGLT2 inhibition in euglycemia
    Source:
    Am J Physiol 306 (2), F188-F193 (2014)
    Abstract:
    In the kidney, the sodium-glucose cotransporters SGLT2 and SGLT1 are thought to account for >90 and ~3% of fractional glucose reabsorption (FGR), respectively. However, euglycemic humans treated with an SGLT2 inhibitor maintain an FGR of 40-50%, mimicking values in Sglt2 knockout mice. Here, we show that oral gavage with a selective SGLT2 inhibitor (SGLT2-I) dose dependently increased urinary glucose excretion (UGE) in wild-type (WT) mice. The dose-response curve was shifted leftward and the maximum response doubled in Sglt1 knockout (Sglt1-/-) mice. Treatment in diet with the SGLT2-I for 3 wk maintained 1.5- to 2-fold higher urine glucose/creatinine ratios in Sglt1-/- vs. WT mice, associated with a temporarily greater reduction in blood glucose in Sglt1-/- vs. WT after 24 h (-33 vs. -11%). Subsequent inulin clearance studies under anesthesia revealed free plasma concentrations of the SGLT2-I (corresponding to early proximal concentration) close to the reported IC50 for SGLT2 in mice, which were associated with FGR of 64 ± 2% in WT and 17 ± 2% in Sglt1-/-. Additional intraperitoneal application of the SGLT2-I (maximum effective dose in metabolic cages) increased free plasma concentrations ~ 10-fold and reduced FGR to 44 ± 3% in WT and to - 1 ± 3% in Sglt1-/-. The absence of renal glucose reabsorption was confirmed in male and female Sglt1/Sglt2 double knockout mice. In conclusion, SGLT2 and SGLT1 account for renal glucose reabsorption in euglycemia, with 97 and 3% being reabsorbed by SGLT2 and SGLT1, respectively. When SGLT2 is fully inhibited by SGLT2-I, the increase in SGLT1-mediated glucose reabsorption explains why only 50-60% of filtered glucose is excreted.
  • Author:
    Kovacs CS; Seshiah V; Swallow R; Jones R; Rattunde H; Woerle HJ; Broedl UC
    Title:
    Empagliflozin improves glycaemic and weight control as add-on therapy to pioglitazone or pioglitazone plus metformin in patients with type 2 diabetes: A 24-week, randomized, placebo-controlled trial
    Source:
    Diabetes Obes Metab 16 (2), 147-158 (2014)
    Abstract:
    Aims: This study investigated the efficacy and tolerability of empagliflozin as add-on to pioglitazone±metformin in patients with type 2 diabetes (T2DM). Methods: Patients with HbA1c .7 and .10% were randomized and treated with once daily empagliflozin 10mg (n=165), empagliflozin 25mg (n=168) or placebo (n=165) as add-on to pioglitazone±metformin for 24weeks. Endpoints included changes from baseline in HbA1c (primary endpoint), fasting plasma glucose (FPG) and body weight at week 24. Results: Adjusted mean±standard error changes in HbA1c were -0.6±0.07% and -0.7±0.07% with empagliflozin 10mg and 25mg, respectively, vs. -0.1±0.07% with placebo (both p<0.001). More patients with HbA1c .7% at baseline achieved HbA1c <7% with empagliflozin 10mg (23.8%) and 25mg (30.0%) vs. placebo (7.7%) (both p<0.001). FPG decreased with empagliflozin (-0.94mmol/l for 10mg and -1.22mmol/l for 25mg) and increased with placebo (+0.36mmol/l; both p<0.001). Adjusted mean±standard error changes in weight were -1.62±0.21kg and -1.47±0.21kg with empagliflozin 10mg and 25mg, respectively, vs. +0.34±0.21kg with placebo (both p<0.001). Similar proportions of patients reported adverse events with empagliflozin (67.3-71.4%) and placebo (72.7%). Confirmed hypoglycaemia was reported by 1.2-2.4% of patients on empagliflozin and 1.8% on placebo. Conclusion: Empagliflozin 10mg and 25mg once daily for 24weeks as add-on to pioglitazone±metformin reduced HbA1c, FPG and weight and were well tolerated in patients with T2DM. © 2013 John Wiley & Sons Ltd.
  • Author:
    Macha S; Rose P; Mattheus M; Cinca R; Pinnetti S; Broedl UC; Woerle HJ
    Title:
    Pharmacokinetics, safety and tolerability of empagliflozin, a sodium glucose cotransporter 2 inhibitor, in patients with hepatic impairment
    Source:
    Diabetes Obes Metab 16 (2), 118-123 (2014)
    Abstract:
    Aims: This open-label, parallel-group study investigated the effect of various degrees of hepatic impairment on the pharmacokinetics, safety and tolerability of the sodium glucose cotransporter 2 inhibitor empagliflozin. Methods: Thirty-six subjects [8 each with mild, moderate or severe hepatic impairment (Child-Pugh classification), and 12 matched controls with normal hepatic function] received a single 50mg dose of empagliflozin. Results: Empagliflozin was rapidly absorbed. After reaching peak levels, plasma drug concentrations declined in a biphasic fashion. Compared with subjects with normal hepatic function, geometric mean ratios (90% confidence interval) of AUC0-. and Cmax were 123.15% (98.89-153.36) and 103.81% (82.29-130.95), respectively, in patients with mild hepatic impairment, 146.97% (118.02-183.02) and 123.31% (97.74-155.55), respectively, in patients with moderate hepatic impairment, and 174.70% (140.29-217.55) and 148.41% (117.65-187.23), respectively, in patients with severe hepatic impairment. Adverse events, all mild or moderate in intensity, were reported in three subjects with moderate hepatic impairment, two subjects with severe hepatic impairment and six subjects with normal hepatic function. Conclusions: Empagliflozin was well tolerated in subjects with hepatic impairment. Increases in empagliflozin exposure were less than twofold in patients with hepatic impairment; therefore no dose adjustment of empagliflozin is required in patients with hepatic impairment. © 2013 John Wiley &amp; Sons Ltd.
  • Author:
    Kishimoto W; Ishiguro N; Ludwig-Schwellinger E; Ebner T; Schaefer O
    Title:
    In vitro predictability of drug-drug interaction likelihood of P-glycoprotein-mediated efflux of dabigatran etexilate based on [I] 2/IC50 threshold
    Source:
    Drug Metab Dispos 42 (2), 257-263 (2014)
    Abstract:
    Dabigatran etexilate, an oral, reversible, competitive, and direct thrombin inhibitor, is an in vitro and in vivo substrate of Pglycoprotein (P-gp). Dabigatran etexilate was proposed as an in vivo probe substrate for intestinal P-gp inhibition in a recent guidance on drug-drug interactions (DDI) from the European Medicines Agency (EMA) and the Food and Drug Administration (FDA). We conducted transcellular transport studies across Caco-2 cell monolayers with dabigatran etexilate in the presence of various P-gp inhibitors to examine how well in vitro IC50 data, in combination with mathematical equations provided by regulatory guidances, predict DDI likelihood. From a set of potential P-gp inhibitors, clarithromycin, cyclosporin A, itraconazole, ketoconazole, quinidine, and ritonavir inhibited P-gp-mediated transport of dabigatran etexilate over a concentration range that may hypothetically occur in the intestine. IC50 values of P-gp inhibitors for dabigatran etexilate transport were comparable to those of digoxin, a well established in vitro and in vivo P-gp substrate. However, IC50 values varied depending whether they were calculated from efflux ratios or permeability coefficients. Prediction of DDI likelihood of P-gp inhibitors using IC 50 values, the hypothetical concentration of P-gp inhibitors, and the cut-off value recommended by both the FDA and EMA were in line with the DDI occurrence in clinical studies with dabigatran etexilate. However, it has to be kept in mind that validity of the cut-off criteria proposed by the FDA and EMA depends on in vitro experimental systems and the IC50-calculation methods that are employed, as IC50 values are substantially influenced by these factors. Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics.
  • Author:
    Ferrannini E; Berk A; Hantel S; Pinnetti S; Hach T; Woerle HJ; Broedl UC
    Title:
    Long-term safety and efficacy of empagliflozin, sitagliptin, and metformin: An active-controlled, parallel-group, randomized, 78-week open-label extension study in patients with type 2 diabetes
    Source:
    Diabetes Care 36 (12), 4015-4021 (2013)
    Abstract:
    Objective-To investigate the long-term safety and efficacy of empagliflozin, a sodium glucose cotransporter 2 inhibitor; sitagliptin; and metformin in patients with type 2 diabetes. Research design and methods-In this randomized, open-label, 78-week extension study of two 12-week, blinded, dose-finding studies of empagliflozin (monotherapy and add-on to metformin) with open-label comparators, 272 patients received 10 mg empagliflozin (166 as add-on to metformin), 275 received 25 mg empagliflozin (166 as add-on to metformin), 56 patients received metformin, and 56 patients received sitagliptin as add-on to metformin. Results-Changes from baseline in HbA1c at week 90 were -0.34 to -0.63% (23.7 to -6.9 mmol/mol) with empagliflozin, -0.56% (26.1 mmol/mol) with metformin, and -0.40% (24.4 mmol/mol) with sitagliptin. Changes from baseline in weight at week 90 were -2.2 to -4.0 kg with empagliflozin, -1.3 kg with metformin, and -0.4 kg with sitagliptin. Adverse events (AEs) were reported in 63.2-74.1%of patients on empagliflozin and 69.6% on metformin or sitagliptin; most AEs were mild or moderate in intensity. Hypoglycemic events were rare in all treatment groups, and none required assistance. AEs consistent with genital infections were reported in 3.0-5.5% of patients on empagliflozin, 1.8% on metformin, and none on sitagliptin. AEs consistent with urinary tract infections were reported in 3.8-12.7% of patients on empagliflozin, 3.6% on metformin, and 12.5% on sitagliptin. Conclusions-Long-term empagliflozin treatment provided sustained glycemic and weight control and was well tolerated with a low risk of hypoglycemia in patients with type 2 diabetes. © 2013 by the American Diabetes Association.
  • Author:
    Kopf S; Oikonomou D; Zdunek D; Von Eynatten M; Hess G; Nawroth PP; Bierhaus A; Humpert PM
    Title:
    Urinary n-acetyl-beta-d-glucosaminidase Excretion: An indicator of neuropathy in type 2 diabetes
    Source:
    Exp Clin Endocrinol Diabetes 121 (10), 601-606 (2013)
    Abstract:
    Objective: The established marker for tubular damage, urinary n-acetyl-beta-d-glucosaminidase is significantly increased in type 1 and 2 diabetes patients and is related to albuminuria and other diabetic complications. In this cross sectional study of type 2 diabetes patients with a history of albuminuria, we studied the relationship between excretion of n-acetyl-beta-d-glucosaminidase in urine and diabetic neuropathy. Methods: 160 type 2 diabetes patients were screened for diabetic peripheral neuropathy and cardiovascular autonomic neuropathy. N-acetyl-beta-d-glucosaminidase excretion was detected in 24 h urine samples. Results: Urinary excretion of n-acetyl-beta-d-glucosaminidase correlated significantly with Â-glucose control (fasting glucose r=0.18; p=0.04; HbA1c r=0.20; p=0.02) and urine albumin excretion (r=0.22; p=0.01). Binary regression analyses showed that increased urinary n-acetyl-beta-d-glucosaminidase concentration is an independent predictor for presence of clinical symptoms of peripheral neuropathy (OR 1.8 [95%CI 1.2-2.74] and vibration deficiency [OR 1.7; 95% CI 1.2-2.66]. There was also a significant negative association between urinary n-acetyl-beta-d- glucosaminidase and E/I-Ratio (r=-0.21, p<0.02) as well as the 30:15-Ratio (r=-0.24; p<0.01) of heart rate variability. Furthermore, increased n-acetyl-beta-d-glucosaminidase excretion independently predicted cardiovascular autonomic diabetic neuropathy with an OR for decreased E/I-Ratio of 1.7 [95%CI 1.1-2.75]; (p<0.02) and 30:15-Ratio:OR 2.4 [95% CI 1.26-4.45]; (p<0.01). Conclusion: Urinary n-acetyl-beta-d-glucosamiÂ-nidase excretion is an independent marker for diabetic peripheral and cardiovascular autonomic neuropathy in type 2 diabetic patients. © J. A. Barth Verlag in Georg Thieme Verlag KG Stuttgart New York ISSN 0947-7349.
  • Author:
    Kanada S; Koiwai K; Taniguchi A; Sarashina A; Seman L; Woerle HJ
    Title:
    Pharmacokinetics, pharmacodynamics, safety and tolerability of 4 weeks' treatment with empagliflozin in Japanese patients with type 2 diabetes mellitus
    Source:
    J Diabetes Invest 4 (6), 613-617 (2013)
    Abstract:
    Introduction: To evaluate the pharmacodynamics, pharmacokinetics, safety and tolerability of empagliflozin in Japanese patients with type 2 diabetes mellitus. Materials and methods: In this 4-week, multiple dose, randomized, parallel-group, double-blind, placebo-controlled trial, patients (n = 100) were randomized to receive 1, 5, 10 or 25 mg of empagliflozin, or placebo once daily. Key end-points were urinary glucose excretion (UGE), fasting plasma glucose (FPG) and eight-point glucose profile. Results: Data are presented for 1, 5, 10, 25 mg of empagliflozin and placebo groups, respectively. Adjusted mean changes from baseline to day 27 in UGE were 40.8, 77.1, 80.9, 93.0 and -2.1 g (P < 0.0001 for all empagliflozin groups vs placebo). Adjusted mean changes from baseline to day 28 in FPG were -1.56, -1.96, -2.31, -2.37 and -0.86 mmol/L (P < 0.01 for all empagliflozin groups vs placebo). Adjusted mean changes from baseline to day 27 in eight-point glucose profile were -1.96, -2.21, -2.42, -2.54 and -0.97 mmol/L (P < 0.01 for all empagliflozin groups vs placebo). Empagliflozin reached peak plasma concentration 1.5-2 h after dosing. Mean steady state terminal elimination half-lives ranged from 13.2 to 18.0 h. Of 100 patients, 25 experienced an adverse event, occurring more frequently for empagliflozin (29.1%) than placebo (9.5%); frequency was not dose related. Conclusions: In Japanese patients with type 2 diabetes mellitus, empagliflozin at doses up to 25 mg once daily for 4 weeks was well tolerated and resulted in significant improvements in glycemic control compared with placebo. This trial was registered with ClinicalTrials.gov (no. NCT00885118). © 2013 Asian Association for the Study of Diabetes and Wiley Publishing Asia Pty Ltd.
  • Author:
    Chan TS; Yu H; Moore A; Khetani SR; Tweedie D
    Title:
    Meeting the challenge of predicting hepatic clearance of compounds slowly metabolized by cytochrome P450 using a novel hepatocyte model, HepatoPac
    Source:
    Drug Metab Dispos 41 (2), 2024-2032 (2013)
    Abstract:
    Generating accurate in vitro intrinsic clearance data is an important aspect of predicting in vivo human clearance. Primary hepatocytes in suspension are routinely used to predict in vivo clearance; however, incubation times have typically been limited to 4-6 hours, which is not long enough to accurately evaluate the metabolic stability of slowly metabolized compounds. HepatoPac is a micropatterened hepatocyte-fibroblast coculture system that can be used for continuous incubations of up to 7 days. This study evaluated the ability of human HepatoPac to predict the in vivo clearance (CL) of 17 commercially available compounds with low to intermediate clearance (<12 ml/min per kg). In vitro half-life for disappearance of each compound was converted to hepatic clearance using the well stirred model, with and without correction for plasma protein binding. Hepatic CL, using three individual donors, was accurately predicted for 10 of 17 compounds (59%; predicted clearance within 2-fold of observed human in vivo clearance values). The accuracy of prediction increased to 76% (13 of 17 compounds) with an acceptance criterion defined as within 3-fold. When considering only low clearance compounds (<5 ml/min per kg), which represented 10 of the 17 compounds, the accuracy of prediction was 60% within 2-fold and 90% within 3-fold. In addition, the turnover of three slowly metabolized compounds (alprazolam, meloxicam, and tolbutamide) in HepatoPac was directly compared with turnover in suspended hepatocytes. The turnover of alprazolam and tolbutamide was approximately 2-fold greater using HepatoPac compared with suspended hepatocytes, which was roughly in line with the extrapolated values (correcting for the longer incubation time and lower cell number with HepatoPac). HepatoPac, but not suspended hepatocytes, demonstrated significant turnover of meloxicam. These results demonstrate the utility of HepatoPac for prediction of in vivo hepatic clearance, particularly with low clearance compounds. Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics.
  • Author:
    Haak T; Meinicke T; Jones R; Weber S; Von Eynatten M; Woerle H-J
    Title:
    Initial combination of linagliptin and metformin in patients with type 2 diabetes: Efficacy and safety in a randomised, double-blind 1-year extension study
    Source:
    Int J Clin Pract 67 (12), 1283-1293 (2013)
    Abstract:
    Objective: To determine the efficacy and safety of linagliptin in initial combination with metformin in patients with type 2 diabetes. Methods: This 1-year randomised, double-blind study was an extension of a 6-month randomised controlled trial, in which adults with type 2 diabetes received one of six treatment regimens (linagliptin 2.5 mg plus metformin 500 mg bid, linagliptin 2.5 mg plus metformin mg 1000 bid, metformin 1000 mg bid, metformin 500 mg bid, linagliptin 5 mg qd or placebo). In the extension, patients in the first three treatment groups continued their regimen (non-switched group, n = 333) while the metformin 500 mg bid, linagliptin 5 mg qd and placebo groups were re-randomised to one of the three continuing regimens (switched group, n = 233). Results: All three non-switched groups maintained reductions in glycosylated haemoglobin (HbA1c; mean ± standard deviation reductions across the 1.5-year period: linagliptin 2.5 plus metformin 1000 bid, -1.63 ± 1.05%; linagliptin 2.5 plus metformin 500 bid, -1.32 ± 1.06%; metformin 1000 bid, -1.25 ± 0.91%) while the switched groups showed additional HbA1c reductions. During the extension, there were no clinically meaningful changes in body weight in any group. Adverse event rates were similar between groups, with most events being mild or moderate, and the incidence of investigator-defined hypoglycaemia was low, with no severe events. Discussion: Initial combination of linagliptin and metformin was well tolerated over the 1-year extension period, with low risk of hypoglycaemia, and improved glycaemic control vs. metformin alone. Conclusion: The initial combination of linagliptin and metformin appears to provide a useful treatment option in patients whose blood glucose levels are increased to an extent that metformin monotherapy may not achieve treatment targets. © 2013 The Authors. International Journal of Clinical Practice published by John Wiley & Sons Ltd.
  • Author:
    Rosenstock J; Seman LJ; Jelaska A; Hantel S; Pinnetti S; Hach T; Woerle HJ
    Title:
    Efficacy and safety of empagliflozin, a sodium glucose cotransporter 2 (SGLT2) inhibitor, as add-on to metformin in type 2 diabetes with mild hyperglycaemia
    Source:
    Diabetes Obes Metab 15 (12), 1154-1160 (2013)
    Abstract:
    Aims: To evaluate the effects of the sodium glucose cotransporter 2 (SGLT2) inhibitor empagliflozin added to metformin for 12weeks in patients with type 2 diabetes. Methods: This dose-ranging, double-blind, placebo-controlled trial randomized 495 participants with type 2 diabetes inadequately controlled on metformin [haemoglobin A1c (HbA1c) >7 to .10%] to receive 1, 5, 10, 25, or 50mg empagliflozin once daily (QD), or placebo, or open-label sitagliptin (100mg QD), added to metformin for 12weeks. The primary endpoint was change in HbA1c from baseline to week 12 (empagliflozin groups versus placebo). Results: Reductions in HbA1c of -0.09 to -0.56% were observed with empagliflozin after 12weeks, versus an increase of 0.15% with placebo (baseline: 7.8-8.1%). Compared with placebo, empagliflozin doses from 5 to 50mg resulted in reductions in fasting plasma glucose (-2 to -28mg/dl vs. 5mg/dl with placebo; p<0.0001) and body weight (-2.3 to -2.9kg vs. -1.2kg; p<0.01). Frequency of adverse events was generally similar with empagliflozin (29.6-48.6%), placebo (36.6%) and sitagliptin (35.2%). Hypoglycaemia rates were very low and balanced among groups. Most frequent adverse events with empagliflozin were urinary tract infections (4.0% vs. 2.8% with placebo) and pollakiuria (2.5% vs. 1.4% with placebo). Genital infections were reported only with empagliflozin (4.0%). Conclusions: Once daily empagliflozin as add-on therapy to metformin was well tolerated except for increased genital infections and resulted in reductions in HbA1c, fasting plasma glucose and body weight in patients with type 2 diabetes inadequately controlled on metformin monotherapy. © 2013 John Wiley & Sons Ltd.
  • Author:
    Strotbek M; Florin L; Koenitzer J; Tolstrup A; Kaufmann H; Hausser A; Olayioye MA
    Title:
    Stable microRNA expression enhances therapeutic antibody productivity of Chinese hamster ovary cells
    Source:
    Metab Eng 20, 157-166 (2013)
    Abstract:
    MicroRNAs (miRNAs) are short non-coding RNAs that post-transcriptionally regulate the expression of different target genes and, thus, enable engineered gene networks to achieve complex phenotypic changes in mammalian cells. We hypothesized that exploiting this feature of miRNAs could improve therapeutic protein production processes by increasing viable cell densities and/or productivity of the mammalian cells used for manufacturing. To identify miRNAs that increase the productivity of producer cells, we performed a genome wide functional miRNA screen by transient transfection of Chinese hamster ovary (CHO) cells stably expressing an IgG1 antibody (CHO-IgG1). Using this approach, we identified nine human miRNAs that improved the productivities not only of the CHO-IgG1 cells but also of CHO cells expressing recombinant human serum albumin (HSA), demonstrating that the miRNAs act in a product-independent manner. We selected two miRNAs (miR-557 and miR-1287) positively impacting the viable cell density and the specific productivity, respectively, and then stably co-expressed them in IgG1 expressing CHO cells. In these cells, higher IgG1 titers were observed in fed-batch cultures whilst product quality was conserved, demonstrating that miRNA-based cell line engineering provides an attractive approach toward the genetic optimization of CHO producer cells for industrial applications. © 2013 The Authors.
  • Author:
    Barnett AH; Huisman H; Jones R; Von Eynatten M; Patel S; Woerle H-J
    Title:
    Linagliptin for patients aged 70 years or older with type 2 diabetes inadequately controlled with common antidiabetes treatments: A randomised, double-blind, placebo-controlled trial
    Source:
    Lancet 382 (9902), 1413-1423 (2013)
    Abstract:
    Background: A substantial proportion of patients with type 2 diabetes are elderly (=65 years) but this group has been largely excluded from clinical studies of glucose-lowering drugs. We aimed to assess the effectiveness of linagliptin, a dipeptidyl peptidase-4 inhibitor, in elderly patients with type 2 diabetes. Methods: In this randomised, double-blind, parallel-group, multinational phase 3 study, patients aged 70 years or older with type 2 diabetes, glycated haemoglobin A1c (HbA1c) of 7.0% or more, receiving metformin, sulfonylureas, or basal insulin, or combinations of these drugs, were randomised (by computer-generated randomisation sequence, concealed with a voice-response system, stratifi ed by HbA1c level [<8.5% vs =8.5%] and insulin use [yes vs no], block size four) in a 2:1 ratio to once-daily oral treatment with linagliptin 5 mg or matching placebo for 24 weeks. Investigators and participants were masked to assignment throughout the study. The primary endpoint was change in HbA1c from baseline to week 24. This trial is registered with ClinicalTrials.gov, number NCT01084005. Findings: 241 community-living outpatients were randomised (162 linagliptin, 79 placebo). Mean age was 74.9 years (SD 4.3). Mean HbA1c was 7.8% (SD 0.8). At week 24, placebo-adjusted mean change in HbA1c with linagliptin was -0.64% (95% CI -0.81 to -0.48, p<0.0001). Overall safety and tolerability were much the same between the linagliptin and placebo groups; 75.9% of patients in both groups had an adverse event (linagliptin n=123, placebo n=60). No deaths occurred. Serious adverse events occurred in 8.6% (14) of patients in the linagliptin group and 6.3% (fi ve) patients in the placebo group; none were deemed related to study drug. Hypoglycaemia was the most common adverse event in both groups, but did not differ between groups (24.1% [39] in the linagliptin group, 16.5% [13] in the placebo group; odds ratio 1.58, 95% CI 0.78-3.78, p=0.2083). Interpretation: In elderly patients with type 2 diabetes linagliptin was efficacious in lowering glucose with a safety profi le similar to placebo. These fi ndings could inform treatment decisions for achieving individualised glycaemic goals with minimal risk in this important population of patients.
  • Author:
    Roden M; Weng J; Eilbracht J; Delafont B; Kim G; Woerle HJ; Broedl UC
    Title:
    Empagliflozin monotherapy with sitagliptin as an active comparator in patients with type 2 diabetes: A randomised, double-blind, placebo-controlled, phase 3 trial
    Source:
    Lancet Diabetes Endocrinol 1 (3), 208-219 (2013)
    Abstract:
    Background: We aimed to investigate the efficacy and tolerability of empagliflozin, an oral, potent, and selective inhibitor of sodium-glucose co-transporter 2, in patients with type 2 diabetes who had not received drug treatment in the preceding 12 weeks. Methods: In our multicentre, randomised, placebo-controlled, phase 3 trial, we enrolled adults (aged .18 years) who had not received oral or injected anti-diabetes treatment in the previous 12 weeks. Eligible patients had HbA1c concentrations of 7-10%. We randomly allocated patients (1:1:1:1) with a computer-generated random sequence, stratified by region, HbA1c, and estimated glomerular filtration rate at screening, to placebo, empagliflozin 10 mg, empagliflozin 25 mg, or sitagliptin 100 mg once daily for 24 weeks. Patients and investigators were masked to treatment assignment. The primary endpoint was change from baseline in HbA1c at week 24 by ANCOVA in all randomly allocated patients who were treated with at least one dose of study drug and had a baseline HbA1c value. This study is completed and registered with ClinicalTrials.gov, number NCT01177813. Findings: Between Aug 12, 2010, and March 19, 2012, we randomly allocated 228 patients to receive placebo, 224 to receive empagliflozin 10 mg, 224 to receive empagliflozin 25 mg, and 223 to receive sitagliptin. Compared with placebo, adjusted mean differences in change from baseline HbA1c at week 24 were -0.74% (95% CI -0.88 to -0.59; p&lt;0.0001) for empagliflozin 10 mg, -0.85% (-0.99 to -0.71; p&lt;0.0001) for empagliflozin 25 mg, and -0.73% (-0.88 to -0.59; p&lt;0.0001) for sitagliptin. 140 (61%) patients in the placebo group reported adverse events (four [2%] severe and six [3%] serious), as did 123 (55%) patients in the empagliflozin 10 mg group (eight [4%] severe and eight [4%] serious), 135 (60%) patients in the empagliflozin 25 mg group (seven [3%] severe and five [2%] serious), and 119 (53%) patients in the sitagliptin group (five [2%] severe and six [3%] serious). Interpretation: Empagliflozin provides a tolerable and efficacious strategy to reduce HbA1c in patients with type 2 diabetes who had not previously received drug treatment. Funding: Boehringer Ingelheim and Eli Lilly. © 2013 Elsevier Ltd.
  • Author:
    Schülert N; Gorodetskaya N; Just S; Dickenson A H; Corradini L; Doods H
    Title:
    Characterization of new animal models of diabetic neuropathy - What can we learn from spinal electrophysiological recordings?
    Source:
    IMI Meeting, Mannheim, Germany, Oct 2013
  • Author:
    Haak T; Meinicke T; Jones R; Weber S; von Eynatten M; Woerle H-J
    Title:
    Initial combination of linagliptin and metformin in patients with type 2 diabetes: Efficacy and safety in a randomised, double-blind 1-year extension study
    Source:
    Int J Clin Pract Article in press (2013)
    Abstract:
    Objective: To determine the efficacy and safety of linagliptin in initial combination with metformin in patients with type 2 diabetes. Methods: This 1-year randomised, double-blind study was an extension of a 6-month randomised controlled trial, in which adults with type 2 diabetes received one of six treatment regimens (linagliptin 2.5 mg plus metformin 500 mg bid, linagliptin 2.5 mg plus metformin mg 1000 bid, metformin 1000 mg bid, metformin 500 mg bid, linagliptin 5 mg qd or placebo). In the extension, patients in the first three treatment groups continued their regimen (non-switched group, n = 333) while the metformin 500 mg bid, linagliptin 5 mg qd and placebo groups were re-randomised to one of the three continuing regimens (switched group, n = 233). Results: All three non-switched groups maintained reductions in glycosylated haemoglobin (HbA1c; mean ± standard deviation reductions across the 1.5-year period: linagliptin 2.5 plus metformin 1000 bid, -1.63 ± 1.05%; linagliptin 2.5 plus metformin 500 bid, -1.32 ± 1.06%; metformin 1000 bid, -1.25 ± 0.91%) while the switched groups showed additional HbA1c reductions. During the extension, there were no clinically meaningful changes in body weight in any group. Adverse event rates were similar between groups, with most events being mild or moderate, and the incidence of investigator-defined hypoglycaemia was low, with no severe events. Discussion: Initial combination of linagliptin and metformin was well tolerated over the 1-year extension period, with low risk of hypoglycaemia, and improved glycaemic control vs. metformin alone. Conclusion: The initial combination of linagliptin and metformin appears to provide a useful treatment option in patients whose blood glucose levels are increased to an extent that metformin monotherapy may not achieve treatment targets. © 2013 The Authors.
  • Author:
    Gorodetskaya N; Calvo M; Bennett D; Doods H
    Title:
    Genetic Models for painful Diabetic Neuropathy: BB/Wor vs ZDF Rats
    Source:
    Schmerzkongress 2013
  • Author:
    Dhamane AD; Martin BC; Brixner DI; Hudson TJ; Said Q
    Title:
    Metabolic monitoring of patients prescribed second-generation antipsychotics
    Source:
    J Psychiatr Pract 19 (5), 360-374 (2013)
    Abstract:
    Objectives. This study evaluated how clinicians monitored glucose, lipids, body mass index (BMI), and blood pressure (BP) of patients being treated with second-generation antipsychotics (SGAs) before and after the publication of the American Diabetes Association (ADA) and American Psychiatric Association (APA) Consensus Statement concerning antipsychotic drugs and obesity and diabetes in February, 2004. Methods. A retrospective analysis of GE Centricity electronic health records for the 2001-2008 period was conducted. SGA-naïve patients receiving monotherapy with any SGA (aripiprazole, clozapine, olanzapine, quetiapine, risperidone, ziprasidone) were identified. Two scenarios were examined: The "Any" monitoring scenario was defined as at least one instance of monitoring of a parameter at any time point during the observation period (from 30 days before beginning the SGA until 395 days after beginning the SGA); the "Full" monitoring scenario was defined as a situation in which the number of times a parameter was monitored during the observation period was equal to the yearly frequency recommended by ADA/APA. Pre- and post-consensus statement monitoring rates were computed and monitoring trends were evaluated by quarterly time intervals using segmented time-series design. Results. The final sample consisted of 24,826 patients, with mean age of 47.9 years, 61% of whom were female. Pre- and post- consensus statement monitoring compared as following: "Any" scenario: BP (92% [pre] vs. 94% [post]), BMI (66% vs. 77%), glucose (60% vs. 65%), lipids (36% vs. 41%); "Full" scenario; BP (72% vs. 75%), BMI (23% vs. 27%), glucose (23% vs. 27%), lipids (17% vs. 20%). Regression analyses found the following per quarter increases in the post-con- sensus statement period for the "Any" scenario: glucose (1.4%, p = 0.003), lipids (1.0%, p = 0.008), BP (0.6%, p = 0.006) and the following per quarter increases for the "Full" scenario: glucose (1.0%, p = 0.002), lipids (1.2%, p < 0.001) and BP (1.3%, p = 0.004). Conclusions. The publication of the Consensus Statement alone did not make a clinically meaningful difference to monitoring rates. Copyright © Lippincott Williams & Wilkins.
  • Author:
    Riggs MM; Staab A; Seman L; Macgregor TR; Bergsma TT; Gastonguay MR; Macha S
    Title:
    Population pharmacokinetics of empagliflozin, a sodium glucose cotransporter 2 inhibitor, in patients with type 2 diabetes
    Source:
    J Clin Pharmacol 53 (10), 1028-1038 (2013)
    Abstract:
    Data from five randomized, placebo-controlled, multiple oral dose studies of empagliflozin in patients with type 2 diabetes mellitus (T2DM;N = 974; 1-100 mg q.d.; .12 weeks) were used to develop a population pharmacokinetic (PK) model for empagliflozin. The model consisted of two-compartmentaldisposition, lagged first-order absorption and first-order elimination, and incorporated appropriate covariates. Population estimates (interindividualvariance, CV%) of oral apparent clearance, central and peripheral volumes of distribution, and inter-compartmental clearance were 9.87 L/h (26.9%), 3.02 L, 60.4 L (30.8%), and 5.16 L/h, respectively. An imposed allometric weight effect was the most influential PK covariate effect, with a maximumeffect on exposure of ±30%, using 2.5th and 97.5th percentiles of observed weights, relative to the median observed weight. Sex and race did not lendadditional description to PK variability beyond allometric weight effects, other than .25% greater oral absorption rate constant for Asian patients. Age,total protein, and smoking/alcohol history did not affect PK parameters. Predictive check plots were consistent with observed data, implying an adequate description of empagliflozin PKs following multiple dosing in patients with T2DM. The lack of marked covariate effects, including weight, suggests that noexposure-based dose adjustments were required within the study population and dose range. © 2013, The American College of Clinical Pharmacology.
  • Author:
    Colosia AD; Palencia R; Khan S
    Title:
    Prevalence of hypertension and obesity in patients with type 2 diabetes mellitus in observational studies: A systematic literature review
    Source:
    Diabetes Metab Syndr Obes Targets Ther 6, 327-338 (2013)
    Abstract:
    Background: Hypertension and obesity are known to contribute, directly or indirectly, to the development of long-term complications of type 2 diabetes mellitus (T2DM). Knowing the prevalence of these comorbidities is important for determining the size of the population that may beneft from strategies that reduce blood pressure and weight while controlling blood glucose. Methods: In this systematic literature review, electronic searches of PubMed, Embase, and the Cochrane Library were conducted to identify observational studies of hypertension and/or obesity prevalence in patients with T2DM throughout the world. The searches were limited to studies reported in English from January 1, 2001 to February 16, 2012. Results: From a total of 2,688 studies, 92 observational studies provided prevalence rates for hypertension and/or obesity specifcally in adults with T2DM. Fifteen studies of specifc subtypes of hypertension or subpopulations with T2DM were subsequently excluded, leaving 78 studies (in 77 articles) for inclusion in this article. Of these, 61studies reported hypertension prevalence, 44 reported obesity prevalence, and 12 reported the prevalence of hypertension with obesity. Most studies had a low risk of bias regarding diagnosis of T2DM (70/78), hypertension (59/69), or obesity (45/47). The continental regions with the most observational studies of hypertension or obesity prevalence were Europe (n = 30) and Asia (n = 26). Hypertension rates typically were high in all regions; most studies presented rates above 50%, and many presented rates above 75%. Obesity rates exceeded 30% in 38 of 44 studies and 50% in 14 of 44 studies, especially those assessing central obesity (based on waist circumference). Among obese adults, hypertension rates were at or above 70% in Asia and above 80% in Europe; rates were lower in North and South America but still above 30%. Conclusion: Around the world, hypertension and obesity, separately or together, are common comorbidities in adults with T2DM. © 2013 Colosia et al. This work is published by Dove Medical Press Ltd.
  • Author:
    Berthold Hocher; Oleg Tsuprykov; Markus Alter; Karoline von Websky; Lyubov Chaykovska; Viktoriia Antonenko1; Jan Rahnenführer; Christoph Reichetzeder
    Title:
    Linagliptin and the Angiotensin II Receptor Blocker Telmisartan Show Comparable Efficacy But Different Renoprotective Pathways in Rats With 5/6 Nephrectomy
  • Author:
    Darsalia V
    Title:
    Insights into the mechanism of action of linagliptin in reducing ischaemic brain damage following stroke in diabetic and non-diabetic mice
    Source:
    49th Annual Meeting Of The European Association For The Study Of Diabetes
  • Author:
    Roden M; Weng J; Eilbracht J; Delafont B; Kim G; Woerle HJ; Broedl UC
    Title:
    Empagliflozin monotherapy with sitagliptin as an active comparator in patients with type 2 diabetes: a randomised, double-blind, placebo-controlled, phase 3 trial
    Source:
    Lancet Diabetes Endocrinol Article in press (2013)
    Abstract:
    Background: We aimed to investigate the efficacy and tolerability of empagliflozin, an oral, potent, and selective inhibitor of sodium-glucose co-transporter 2, in patients with type 2 diabetes who had not received drug treatment in the preceding 12 weeks. Methods: In our multicentre, randomised, placebo-controlled, phase 3 trial, we enrolled adults (aged .18 years) who had not received oral or injected anti-diabetes treatment in the previous 12 weeks. Eligible patients had HbA1c concentrations of 7-10%. We randomly allocated patients (1:1:1:1) with a computer-generated random sequence, stratified by region, HbA1c, and estimated glomerular filtration rate at screening, to placebo, empagliflozin 10 mg, empagliflozin 25 mg, or sitagliptin 100 mg once daily for 24 weeks. Patients and investigators were masked to treatment assignment. The primary endpoint was change from baseline in HbA1c at week 24 by ANCOVA in all randomly allocated patients who were treated with at least one dose of study drug and had a baseline HbA1c value. This study is completed and registered with ClinicalTrials.gov, number NCT01177813. Findings: Between Aug 12, 2010, and March 19, 2012, we randomly allocated 228 patients to receive placebo, 224 to receive empagliflozin 10 mg, 224 to receive empagliflozin 25 mg, and 223 to receive sitagliptin. Compared with placebo, adjusted mean differences in change from baseline HbA1c at week 24 were -0.74% (95% CI -0.88 to -0.59; p&lt;0.0001) for empagliflozin 10 mg, -0.85% (-0.99 to -0.71; p&lt;0.0001) for empagliflozin 25 mg, and -0.73% (-0.88 to -0.59; p&lt;0.0001) for sitagliptin. 140 (61%) patients in the placebo group reported adverse events (four [2%] severe and six [3%] serious), as did 123 (55%) patients in the empagliflozin 10 mg group (eight [4%] severe and eight [4%] serious), 135 (60%) patients in the empagliflozin 25 mg group (seven [3%] severe and five [2%] serious), and 119 (53%) patients in the sitagliptin group (five [2%] severe and six [3%] serious). Interpretation: Empagliflozin provides a tolerable and efficacious strategy to reduce HbA1c in patients with type 2 diabetes who had not previously received drug treatment. Funding: Boehringer Ingelheim and Eli Lilly. © 2013 Elsevier Ltd. All rights reserved.
  • Author:
    Barnett AH; Huisman H; Jones R; von Eynatten M; Patel S; Woerle H-J
    Title:
    Linagliptin for patients aged 70 years or older with type 2 diabetes inadequately controlled with common antidiabetes treatments: a randomised, double-blind, placebo-controlled trial
    Source:
    Lancet Article in press (2013)
    Abstract:
    Background: A substantial proportion of patients with type 2 diabetes are elderly (.65 years) but this group has been largely excluded from clinical studies of glucose-lowering drugs. We aimed to assess the effectiveness of linagliptin, a dipeptidyl peptidase-4 inhibitor, in elderly patients with type 2 diabetes. Methods: In this randomised, double-blind, parallel-group, multinational phase 3 study, patients aged 70 years or older with type 2 diabetes, glycated haemoglobin A1c (HbA1c) of 7.0% or more, receiving metformin, sulfonylureas, or basal insulin, or combinations of these drugs, were randomised (by computer-generated randomisation sequence, concealed with a voice-response system, stratified by HbA1c level [&lt;8.5% vs .8.5%] and insulin use [yes vs no], block size four) in a 2:1 ratio to once-daily oral treatment with linagliptin 5 mg or matching placebo for 24 weeks. Investigators and participants were masked to assignment throughout the study. The primary endpoint was change in HbA1c from baseline to week 24. This trial is registered with ClinicalTrials.gov, number NCT01084005. Findings: 241 community-living outpatients were randomised (162 linagliptin, 79 placebo). Mean age was 74.9 years (SD 4.3). Mean HbA1c was 7.8% (SD 0.8). At week 24, placebo-adjusted mean change in HbA1c with linagliptin was -0.64% (95% CI -0.81 to -0.48, p&lt;0.0001). Overall safety and tolerability were much the same between the linagliptin and placebo groups; 75.9% of patients in both groups had an adverse event (linagliptin n=123, placebo n=60). No deaths occurred. Serious adverse events occurred in 8.6% (14) of patients in the linagliptin group and 6.3% (five) patients in the placebo group; none were deemed related to study drug. Hypoglycaemia was the most common adverse event in both groups, but did not differ between groups (24.1% [39] in the linagliptin group, 16.5% [13] in the placebo group; odds ratio 1.58, 95% CI 0.78-3.78, p=0.2083). Interpretation: In elderly patients with type 2 diabetes linagliptin was efficacious in lowering glucose with a safety profile similar to placebo. These findings could inform treatment decisions for achieving individualised glycaemic goals with minimal risk in this important population of patients. Funding: Boehringer Ingelheim. © 2013 Elsevier Ltd. All rights reserved.
  • Author:
    Macha S; Mattheus M; Halabi A; Pinnetti S; Woerle HJ; Broedl UC
    Title:
    Pharmacokinetics, pharmacodynamics and safety of empagliflozin, a sodium glucose cotransporter 2 (SGLT2) inhibitor, in subjects with renal impairment
    Source:
    Diabetes Obes Metab Article in press (2013)
    Abstract:
    Aims: Empagliflozin is a selective sodium glucose cotransporter 2 (SGLT2) inhibitor that inhibits renal glucose reabsorption and is being investigated for the treatment of type 2 diabetes mellitus (T2DM). Methods: In this open-label study, the effect of renal impairment on the pharmacokinetics, pharmacodynamics and safety of a 50mg dose of empagliflozin was investigated in 40 subjects, grouped according to estimated glomerular filtration rate (eGFR). Results: Maximum empagliflozin plasma concentrations were similar in subjects with normal renal function and renal impairment. Area under the empagliflozin concentration-time curve (AUC0-.) values increased by approximately 18, 20, 66 and 48% in subjects with mild, moderate, severe renal impairment and renal failure/end stage renal disease (ESRD), respectively, in comparison to healthy subjects. This was attributed to decreased renal clearance (CLR). Urinary glucose excretion (UGE) decreased with increasing renal impairment and correlated with decreased eGFR and CLR. Empagliflozin was well tolerated, with no increase in adverse events associated with renal impairment. Conclusions: Renal insufficiency resulted in decreased CLR of empagliflozin, moderately increased systemic exposure and decreased UGE. A single 50mg dose of empagliflozin was well tolerated in subjects with normal renal function and any degree of renal impairment. The pharmacokinetic results of this study indicate that no dose adjustment of empagliflozin is required in patients with renal impairment. © 2013 John Wiley &amp; Sons Ltd.
  • Author:
    Gallwitz B; Rosenstock J; Woerle H-J
    Title:
    Authors' reply
    Source:
    Lancet 381 (9861), 115-116 (2013)
  • Author:
    Keizo Kanasaki; Sen Shi1; Megumi Kanasaki; Jinhua He1; Takako Nagai; Yuka Nakamura; Yasuhito Ishigaki; Munehiro Kitada1; Swayam Prakash Srivastav; Daisuke Koya1
    Title:
    Linagliptin-mediated DPP-4 inhibition ameliorates kidney fibrosis in streptozotocin-induced diabetic mice by inhibiting endothelial-to-mesenchymal transition in a therapeutic regimen
    Abstract:
    Kidney fibrosis is the final common of all progressive chronic kidney diseases, of which diabetic nephropathy is the leading cause. Endothelial-to-mesenchymal transition (EndMT) has emerged as one of the most important origins of matrix-producing fibroblasts. Dipeptidyl peptidase-4 (DPP-4) inhibitors have been introduced into the market as anti-diabetic drugs. Here, we found that the DPP-4 inhibitor linagliptin cured kidney fibrosis in type 1 diabetic mice without altering their blood glucose levels. Streptozotocin-induced diabetic CD1 mice exhibited severe kidney fibrosis and strong immunoreactivity for DPP-4 24 weeks after the onset of diabetes. At 20 weeks after the onset of diabetes, the mice were treated with linagliptin for 4 weeks. Linagliptin-treated diabetic mice exhibited an amelioration of kidney fibrosis and restored normal kidney structure. These anti-fibrotic effects of linagliptin were associated with the inhibition of EndMT. The therapeutic effects of linagliptin on diabetic kidneys were associated with the suppression of profibrotic programs, as assessed by mRNA microarray analysis. We found that the induction of DPP-4 observed in diabetic kidneys may be associated with suppressed levels of microRNA29s in diabetic mice. Using cultured endothelial cells, we found that linagliptin inhibited TGF.2-induced EndMT and the motility of fibroblast-like EndMT cells. These results indicate the possible novel pleiotropic action of linagliptin to restore normal kidney function in diabetic patients with renal impairment.
  • Author:
    Wüster T; Kaczybura N; Brückner R; Keller M
    Title:
    Synthesis of enantiomerically pure model compounds of the glucose-6-phosphate-T1-translocase inhibitors kodaistatins A-D. Inferences with regard to the stereostructure of the natural products
    Source:
    Tetrahedron 69 (36), 7785-7809 (2013)
    Abstract:
    The kodaistatins A and C (5a,b) inhibit a step in glucose-metabolism at .100 nM concentrations. This makes them potential 'leads' in the therapy of diabetes. We elucidated the (S)-configuration of the side-chain stereocenter of kodaistatin A by ozonolysis/reduction. The 13C NMR shifts of kodaistatin A model cis-11 suggest that the diol moiety in the dihydroxycyclopentanone core of kodaistatin is trans-configured. This model was prepared from the Feringa lactone (21) and (S)-2-methylbutanal (27) in 23 steps (14 steps in the longest linear sequence). We employed the same strategy for the simplified kodaistatin A model iso-cis-12, which resulted from the same substrates in 11 steps (6 steps in the longest linear sequence). The cyclopentenone cores of both targets stemmed from a C4+C1 approach. The C4 components were masked 'tartaric ketones' (16a,b) and a masked 'tartaric aldehyde' (18), respectively. The C1 components were the lithium-derivatives of the side-chain bearing phosphonates 19 and 22, respectively. The desired acylation/deprotonation/Horner-Wadsworth- Emmons tandem reaction succeeded in a single operation with the 'tartaric aldehyde' 18 but required partly or exclusively additional operations when we incorporated the 'tartaric ketones' 16a or 16b, respectively. The 'tartaric ketones' 16a,b contained an .-siloxyethyl substituent. It is noteworthy that it had to be introduced by adding the benzyltrimethylammonium enolate of lactone 18 to acetaldehyde because the lithium enolate of this lactone fragmented by an acetone-releasing .-elimination. © 2013 Elsevier Ltd. All rights reserved.
  • Author:
    Schülert N
    Title:
    Electrophysiological characterization of different animal models for diabetes type-1 and type-Il induced neuropathic pain - what can we learn from spinal recordings?
    Source:
    IMI workshop in Stevenage, UK
  • Author:
    Schülert N
    Title:
    Electrophysiological characterization of different animal models for diabetestype 1 and type 2 induced neuropathic pain - what can we learn from spinal recordings?
    Source:
    Presentation at the EMTRAIN PhD Workshop (IMI) in Stevenage, GB, Apr 14-17, 2013
  • Author:
    Müller H-P; Niessen HG; Kaulisch T; Ludolph AC; Kassubek J; Stiller D
    Title:
    MRI allows for longitudinal quantitative analysis of body fat composition in rats: An analysis of sibutramine-associated changes at the group level
    Source:
    Magn Reson Imaging 31 (7), 1150-1155 (2013)
    Abstract:
    Purpose: Body fat distribution changes are associated with multiple alterations in metabolism. Therefore, the assessment of body fat compartments by MRI in animal models is a promising approach to obesity research. Standard T1-weighted (T1w) whole body MRI was used here to quantify different effects in the subcutaneous and visceral fat compartments in rats under treatment with an anorexiant. Materials and methods: Twenty rats on a high caloric diet were investigated by the identical MRI protocol at baseline and after seven weeks. Ten rats received a treatment with sibutramine, 10 rats served as vehicle control group. To longitudinally assess body fat components, MRI analysis was used with two approaches: 2D slicewise graphic analysis (SGA) was compared with an automated 3D analysis algorithm (3DA). Results: At the group level, fat volume differences showed a longitudinal increase of subcutaneous and visceral fat volumes for the control group, whereas the sibutramine group showed stable subcutaneous fat volumes and decrease in visceral fat volumes. SGA and 3DA volume determination showed significant correlations for subcutaneous fat volume (C. = 0.85, p. <. 0.001), visceral fat volume (C. = 0.87, p. <. 0.001), and total fat volume (C. = 0.90, p. <. 0.001). Conclusion: It could be demonstrated that computer-based analysis of T1w MRI could be used to longitudinally assess changes in body fat compartments in rats at the group level. In detail, it was possible to investigate the effect of sibutramine separate on the fat compartments in rats. © 2013 Elsevier Inc.
  • Author:
    Inagaki N; Watada H; Murai M; Kagimura T; Gong Y; Patel S; Woerle H-J
    Title:
    Linagliptin provides effective, well-tolerated add-on therapy to pre-existing oral antidiabetic therapy over 1year in Japanese patients with type 2 diabetes
    Source:
    Diabetes Obes Metab 15 (9), 833-843 (2013)
    Abstract:
    Aims: To evaluate the long-term safety and efficacy of linagliptin as add-on therapy to one approved oral antidiabetic drug (OAD) in Japanese patients with type 2 diabetes mellitus and insufficient glycaemic control. Methods: This 52-week, multicentre, open-label, parallel-group study evaluated once-daily linagliptin 5mg as add-on therapy to one OAD [biguanide, glinide, glitazone, sulphonylurea (SU) or .-glucosidase inhibitors (A-GI)] in 618 patients. After a 2-week run-in, patients on SU or A-GI were randomized to either linagliptin (once daily, 5mg) or metformin (twice or thrice daily, up to 2250mg/day) as add-on therapy. Patients receiving the other OADs received linagliptin add-on therapy (non-randomized). Results: Adverse events were mostly mild or moderate, and rates were similar across all groups. Hypoglycaemic events were rare, except in the SU group. Overall, 26 (5.8%) hypoglycaemic events were reported in patients receiving linagliptin (non-randomized). Hypoglycaemic events were similar for linagliptin and metformin added to A-GI (1/61 vs. 2/61, respectively) or SU (17/124 vs. 10/63, respectively). Significant reductions in glycated haemoglobin (HbA1c) levels (between -0.7 and -0.9%) occurred throughout the study period for the background therapy groups that received linagliptin (baseline HbA1c 7.9-8.1%). The decline in HbA1c levels was indistinguishable between linagliptin and metformin groups when administered as add-on therapy to A-GI or SU. Conclusions: Once-daily linagliptin showed safety and tolerability over 1year and provided effective add-on therapy leading to significant HbA1c reductions, similar to metformin, over 52weeks in Japanese patients. © 2013 Blackwell Publishing Ltd.
  • Author:
    Gelhorn HL; Stringer SM; Brooks A; Thompson C; Monz BU; Boye KS; Hach T; Lund SS; Palencia R
    Title:
    Preferences for medication attributes among patients with type 2 diabetes mellitus in the UK
    Source:
    Diabetes Obes Metab 15 (9), 802-809 (2013)
    Abstract:
    Aim: To examine preferences for oral medication attributes among participants with early and advanced type 2 diabetes mellitus (T2DM) in the UK using a discrete choice experiment (DCE). Methods: A web-based DCE was administered where participants indicated which medication they preferred from two different hypothetical oral anti-diabetic (OAD) medication profiles, each composed of differing levels of seven attributes (efficacy, hypoglycaemic events, weight change, gastrointestinal/nausea side effects, urinary tract infection and genital infection, blood pressure and cardiovascular risk) for 20 sets of pair-wise comparisons. A random effects multinomial logit regression model was used to estimate the preference weight (PW) for each of the attribute levels, and the relative importance (RI) of each attribute was calculated. Analyses were conducted for the overall sample and for medication and gender subgroups. Results: The final sample included 100 participants with a mean age of 62.9 (SD 11.1) years and comparable numbers of participants of each gender (51% male, 49% female). The majority of the participants were White-British (92%). The total PW and corresponding RI were highest for four of the seven attributes: hypoglycaemic events (PW=1.98; RI=24.7%), weight change (PW=1.65; RI=20.6%), gastrointestinal/nausea side effects (PW=1.49; RI=18.6%) and efficacy (PW=1.44; RI=18.0%). The RI values differed for some attributes across gender and number of current T2DM medication subgroups. Conclusion: The results suggest that hypoglycaemia, weight change, gastrointestinal side effects and efficacy are of primary importance to patients in their OAD preferences in T2DM. These four attributes comprised over 80% of the RI. © 2013 Blackwell Publishing Ltd.
  • Author:
    Mayoux E; Luippold G; Mark M
    Title:
    Durable effect of empagliflozin on glucose homeostasis independent of the disease state of type 2 diabetes in ZDF rats
  • Author:
    Zeng Z; Yang J-K; Tong N; Yan S; Zhang X; Gong Y; Woerle H-J
    Title:
    Efficacy and safety of linagliptin added to metformin and sulphonylurea in Chinese patients with type 2 diabetes: A sub-analysis of data from a randomised clinical trial
    Source:
    Curr Med Res Opin 29 (8), 921-929 (2013)
    Abstract:
    Objectives: To evaluate the efficacy and safety of linagliptin in Chinese patients with type 2 diabetes mellitus (T2DM) inadequately controlled by metformin and sulphonylurea. Research design and methods: Data for a pre-defined Chinese subgroup who participated in a Phase III randomised, placebo-controlled, 24 week trial (NCT00602472) were analysed. The primary endpoint was change in HbA1c from baseline to 24 weeks. Apart from safety endpoints, secondary endpoints included changes in FPG and measures of insulin secretion and resistance. Results: A total of 192 Chinese patients with T2DM participated in the pre-defined analysis; 144 and 48 patients received linagliptin or placebo, respectively, added to metformin and sulphonylurea. Baseline characteristics (mean [±SD]) for linagliptin and placebo were similar: HbA1c: 8.1% (±0.85) and 8.1% (±0.84); body mass index: 25.9 (±3.2) and 25.6 (±3.4) kg/m2, respectively. Placebo-corrected mean (±SE) change in HbA1c from baseline at 24 weeks was -0.68% (0.14) with linagliptin-based treatment (95% CI: -0.96 to -0.39; P&lt;0.0001). Placebo-corrected mean (±SE) change in FPG from baseline at 24 weeks with linagliptin was -18.8 (6.5) mg/dL (-1.0 [0.4] mmol/L; 95% CI: -31.7 to -5.9; P=0.0044). Overall adverse event (AE) rates with linagliptin and placebo including background medication were similar (38.9% and 43.8%, respectively). Drug-related AEs were reported by 12.5% and 2.1% of linagliptin and placebo patients, respectively. Differences were due to hypoglycaemia (10.4% and 0.0%, respectively). No severe hypoglycaemia was reported in either group of this sub-population. Conclusion: Linagliptin in combination with metformin and sulphonylurea has a favourable safety profile and is an efficacious and well tolerated treatment option for Chinese patients with inadequately controlled T2DM. Reduction of sulphonylurea dose should be considered to minimise risk of hypoglycaemia. Although the findings of this pre-specified sub-analysis may be limited by the number of patients in the subgroup, the results were generally consistent with those for the overall population. © 2013 Informa UK Ltd.
  • Author:
    Alter Markus L; Ott Ina M; Von Websky Karoline; Tsuprykov Oleg; Sharkovska Yuliya; Krause-Relle Katharina; Hocher Berthold
    Title:
    DPP-4 inhibition on top of angiotensin receptor blockade offers a new therapeutic approach for diabetic nephropathy.
    Source:
    Kidney Blood Press Res 36 (1), 119-130 (2012)
    Abstract:
    BACKGROUND: The need for an improved treatment for diabetic nephropathy is greatest in patients who do not adequately respond to angiotensin II receptor blockers (ARBs). This study investigated the effect of the novel dipeptidyl peptidase-4 inhibitor linagliptin alone and in combination with the ARB telmisartan on the progression of diabetic nephropathy in diabetic endothelial nitric oxide synthase (eNOS) knockout mice. METHODS: Sixty male eNOS knockout C57BL/6J mice were divided into four groups after receiving intraperitoneal highdose streptozotocin: telmisartan (1 mg/kg), linagliptin (3 mg/kg), linagliptin + telmisartan (3 mg/kg + 1 mg/kg) and vehicle. Fourteen mice were used as non-diabetic controls. RESULTS: After 12 weeks, urine and blood were obtained and blood pressure measured. Glucose concentrations were increased and similar in all diabetic groups. Telmisartan alone reduced systolic blood pressure by 5.9 mmHg versus diabetic controls (111.2 ± 2.3 mmHg vs 117.1 ± 2.2 mmHg; mean ± SEM; P=0.071). Combined treatment significantly reduced albuminuria compared with diabetic controls (71.7 ± 15.3 µg/24 h vs. 170.8 ± 34.2 µg/24 h; P=0.017), whereas the effects of single treatment with either telmisartan (97.8 ± 26.4 µg/24 h) or linagliptin (120.8 ± 37.7 µg/24 h) were not statistically significant. DPP-4 inhibition, alone and in combination, led to significantly lower plasma osteopontin levels compared with telmisartan alone. Histological analysis revealed reduced glomerulosclerosis after Linagliptin alone and in combination with telmisartan in comparison to non treated diabetic animals (p<0.01 and p<0.05). Kidney malonaldehyde immune-reactivity, a marker of oxidative stress, was significantly lower in animals treated with linagliptin. CONCLUSIONS: DPP-4 inhibition on top of ARB treatment significantly reduced urinary albumin excretion and oxidative stress in diabetic eNOS knockout mice. Linagliptin on top of an angiotensin II receptor blocker may offer a new therapeutic approach for patients with diabetic nephropathy
  • Author:
    Ley L; Schumacher H
    Title:
    Telmisartan plus amlodipine single-pill combination for the management of hypertensive patients with a metabolic risk profile (added-risk patients
    Source:
    Curr Med Res Opin 29 (1), 41-53 (2013)
    Abstract:
    OBJECTIVE: Hypertensive patients with metabolic risk factors, including obesity, diabetes, and metabolic syndrome, often require a combination of antihypertensive agents to achieve blood pressure (BP) targets. This article considers the evidence supporting telmisartan/amlodipine combination therapy for the treatment of hypertension in patients with metabolic risk factors. METHODS: Clinical trials of telmisartan/amlodipine at doses of 40-80.mg/5-10.mg (T40-80/A5-10) in free, fixed-dose and single-pill combinations were identified through electronic searches (MEDLINE and congress abstracts) up to and including June 2012, and from the Boehringer Ingelheim (BI) trial database. All identified trials were reviewed for data on hypertensive patients with obesity, diabetes, or both. Post-hoc subgroup analyses were carried out using the BI database to determine the relevant information if it was not previously reported. RESULTS: Thirteen clinical trials including 6886 patients were identified with data relevant for inclusion in this review. The telmisartan/amlodipine combination allowed a high proportion of hypertensive patients with metabolic conditions to achieve BP targets, particularly among patients who had previously failed to achieve BP targets with monotherapy. BP reductions and goal rate achievement were similarly high among patients with and without the presence of metabolic risk factors. BP reductions were maintained throughout the 24.h dosing period, and 24.h goal rates were obtained in a high proportion of patients. Particularly large reductions in BP with telmisartan/amlodipine were recorded among patients with severe hypertension (systolic BP .180.mmHg). CONCLUSIONS: The results of this post-hoc analysis further support the ability of the telmisartan/amlodipine combination to effectively reduce BP in hypertensive patients with obesity, diabetes, or metabolic syndrome, enabling the majority of patients to achieve target BP. This combination is also well tolerated, and may be considered a suitable option for these added-risk hypertensive patients.
  • Author:
    Friedrich Christian; Emser Angela; Woerle Hans-Juergen; Graefe-Mody Ulrike
    Title:
    Renal Impairment Has No Clinically Relevant Effect on the Long-Term Exposure of Linagliptin in Patients With Type 2 Diabetes.
    Source:
    Am J Ther (2013)
    Abstract:
    Linagliptin is a dipeptidyl peptidase-4 (DPP-4) inhibitor with a primarily nonrenal route of excretion. Consequently, renal impairment should not substantially affect drug exposure. This analysis was undertaken to compare steady-state trough concentrations of linagliptin among patients with type-2 diabetes receiving linagliptin 5 mg in phase 3 studies. Data were pooled from 3 randomized studies from the global phase 3 program of linagliptin (5 mg daily in each) in patients with type-2 diabetes. These studies were selected for their inclusion of pharmacokinetic data. Linagliptin plasma concentrations were available for 969 patients who were determined by estimated glomerular filtration rate to have normal renal function (n = 438), mild renal impairment (RI) (n = 429), moderate RI (n = 44), or severe RI (n = 58). In patients with normal renal function, the geometric mean linagliptin trough concentration (coefficient of variation) was 5.93 nmol/L (56.3%); in patients with mild, moderate, or severe RI, geometric mean concentrations were 6.07 nmol/L (62.9%), 7.34 nmol/L (58.6%), and 8.13 nmol/L (49.8%), respectively. In patients with type-2 diabetes, RI had a minor effect on linagliptin exposure. Therefore, neither dose-adjustment nor drug-related monitoring of estimated glomerular filtration rate is necessary for patients with RI.
  • Author:
    Dua R; Lez Perez V; Paine M F; Frederick K S; Denton C L; Scarlett Y V; Fisher M B
    Title:
    Direct n-glucuronidation of the CYP3A probe midazolam: Effects of a CYP3A and dual CYP3A/UGT1A4 inhibitor in healthy volunteers.
    Source:
    Clin Pharmacol Ther 93 (1), 11 (2013)
    Abstract:
    BACKGROUND: Midazolam is a widely used FDA-recommended CYP3A probe substrate. The primary route of metabolism, 1'- hydroxylation, was shifted to direct N-glucuronidation, mediated by UGT1A4, under CYP3A-inhibited conditions in human hepatocytes Translation to the clinic was evaluated by comparing the effects of the CYP3A inhibitor, indinavir, and the dual CYP3A/UGT1A4 inhibitor, ritonavir, on the pharmacokinetics of midazolam and metabolites in healthy volunteers METHODS: Participants (n=12) enrolled in a prospective, randomized, open-label, three-way crossover study. They received indinavir (800 mg q8h x 3) or ritonavir (300 mg q12h x 2) with a snack or snack alone (control). Midazolam syrup (2.5 mg) was administered 1h after the second dose of inhibitor. Plasma was collected (0-12h) post-midazolam administration and analyzed for midazolam and metabolites by LC/MS/MS. Pharmacokinetics were evaluated via noncompartmental analysis (Phoenix WinNonlin v.6.3) RESULTS: Relative to control, both inhibitors increased midazolam and midazolam N-glucuronide geometric mean AUC0-12h by .apprx.8-fold (p<0.0001) and .apprx.4-fold (p<0.0001), respectively. Indinavir decreased 1'-hydroxymidazolam AUC0-12h by 42% (p=0.02); ritonavir decreased 1'-hydroxymidazolam concentrations to below limits of quantification Indinavir and ritonavir decreased 1'-hydroxymidazolam glucuronide AUC0-12h by 54% (p<0.0001) and 85%, respectively CONCLUSION: The unanticipated increase in midazolam N-glucuronide AUC0-12h in the presence of ritonavir indicated no inhibition of UGT1A4 at the dose tested. Consistent with in vitro observations, ritonavir was a more potent inhibitor of CYP3A in vivo than indinavir. The decrease in 1'-hydroxymidazolam exposure by both inhibitors was accompanied by an increase in midazolam N-glucuronide exposure, suggesting that midazolam metabolism was diverted partly from the CYP3A- to the UGT1A4-mediated pathway under CYP3A-inhibited conditions.
  • Author:
    Macha S; Rose P; Mattheus M; Pinnetti S; Woerle HJ
    Title:
    Lack of drug-drug interaction between empagliflozin, asodium glucose cotransporter 2 inhibitor, and warfarin inhealthy volunteers
    Source:
    Diabetes Obes Metab 15 (4), 316-323 (2013)
    Abstract:
    AIM: To investigate potential drug-drug interactions between empagliflozin and warfarin. METHODS: Healthy subjects (n.=.18) received empagliflozin 25.mg qd for 5.days (treatment A), followed by empagliflozin 25.mg qd for 7.days (days 6-12) with a single 25.mg dose of warfarin on day 6 (treatment B), and a single 25.mg dose of warfarin alone (treatment C), in an open-label, crossover study. Subjects received treatments in sequence AB_C or C_AB with a washout period of .14.days between AB and C or C and AB. RESULTS: Warfarin had no effect on empagliflozin area under concentration-time curve or maximum plasma concentration at steady-state (AUC(.,ss) or C(max,ss)): geometric mean ratios (GMRs) (90% confidence intervals [CI]) were 100.89% (96.86, 105.10) and 100.64% (89.79, 112.80), respectively. Empagliflozin had no effect on AUC from 0.h to infinity (AUC(0-.)) or C(max) for R- or S-warfarin (GMRs [90% CI] for AUC(0-.): 98.49% [95.29, 101.80] and 95.88% [93.40, 98.43], respectively; C(max): 97.89% [91.12, 105.15] and 98.88% [91.84, 106.47], respectively). Empagliflozin had no clinically relevant effects on warfarin's anticoagulant activity (international normalised ratio [INR]) (GMR [95% CI] for peak INR: 0.87 [0.73, 1.04]; area under the effect-time curve from 0 to 168.h: 0.88 [0.79, 0.98]. No drug-related adverse events were reported for empagliflozin after monotherapy or combined administration. The combination of empagliflozin and warfarin was well tolerated. CONCLUSIONS: No drug-drug interactions were observed between empagliflozin and warfarin, indicating that empagliflozin and warfarin can be co-administered without dosage adjustments of either drug.
  • Author:
    Hutzler James Matthew; Obach Ronald Scott; Dalvie Deepak; Zientek Michael A
    Title:
    Strategies for a comprehensive understanding of metabolism by aldehyde oxidase.
    Source:
    Expert Opin Drug Metab Toxicol 9 (2), 153-168 (2013)
    Abstract:
    Introduction: Aldehyde oxidase (AO) is a drug-metabolizing molybdo-fla-voenzyme with profound species differences in expression and activity toward various substrates. The contribution of this enzyme to the metabolism and clearance of heterocyclic-containing xenobiotics appears to have increased in recent years, but has not always been identified prior to clinical studies. As a result, drug candidates have been negatively impacted in development.Areas covered: This review provides the most recent in vitro and in vivo strategies for the drug metabolism-pharmacokinetic (DMPK) scientist. The review details approaches for confirmation of AO as an operable metabolic pathway, estimating clearance and fraction of total metabolism, and identification of an appropriate surrogate species for human AO activity for evaluating safety of clinically relevant metabolites.Expert opinion: As the role of AO in metabolism of new drug molecules continues to emerge, it is critical that DMPK scientists have the most updated methodologies to enable formulation of a thorough experimental plan to understand the potential implications of this metabolic pathway. Whether it is higher-than-expected clearance, contributing to an unfavorable half-life, or the formation of an AO-derived disproportionate human metabolite (DHM), such a plan would serve to minimize complications or attrition of drug candidates due to unforeseen issues in the clinic.
  • Author:
    Tweedie D; Polli JW; Berglund EG; Huang SM; Zhang L; Poirier A; Chu X; Feng BA
    Title:
    Transporter studies in drug development: Experience to date and follow-up on decision trees from the international transporter consortium
    Source:
    Clin Pharmacol Ther 94 (1), 113-125 (2013)
    Abstract:
    The International Transporter Consortium (ITC) organized a second workshop in March 2012 to expand on the themes developed during the inaugural ITC workshop held in 2008. The final session of the workshop provided perspectives from regulatory and industry-based scientists, with input from academic scientists, and focused primarily on the decision trees published from the first workshop. These decision trees have become a central part of subsequent regulatory drug-drug interaction (DDI) guidances issued over the past few years. © 2013 American Society for Clinical Pharmacology and Therapeutics.
  • Author:
    Sarashina A; Koiwai K; Seman LJ; Yamamura N; Taniguchi A; Negishi T; Sesoko S; Woerle HJ; Dugi K
    Title:
    Safety, tolerability, pharmacokinetics and pharmacodynamics of single doses of empagliflozin, a sodium glucose cotransporter 2 (SGLT2) inhibitor, in healthy Japanese subjects
    Source:
    Drug Metab Pharmacokinet 28 (3), 213-219 (2013)
    Abstract:
    This randomized, placebo-controlled within dose groups, double-blind, single rising dose study investigated the safety, tolerability, pharmacokinetics and pharmacodynamics of 1mg to 100 mg doses of empagliflozin in 48 healthy Japanese male subjects. Empagliflozin was rapidly absorbed, reaching peak levels in 1.25 to 2.50 h; thereafter, plasma concentrations declined in a biphasic fashion, with mean terminal elimination half-life ranging from 7.76 to 11.7 h. Increase in empagliflozin exposure was proportional to dose. Oral clearance was dose independent and ranged from 140 to 172 mL/min. In the 24 h following 100 mg empagliflozin administration, the mean (%CV) amount of glucose excreted in urine was 74.3 (17.1) g. The amount and the maximum rate of glucose excreted via urine increased with dose of empagliflozin. Nine adverse events, all of mild intensity, were reported by 8 subjects (7 with empagliflozin and 1 with the placebo). No hypoglycemia was reported. In conclusion, 1mg to 100 mg doses of empagliflozin had a good safety and tolerability profile in healthy Japanese male subjects. Exposure to empagliflozin was dose proportional. The amount and rate of urinary glucose excretion were higher with empagliflozin than with the placebo, and increased with empagliflozin dose. © 2013 by the Japanese Society for the Study of Xenobiotics (JSSX).
  • Author:
    Kanada S; Koiwai K; Taniguchi A; Sarashina A; Seman L; Woerle HJ
    Title:
    Pharmacokinetics, pharmacodynamics, safety and tolerability of 4 weeks' treatment with empagliflozin in Japanese patients with type 2 diabetes mellitus
    Source:
    J Diabetes Invest Article in press (2013)
    Abstract:
    Introduction: To evaluate the pharmacodynamics, pharmacokinetics, safety and tolerability of empagliflozin in Japanese patients with type 2 diabetes mellitus. Materials and methods: In this 4-week, multiple dose, randomized, parallel-group, double-blind, placebo-controlled trial, patients (n = 100) were randomized to receive 1, 5, 10 or 25 mg of empagliflozin, or placebo once daily. Key end-points were urinary glucose excretion (UGE), fasting plasma glucose (FPG) and eight-point glucose profile. Results: Data are presented for 1, 5, 10, 25 mg of empagliflozin and placebo groups, respectively. Adjusted mean changes from baseline to day 27 in UGE were 40.8, 77.1, 80.9, 93.0 and -2.1 g (P < 0.0001 for all empagliflozin groups vs placebo). Adjusted mean changes from baseline to day 28 in FPG were -1.56, -1.96, -2.31, -2.37 and -0.86 mmol/L (P < 0.01 for all empagliflozin groups vs placebo). Adjusted mean changes from baseline to day 27 in eight-point glucose profile were -1.96, -2.21, -2.42, -2.54 and -0.97 mmol/L (P < 0.01 for all empagliflozin groups vs placebo). Empagliflozin reached peak plasma concentration 1.5-2 h after dosing. Mean steady state terminal elimination half-lives ranged from 13.2 to 18.0 h. Of 100 patients, 25 experienced an adverse event, occurring more frequently for empagliflozin (29.1%) than placebo (9.5%); frequency was not dose related. Conclusions: In Japanese patients with type 2 diabetes mellitus, empagliflozin at doses up to 25 mg once daily for 4 weeks was well tolerated and resulted in significant improvements in glycemic control compared with placebo. This trial was registered with ClinicalTrials.gov (no. NCT00885118). © 2013 Asian Association for the Study of Diabetes and Wiley Publishing Asia Pty Ltd.
  • Author:
    Rosenstock J; Marx N; Kahn SE; Zinman B; Kastelein JJ; Lachin JM; Bluhmki E; Patel S; Johansen O-E; Woerle H-J
    Title:
    Cardiovascular outcome trials in type 2 diabetes and the sulphonylurea controversy: Rationale for the active-comparator CAROLINA trial
    Source:
    Diabetes Vasc Dis Res 10 (4), 289-301 (2013)
    Abstract:
    Sulphonylureas (SUs) are widely used glucose-lowering agents in type 2 diabetes mellitus (T2DM) with apparent declining efficacy over time. Concerns have been raised from observational retrospective studies on the cardiovascular (CV) safety of SUs but there are few long-term data on CV outcomes from randomized controlled trials (RCTs) involving the use of this class of agents. Most of the observational studies and registry data are conflicting and vary with study population and methodology used for analyses. To address the SU controversy, we reviewed the recently published literature (until end of the year 2011) to evaluate the impact of SUs on CV outcomes in modern, longer-term (.72 weeks) RCTs where they were compared in a head-to-head fashion versus an active comparator or were used as part of a treatment strategy. We identified 15 trials and found no report of an increase in the incidence of CV events with the use of SUs. However, the available data are limited, and, most importantly, there was no adequately powered formal head-to-head CV outcome trial designed to address CV safety. Since SUs are still being advocated as second-line therapy added-on to metformin, as one of several classes, and in certain circumstances first-line therapy in T2DM management, definitive data from a dedicated RCT addressing the CV safety question with SUs would be informative. Cardiovascular Outcome Study of Linagliptin versus Glimepiride in Patients with Type 2 Diabetes (CAROLINA) is such a trial, ongoing since November 2010, and is currently the largest head-to-head CV outcome trial that involves a comparison of a SU (glimepiride) with a dipeptidyl peptidase-4 (DPP-4) inhibitor (linagliptin) and will provide a unique perspective with respect to CV outcomes with these two commonly used agents. © The Author(s) 2013.
  • Author:
    Shah P; Ardestani A; Dharmadhikari G; Laue S; Schumann DM; Kerr-Conte J; Pattou F; Klein T; Maedler K
    Title:
    The DPP-4 inhibitor linagliptin restores .-cell function and survival in human isolated islets through GLP-1 stabilization
    Source:
    J Clin Endocrinol Metab 98 (7), E1163-E1172 (2013)
    Abstract:
    Context: Inhibition of dipeptidyl peptidase-4 (DPP-4) is a potent strategy to increase glucose-dependent insulinotropic polypeptide and glucagon like peptide 1 (GLP-1) induced insulin secretion in diabetes. It is important to know whether new drugs approved for the treatment of type 2 diabetes have direct effects on the .-cell. Objective: Herein we investigated the effect of linagliptin, a novel DPP-4 inhibitor, on .-cell function and survival. Design: Human islets were exposed to a diabetic milieu (11.1-33.3 mM glucose, 0.5 mM palmitate, the mixture of 2 ng/mL IL-1.+ 1000 U/mL interferon-., or 50 .M H2O2) with or without 500 ng/mL IL-1 receptor antagonist (IL-1Ra) or 30-50 nM linagliptin. Results: Linagliptin restored .-cell function and turnover, which was impaired when islets were exposed to elevated glucose, palmitate, cytokines, or H 2O2. Pretreatment with IL-1Ra was similarly effective, except against H2O2 treatment. Nitrotyrosine concentrations in islet lysates, an indicator of oxidative stress, were highly elevated under diabetic conditions but not in islets treated with linagliptin or IL-1Ra. Linagliptin also reduced cytokine secretion and stabilized GLP-1 in islet supernatants. Conclusions: We show that the novel DPP-4 inhibitor linagliptin protected from gluco-, lipo-, and cytokine-toxicity and stabilized active GLP-1 secreted from human islets. This provides a direct GLP-1 mediated protective effect of linagliptin on .-cell function and survival. Copyright © 2013 by The Endocrine Society.
  • Author:
    Yang F; Ye J; Pomerantz K; Stewart M
    Title:
    Potential modification of the UKPDS risk engine and evaluation of macrovascular event rates in controlled clinical trials
    Source:
    Diabetes Metab Syndr Obes Targets Ther 6, 247-256 (2013)
    Abstract:
    Background: The aim of this study was to evaluate a modified UKPDS risk engine in order to establish a risk prediction benchmark for the general diabetes population. Methods: Data sources were summary demographic and risk factor data from the major type 2 diabetes mellitus outcomes studies, including ACCORD, ADVANCE, VADT, RECORD, PROactive, ADOPT, and BARI 2D. Patients in these studies spanned a wide spectrum of disease, from drug-naidieve to insulin-dependent. Cardiovascular events/major adverse coronary events (CVE/MACE) were primary or safety end points. Overall observed rates for cardiovascular events/MACE were summarized, and the observed annualized event rates were calculated using linear approximation. Simulation studies were then conducted using original (cardiovascular history excluded) and modified (cardiovascular history included) United Kingdom Prospective Diabetes Study (UKPDS) models; the predicted event rates were then compared with the observed event rates for all studies. The consistency of the predicted rates derived from each model was then evaluated using descriptive statistics and linear regression. Results: The original UKPDS model tended to overestimate event rates across studies. The ratio of predicted events versus observed MACE ranged from 0.9 to 2.0, with mean of 1.5 ± 0.4 and a coefficient of variation of 26% (R2=0.80). However, cardiovascular risk predictions were more precise using a modified UKPDS model; the ratio of predicted versus observed MACE events ranged from 1.8 to 2.4, with a mean of 2.1 ± 0.25 and a coefficient of variation of 13% (R2=0.94). Conclusion: A modified UKPDS model which includes adjustments for prior cardiovascular history has the potential for use as a tool for benchmarking and may be useful for predicting cardiovascular rates in clinical studies. This modification could be further evaluated, recalibrated, and validated using patient-level information derived from prospective clinical studies to yield greater predictability. © 2013 Yang et al, publisher and licensee Dove Medical Press Ltd.
  • Author:
    Ferrannini E; Seman L; Seewaldt-Becker E; Hantel S; Pinnetti S; Woerle HJ
    Title:
    A Phase IIb, randomized, placebo-controlled study of the SGLT2 inhibitor empagliflozin in patients with type 2 diabetes
    Source:
    Diabetes Obes Metab 15 (8), 721-728 (2013)
    Abstract:
    Aim: This Phase IIb, randomized, double-blind, placebo-controlled trial evaluated the efficacy, safety, tolerability and pharmacokinetics of empagliflozin in patients with type 2 diabetes. Methods: Four hundred and eight patients (treatment-naïve or after a 4-week wash-out period) were randomized to receive empagliflozin 5, 10 or 25mg once daily, placebo or open-label metformin for 12weeks. The primary endpoint was change in haemoglobin A1c (HbA1c) after 12weeks. Results: After 12weeks' treatment, empagliflozin showed dose-dependent reductions in HbA1c from baseline [5mg: -0.4%, 10mg: -0.5%, 25mg: -0.6%; all doses p<0.0001 vs. placebo (+0.09%)]. Fasting plasma glucose (FPG) decreased with empagliflozin [5mg: -1.29mmol/l, 10mg: -1.61mmol/l, 25mg: -1.72mmol/l; all doses p<0.0001 vs. placebo (+0.04mmol/l)]. Body weight decreased in all empagliflozin groups (all doses p<0.001 vs. placebo). The incidence of adverse events (AEs) was similar in the placebo (32.9%) and empagliflozin (29.1%) groups. The most frequently reported AEs on empagliflozin were pollakiuria (3.3% vs. 0% for placebo), thirst (3.3% vs. 0% for placebo) and nasopharyngitis (2.0% vs. 1.2% for placebo). AEs consistent with urinary tract infections (UTIs) were reported in four (1.6%) patients on empagliflozin vs. one (1.2%) on placebo. Genital infections were reported in five (2%) patients on empagliflozin vs. 0% on placebo. No UTIs or genital infections led to premature discontinuation. Conclusions: In patients with type 2 diabetes, empagliflozin resulted in dose-dependent, clinically meaningful reductions in HbA1c and FPG, and reductions in body weight compared with placebo. Empagliflozin was well-tolerated with a favourable safety profile. © 2013 Blackwell Publishing Ltd.
  • Author:
    Cirino Giuseppe; Mariarosaria Bucci; Emma Mitidieri; Angela Ianaro; Elisabetta Panza
    Title:
    Linagliptin Rescues Vascular Response in Non-obese Diabetic Mice: Involvement of the L-Arginine/e-NOS Pathway
  • Author:
    Ohmura T; Tsunenari I; Seidler R; Chachin M; Hayashi T; Konomi A; Matsumaru T; Sumida T; Hayashi N; Horie Y
    Title:
    Renoprotective effects of telmisartan on renal injury in obese Zucker rats.
    Source:
    Acta Diabetol 49 (Suppl 1), 15-24 (2012)
    Abstract:
    The purpose of the present study was to investigate the renoprotective effect of telmisartan, an angiotensin II receptor antagonist, on the early stages of diabetic nephropathy in obese Zucker rats, which is a type 2-related diabetes mellitus model. Telmisartan 1, 3 or 10 mg/kg/day was orally administered to 7-week-old rats that demonstrated glucose tolerance without albuminuria or proteinuria, for 24 consecutive weeks (Experiment A). In another experiment (Experiment B), oral administration of telmisartan 10 mg/kg/day was initiated at the age of 16 weeks after the rats demonstrated marked proteinuria, and continued for 24 weeks. Telmisartan inhibited the increase in proteinuria and albuminuria in a dose-dependent manner, and the inhibition for all telmisartan groups was statistically significant by the completion of administration (Experiment A). Telmisartan also displayed similar inhibitory effects on proteinuria and albuminuria in Experiment B. Histologically, telmisartan [3 and 10 mg/kg/day] was associated with a significant decrease in the progression of glomerulosclerosis, and significantly improved interstitial cell infiltration, interstitial fibrosis and dilation and atrophy of renal tubules. Furthermore, telmisartan treatment was associated with a tendency towards normalized plasma lipids (total cholesterol and triglyceride). Our results suggest that telmisartan has a definite renoprotective effect against renal injury in type II diabetic nephropathy.
  • Author:
    Bentz J; O'Connor MP; Bednarczyk D; Coleman J; Lee C; Palm J; Pak YA; Perloff ES; Reyner E; Balimane P; Brännström M; Chu X; Funk C; Guo A; Hanna I; Herédi-Szabó K; Hillgren K; Li L; Hollnack-Pusch E; Jamei M; Lin X; Mason AK; Neuhoff S; Patel A; Podila L; Plise E; Rajaraman G; Salphati L; Sands E; Taub ME; Taur J-S; Weitz D; Wortelboer HM; Xia CQ; Xiao G; Yabut J; Yamagata T; Zhang L; Ellens H
    Title:
    Variability in P-Glycoprotein Inhibitory Potency (IC50) Using Various in Vitro Experimental Systems: Implications for Universal Digoxin Drug- Drug Interaction Risk Assessment Decision Criterias
    Source:
    Drug Metab Dispos 41 (7), 1347-1366 (2013)
    Abstract:
    A P-glycoprotein (P-gp) IC50 working group was established with 23 participating pharmaceutical and contract research laboratories and one academic institution to assess interlaboratory variability in P-gp IC 50 determinations. Each laboratory followed its in-house protocol to determine in vitro IC50 values for 16 inhibitors using four different test systems: human colon adenocarcinoma cells (Caco-2; eleven laboratories), Madin-Darby canine kidney cells transfected with MDR1 cDNA (MDCKII-MDR1; six laboratories), and Lilly Laboratories Cells-Porcine Kidney Nr. 1 cells transfected with MDR1 cDNA (LLCPK1- MDR1; four laboratories), and membrane vesicles containing human P-glycoprotein (P-gp; five laboratories). For cell models, various equations to calculate remaining transport activity (e.g., efflux ratio, unidirectional flux, net-secretory-flux) were also evaluated. The difference in IC50 values for each of the inhibitors across all test systems and equations ranged from a minimum of 20- and 24-fold between lowest and highest IC50 values for sertraline and isradipine, to a maximum of 407- and 796-fold for telmisartan and verapamil, respectively. For telmisartan and verapamil, variability was greatly influenced by data from one laboratory in each case. Excluding these two data sets brings the range in IC50 values for telmisartan and verapamil down to 69- and 159-fold. The efflux ratiobased equation generally resulted in severalfold lower IC 50 values compared with unidirectional or net-secretory-flux equations. Statistical analysis indicated that variability in IC50 values was mainly due to interlaboratory variability, rather than an implicit systematic difference between test systems. Potential reasons for variability are discussed and the simplest, most robust experimental design for P-gp IC 50 determination proposed. The impact of these findings on drug-drug interaction risk assessment is discussed in the companion article (Ellens et al., 2013) and recommendations are provided. © 2013 by The American Society for Pharmacology.
  • Author:
    Heise T; Seewaldt-Becker E; Macha S; Hantel S; Pinnetti S; Seman L; Woerle HJ
    Title:
    Safety, tolerability, pharmacokinetics and pharmacodynamics following 4 weeks' treatment with empagliflozin once daily in patients with type 2 diabetes
    Source:
    Diabetes Obes Metab 15 (7), 613-621 (2013)
    Abstract:
    Aim: To investigate the safety, tolerability, pharmacokinetics and pharmacodynamics of empagliflozin in patients with type 2 diabetes following oral administration of 10, 25 or 100 mg doses once daily over 28 days. Methods: A total of 78 patients were assigned to empagliflozin 10 mg (n=16), 25 mg (n=16) or 100 mg (n=30) or placebo (n=16) for 28 days. Assessments included adverse events (AEs) and pharmacokinetic and pharmacodynamic endpoints. Results: Empagliflozin exposure increased dose-proportionally over the dose range 10-100 mg and showed linear pharmacokinetics with respect to time. Urinary glucose excretion (UGE) increased from baseline to day 1 by 74, 90 and 81 g with empagliflozin 10, 25 and 100 mg, respectively. The increases in UGE were maintained over 28 days with multiple dosing. Virtually no change in UGE was observed in the placebo group. Significant reductions from baseline in mean daily plasma glucose and fasting plasma glucose were observed with empagliflozin compared with placebo. The incidence of AEs was similar in the empagliflozin and placebo groups (50.0, 56.3 and 66.7% with empagliflozin rising doses and 62.5% with placebo). The most frequently reported AEs were pollakiuria (10.3%), nasopharyngitis (9.0%), constipation (9.0%) and headache (7.7%). Conclusions: Oral administration of empagliflozin at doses of 10, 25 or 100 mg once daily over 28 days resulted in significant increases in UGE and reductions in blood glucose compared with placebo, and were well tolerated in patients with type 2 diabetes. © 2013 Blackwell Publishing Ltd
  • Author:
    Ellens H; Deng S; Coleman J; Bentz J; Taub ME; Ragueneau-Majlessi I; Chung SP; Herédi-Szabó K; Neuhoff S; Palm J; Balimane P; Zhang L; Jamei M; Hanna I; O'connor M; Bednarczyk D; Forsgard M; Chu X; Funk C; Guo A; Hillgren KM; Li L; Pak AY; Perloff ES; Rajaraman G; Salphati L; Taur J-S; Weitz D; Wortelboer HM; Xia CQ; Xiao G; Yamagata T; Lee CA
    Title:
    Application of receiver operating characteristic analysis to refine the prediction of potential digoxin drug interactionss
    Source:
    Drug Metab Dispos 41 (7), 1367-1374 (2013)
    Abstract:
    In the 2012 Food and Drug Administration (FDA) draft guidance on drug-drug interactions (DDIs), a new molecular entity that inhibits Pglycoprotein (P-gp) may need a clinical DDI study with a P-gp substrate such as digoxin when themaximumconcentration of inhibitor at steady state divided by IC50 ([I1]/IC50) is0.1 or concentration of inhibitor based on highest approved dose dissolved in 250 ml divide by IC50 ([I2]/IC 50) is10. In this article, refined criteria are presented, determined by receiver operating characteristic analysis, using IC50 values generated by 23 laboratories. P-gp probe substrates were digoxin for polarized cell-lines and N-methyl quinidine or vinblastine for P-gp overexpressed vesicles. Inhibition of probe substrate transport was evaluated using 15 known P-gp inhibitors. Importantly, the criteria derived in this article take into account variability in IC50 values. Moreover, they are statistically derived based on the highest degree of accuracy in predicting true positive and true negative digoxin DDI results. The refined criteria of [I1]/IC50 0.03 and [I2]/IC50 45 and FDA criteria were applied to a test set of 101 in vitro-in vivo digoxin DDI pairs collated from the literature. The number of false negatives (none predicted but DDI observed) were similar, 10 and 12%, whereas the number of false positives (DDI predicted but not observed) substantially decreased from 51 to 40%, relative to the FDA criteria. On the basis of estimated overall variability in IC50 values, a theoretical 95%confidence interval calculation was developed for single laboratory IC 50 values, translating into a range of [I1]/IC50 and [I2]/IC50 values. The extent by which this range falls above the criteria is a measure of risk associated with the decision, attributable to variability in IC50 values. © 2013 by The American Society for Pharmacology.
  • Author:
    Meyers J; Yu Y; Kaye J A; Davis K L
    Title:
    Medicare fee-for-service enrollees with primary acute myeloid leukemia: An analysis of treatment patterns, survival, and healthcare resource utilization and costs
    Source:
    Appl Health Econ Health Policy 11 (3), 275-286 (2013)
    Abstract:
    Background: Acute myeloid leukemia (AML) is the most common form of acute leukemia affecting adults, with incidence increasing with patient age. Previous studies have found that older AML patients, constituting the majority of the AML population, generally have poor outcomes, high healthcare expenditures, and median survival of <3 months. Because up-to-date information on treatment patterns, survival trends, and costs of care for elderly AML patients are lacking in the literature, we examined Medicare fee-for-service enrollees with primary AML to update these estimates and report on changes in treatment for this population. Objective: The primary objective of this study was to examine real-world data on treatment patterns, survival, and costs in elderly patients with primary AML. Factors associated with receipt of chemotherapy and with mortality also were assessed. Methods: This is a retrospective database analysis using the Surveillance, Epidemiology, and End Results cancer registry and linked Medicare claims. Patients aged 65 years and older, who were newly diagnosed with AML between 1 January 1997 and 31 December 2007 were selected if they had no previous neoplasm or hematological disease. Patients were followed until death or to the end of the observation period (31 December 2007). Study measures included chemotherapy and supportive care (SC) received, survival time, and all-cause healthcare utilization and costs accrued from AML diagnosis until death or observation period end. Regression analyses assessed factors associated with receipt of chemotherapy (logistic) and mortality among chemotherapy and SC users (Cox). Results: Of the 4,058 patients meeting the inclusion criteria, 43 % received chemotherapy; 57 % received SC only. Among patients receiving chemotherapy, 69.1 % died within 1 year; median survival was 7.0 months. Among patients receiving only SC, 95.0 % died within 1 year; median survival was 1.5 months. The most significant factors associated with receipt of chemotherapy were patient age [odds ratio (OR) = 0.420 among patients 75-84 years and 0.099 among patients 85+ years, compared with patients aged 65-74 years) and Charlson Comorbidity Index (CCI) score (OR = 0.614 for patients with a CCI = 2 or 3 and 0.707 for patients with a CCI >3, compared with patients with a CCI = 0) (all P < 0.001). The most significant factors associated with mortality among patients receiving chemotherapy were patient age [hazard ratio (HR) = 1.321 among patients 75-84 years and 1.832 among patients 85+ years, compared with patients aged 65-74 years] and CCI score (OR = 1.287 for patients with a CCI = 2 or 3 and 1.220 for patients with a CCI >3, compared with patients with a CCI = 0) (all P < 0.01). Mean (standard deviation) all-cause healthcare costs were $96,078 ($109,072); the largest component was inpatient utilization (76.3 %). Conclusions: Younger patients with fewer comorbidities were more likely to receive chemotherapy and had longer survival. AML is associated with a substantial economic burden, and treatment outcomes appear to be suboptimal, with limited therapy options currently available. © 2013 Springer International Publishing Switzerland.
  • Author:
    Kempf K; Martin S; Haastert B; Schneider M
    Title:
    Diagnostic accuracy of a standardized carbohydrate-rich breakfast compared to an oral glucose tolerance test in occupational medicine [Diagnostische Genauigkeit eines standardisierten kohlenhydrathaltigen Frühstücks im Vergleich zum oralen Glukosetoleranztest in der betriebsmedizinischen Praxis]
    Source:
    Dtsch Med Wochenschr 138 (24), 1297-1303 (2013)
    Abstract:
    Background: Increasing prevalence of type 2 diabetes mellitus is not only a problem for the health care system but also impairs working environment. In order to reduce costs by illness and early retirement and the development of diabetic complications occupational medicine is important for early diabetes detection. However, the diagnostic gold standard, oral glucose tolerance test (oGTT), is rarely accepted. Aim of our investigation was to evaluate diagnostic accuracy of a standardizable and cost-effective test-breakfast in comparison to oGTT which might be accepted in workplace. Methods: During a workplace health promotion program diagnostic accuracy (sensitivity and specificity) of a test-breakfast (index test) was analyzed in a random-cross-over-design with healthy volunteers in comparison to an oGTT (reference test). Results: 278 subjects participated and rated the health promotion program to be useful (99 %). 74 % stated that they preferred the test-breakfast in contrast to the oGTT. Both screening methods showed comparable plasma glucose and insulin curves. The plasma glucose levels measured capillary and venously during test-breakfast and oGTT were very consistent. Differences were only seen for the 2 h plasma glucose values in the fully adjusted model. The test-breakfast demonstrated high sensitivity and specificity for diabetes diagnosis compared to the reference test with highly comparable results, i. e. 8 persons (2,9 %) newly diagnosed with diabetes by the test-breakfast vs. 7 (2,5 %) by oGTT. Conclusion: A test-breakfast seems to be a useful first screening instrument to increase the compliance of occupational health promotions and might improve early diabetes diagnosis. © Georg Thieme Verlag KG - Stuttgart - New York.
  • Author:
    Mayoux Eric
    Title:
    The SGLT2 inhibitor empagliflocin ameliorates albuminuria in BTBR ob/ob type 2 diabetic mice with and without hypertension.
  • Author:
    Trevithick J R; Bantseev V; Hirst M; Dzialoszynski T M; Sanford E S
    Title:
    Is pycnogenol a double-edged sword? Cataractogenic in vitro, but reduces cataract risk in diabetic rats
    Source:
    Curr Eye Res 38 (7), 751-760 (2013)
    Abstract:
    Purpose: Pycnogenol was used (a) to study its antioxidant activity, (b) to study its effects on lens integrity in organ culture and (c) in vivo to determine whether it could reduce the damage in model diabetic cataract. Methods: For (a) our luminescent antioxidant assay was used, (b) lenses were incubated in medium 199, with 55.6 mM glucose. Lenses were stained with 0.014 mM rhodamine 123 for 15 min to stain mitochondria, immobilized in 1% agarose in M199, and the equatorial region examined by a Zeiss confocal microscope. For (c) cataract grades of streptozotocin diabetic rats fed 1% pycnogenol were followed for 12 weeks. Results: (a) Pycnogenol in vitro was an antioxidant when challenged with peroxide. (b) In vitro, when [570 mg/L] pycnogenol in dimethyl sulfoxide (DMSO) was used, lenses turned opaque after 3 d of incubation, in both pycnogenol controls and glucose + pycnogenol. Normal controls (DMSO, n = 4) and controls (n = 4) remained clear after 8 d of incubation. After 3 d of incubation with pycnogenol, cumulative protein leakage was greater than 0.28 mg/mL versus 8 d controls (0.018 mg/mL). Similar damage occurred at pycnogenol concentrations as low as 20 mg/L. The 20 mg/L pycnogenol control showed mitochondrial death, and calcium concentration in the lens equatorial differentiating fiber cells increased. (c) In vivo feeding pycnogenol resulted in similar growth and body condition for diabetic rats, and lower cataract grades at 9 and 11 weeks: final serum glucose levels were not significantly different, but glycohemoglobin A1 levels were significantly lower (83.9% of normal, p < 0.05) in pycnogenol-fed diabetic rats. Conclusions: Although it appears that pycnogenol has a potential toxic effect on incubated lenses, it appears in vivo to have a marginal protective effect, and also significantly reduces glycation of proteins. Supported by Cognis US (formerly Henkel Chemical Co.) and Horphag Research. © Informa Healthcare USA, Inc.
  • Author:
    van Ryn J; Litzenburger T; Gan G; Coble K; Schurer J
    Title:
    In Vitro Characterization, Pharmacokinetics and Reversal of Supratherapeutic Doses of Dabigatran-Induced Bleeding in Rats by a Specific Antibody Fragment Antidote to Dabigatran
    Source:
    International Stroke Conference, Honolulu, Feb 6-8, 2013
  • Author:
    van Ryn J; Schurer J; Kink-Eiband M; Litzenburger T; Clemens A
    Title:
    Reversal of dabigatran clotting activity in the rat ex vivo by a specific and selective antibody fragment antidote: are there non-specific effects on warfarin, rivaroxaban and apixaban?
    Source:
    European Society of Cardiology (ESC), Amsterdam, August 31-September 4, 2013
  • Author:
    Renda G; Malatesta G; Lanuti P; Bucciarelli V; Candelori L; Moretti L; van Ryn J; Marchisio M; Miscia S; de Caterina R
    Title:
    Effects of the direct thrombin inhibitor dabigatran etexilate vs warfarin on platelet function in patients with atrial fibrillation
    Source:
    European Society of Cardiology (ESC), Amsterdam, August Aug 31-Sep 4, 2013
  • Author:
    Mader M; Hausding M; Schuhmacher S; Oelze M; Steven S; Daub S; Schulz E; Münzel T; Klein T; Daiber A
    Title:
    Comparison of Linagliptin and Liraglutide on Survival in Experimental Sepsis
    Source:
    EASD, September 2013, Barcelona
  • Author:
    Bischoff Dr D
    Title:
    Slide decks: GTM Strategy GSH Screening Reactive Metabolites
    Source:
    For personal scientific exchange with Pharma industry colleagues
  • Author:
    Blech Dr Stefan
    Title:
    Resolving the microcosmos of complex samples: UPLC/TWIMS/high res. MSE for the analysis of in vivo drug metabolism studies, Proceedings
    Source:
    APA (Applied Pharmaceutical Analysis) Conference, Boston, MA (USA), September 16 - 18, 2013
  • Author:
    Gelhorn HL; Stringer SM; Brooks A; Thompson C; Monz BU; Boye KS; Hach T; Lund SS; Palencia R
    Title:
    Preferences for medication attributes among patients with type 2 diabetes mellitus in the UK
    Source:
    Diabetes Obes Metab Article in press (2013)
    Abstract:
    Aim: To examine preferences for oral medication attributes among participants with early and advanced type 2 diabetes mellitus (T2DM) in the UK using a discrete choice experiment (DCE). Methods: A web-based DCE was administered where participants indicated which medication they preferred from two different hypothetical oral anti-diabetic (OAD) medication profiles, each composed of differing levels of seven attributes (efficacy, hypoglycaemic events, weight change, gastrointestinal/nausea side effects, urinary tract infection and genital infection, blood pressure and cardiovascular risk) for 20 sets of pair-wise comparisons. A random effects multinomial logit regression model was used to estimate the preference weight (PW) for each of the attribute levels, and the relative importance (RI) of each attribute was calculated. Analyses were conducted for the overall sample and for medication and gender subgroups. Results: The final sample included 100 participants with a mean age of 62.9 (SD 11.1) years and comparable numbers of participants of each gender (51% male, 49% female). The majority of the participants were White-British (92%). The total PW and corresponding RI were highest for four of the seven attributes: hypoglycaemic events (PW=1.98; RI=24.7%), weight change (PW=1.65; RI=20.6%), gastrointestinal/nausea side effects (PW=1.49; RI=18.6%) and efficacy (PW=1.44; RI=18.0%). The RI values differed for some attributes across gender and number of current T2DM medication subgroups. Conclusion: The results suggest that hypoglycaemia, weight change, gastrointestinal side effects and efficacy are of primary importance to patients in their OAD preferences in T2DM. These four attributes comprised over 80% of the RI. © 2013 Blackwell Publishing Ltd.
  • Author:
    Grandfils N; Detournay B; Attali C; Joly D; Simon D; Vergès B; Toussi M; Briand Y; Delaitre O
    Title:
    Glucose lowering therapeutic strategies for type 2 diabetic patients with chronic kidney disease in primary care setting in France: A cross-sectional study
    Source:
    Int J Endocrinol art.no.640632 (2013)
    Abstract:
    Aim. To understand glucose lowering therapeutic strategies of French general practitioners (GPs) in the management of type 2 diabetes mellitus (T2DM) patients with chronic kidney disease (CKD). Methods. A multicenter cross-sectional study was conducted from March to June 2011 among a sample of French GPs who contribute to the IMS Lifelink Disease Analyzer database. Eligible patients were those with T2DM and moderate-to-severe CKD who visited their GPs at least once during the study period. Data were collected through electronic medical records and an additional questionnaire. Results. 116 GPs included 297 patients: 86 with stage 3a (Group 1, GFR = 45-60 mL/min/1.73 m 2) and 211 with stages 3b, 4, or 5 (Group 2, GFR &lt; 45 mL/min/1.73 m2). Patients' mean age was approximately 75 years. Insulin was used in 19% of patients, and was predominant in those with severe CKD. More than two-thirds of patients were treated with glucose lowering agents which were either contraindicated or not recommended for CKD. Conclusion Physicians most commonly considered the severity of diabetes and not CKD in their therapeutic decision making, exposing patients to potential iatrogenic risks. The recent patient oriented approach and individualization of glycemic objectives according to patient profile rather than standard HbA1c would improve this situation. © 2013 N. Grandfils et al
  • Author:
    Gross J L; Rogers J; Polhamus D; Gillespie W; Friedrich C; Gong Y; Monz B U; Patel S; Staab A; Retlich S
    Title:
    A novel model-based meta-analysis to indirectly estimate the comparative efficacy of two medications: An example using DPP-4 inhibitors, sitagliptin and linagliptin, in treatment of type 2 diabetes mellitus
    Source:
    BMJ Open 3 (3) art.no. e001844 (2013)
    Abstract:
    Objectives: To develop a longitudinal statistical model to indirectly estimate the comparative efficacies of two drugs, using model-based meta-analysis (MBMA). Comparison of two oral dipeptidyl peptidase (DPP)-4 inhibitors, sitagliptin and linagliptin, for type 2 diabetes mellitus (T2DM) treatment was used as an example. Design: Systematic review with MBMA. Data sources: MEDLINE, EMBASE, http://www. ClinicalTrials.gov, Cochrane review of DPP-4 inhibitors for T2DM, sitagliptin trials on Food and Drug Administration website to December 2011 and linagliptin data from the manufacturer. Eligibility criteria for selecting studies: Double-blind, randomised controlled clinical trials, =12 weeks' duration, that analysed sitagliptin or linagliptin efficacies as changes in glycated haemoglobin (HbA1c) levels, in adults with T2DM and HbA1c >7%, irrespective of background medication. Model development and application: A Bayesian model was fitted (Markov Chain Monte Carlo method). The final model described HbA1c levels as function of time, dose, baseline HbA1c, washout status/duration and ethnicity. Other covariates showed no major impact on model parameters and were not included. For the indirect comparison, a population of 1000 patients was simulated from the model with a racial composition reflecting the average racial distribution of the linagliptin trials, and baseline HbA1c of 8%. Results: The model was developed using longitudinal data from 11 234 patients (10 linagliptin, 15 sitagliptin trials), and assessed by internal evaluation techniques, demonstrating that the model adequately described the observations. Simulations showed both linagliptin 5 mg and sitagliptin 100 mg reduced HbA1c by 0.81% (placebo-adjusted) at week 24. Credible intervals for participants without washout were-0.88 to-0.75 (linagliptin) and-0.89 to-0.73 (sitagliptin), and for those with washout,-0.91 to-0.76 (linagliptin) and-0.91 to-0.75 (sitagliptin).
  • Author:
    Jain R; Jain D; Liu Q; Bartosinska B; Wang J; Schumann D; Kauschke S G; Eickelmann P; Piemonti L; Gray N S; Lammert E
    Title:
    Pharmacological inhibition of Eph receptors enhances glucose-stimulated insulin secretion from mouse and human pancreatic islets
    Source:
    Diabetologia 56 (6), 1350-1355 (2013)
    Abstract:
    Aims/hypothesis: Type 2 diabetes is characterised by impaired glucose-stimulated insulin secretion (GSIS) from pancreatic islets. Since erythropoietin-producing hepatoma (Eph)-ephrin bidirectional signalling fine-tunes GSIS from pancreatic beta cells, we investigated Eph receptor tyrosine kinases (RTK) as potential drug targets for selectively increasing GSIS. Methods: Insulin secretion assays were carried out using mouse and human pancreatic islets as well as mouse insulinoma (MIN6) cells in the presence or absence of two Eph RTK inhibitors. Furthermore, the most potent inhibitor was injected into mice to evaluate its effects on glucose tolerance and plasma insulin levels. Results: We showed that the Eph RTK inhibitors selectively increased GSIS from MIN6 cells as well as mouse and human islets. Our results also showed that the insulin secretory effects of these compounds required Eph-ephrin signalling. Finally, pharmacological inhibition of Eph receptor signalling improved glucose tolerance in mice. Conclusions/interpretation: We showed for the first time that Eph RTKs represent targets for small molecules to selectively increase GSIS and improve glucose tolerance. © 2013 Springer-Verlag Berlin Heidelberg.
  • Author:
    Del Prato S; Taskinen M-R; Owens D R; Von Eynatten M; Emser A; Gong Y; Chiavetta S; Patel S; Woerle H-J
    Title:
    Efficacy and safety of linagliptin in subjects with type 2 diabetes mellitus and poor glycemic control: Pooled analysis of data from three placebo-controlled phase III trials
    Source:
    J Diabetes Complications 27 (3), 274-279 (2013)
    Abstract:
    Aims To evaluate the efficacy/safety of dipeptidyl peptidase-4 inhibitor, linagliptin, in subjects with insufficiently controlled type 2 diabetes mellitus (T2DM), and factors influencing treatment response. Methods Pooled analysis of data from 2258 subjects in three 24-week phase III, randomized, placebo-controlled, parallel-group studies, who received oral linagliptin (5 mg/day) or placebo as monotherapy, added-on to metformin, or added-on to metformin plus sulfonylurea was performed. Results Among 388 subjects with HbA1c ? 9.0%, adjusted mean baseline HbA1c (9.4% both groups) declined to 8.3% in linagliptin group and 9.1% in placebo group at 24 weeks (P <.0001) and adjusted mean change from baseline was 1.2% (vs. 0.4%, placebo). Linagliptin significantly lowered fasting plasma glucose levels vs. placebo (1.6 mmol/l vs. 0.4 mmol/l); treatment difference, 1.1 mmol/l (95% CI, - 1.7 to - 0.5). Treatment and washout of previous oral antidiabetes drugs were the only factors to independently affect HbA1c change at week 24. Adverse event rates were similar for linagliptin (61.9%) and placebo (62.7%). Hypoglycemia was rare with linagliptin monotherapy/add-on to metformin (? 1%) and increased when linagliptin was added to metformin plus sulfonylurea (linagliptin, 17.9% vs. placebo, 8.3%). Conclusions Linagliptin was an effective, well-tolerated treatment in subjects with T2DM and insufficient glycemic control, both as monotherapy or added-on to metformin/metformin plus sulfonylurea. © 2013 Elsevier Inc.
  • Author:
    Inagaki N; Watada H; Murai M; Kagimura T; Gong Y; Patel S; Woerle H-J
    Title:
    Linagliptin provides effective, well-tolerated add-on therapy to pre-existing oral antidiabetic therapy over 1year in Japanese patients with type 2 diabetes
    Source:
    Diabetes Obes Metab Article in Press (2013)
    Abstract:
    Aims: To evaluate the long-term safety and efficacy of linagliptin as add-on therapy to one approved oral antidiabetic drug (OAD) in Japanese patients with type 2 diabetes mellitus and insufficient glycaemic control. Methods: This 52-week, multicentre, open-label, parallel-group study evaluated once-daily linagliptin 5mg as add-on therapy to one OAD [biguanide, glinide, glitazone, sulphonylurea (SU) or ?-glucosidase inhibitors (A-GI)] in 618 patients. After a 2-week run-in, patients on SU or A-GI were randomized to either linagliptin (once daily, 5mg) or metformin (twice or thrice daily, up to 2250mg/day) as add-on therapy. Patients receiving the other OADs received linagliptin add-on therapy (non-randomized). Results: Adverse events were mostly mild or moderate, and rates were similar across all groups. Hypoglycaemic events were rare, except in the SU group. Overall, 26 (5.8%) hypoglycaemic events were reported in patients receiving linagliptin (non-randomized). Hypoglycaemic events were similar for linagliptin and metformin added to A-GI (1/61 vs. 2/61, respectively) or SU (17/124 vs. 10/63, respectively). Significant reductions in glycated haemoglobin (HbA1c) levels (between -0.7 and -0.9%) occurred throughout the study period for the background therapy groups that received linagliptin (baseline HbA1c 7.9-8.1%). The decline in HbA1c levels was indistinguishable between linagliptin and metformin groups when administered as add-on therapy to A-GI or SU. Conclusions: Once-daily linagliptin showed safety and tolerability over 1year and provided effective add-on therapy leading to significant HbA1c reductions, similar to metformin, over 52weeks in Japanese patients. © 2013 John Wiley & Sons Ltd.
  • Author:
    Müller H-P; Niessen H G; Kaulisch T; Ludolph A C; Kassubek J; Stiller D
    Title:
    MRI allows for longitudinal quantitative analysis of body fat composition in rats: An analysis of sibutramine-associated changes at the group level
    Source:
    Magn Reson Imaging Article in press (2013)
    Abstract:
    Purpose: Body fat distribution changes are associated with multiple alterations in metabolism. Therefore, the assessment of body fat compartments by MRI in animal models is a promising approach to obesity research. Standard T1-weighted (T1w) whole body MRI was used here to quantify different effects in the subcutaneous and visceral fat compartments in rats under treatment with an anorexiant. Materials and methods: Twenty rats on a high caloric diet were investigated by the identical MRI protocol at baseline and after seven weeks. Ten rats received a treatment with sibutramine, 10 rats served as vehicle control group. To longitudinally assess body fat components, MRI analysis was used with two approaches: 2D slicewise graphic analysis (SGA) was compared with an automated 3D analysis algorithm (3DA). Results: At the group level, fat volume differences showed a longitudinal increase of subcutaneous and visceral fat volumes for the control group, whereas the sibutramine group showed stable subcutaneous fat volumes and decrease in visceral fat volumes. SGA and 3DA volume determination showed significant correlations for subcutaneous fat volume (C = 0.85, p < 0.001), visceral fat volume (C = 0.87, p < 0.001), and total fat volume (C = 0.90, p < 0.001). Conclusion: It could be demonstrated that computer-based analysis of T1w MRI could be used to longitudinally assess changes in body fat compartments in rats at the group level. In detail, it was possible to investigate the effect of sibutramine separate on the fat compartments in rats. © 2013 Elsevier Inc. All rights reserved.
  • Author:
    Chen S Y; Lee Y C; Alas V; Greene M; Brixner D
    Title:
    Outcomes associated with concordance of oral antidiabetic drug treatments to prescribing information in patients with type 2 diabetes mellitus and chronic kidney disease
    Source:
    J. Med. Econ.
    Source:
    J Med Econ 16 (5), 586-595 (2013)
    Abstract:
    Objectives: This retrospective study aims to examine the association between prescribing information (PI)-concordant oral antidiabetic drug (OAD) treatment and clinical and economic outcomes in patients with type 2 diabetes mellitus and stages 3-5 chronic kidney disease (CKD). Methods: The study used a large, national administrative claims database with laboratory findings to identify patients with a diagnosis of diabetes and indication of stages 3-5 CKD (first observed indication as the index date) between 1/1/2005 and 30/06/2009. OADs prescribed during 6 months following the index date (baseline period) were evaluated and patients were considered non-PI-concordant if any did not meet the recommendations regarding patients with renal impairment. Glycemic control and measures of healthcare costs (standardized to 2010 US dollars using the Consumer Price Index) and resource utilization were assessed during the 12 months following the baseline period. Severe hypoglycemic events were assessed after the baseline period until lost to follow-up. Regression analyses were performed after adjusting for demographic and clinical characteristics. Results: Among the 3300 patients included in the study, 2454 (74.4%) were non-PI-concordant. The non-PI-concordant patients had higher risk of severe hypoglycemic events identified in all settings (HR=1.35, 95% CI: 1.10-1.67) and events identified in inpatient hospital setting (HR=2.51, 95% CI: 1.49-4.22), were more likely to have inpatient hospital admissions (OR=1.27, 95% CI: 1.02-1.57), and were less likely to have glycemic control (OR=0.56, 95% CI: 0.44-0.71). Annual diabetes-related cost was $1638 higher in the non-PI-concordant cohort (p=0.0048). Limitation: The retrospective cohort design does not allow for conclusions to be drawn on the causal effect of PI-concordant use based on the associations observed. Conclusion: Our findings suggest PI-concordant treatment to be associated with better clinical and diabetes-associated economic outcomes. Future research is warranted to confirm the associations found in this study. © 2013 Informa UK Ltd All rights reserved: reproduction in whole or part not permitted.
  • Author:
    Mollnau H; Oelze M; Zinßius E; hausding M; Wu Z; Knorr M; Ghaemi Kerahrodi J; Kröller-Schön S; Jansen T; Teutsch C; Foster C; Li H; Wenzel P; Schulz E; Münzel T; Daiber A
    Title:
    Effects of telmisartan or amlodipine monotherapy versus telmisartan/amlodipine combination therapy on vascular dysfunction and oxidative stress in diabetic rats
    Source:
    Naunyn Schmiedebergs Arch Pharmacol 386 (5), 405-419 (2013)
    Abstract:
    Our previous studies identified potent antioxidant effects and improvement of vascular function by telmisartan therapy in experimental diabetes and nitrate tolerance. The present study compared the beneficial effects of single telmisartan or amlodipine versus telmisartan/amlodipine combination therapy (T+A) in streptozotocin (STZ)-induced type 1 diabetic rats. Male Wistar rats were injected once with STZ (60 mg/kg, i.v.) and 1 week later the drugs (telmisartan, amlodipine, or T+A) were administrated orally by a special diet (2.5-5 mg kg-1 day-1) for another 7 weeks. We only observed a marginal beneficial on-top effect of T+A therapy over the single drug regimen that was most evident in the improvement of endothelial function (acetylcholine response) and less pronounced in the reduction of whole blood, vascular and cardiac oxidative stress (blood leukocyte oxidative burst, aortic dihydroethidine and 3-nitrotyrosine staining, as well as cardiac NADPH oxidase activity and uncoupling of endothelial nitric oxide synthase) in diabetic rats. These effects on oxidative stress parameters were paralleled by those on the expression pattern of NADPH oxidase and nitric oxide synthase isoforms. In addition, development of mild hypotension in the T+A-treated rats was observed. Reasons for this moderate synergistic effect of T+A therapy may be related to the potent beneficial effects of telmisartan alone and the fact that amlodipine and telmisartan share similar pathways to improve endothelial function. Moreover, hypotension in the T+A-treated rats could partially antagonize the beneficial additive effects by counter-regulatory mechanisms (e.g., activation of the renin-angiotensin-aldosterone system). © 2013 Springer-Verlag Berlin Heidelberg.
  • Author:
    Zhu D; Bays H; Gao P; Mattheus M; Voelker B; Ruilope L M
    Title:
    Efficacy and tolerability of a single-pill combination of telmisartan 80 mg and hydrochlorothiazide 25 mg according to age, gender, race, hypertension severity, and previous antihypertensive use: Planned analyses of a randomized trial
    Source:
    Integr Blood Press Control 6 (2) (2013)
    Abstract:
    Background: The purpose of this work was to describe the efficacy and safety of a telmisartan 80 mg + hydrochlorothiazide 25 mg (T80/H25) single-pill combination therapy in patients with moderate-severe hypertension (mean seated trough cuff systolic blood pressure [BP] ? 160 mmHg and diastolic BP ? 100 mmHg) in specific patient subpopulations. Methods: This was a planned analysis of a double-blind, multicenter, parallel-group trial that demonstrated the superiority of a single-pill combination of T80/H25 versus T80 monotherapy in terms of systolic BP change from baseline to week 7. Subpopulations included older (aged ? 65 years) versus younger, gender, race, hypertension severity, and prior antihypertensive therapy. Endpoints were change from baseline in mean seated trough cuff systolic and diastolic BP, proportion of patients achieving their BP goal (systolic/diastolic BP < 140/90 mmHg), and proportion of patients attaining systolic BP reductions of > 30 mmHg and > 40 mmHg. Results: Across all subgroups, the T80/H25 single-pill combination provided consistently greater systolic and diastolic BP reductions than T80 and more patients had systolic BP reductions of > 30 mmHg. In the T80 and T80/H25 groups, BP control was achieved in 34.1% and 48.8% of men, 35.5% and 62.7% of women, 34.5% and 56.6% of Asians, 22.6% and 38.6% of blacks, 36.7% and 57.8% of whites, 36.9% and 57.5% of patients < 65 years, 29.3% and 49.3% ?65 years, 44.2% and 66.2% of those with grade 2 hypertension, 20.4% and 39.4% of those with grade 3 hypertension, 38.9% and 53.2% of previously untreated patients, 38.1% and 62.5% of patients previously treated with one antihypertensive, and 29.7% and 48.9% of patients previously treated with two or more antihypertensive agents respectively. Treatment was generally well tolerated across the patient subgroups. Conclusion: The T80/H25 single-pill combination provides consistent BP reductions and higher goal attainment rates versus T80 across a range of hypertensive patient subgroups, which are likely to have a positive impact on patients' cardiovascular risk. © 2013 Zhu et al, publisher and licensee Dove Medical Press Ltd.
  • Author:
    Macha S; Sennewald R; Rose P; Schoene K; Pinnetti S; Woerle H J; Broedl U C
    Title:
    Lack of Clinically Relevant Drug-Drug Interaction Between Empagliflozin, a Sodium Glucose Cotransporter 2 Inhibitor, and Verapamil, Ramipril, or Digoxin in Healthy Volunteers
    Source:
    Clin Ther 35 (3), 226-235 (2013)
    Abstract:
    Background: Empagliflozin is a sodium glucose cotransporter 2 inhibitor in clinical development as a treatment for type 2 diabetes mellitus. Objective: The goal of this study was to investigate potential drug-drug interactions between empagliflozin and verapamil, ramipril, and digoxin in healthy volunteers. Methods: The potential drug-drug interactions were evaluated in 3 separate trials. In the first study, 16 subjects were randomized to receive single-dose empagliflozin 25 mg alone or single-dose empagliflozin 25 mg with single-dose verapamil 120 mg. In the second study, 23 subjects were randomized to receive empagliflozin 25 mg once daily (QD) for 5 days, ramipril (2.5 mg on day 1 then 5 mg QD on days 2-5) for 5 days or empagliflozin 25 mg with ramipril (2.5 mg on day 1 then 5 mg QD on days 2-5) for 5 days. In the third study, 20 subjects were randomized to receive single-dose digoxin 0.5 mg alone or empagliflozin 25 mg QD for 8 days with single-dose digoxin 0.5 mg on day 5. Results: Exposure of empagliflozin was not affected by coadministration with verapamil (AUC0-?: geometric mean ratio [GMR], 102.95%; 90% CI, 98.87-107.20; Cmax: GMR, 92.39%; 90% CI, 85.38-99.97) or ramipril (AUC over a uniform dosing interval ? at steady state [AUC?,ss]: GMR, 96.55%; 90% CI, 93.05-100.18; Cmax at steady state [Cmax,ss]: GMR, 104.47%; 90% CI 97.65-111.77). Empagliflozin had no clinically relevant effect on exposure of ramipril (AUC?,ss: GMR, 108.14%; 90% CI 100.51-116.35; Cmax,ss: GMR, 103.61%; 90% CI, 89.73-119.64) or its active metabolite ramiprilat (AUC?,ss: GMR, 98.67%; 90% CI, 96.00-101.42; Cmax,ss: GMR, 98.29%; 90% CI, 92.67-104.25). Coadministration of empagliflozin had no clinically meaningful effect on digoxin AUC0-? (GMR, 106.11%; 90% CI, 96.71-116.41); however, a slight increase in Cmax was observed that was not considered clinically relevant (GMR, 113.94%; 90% CI, 99.33-130.70). All treatments were well tolerated. There were no serious adverse events or adverse events leading to discontinuation in any of the studies. Conclusions: No dose adjustment of empagliflozin is required when coadministered with ramipril or verapamil, and no dose adjustment of digoxin or ramipril is required when coadministered with empagliflozin. ClinicalTrials.gov identifiers: NCT01306175 (digoxin), NCT01276301 (verapamil), and NCT01284621 (ramipril). © 2013 Elsevier HS Journals, Inc.
  • Author:
    Ebner T; Schänzle G; Weber W; Sent U; Elliot J
    Title:
    In vitro glucuronidation of the angiotensin II receptor antagonist telmisartan in the cat: A comparison with other species
    Source:
    J Vet Pharmacol Ther 36 (2), 154-160 (2013)
    Abstract:
    Glucuronidation of telmisartan comprises nearly its entire metabolic clearance in several mammalian species including human. However, data were lacking for the cat, a species noted for its inability to glucuronidate some drugs. Therefore, the glucuronidation of telmisartan was investigated using feline liver microsomes and compared to liver microsomes of rats, dogs, and human, intestinal human microsomes and cell lines expressing human UDP-glucuronosyltransferases (UGT). Incubation of telmisartan with cat liver microsomes readily yielded telmisartan glucuronide, and pooled (N=3 for each gender) cat liver microsomes even showed the highest glucuronidation rate (cat&gt;dog&gt;&gt;human&gt;rat). Michaelis Menten kinetics were observed with Km of 7.5 and 10?m and Vmax of 3.9 and 3.3nmol/min/mg for male and female cats, respectively. Confirming the in vitro data, telmisartan glucuronide was detected as the major circulating metabolite in cat plasma. To elucidate which UGT enzymes are involved, telmisartan was incubated with cell lines expressing human UGTs. The highest glucuronidation activity was observed for UGT1A8, UGT1A7, and UGT1A9. In conclusion, telmisartan was effectively glucuronidated in cats. Defects of the UGT1A6 gene in cats do not affect the glucuronidation of telmisartan as it is not a substrate of human UGT1A6. © 2012 Blackwell Publishing Ltd.
  • Author:
    Jain R; Jain D; Liu Q; Bartosinska B; Wang J; Schumann D; Kauschke S G; Eickelmann P; Piemonti L; Gray N S; Lammert E
    Title:
    Pharmacological inhibition of Eph receptors enhances glucose-stimulated insulin secretion from mouse and human pancreatic islets
    Source:
    Diabetologia, 1-6 Article in Press (2013)
    Abstract:
    Aims/hypothesis: Type 2 diabetes is characterised by impaired glucose-stimulated insulin secretion (GSIS) from pancreatic islets. Since erythropoietin-producing hepatoma (Eph)-ephrin bidirectional signalling fine-tunes GSIS from pancreatic beta cells, we investigated Eph receptor tyrosine kinases (RTK) as potential drug targets for selectively increasing GSIS. Methods: Insulin secretion assays were carried out using mouse and human pancreatic islets as well as mouse insulinoma (MIN6) cells in the presence or absence of two Eph RTK inhibitors. Furthermore, the most potent inhibitor was injected into mice to evaluate its effects on glucose tolerance and plasma insulin levels. Results: We showed that the Eph RTK inhibitors selectively increased GSIS from MIN6 cells as well as mouse and human islets. Our results also showed that the insulin secretory effects of these compounds required Eph-ephrin signalling. Finally, pharmacological inhibition of Eph receptor signalling improved glucose tolerance in mice. Conclusions/interpretation: We showed for the first time that Eph RTKs represent targets for small molecules to selectively increase GSIS and improve glucose tolerance. © 2013 Springer-Verlag Berlin Heidelberg.
  • Author:
    Blech S; Laux R
    Title:
    Resolving the microcosmos of complex samples: UPLC/travelling wave ion mobility separation high resolution mass spectrometry for the analysis of in vivo drug metabolism studies
    Source:
    Int J Ion Mobil Spectrom 16 (1), 5-17 (2013)
    Abstract:
    In vivo drug metabolism studies with low concentrations of analytes and high matrix burden are challenging. Of special interest are 'first-in-man' studies in early stages of pharmaceutical development that do not use 14C labeled drug candidates. Beside conventional MS-fishing techniques which are biased towards known/expected metabolites and mass defect filtration procedures, this paper focuses on the untargeted/unbiased analysis of drug related compounds in complex matrices using two orthogonal separation techniques: UPLC and TWIMS. Standard sample material after oral administration of a drug compound to rats was investigated by UPLC/TWIMS in MSE acquisition mode using interlaced collision energies for the parallel detection of [M+H]+ parent ions and fragments. Due to the fragmentation after ion mobility separation in the transfer region of the Synapt G2-triwave device, [M+H]+ ion species are aligned with their related fragments by virtue of possessing the same retention time and drift time profile. Four dimensional data analysis of the continuum raw data was performed by automated peak picking and alignment within the MSE viewer software. As result, completely purified MS- and MS/MS-data of metabolites were extracted from raw mass data with high matrix burden and were used without compromise for structure elucidation. This analytical methodology is universally applicable for the unbiased/untargeted and robust analysis of any analyte of interest in complex matrices, including small molecules, peptides and proteins. The high quality data files can be used as data repositories for the purpose of retrospective analysis which is of particular interest for the long term process in drug development. © 2012 The Author(s).
  • Author:
    Ferrannini E; Seman L; Seewaldt-Becker E; Hantel S; Pinnetti S; Woerle J J
    Title:
    A Phase IIb, randomized, placebo-controlled study of the SGLT2 inhibitor empagliflozin in patients with type 2 diabetes
    Source:
    Diabetes Obes Metab Article in Press (2013)
    Abstract:
    Aim: This Phase IIb, randomized, double-blind, placebo-controlled trial evaluated the efficacy, safety, tolerability and pharmacokinetics of empagliflozin in patients with type 2 diabetes. Methods: Four hundred and eight patients (treatment-naïve or after a 4-week wash-out period) were randomized to receive empagliflozin 5, 10 or 25mg once daily, placebo or open-label metformin for 12weeks. The primary endpoint was change in haemoglobin A1c (HbA1c) after 12weeks. Results: After 12weeks' treatment, empagliflozin showed dose-dependent reductions in HbA1c from baseline [5mg: -0.4%, 10mg: -0.5%, 25mg: -0.6%; all doses p<0.0001 vs. placebo (+0.09%)]. Fasting plasma glucose (FPG) decreased with empagliflozin [5mg: -1.29mmol/l, 10mg: -1.61mmol/l, 25mg: -1.72mmol/l; all doses p<0.0001 vs. placebo (+0.04mmol/l)]. Body weight decreased in all empagliflozin groups (all doses p<0.001 vs. placebo). The incidence of adverse events (AEs) was similar in the placebo (32.9%) and empagliflozin (29.1%) groups. The most frequently reported AEs on empagliflozin were pollakiuria (3.3% vs. 0% for placebo), thirst (3.3% vs. 0% for placebo) and nasopharyngitis (2.0% vs. 1.2% for placebo). AEs consistent with urinary tract infections (UTIs) were reported in four (1.6%) patients on empagliflozin vs. one (1.2%) on placebo. Genital infections were reported in five (2%) patients on empagliflozin vs. 0% on placebo. No UTIs or genital infections led to premature discontinuation. Conclusions: In patients with type 2 diabetes, empagliflozin resulted in dose-dependent, clinically meaningful reductions in HbA1c and FPG, and reductions in body weight compared with placebo. Empagliflozin was well-tolerated with a favourable safety profile. © 2013 Blackwell Publishing Ltd.
  • Author:
    Mollnau H; Oelze M; Zinßius E; Hausding M; Wu Z; Knorr M; Ghaemi Kerahrodi J; Kröller-Schön S; Jansen T; Teutsch C; Foster C; Li H; Wenzel P; Schulz E; Münzel T; Daiber A
    Title:
    Effects of telmisartan or amlodipine monotherapy versus telmisartan/amlodipine combination therapy on vascular dysfunction and oxidative stress in diabetic rats
    Source:
    Naunyn-Schmiedebergs Arch Pharmacol, 1-15 Article in Press ( 2013)
    Abstract:
    Our previous studies identified potent antioxidant effects and improvement of vascular function by telmisartan therapy in experimental diabetes and nitrate tolerance. The present study compared the beneficial effects of single telmisartan or amlodipine versus telmisartan/amlodipine combination therapy (T+A) in streptozotocin (STZ)-induced type 1 diabetic rats. Male Wistar rats were injected once with STZ (60 mg/kg, i.v.) and 1 week later the drugs (telmisartan, amlodipine, or T+A) were administrated orally by a special diet (2.5-5 mg kg-1 day-1) for another 7 weeks. We only observed a marginal beneficial on-top effect of T+A therapy over the single drug regimen that was most evident in the improvement of endothelial function (acetylcholine response) and less pronounced in the reduction of whole blood, vascular and cardiac oxidative stress (blood leukocyte oxidative burst, aortic dihydroethidine and 3-nitrotyrosine staining, as well as cardiac NADPH oxidase activity and uncoupling of endothelial nitric oxide synthase) in diabetic rats. These effects on oxidative stress parameters were paralleled by those on the expression pattern of NADPH oxidase and nitric oxide synthase isoforms. In addition, development of mild hypotension in the T+A-treated rats was observed. Reasons for this moderate synergistic effect of T+A therapy may be related to the potent beneficial effects of telmisartan alone and the fact that amlodipine and telmisartan share similar pathways to improve endothelial function. Moreover, hypotension in the T+A-treated rats could partially antagonize the beneficial additive effects by counter-regulatory mechanisms (e.g., activation of the renin-angiotensin-aldosterone system). © 2013 Springer-Verlag Berlin Heidelberg.
  • Author:
    Yu H; Tweedie D
    Title:
    A Perspective on the contribution of metabolites to drug-drug interaction potential: The need to consider both circulating levels and inhibition potency
    Source:
    Drug Metab Dispos 41 (3), 536-540 (2013)
    Abstract:
    The 2012 drug-drug interaction (DDI) guidance from the European Medicines Agency (EMA) and the draft DDI guidance from the Food and Drug Administration (FDA) have proposed that metabolites present at <25% of the parent area under the time-concentration curve (AUC) (EMA and FDA) and <10% of the total drug-related exposure (EMA) should be investigated in vitro for their DDI potential. This commentary attempts to rationalize the clinically relevant levels of metabolite(s) that contribute to DDI by considering not only the abundance but also inhibition potency, physicochemical properties, and structural alerts of the metabolite. A decision tree is proposed for levels of metabolites that could trigger in vitro DDI assessment. When the parent is an inhibitor of cytochrome P450s (P450s), clinical DDI studies will assess the in vivo DDI effect of the combination of parent and metabolite(s). When the parent is not a P450 inhibitor, it is important to assess the inhibition potential of abundant metabolites in vitro. The proposal is to apply a default cutoff value of metabolite level which is 100% of the parent AUC. It is important to note that exceptions can occur, and different metabolite levels may be considered depending on the physiochemical properties of metabolites (e.g., increased lipophilicity) and whether the metabolite contains structural alerts for DDI (e.g., mechanism-based inhibition). A key objective of this commentary is to stimulate discussions among the scientific community on this important topic, so that appropriate in vitro metabolism studies are conducted on metabolites, to ensure the safety of drugs in development balanced with the desire to avoid creating unnecessary studies that will add little to no value in ensuring patient safety. Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics.
  • Author:
    Macha S; Rose P; Mattheus M; Pinnetti S; Woerle H J
    Title:
    Lack of drug-drug interaction between empagliflozin, a sodium glucose cotransporter 2 inhibitor, and warfarin in healthy volunteers
    Source:
    Diabetes Obes Metab 15 (4), 316-323 (2013)
    Abstract:
    Aim: To investigate potential drug-drug interactions between empagliflozin and warfarin. Methods: Healthy subjects (n=18) received empagliflozin 25mg qd for 5days (treatment A), followed by empagliflozin 25mg qd for 7days (days 6-12) with a single 25mg dose of warfarin on day 6 (treatment B), and a single 25mg dose of warfarin alone (treatment C), in an open-label, crossover study. Subjects received treatments in sequence AB_C or C_AB with a washout period of ?14days between AB and C or C and AB. Results: Warfarin had no effect on empagliflozin area under concentration-time curve or maximum plasma concentration at steady-state (AUC?,ss or Cmax,ss): geometric mean ratios (GMRs) (90% confidence intervals [CI]) were 100.89% (96.86, 105.10) and 100.64% (89.79, 112.80), respectively. Empagliflozin had no effect on AUC from 0h to infinity (AUC0-?) or Cmax for R- or S-warfarin (GMRs [90% CI] for AUC0-?: 98.49% [95.29, 101.80] and 95.88% [93.40, 98.43], respectively; Cmax: 97.89% [91.12, 105.15] and 98.88% [91.84, 106.47], respectively). Empagliflozin had no clinically relevant effects on warfarin's anticoagulant activity (international normalised ratio [INR]) (GMR [95% CI] for peak INR: 0.87 [0.73, 1.04]; area under the effect-time curve from 0 to 168h: 0.88 [0.79, 0.98]. No drug-related adverse events were reported for empagliflozin after monotherapy or combined administration. The combination of empagliflozin and warfarin was well tolerated. Conclusions: No drug-drug interactions were observed between empagliflozin and warfarin, indicating that empagliflozin and warfarin can be co-administered without dosage adjustments of either drug. © 2012 Blackwell Publishing Ltd.
  • Author:
    Araki E; Kawamori R; Inagaki N; Watada H; Hayashi N; Horie Y; Sarashina A; Thiemann S; von Eynatten M; Dugi K; Woerle H-J
    Title:
    Long-term safety of linagliptin monotherapy in Japanese patients with type 2 diabetes
    Source:
    Diabetes Obes Metab 15 (4), 364-371 (2013)
    Abstract:
    Aims: In a phase III study conducted among Japanese patients with type 2 diabetes mellitus (T2DM), linagliptin 5 and 10mg showed clinically meaningful improvements in glycaemic parameters after 12 and 26weeks compared with placebo and voglibose, respectively. This extension study assessed long-term tolerability of linagliptin over 52weeks. Methods: Japanese patients with T2DM who completed either phase of a 12-week/26-week study comparing linagliptin monotherapy with placebo or voglibose were eligible to enrol. In the extension study, the comparator groups switched to linagliptin 5 or 10mg, while the linagliptin groups maintained dosage. Results: In all, 540 patients received at least one dose of linagliptin 5 or 10mg and 494 completed the extension. Long-term treatment with linagliptin was well tolerated; adverse events (AEs) of special interest and serious AEs occurred in small percentages of patients. Drug-related AEs occurred in 10.2 and 10.6% of patients in the linagliptin 5- and 10-mg groups, respectively, and discontinuations due to drug-related AEs occurred in 1.1 and 0.7%, respectively. Only one (0.4%) patient in each dose group experienced investigator-defined hypoglycaemia during the treatment period (both events were non-severe). Body weight was not clinically altered in either group. The glycated haemoglobin A1c profiles over time were similar with linagliptin 5 and 10mg. Conclusions: These findings provide evidence for the safety and tolerability of oral linagliptin at either 5 or 10mg for up to 52weeks for the treatment of Japanese patients with T2DM, without clinically relevant increase in the risk of hypoglycaemia or weight gain. © 2012 Blackwell Publishing Ltd.
  • Author:
    Barnett A H; Patel S; Harper R; Toorawa R; Thiemann S; von Eynatten M; Woerle H-J
    Title:
    Linagliptin monotherapy in type 2 diabetes patients for whom metformin is inappropriate: An 18-week randomized, double-blind, placebo-controlled phase iii trial with a 34-week active-controlled extension
    Source:
    Diabetes Obes Metab 14 (12), 1145-1154 (2012)
    Abstract:
    Aims: To investigate the efficacy and safety of linagliptin, a dipeptidyl peptidase-4 inhibitor, in type 2 diabetes mellitus (T2DM) patients for whom metformin was inappropriate. Methods: This 1-year double-blind study (ClinicalTrials.gov, NCT00740051) enrolled T2DM patients with inadequate glycaemic control, treatment-näive [glycated haemoglobin (HbA1c) 7.0-10.0%] or previously treated with one oral antidiabetes drug (HbA1c 6.5-9.0% before washout), ineligible for metformin because of contraindications (e.g. renal impairment) or previous intolerable side effects. Patients were randomized to monotherapy with linagliptin 5 mg once daily (n=151) or placebo (n=76) for 18weeks, after which placebo patients switched to glimepiride 1-4 mg once daily and treatments continued for another 34weeks. The primary endpoint was change from baseline in HbA1c after 18weeks (full-analysis set, last observation carried forward). Results: At week 18, adjusted mean difference in change from baseline HbA1c (8.1%) was -0.60% (95% confidence interval -0.88, -0.32; p<0.0001) (-0.39% with linagliptin, +0.21% with placebo). At week 52, mean HbA1c was decreased from baseline in both groups [linagliptin: -0.44%; placebo/glimepiride: -0.72% (observed cases)]. Adverse events occurred in 40.4 and 48.7% of linagliptin and placebo patients, respectively, during the initial 18 weeks. During the 34-week extension, patients receiving linagliptin experienced less hypoglycaemia (2.2% vs. 7.8%) and no weight gain (mean change from baseline of -0.2 and +1.3 kg, respectively) compared with glimepiride patients. Conclusions: In T2DM patients for whom metformin was inappropriate, linagliptin improved glycaemic control and was well tolerated, with less hypoglycaemia and relative weight loss compared with glimepiride. © 2012 Blackwell Publishing Ltd.
  • Author:
    Del Prato S; Taskinen M-R; Owens D R; von Eynatten M; Emser A; Gong Y; Chiavetta S; Patel S; Woerle H-J
    Title:
    Efficacy and safety of linagliptin in subjects with type 2 diabetes mellitus and poor glycemic control: Pooled analysis of data from three placebo-controlled phase III trials
    Source:
    J Diabetes Complications Article in Press (2013)
    Abstract:
    Aims: To evaluate the efficacy/safety of dipeptidyl peptidase-4 inhibitor, linagliptin, in subjects with insufficiently controlled type 2 diabetes mellitus (T2DM), and factors influencing treatment response. Methods: Pooled analysis of data from 2258 subjects in three 24-week phase III, randomized, placebo-controlled, parallel-group studies, who received oral linagliptin (5 mg/day) or placebo as monotherapy, added-on to metformin, or added-on to metformin plus sulfonylurea was performed. Results: Among 388 subjects with HbA1c ? 9.0%, adjusted mean baseline HbA1c (9.4% both groups) declined to 8.3% in linagliptin group and 9.1% in placebo group at 24 weeks (P < .0001) and adjusted mean change from baseline was 1.2% (vs. 0.4%, placebo). Linagliptin significantly lowered fasting plasma glucose levels vs. placebo (1.6 mmol/l vs. 0.4 mmol/l); treatment difference, 1.1 mmol/l (95% CI, - 1.7 to - 0.5). Treatment and washout of previous oral antidiabetes drugs were the only factors to independently affect HbA1c change at week 24. Adverse event rates were similar for linagliptin (61.9%) and placebo (62.7%). Hypoglycemia was rare with linagliptin monotherapy/add-on to metformin (? 1%) and increased when linagliptin was added to metformin plus sulfonylurea (linagliptin, 17.9% vs. placebo, 8.3%). Conclusions: Linagliptin was an effective, well-tolerated treatment in subjects with T2DM and insufficient glycemic control, both as monotherapy or added-on to metformin/metformin plus sulfonylurea. © 2012 Elsevier Inc. All rights reserved.
  • Author:
    McGill J B; Sloan L; Newman J; Patel S; Sauce C; Von Eynatten M; Woerle H-J
    Title:
    Long-term efficacy and safety of linagliptin in patients with type 2 diabetes and severe renal impairment: A 1-year, randomized, double-blind, placebo-controlled study
    Source:
    Diabetes Care 36 (2), 237-244 (2013)
    Abstract:
    OBJECTIVE-This placebo-controlled study assessed long-term efficacy and safety of the dipeptidyl peptidase-4 inhibitor linagliptin in patients with type 2 diabetes and severe renal impairment (RI). RESEARCHDESIGN AND METHODS-Inthis1-year,double-blind study,133 patients with type 2 diabetes (HbA1c 7.0-10.0%) and severe RI (estimated glomerular filtration rate [eGFR] &lt;30 mL/min/1.73 m2) at screening were randomized to linagliptin 5 mg (n = 68) or placebo (n = 65) once daily, added to existing background therapy. The primary efficacy end point was HbA1c change from baseline to week 12. Efficacy and safety end points were assessed after 1 year. RESULTS-At week 12, adjusted mean HbA1c decreased by -0.76% with linagliptin and -0.15% with placebo (treatment difference, -0.60%; 95% CI -0.89 to -0.31; P &lt; 0.0001). HbA1c improvements were sustained with linagliptin (-0.71%) over placebo (0.01%) at 1 year (treatment difference -0.72%, 21.03 to -0.41; P &lt; 0.0001). Mean insulin doses decreased by 26.2 units with linagliptin and -0.3 units with placebo. Overall adverse event incidence was similar over 1 year (94.1 vs. 92.3%). Incidence of severe hypoglycemia with linagliptin and placebo was comparably low (three patients per group). Linagliptin and placebo had little effect on renal function (median change in eGFR, -0.8 vs. -2.2 mL/min/1.73 m2), and no drug-related renal failure occurred. CONCLUSIONS-In patients with type 2 diabetes and severe RI, linagliptin provided clinically meaningful improvements in glycemic control with very low risk of severe hypoglycemia, stable body weight, and no cases of drug-related renal failure. The potential for linagliptin to spare insulin and provide long-term renal safety warrants further investigations.© 2013 by the American Diabetes Association.
  • Author:
    Heise T; Seewaldt-Becker E; Macha S; Hantel S; Pinnetti S; Seman L; Woerle H J
    Title:
    Safety, tolerability, pharmacokinetics and pharmacodynamics following 4 weeks' treatment with empagliflozin once daily in patients with type 2 diabetes
    Source:
    Diabetes Obes. Metab. Article in Press (2013)
    Abstract:
    Aim: To investigate the safety, tolerability, pharmacokinetics and pharmacodynamics of empagliflozin in patients with type 2 diabetes following oral administration of 10, 25 or 100 mg doses once daily over 28 days. Methods: A total of 78 patients were assigned to empagliflozin 10 mg (n=16), 25 mg (n=16) or 100 mg (n=30) or placebo (n=16) for 28 days. Assessments included adverse events (AEs) and pharmacokinetic and pharmacodynamic endpoints. Results: Empagliflozin exposure increased dose-proportionally over the dose range 10-100 mg and showed linear pharmacokinetics with respect to time. Urinary glucose excretion (UGE) increased from baseline to day 1 by 74, 90 and 81 g with empagliflozin 10, 25 and 100 mg, respectively. The increases in UGE were maintained over 28 days with multiple dosing. Virtually no change in UGE was observed in the placebo group. Significant reductions from baseline in mean daily plasma glucose and fasting plasma glucose were observed with empagliflozin compared with placebo. The incidence of AEs was similar in the empagliflozin and placebo groups (50.0, 56.3 and 66.7% with empagliflozin rising doses and 62.5% with placebo). The most frequently reported AEs were pollakiuria (10.3%), nasopharyngitis (9.0%), constipation (9.0%) and headache (7.7%). Conclusions: Oral administration of empagliflozin at doses of 10, 25 or 100 mg once daily over 28 days resulted in significant increases in UGE and reductions in blood glucose compared with placebo, and were well tolerated in patients with type 2 diabetes. © 2013 Blackwell Publishing Ltd
  • Author:
    Ishiguro N; Shimuzu H; Kishimoto W; Ebner T; Schaefer O
    Title:
    Evaluation and prediction of potential drug-drug interactions of linagliptin using in vitro cell culture methods.
    Source:
    Drug Metab Dispos 41 (1), 149-158 (2013)
    Abstract:
    Linagliptin is a highly potent dipeptidyl peptidase-4 (DPP-4) inhibitor approved for the treatment of type 2 diabetes. Unlike other DPP-4 inhibitors, linagliptin is cleared primarily via the bile and gut. We used a panel of stably and transiently transfected cell lines to elucidate the carrier-mediated transport processes that are involved in linagliptin disposition in vivo and to assess the potential for drug-drug interactions (DDIs). Our results demonstrate that linagliptin is a substrate of organic cation transporter 2 (OCT2) and P-glycoprotein (P-gp) but not of organic anion-transporting polypeptide 1B1 and 1B3; organic anion transporter 1, 3, and 4; OCT1; or organic cation/carnitine transporter 1 and 2, suggesting that OCT2 and P-gp play a role in the disposition of linagliptin in vivo. Linagliptin inhibits transcellular transport of digoxin by P-gp with an apparent IC50 of 66.1 ?M, but it did not inhibit activity of multidrug resistance-associated protein 2 and breast cancer resistance protein as represented by transport of probe substrate into membrane vesicles from respective transporter-expressing cells. In addition, the inhibitory effect of linagliptin on major solute carrier transporter isoforms was investigated. Linagliptin showed inhibitory potency against only OCT1 and OCT2 out of all major solute carrier transporter isoforms examined, and those inhibition potencies, evaluated using three different in vitro probe substrates, were substrate-specific. Considering the low therapeutic plasma concentration of linagliptin, our data clearly suggest a very low risk for transporter-mediated DDIs with comedications in clinical practice. Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics.
  • Author:
    Rauch T; Graefe-Mody U; Deacon CF; Ring A; Holst JJ; Woerle H-J; Dugi KA; Heise T
    Title:
    Linagliptin increase incretin levels, lowers glucagon and improves glycemic control in type 2 diabetes melitus.
    Source:
    Diabetes Ther 3 (1), 1-14 (2012)
    Abstract:
    Introduction: Linagliptin is a xanthine-based dipeptidyl peptidase (DPP)-4 inhibitor that is now available in numerous countries worldwide for the treatment of type 2 diabetes mellitus (T2DM). The aim of this study was to evaluate further the mechanisms underlying the improvements in glycemic control observed with linagliptin. The effects of linagliptin on DPP-4, pharmacodynamic parameters, and glycemic control versus placebo were assessed in patients with inadequately controlled T2DM. Methods: Patients in this phase 2a, multicenter, randomized, double-blind, placebo-controlled study received placebo (n = 40) or linagliptin 5mg (n = 40). Sitagliptin 100 mg (n = 41) once daily for 4 weeks was included for exploratory purposes. Primary endpoints for linagliptinversus placebo: change from baseline to day 28 in 24-h weighted mean glucose (WMG) and intact glucagon-like peptide (GLP)-1 area under the time-effect curve between 0 and 2 h (AUECO-2h) following meal tolerance test on day 28. Results: Linagliptin increased intact GLP-1 AUECO-2h (+18.1 pmol/h/L) and lowered 24-h WMG (-1.1 mmol/L) versus placebo (both P\0.0001) after 28 days. Intact glucosedependent insulinotropic polypeptide increased in line with GLP-1 (+91.4 pmol/h/L increase vs. placebo; P\0.0001). Glycated hemoglobin (-0.22%; P = 0.0021), fasting plasma glucose (-0.6 mnnol/L; P = 0.0283), and glucose (AUECO-3h) (-5.9 mmol/h/L; P\0.0001) improved significantly with linagliptin versus placebo. Most adverse events were mild; hypoglycemia or serious adverse events were not reported. Sustained DPP-4 inhibition (C80%) throughout the treatment period was accompanied by significant reductions in glucagon starting at day 1 of linagliptin administration. Conclusion: Linagliptin was well tolerated and effectively inhibited plasma DPP-4 activity in patients with T2DM, producing immediate improvements in incretin levels, glucagon suppression, and glycemic control that were maintained throughout the study period. © The Author(s) 2012.
  • Author:
    Catchpole B; Adams JP; Holder AL; Short AD; Ollier WER; Kennedy LJ
    Title:
    Genetics of canine diabetes melitus: Are the diabetes susceptibility genes identified in humans involved in breed susceptibility to diabetes melitus in dogs?
    Source:
    Vet J (Lond) 195 (2), 139-147 (2013)
    Abstract:
    Diabetes mellitus is a common endocrinopathy in companion animals, characterised by hyperglycaemia, glycosuria and weight loss, resulting from an absolute or relative deficiency in the pancreatic hormone insulin. There are breed differences in susceptibility to diabetes mellitus in dogs, with the Samoyed breed being overrepresented, while Boxers are relatively absent in the UK population of diabetic dogs, suggesting that genetic factors play an important role in determining susceptibility to the disease. A number of genes, linked with susceptibility to diabetes mellitus in humans, are associated with an increased risk of diabetes mellitus in dogs, some of which appear to be relatively breed-specific. Diabetes mellitus in dogs has been associated with major histocompatibility complex (MHC) class II genes (dog leucocyte antigen; DLA), with similar haplotypes and genotypes being identified in the most susceptible breeds. A region containing a variable number of tandem repeats (VNTR) and several polymorphisms have been identified in the canine insulin gene, with some alleles associated with susceptibility or resistance to diabetes mellitus in a breed-specific manner. Polymorphisms in the canine CTLA4 promoter and in other immune response genes are associated with susceptibility to diabetes mellitus in a number of pedigree breeds. Genome wide association studies are currently underway that should shed further light on the genetic factors responsible for the breed profile seen in the diabetic dog population.
  • Author:
    Brambillasca S; Altkrueger A; Colombo SF; Friederich A; Eickelmann P; Mark M; Borgese N; Solimena M
    Title:
    CDK5 regulatory subunit-associated protein 1-like 1 (CDKAL1) is a tail anchored protein in the endoplasmic reticulum (ER) insulinoma cells.
    Source:
    J Biol Chem 287 (50), 41808-41819 (2012)
    Abstract:
    Genome-wide association studies have led to the identification of numerous susceptibility genes for type 2 diabetes. Among them is Cdkal1, which is associated with reduced ?-cell function and insulin release. Recently, CDKAL1 has been shown to be a methylthiotransferase that modifies tRNA Lys to enhance translational fidelity of transcripts, including the one encoding proinsulin. Here, we report that out of several CDKAL1 isoforms deposited in public databases, only isoform 1, which migrates as a 61-kDa protein by SDS-PAGE, is expressed in human islets and pancreatic insulinoma INS-1 and MIN6 cells. We show that CDKAL1 is a novel member of the tail-anchored protein family and exploits the TCR40/Get3-assisted pathway for insertion of its C-terminal transmembrane domain into the endoplasmic reticulum. Using endo-beta-N-acetylglucosaminidase H and peptide:N-glycosidase F sensitivity assays on CDKAL1 constructs carrying an N-glycosylation site within the luminal domain, we further established that CDKAL1 is an endoplasmic reticulum-resident protein. Moreover, we observed that silencing CDKAL1 in INS-1 cells reduces the expression of secretory granule proteins prochromogranin A and proICA512/ICA512-TMF, in addition to proinsulin and insulin. This correlated with reduced glucose-stimulated insulin secretion. Taken together, our findings provide new insight into the role of CDKAL1 in insulin-producing cells and help to understand its involvement in the pathogenesis of diabetes. © 2012 by The American Society for Biochemistry and Molecular Biology Inc.
  • Author:
    Macha S; Rose P; Mattheus M; Pinnetti S; Woerle HJ
    Title:
    Lack of drug-drug interaction between empagliflozin, a sodium glucose cotransporter 2 inhibitor, and warfarin in healthy volunteers.
    Source:
    Diabetes, Obes Metab Article in Press (2012)
  • Author:
    Araki E; Kawamori R; Inagaki N; Watada H; Hayashi N; Horie Y; Sarashina A; Thiemann S; von Eynatten M; Dugi K; Woerle H-J
    Title:
    Long-term safety of linagliptin monotherapy in Japanese patients with type 2 diabetes.
    Source:
    Diabetes, Obes Metab Article in Press (2012)
  • Author:
    Friedrich C; Shi X; Zeng P; Ring A; Woerle H-J; Patel S
    Title:
    Pharmacokinetics of single and multiple oral doses of 5 mg linagliptn in healthy Chinese volunteers.
    Source:
    Int J Clin Pharmacol Ther 50 (12), 889-895 (2012)
  • Author:
    Thrasher J; Daniels K; Patel S; Whettekey J
    Title:
    Black/African American patients with type 2 diabetes melitus: Study design and baseline patient characteristics from a randomized clinical trial of linagliptin.
    Source:
    Expert Opin Pharmacother 13 (17), 2443-2452 (2012)
  • Author:
    Gomis R; Owens DR; Taskinen M-R; Del Prato S; Patel S; Pivovarova A; Schlosser A; Woerle H-J
    Title:
    Long-term safety and efficacy of linagliptin as monotherapy or in combination with other oral glucose-lowering agents in 2121 subjects with type 2 diabetes: Up to 2 years exposure in 24-week phase II trials followed by a 78-week open-label extension.
    Source:
    Int J Clin Pract 66 (8), 731-740 (2012)
    Abstract:
    Aim: The aim of this study was to evaluate the long-term safety, tolerability and efficacy of the dipeptidyl peptidase-4 inhibitor linagliptin given either alone or in combination with other oral glucose-lowering agents in persons with type 2 diabetes. Methods: A 78-week open-label extension study evaluated subjects who participated in one of four preceding 24-week, randomised, double-blind, placebo-controlled parent trials and who received linagliptin, linagliptin + metformin, linagliptin + metformin + a sulphonylurea or linagliptin + pioglitazone (all with linagliptin administered orally once daily). Individuals receiving one of these treatments during a previous trial continued the same treatment (n = 1532) for up to a total of 102 weeks, whereas those previously receiving placebo were switched to linagliptin (n = 589). All 2121 participants received at least one dose of the trial medication and were included in the primary safety analysis. Results: In subjects previously receiving active treatment, the glycosylated haemoglobin A 1c reduction achieved during the 24-week parent trials was sustained through the 78-week extension period (change from baseline to week 102: -0.8%). Drug-related adverse events were experienced by 14.3% of participants. Hypoglycaemia occurred in 13.9% of participants and was similar between those previously receiving treatment (13.6%) and those switching from placebo to linagliptin (14.6%). Hypoglycaemia occurred most frequently with the use of metformin + a sulphonylurea background therapy (11%). Overall, no clinically relevant changes in body weight were observed. Conclusion: Long-term treatment with linagliptin was well tolerated with no change in the safety profile observed during the extension study. Sustained long-term glycaemic control was maintained for up to 102 weeks with either linagliptin monotherapy or linagliptin in combination with other oral glucose-lowering agents
  • Author:
    Wu L H; Huang C C; Adhikarakunnathu S; San Mateo L R; Duffy K E; Rafferty P; Bugelski P; Raymond H; Deutsch H; Picha K; Ward C K; Alexoupolou L; Flavell R A; Mbow M L; Susulic V S
    Title:
    Loss of toll-like receptor 3 function improves glucose tolerance and reduces liver steatosis in obese mice
    Source:
    Metabolism 61 (11), 1633-1645 (2012)
    Abstract:
    Objective: Emerging evidence suggests a link between innate immunity and development of type 2 diabetes mellitus (T2D); however, the molecular mechanisms linking them are not fully understood. Toll-like Receptor 3 (TLR3) is a pathogen pattern recognition receptor that recognizes the double-stranded RNA of microbial or mammalian origin and contributes to immune responses in the context of infections and chronic inflammation. The objective of this study was to determine whether TLR3 activity impacts insulin sensitivity and lipid metabolism. Materials and Methods: Wild type (WT) and TLR3 knock-out (TLR3 -/-) mice were fed a high fat diet (HFD) and submitted to glucose tolerance tests (GTTs) over a period of 33 weeks. In another study, the same group of mice was treated with a neutralizing monoclonal antibody (mAb) against mouse TLR3. Results: TLR3 -/- mice fed an HFD developed obesity, although they exhibited improved glucose tolerance and lipid profiles compared with WT obese mice. In addition, the increase in liver weight and lipid content normally observed in WT mice on an HFD was significantly ameliorated in TLR3 -/- mice. These changes were accompanied by up-regulation of genes involved in cholesterol efflux such as PPAR?, LXR?, and LXR?-targeting genes and down-regulation of pro-inflammatory cytokine and chemokine genes in obese TLR3 -/- mice. Furthermore, global gene expression profiling in liver demonstrated TLR3-specific changes in both lipid biosynthesis and innate immune response pathways. Conclusions: TLR3 affects glucose and lipid metabolism as well as inflammatory mediators, and findings in this study reveal a new role for TLR3 in metabolic homeostasis. This suggests antagonizing TLR3 may be a beneficial therapeutic approach for the treatment of metabolic diseases. © 2012 Elsevier Inc. All rights reserved.
  • Author:
    Graefe-Mody U; Friedrich C; Port A; Ring A; Retlich S; Heise T; Halabi A; Woerle H-J
    Title:
    Author response to letter from Snyder et al. regarding manuscript entitled 'Effect of renal impairment on the pharmacokinetics of the dipeptidyl peptidase-4 inhibor, linapliptin' by Graefe-Mody et al.
    Source:
    Diabetes Obes Metab 14 (7), 671-672 (2012)
    Abstract:
    no abstract available
  • Author:
    Klein T; Niessen H G; Ittrich C; Mayoux E; Mueller H P; Cheetham S; Stiller D; Kassubek J; Mark M
    Title:
    Evaluation of body fat composition after linagliptin treatment in a rat model of diet-induced obesity: A magnetic resonance spectroscopy study in comparison with sibutramine
    Source:
    Diabetes Obes Metab 14 (11), 1050-1053 (2012)
    Abstract:
    The effects of linagliptin on fat content in diet-induced obese rats were compared with those of the appetite suppressant sibutramine. Female Wistar rats fed a high-fat diet (HFD) for 3months received vehicle, linagliptin (10mg/kg) or sibutramine (5mg/kg) treatment orally, once daily for 6 additional weeks, while continuing the HFD. Magnetic resonance spectroscopy analysis of fat content was performed at baseline and at the end of the 6-week treatment period. Linagliptin treatment profoundly reduced hepatic fat compared with vehicle, with an effect comparable to that of sibutramine. The vehicle-corrected mean change (95% CI) from baseline in hepatic fat and intramyocellular lipid was -59.0% (-104.3%, -13.6%; p=0.015) and -62.1% (-131.6%, 7.4%; p=0.073), respectively, for linagliptin compared with -54.3% (-101.5%, -7.1%; p=0.027) and -72.4% (-142.4%, -2.4%; p=0.044), respectively, for sibutramine. © 2012 Blackwell Publishing Ltd.
  • Author:
    Owens D R; Del Prato S; Taskinen M R; Gomis R; Forst T; Woerle JH J
    Title:
    Response Letter to D. Singh-Franco et al.
    Source:
    Diabetes Obes Metab 14 (11), 1054-1055 (2012)
    Abstract:
    -
  • Author:
    Schuermann C; Linke A; Engelmann-Pilger K; Steinmetz C; Mark M; Pfeilschifter J; Klein T; Frank S
    Title:
    The dipeptidyl peptidase-4 inhibitor linagliptin attenuates inflammation and accelerates epithelialization in wounds of diabetic ob/ob mice.
    Source:
    J Pharmacol Exp Ther 342 (1), 71-80 (2012)
    Abstract:
    In recent years, new and effective therapeutic agents for blood glucose control have been added to standard diabetes therapies: dipeptidyl peptidase-4 (DPP-4) inhibitors, which prolong the bioavailability of the endogenously secreted incretin hormone glucagon-like peptide-1 (GLP-1). Full-thickness excisional wounding was performed in wild-type (C57BL/6J) and diabetic [C57BL/6J-obese/obese (ob/ob)] mice. DPP-4 activity was inhibited by oral administration of linagliptin during healing. Wound tissue was analyzed by using histological, molecular, and biochemical techniques. In healthy mice, DPP-4 was constitutively expressed in the keratinocytes of nonwounded skin. After skin injury, DPP-4 expression declined and was lowest during the most active phase of tissue reassembly. In contrast, in ob/ob mice, we observed increasing levels of DPP-4 at late time points, when delayed tissue repair still occurs. Oral administration of the DPP-4 inhibitor linagliptin strongly reduced DPP-4 activity, stabilized active GLP-1 in chronic wounds, and improved healing in ob/ob mice. At day 10 postwounding, linagliptin-treated ob/ob mice showed largely epithelialized wounds characterized by the absence of neutrophils. In addition, DPP-4 inhibition reduced the expression of the proinflammatory markers cyclooxygenase-2 and macrophage inflammatory protein-2, but enhanced the formation of myofibroblasts in healing wounds from ob/ob mice. Our data suggest a potentially beneficial role of DPP-4 inhibition in diabetes-affected wound healing. Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics.
  • Author:
    Ross S A; Rafeiro E; Meinicke T; Toorawa R; Weber-Born S; Woerle H J
    Title:
    Efficacy and safety of linagliptin 2.5mg twice daily versus 5mg once daily in patients with type 2 diabetes inadequately controlled on metformin: A randomised, double-blind, placebo-controlled trial
    Source:
    Curr Med Res Opin 28 (9), 1465-1474 (2012)
    Abstract:
    Objective: Glycaemic control in patients with type 2 diabetes (T2DM) is often not achieved or not sustained using monotherapy such as metformin, necessitating the addition of other antihyperglycaemic agents. Linagliptin, a dipeptidyl peptidase-4 inhibitor, is licensed for 5mg once-daily dosing. As metformin is administered twice daily, a fixed-dose combination of these compounds would require twice-daily administration of linagliptin. This study evaluated whether 2.5mg twice-daily dosing of linagliptin has comparable efficacy and safety to 5mg once-daily dosing when given in addition to metformin twice daily in patients with inadequate glycaemic control. Methods: A total of 491 T2DM patients with glycated haemoglobin (HbA1c) 7.010.0 were randomised (5:5:1) to double-blind treatment with linagliptin 2.5mg twice daily, 5mg once daily or placebo, respectively, in addition to continuing metformin twice daily (?1500mg/day or maximally tolerated dose). The primary endpoint was change from baseline in HbA1c after 12 weeks. ClinicalTrials.gov, NCT01012037. Results: Mean baseline HbA1c for all patients was 7.97. After 12 weeks, linagliptin 2.5mg twice daily and 5mg once daily both significantly reduced HbA1c (placebo-adjusted changes from baseline-0.74 (95 CI-0.97,-0.52) and-0.80 (95 CI-1.02,-0.58), respectively, both p<0.0001). The treatment difference (twice daily-once daily) between the linagliptin regimens was 0.06 (95 CI-0.07, 0.19), the upper bound of which was less than the predefined noninferiority margin (0.35). The overall incidence of adverse events with linagliptin 2.5mg twice daily, 5mg once daily and placebo was 43.0, 34.8, and 38.6 respectively. Hypoglycaemia was rare (3.1 with linagliptin 2.5mg twice daily, 0.9 with 5mg once daily, 2.3 with placebo) with no severe episodes. Study limitations include duration, patient population (mainly white) and absence of postprandial glucose data. Conclusions: Linagliptin 2.5mg twice daily had non-inferior HbA1c-lowering effects after 12 weeks compared to 5mg once daily, with comparable safety and tolerability, in T2DM patients inadequately controlled with metformin. © 2012 Informa UK Ltd All rights reserved.
  • Author:
    Alvheim A R; Malde M K; Osei-Hyiaman D; Hong Lin Y; Pawlosky R J; Madsen L; Kristiansen K; Frøyland L; Hibbeln J R
    Title:
    Dietary linoleic acid elevates endogenous 2-AG and anandamide and induces obesity
    Source:
    Obesity 20 (10), 1984-1994 (2012)
    Abstract:
    Suppressing hyperactive endocannabinoid tone is a critical target for reducing obesity. The backbone of both endocannabinoids 2-arachidonoylglycerol (2-AG) and anandamide (AEA) is the-6 fatty acid arachidonic acid (AA). Here we posited that excessive dietary intake of linoleic acid (LA), the precursor of AA, would induce endocannabinoid hyperactivity and promote obesity. LA was isolated as an independent variable to reflect the dietary increase in LA from 1 percent of energy (en%) to 8 en% occurring in the United States during the 20th century. Mice were fed diets containing 1 en% LA, 8 en% LA, and 8 en% LA 1 en% eicosapentaenoic acid (EPA) docosahexaenoic acid (DHA) in medium-fat diets (35 en% fat) and high-fat diets (60 en%) for 14 weeks from weaning. Increasing LA from 1 en% to 8 en% elevated AA-phospholipids (PL) in liver and erythrocytes, tripled 2-AG 1-AG and AEA associated with increased food intake, feed efficiency, and adiposity in mice. Reducing AA-PL by adding 1 en% long-chain-3 fats to 8 en% LA diets resulted in metabolic patterns resembling 1 en% LA diets. Selectively reducing LA to 1 en% reversed the obesogenic properties of a 60 en% fat diet. These animal diets modeled 20th century increases of human LA consumption, changes that closely correlate with increasing prevalence rates of obesity. In summary, dietary LA increased tissue AA, and subsequently elevated 2-AG 1-AG and AEA resulting in the development of diet-induced obesity. The adipogenic effect of LA can be prevented by consuming sufficient EPA and DHA to reduce the AA-PL pool and normalize endocannabinoid tone.
  • Author:
    Brand T; MacHa S; Mattheus M; Pinnetti S; Woerle H J
    Title:
    Pharmacokinetics of Empagliflozin, a Sodium Glucose Cotransporter-2 (SGLT-2) Inhibitor, Coadministered with Sitagliptin in Healthy Volunteers
    Source:
    Adv Ther 29 (10), 889-899 (2012)
    Abstract:
    Introduction: This randomized, open-label, crossover study investigated potential drug-drug interactions between the sodium glucose cotransporter-2 (SGLT-2) inhibitor empagliflozin and the dipeptidyl peptidase-4 (DPP-4) inhibitor sitagliptin. Empagliflozin is a potent and selective SGLT-2 inhibitor that lowers blood glucose levels by inhibiting renal glucose reabsorption, leading to an increase in urinary glucose excretion. Sitagliptin lowers blood glucose through an insulin-dependent mechanism of action. Methods: Sixteen healthy male volunteers received three treatments (A, B, C) in one of two treatment sequences (AB then C, or C then AB). In treatment AB, 50 mg empagliflozin was administered once daily (q.d.) for 5 days (treatment A), immediately followed by coadministration of 50 mg empagliflozin q.d. and 100 mg sitagliptin q.d. over 5 days (treatment B). In treatment C, 100 mg sitagliptin was administered q.d. for 5 days. A washout period of ?7 days separated treatments AB and C. Results: Coadministration of sitagliptin with empagliflozin did not have a clinically relevant effect on the area under the concentration-time curve of the analyte in plasma at steady state over a uniform dosing interval ? (AUC ?,ss) (geometric mean ratio [GMR] 110.4; 90% confidence interval [CI] 103.9, 117.3) or maximum measured concentration of the analyte in plasma at steady state over a uniform dosing interval ? (C max,ss) (GMR 107.6; 90% CI 97.0, 119.4) of empagliflozin. Coadministration of empagliflozin with sitagliptin did not have a clinically meaningful effect on the AUC ?,ss (GMR 103.1; 90% CI 98.9, 107.3) or C max,ss (GMR 108.5; 90% CI 100.7, 116.9) of sitagliptin. Empagliflozin and sitagliptin were well tolerated when given alone or in combination. Five subjects (31.3%) reported at least one adverse event (AE): three (18.8%) experienced an AE while receiving empagliflozin monotherapy and three (18.8%) while receiving sitagliptin monotherapy. No adverse events were reported during the coadministration period. No AEs were regarded as drug-related by the investigator. Conclusion: These results indicate that empagliflozin and sitagliptin can be coadministered without dose adjustments. © 2012 Springer Healthcare.
  • Author:
    Barnett A H; Patel S; Harper R; Toorawa R; Thiemann S; Von Eynatten M; Woerle H J
    Title:
    Linagliptin monotherapy in type 2 diabetes patients for whom metformin is inappropriate: An 18-week randomized, double-blind, placebo-controlled phase III trial with a 34-week active-controlled extension
    Source:
    Diabetes Obes Metab 14 (12), 1145-1154 (2012)
    Abstract:
    Aims: To investigate the efficacy and safety of linagliptin, a dipeptidyl peptidase-4 inhibitor, in type 2 diabetes mellitus (T2DM) patients for whom metformin was inappropriate. Methods: This 1-year double-blind study (ClinicalTrials.gov, NCT00740051) enrolled T2DM patients with inadequate glycaemic control, treatment-naïve [glycated haemoglobin (HbA1c) 7.0-10.0%] or previously treated with one oral antidiabetes drug (HbA1c 6.5-9.0% before washout), ineligible for metformin because of contraindications (e.g. renal impairment) or previous intolerable side effects. Patients were randomized to monotherapy with linagliptin 5mg once daily (n=151) or placebo (n=76) for 18weeks, after which placebo patients switched to glimepiride 1-4mg once daily and treatments continued for another 34weeks. The primary endpoint was change from baseline in HbA1c after 18weeks (full-analysis set, last observation carried forward). Results: At week 18, adjusted mean difference in change from baseline HbA1c (8.1%) was -0.60% (95% confidence interval -0.88, -0.32; p<0.0001) (-0.39% with linagliptin, +0.21% with placebo). At week 52, mean HbA1c was decreased from baseline in both groups [linagliptin: -0.44%; placebo/glimepiride: -0.72% (observed cases)]. Adverse events occurred in 40.4 and 48.7% of linagliptin and placebo patients, respectively, during the initial 18weeks. During the 34-week extension, patients receiving linagliptin experienced less hypoglycaemia (2.2% vs. 7.8%) and no weight gain (mean change from baseline of -0.2 and +1.3kg, respectively) compared with glimepiride patients. Conclusions: In T2DM patients for whom metformin was inappropriate, linagliptin improved glycaemic control and was well tolerated, with less hypoglycaemia and relative weight loss compared with glimepiride. © 2012 Blackwell Publishing Ltd.
  • Author:
    Glund S; Schoelch C; Thomas L; Niessen H G; Stiller D; Roth G J; Neubauer H
    Title:
    Inhibition of Acetyl-CoA carboxylase 2 enhances skeletal muscle fatty acid oxidation and improves whole-body glucose homeostasis in db/db mice
    Source:
    Diabetologia 55 (7), 2044-2053 (2012)
    Abstract:
    Aims/hypothesis: Excessive ectopic lipid deposition contributes to impaired insulin action in peripheral tissues and is considered an important link between obesity and type 2 diabetes mellitus. Acetyl-CoA carboxylase 2 (ACC2) is a key regulatory enzyme controlling skeletal muscle mito-chondrial fatty acid oxidation; inhibition of ACC2 results in enhanced oxidation of lipids. Several mouse models lacking functional ACC2 have been reported in the literature. However, the phenotypes of the different models are inconclusive with respect to glucose homeostasis and protection from diet-induced obesity. Methods: Here, we studied the effects of pharmacological inhibition of ACC2 using as a selective inhibitor the S enantiomer of compound 9c ([S]-9c). Selectivity was confirmed in biochemical assays using purified human ACC1 and ACC2. Results:(S)-9c significantly increased fatty acid oxidation in isolated extensor digitorum longus muscle from different mouse models (EC 50 226 nmol/l). Accordingly, short-term treatment of mice with (S)-9c decreased malonyl-CoA levels in skeletal muscle and concomitantly reduced intramyocellular lipid levels. Treatment of db/db mice for 70 days with (S)-9c (10 and 30 mg/kg, by oral gavage) resulted in improved oral glucose tolerance (AUC-36%, p&lt;0.05), enhanced skeletal muscle 2-deoxy-2-[18F]fluoro-D-glucose (FDG) uptake, as well as lowered prandial glucose (-31%, p&lt;0.01) and HbA1c (-0.7%, p&lt;0.05). Body weight, liver triacyl-glycerol, plasma insulin and pancreatic insulin content were unaffected by the treatment. Conclusions/interpretation: In conclusion, the ACC2-selective inhibitor (S)-9c revealed glucose-lowering effects in a mouse model of diabetes mellitus. © springer-verlag 2012.
  • Author:
    Lewin A J; Arvay L; Liu D; Patel S; Von Eynatten M; Woerle H J
    Title:
    Efficacy and Tolerability of Linagliptin Added to a Sulfonylurea Regimen in Patients With Inadequately Controlled Type 2 Diabetes Mellitus: An 18-Week, Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial
    Source:
    Clin Ther 34 (9), 1909-1919 15 (2012)
    Abstract:
    Background: Some patients with type 2 diabetes mellitus (T2DM) receiving monotherapy with a sulfonylurea (SU) are unable to meet recommended glycemic targets over the long term and require additional pharmacologic agents to maintain glycemic control. This study was designed to assess the utility of adjunctive therapy with the dipeptidyl peptidase (DPP)-4 inhibitor linagliptin in patients with T2DM inadequately controlled with SU monotherapy. Objective: To assess the efficacy and tolerability of linagliptin as add-on therapy in patients with inadequately controlled T2DM despite background therapy with an SU. Methods: In this Phase III, multicenter, randomized, double-blind, placebo-controlled trial, patients with inadequately controlled T2DM on SU monotherapy were randomly assigned to receive treatment with linagliptin 5 mg once daily (n = 161) or placebo (n = 84) for 18 weeks. The primary end point was the mean change in hemoglobin (Hb) A 1c from baseline to week 18, evaluated using ANCOVA. Tolerability was assessed using laboratory analysis, spontaneous reporting, and physical examination and interview. Results: Mean baseline characteristics were similar in the linagliptin and placebo groups. Linagliptin treatment was associated with a placebo-corrected mean (95% CI) change in HbA 1c from baseline (8.6%) to 18 weeks of -0.47% (-0.70 to -0.24; P &lt; 0.0001). Patients in the linagliptin group were more likely compared with placebo to achieve the HbA 1c target level of &lt;7.0% after 18 weeks of treatment (15.2% vs 3.7%, respectively; odds ratio [OR] = 6.5; 95% CI, 1.7-24.8; P = 0.007). Similarly, patients in the linagliptin group were more likely to achieve an HbA 1c reduction of ?0.5% compared with those in the placebo group (57.6% vs 22.0%; OR = 5.1, 95% CI 2.7-9.6; P &lt; 0.0001). The overall frequency of adverse events was similar between the linagliptin and placebo groups (42.2% vs 42.9%). The incidences of hypoglycemic events were not significantly different between the 2 groups (5.6% vs 4.8%), and none of the hypoglycemic episodes were assessed as severe by the investigator. The difference in the changes in mean body weight was not significant (+0.43 vs -0.01 kg; P = 0.12). Conclusions: The addition of linagliptin to SU therapy for 18 weeks in these patients with T2DM was associated with statistically significant and clinically meaningful reductions in HbA 1c compared with placebo. The overall tolerability of linagliptin was similar to that of placebo, with a low risk for hypoglycemia and no significant weight gain. These findings support the use of linagliptin as adjunctive therapy in patients with T2DM inadequately controlled on SU monotherapy. ClinicalTrials.gov identifier: NCT00819091. © 2012 Elsevier HS Journals, Inc..
  • Author:
    Jelsing J; Vrang N; van Witteloostuijn SB; Mark M; Klein T
    Title:
    The DPP4 inhibitor linagliptin delays the onset of diabetes and: Preserves ?-cell mass in non-obese diabetic mice
    Source:
    J Endocrinol 214 (3), 381-387 (2012)
    Abstract:
    Recent data indicate that dipeptidyl peptidase 4 (DPP4) inhibitors have anti-inflammatory and ?-cell-sparing effects in animal models of type 1 diabetes. To evaluate the effects of the DPP4 inhibitor linagliptin on ?-cell mass and insulinitis, we examined the progression of diabetes (blood glucose >11 mmol/l) in non-obese diabetic (NOD) mice with terminal stereological assessment of cellular pancreatic changes. Female NOD mice were fed a normal chow diet or a diet containing linagliptin 0.083 g/kg chow for 60 days. At study end, the incidence of diabetes in linagliptin-treated mice was reduced by almost 50% compared with vehicle (10 of 31 mice vs 18 of 30 mice, P=0.021). The total islet mass and total ?-cell mass, identified by insulin immunoreactivity, were greater in non-diabetic linagliptin-treated mice compared with nondiabetic vehicle-treated mice (P<0.01 for both) but were greatly reduced in diabetic mice irrespective of treatment. No changes were seen in the a, d and g endocrine cell pool. Moreover, the total mass of lymphocyte insulinitis was significantly reduced in linagliptin-treated mice compared with vehicle. The data indicate that linagliptin treatment delays the onset of diabetes in NOD mice by protecting ?-cell mass. © 2012 Society for Endocrinology.
  • Author:
    Vickers S P; Cheetham S C; Birmingham G D; Rowley H L; Headland K R; Dickinson K; Grempler R; Hocher B; Mark M; Klein T
    Title:
    Effects of the DPP-4 inhibitor, linagliptin, in diet-induced obese rats: A comparison in naive and exenatide-treated animals
    Source:
    Clin Lab (Heidelberg) 58 (7-8), 787-799 (2012)
    Abstract:
    Background: To assess the chronic effect of the DPP-4 inhibitor, linagliptin, alone, in combination with exenatide, and during exenatide withdrawal, in diet-induced obese (DIO) rats. Methods: Female Wistar rats were exposed to a cafeteria diet to induce obesity. Animals were then dosed with vehicle or linagliptin (3 mg/kg PO) orally once-daily for a 28 day period. In a subsequent study, rats received exenatide (either 3 or 30 ?g/kg/day) or vehicle by osmotic mini-pump for 28 days. In addition, groups of animals were dosed orally with linagliptin either alone or in combination with a 3 ?g/kg/day exenatide dose for the study duration. In a final study, rats were administered exenatide (30 ?g/kg/day) or vehicle by osmotic mini-pump for eleven days. Subsequently, exenatide-treated animals were transferred to vehicle or continued exenatide infusion for a further ten days. Animals transferred from exenatide to vehicle were also dosed orally with either vehicle or linagliptin. In all studies, body weight, food and water intake were recorded daily and relevant plasma parameters and carcass composition were determined. Results: In contrast to exenatide, linagliptin did not significantly reduce body weight or carcass fat in DIO rats versus controls. Linagliptin augmented the effect of exenatide to reduce body fat when given in combination but did not affect the body weight response. In rats withdrawn from exenatide, weight regain was observed such that body weight was not significantly different to controls. Linagliptin reduced weight regain after withdrawal of exenatide such that a significant difference from controls was evident. Conclusions: These data demonstrate that linagliptin does not significantly alter body weight in either untreated or exenatide-treated DIO rats, although it delays weight gain after exenatide withdrawal. This finding may suggest the utility of DPP-4 inhibitors in reducing body weight during periods of weight gain.
  • Author:
    Diederichs CP; Wellmann J; Bartels DB; Ellert U; Hoffmann W; Berger K
    Title:
    How to weight chronic diseases in multimorbidity indices? Development of a new method on the basis of individual data from five population-based studies
    Source:
    J Clin Epidemiol 65 (6), 679-685 (2012)
    Abstract:
    Objective: In multimorbidity indices, chronic conditions are often weighted according to their severity or their impact on different outcomes. These weights are mostly developed on the basis of only one study population by using very specific study participants, such as hospital patients. To overcome the limited validity of the indices, mean weights across five population-based studies were calculated according to the impact of diseases on self-reported health status. Study Design and Setting: Individual data was provided from the National Health Interview and Examination Survey (n = 1,010), Dortmund Health Study (n = 281), Memory and Morbidity in Augsburg Elderly Study (n = 385), Survey of Health, Aging and Retirement in Europe Study (n = 1,278), and Study of Health in Pomerania Study (n = 962). By using logistic regression analysis, odds ratios (ORs) were calculated for reporting a fair or poor health status resulting from one of 10 different chronic conditions compared with a reference group without the specific disease, controlling for age and sex. If the results were homogenous across studies (I 2 < 40%), significant pooled ORs were considered valid weights for a multimorbidity index. Results: Myocardial infarction has the highest impact on self-reported health status across studies with a pooled OR of 3.9, followed by chronic obstructive pulmonary disease (pooled OR: 3.1). A medium impact was observed for arthrosis, asthma, diabetes mellitus, and osteoporosis. Conclusion: This method provided valid weights for seven chronic conditions. © 2012 Elsevier Inc. All rights reserved.
  • Author:
    Haak T; Meinicke T; Jones R; Weber S; Eynatten MV; Woerle HJ
    Title:
    Initial combination of linagliptin and metformin improves glycaemic control in type 2 diabetes: A randomized, double-blind, placebo-controlled study.
    Source:
    Diabetes Obes Metab 14 (6), 565-574 (2012)
    Abstract:
    Aims: To evaluate the efficacy and safety of initial combination therapy with linagliptin plus metformin versus linagliptin or metformin monotherapy in patients with type 2 diabetes. Methods: In this 24-week, double-blind, placebo-controlled, Phase III trial, 791 patients were randomized to one of six treatment arms. Two free combination therapy arms received linagliptin 2.5 mg twice daily (bid) + either low (500 mg) or high (1000 mg) dose metformin bid. Four monotherapy arms received linagliptin 5 mg once daily, metformin 500 mg or 1000 mg bid or placebo. Patients with haemoglobin A1c (HbA1c) =11.0% were not eligible for randomization and received open-label linagliptin + high-dose metformin. Results: The placebo-corrected mean (95% confidence interval) change in HbA1c from baseline (8.7%) to week 24 was -1.7% (-2.0, -1.4) for linagliptin + high-dose metformin, -1.3% (-1.6, -1.1) for linagliptin + low-dose metformin, -1.2% (-1.5, -0.9) for high-dose metformin, -0.8% (-1.0, -0.5) for low-dose metformin and -0.6 (-0.9, -0.3) for linagliptin (all p < 0.0001). In the open-label arm, the mean change in HbA1c from baseline (11.8%) was -3.7%. Hypoglycaemia occurred at a similar low rate with linagliptin + metformin (1.7%) as with metformin alone (2.4%). Adverse event rates were comparable across treatment arms. No clinically significant changes in body weight were noted. Conclusions: Initial combination therapy with linagliptin plus metformin was superior to metformin monotherapy in improving glycaemic control, with a similar safety and tolerability profile, no weight gain and a low risk of hypoglycaemia. © 2012 Blackwell Publishing Ltd.
  • Author:
    Wright S; Singh RP; Retlich S; Graefe-Mody U; Derendorf H
    Title:
    The concentration-dependent binding of linagliptin (BI 1356) and its implication on efficacy and safety.
    Source:
    Int J Clin Pharmacol Ther 50 (5), 323-330 (2012)
    Abstract:
    Objectives: Linagliptin (BI 1356) is a dipeptidyl peptidase-4 (DPP-4) inhibitor for treatment of Type 2 diabetes which recently gained approval in the US, Europe, and Japan. Linagliptin showed nonlinear pharmacokinetics after intravenous and oral administration, which is due to a concentration-dependent protein binding of linagliptin to its target enzyme DPP-4. The aim of this analysis was to investigate this target-mediated binding of linagliptin and its implication on efficacy and safety. Methods: Pharmacokinetic modeling and simulations were performed using a two-compartment model with concentration-dependent binding in the central and in one peripheral compartment. The optimum therapeutic dose with minimal off-target side effects was simulated assuming that an antidiabetic effect of linagliptin was due to the linagliptin concentration bound to DPP-4 and that off-target side effects were related to free linagliptin. Results: The difference between steady state AUCs of specifically bound and free linagliptin was maximized at oral doses of 2 - 5 mg. Since plasma DPP-4 inhibition increased slightly from 2.5 to 10 mg, pharmacokinetic simulations and the pharmacodynamic measurements taken together suggest that 5 mg linagliptin could be considered an optimum dose. Simulations with missed doses and additional doses at steady state showed the effect on DPP-4 bound linagliptin and change in DPP-4 inhibition was minimal after missing one 5 mg oral dose of linagliptin while two doses of 5 mg linagliptin resulted in a less than proportional increase of steady state AUC of free linagliptin. Conclusions: Results from modeling and simulation support a stable antidiabetic effect of linagliptin over 24 h at steady state and further indicate a low risk for off-target side effects. ©2012 Dustri-Verlag Dr. K. Feistle.
  • Author:
    Wu LH; Huang CC; Adhikarakunnathu S; San Mateo LR; Duffy KE; Rafferty P; Bugelski P; Raymond H; Deutsch H; Picha K; Ward CK; Alexoupolou L; Flavell RA; Mbow ML; Susulic VS
    Title:
    Loss of toll-like receptor 3 function improves glucose tolerance and reduces liver steatosis in obese mice.
  • Author:
    Riether D
    Title:
    Selective cannabinoid receptor 2 modulators: A patent review 2009 present.
    Source:
    Expert Opin Ther Pat 22 (5), 495-510 (2012)
    Abstract:
    Introduction: The activation of the cannabinoid receptor 2 (CB2) affects a myriad of immune responses from inflammation to neuroprotection, demonstrates analgesic effects and suppresses responses in many animal models of pain. Questions around the involvement of CB1 activation in these effects remain, but efforts have been directed toward the discovery of highly selective CB2 modulators lacking the psychotropic effects of cannabinoids, which are mediated by the CB1 receptor.Areas covered: This review covers the patent literature which was published since April 2009 on CB2 selective modulators. It provides a general summary of the CB2 biology supporting the interest in CB2 as a drug target, new potential therapeutic indications and the development status of selective CB2 agonists.Expert opinion: There is a continuous interest in the CB2 receptor as a drug target. Many highly selective compounds of various chemotypes have been identified and their analgesic effects in animal models further support the potential of this mechanism in pain therapy. Several companies have initiated clinical trials. While some of these have been terminated for various reasons, one can anticipate the emergence of new drugs from CB2 modulation once a better understanding around the cannabinoid receptors is gained. © 2012 Informa UK, Ltd.
  • Author:
    Alvheim AR; Malde MK; Osei-Hyiaman D; Hong Lin Y; Pawlosky R; Madsen L; Kristiansen K; Froyland L; Hibbeln JR
    Title:
    Dietary linoleic acid elevates endogenous 2-AG and anandamide and induces obesity.
    Source:
    Obesity Article in Press (2012)
  • Author:
    Gallwitz B; Rosenstock J; Rauch T; Bhattachary S; Patel S; Von Eynatten M; Dugi K A; Woerle H J
    Title:
    2-year efficacy and safety of linagliptin compared with glimepiride in patients with type 2 diabetes inadequately controlled on metformin: A randomised, double-blind, non-inferiority trial
    Source:
    Lancet 380 (9840), 475-483 (2012)
    Abstract:
    Background Addition of a sulphonylurea to metformin improves glycaemic control in type 2 diabetes, but is associated with hypoglycaemia and weight gain. We aimed to compare a dipeptidyl peptidase-4 inhibitor (linagliptin) against a commonly used sulphonylurea (glimepiride). Methods In this 2-year, parallel-group, non-inferiority double-blind trial, outpatients with type 2 diabetes and glycated haemoglobin A 1c (HbA 1c) 6·5-10·0% on stable metformin alone or with one additional oral antidiabetic drug (washed out during screening) were randomly assigned (1:1) by computer-generated random sequence via a voice or web response system to linagliptin (5 mg) or glimepiride (1-4 mg) orally once daily. Study investigators and participants were masked to treatment assignment. The primary endpoint was change in HbA 1c from baseline to week 104. Analyses included all patients randomly assigned to treatment groups who received at least one dose of treatment, had a baseline HbA 1c measurement, and had at least one on-treatment HbA 1c measurement. This trial is registered at ClinicalTrials.gov, number NCT00622284. Findings 777 patients were randomly assigned to linagliptin and 775 to glimepiride; 764 and 755 were included in analysis of the primary endpoint. Reductions in adjusted mean HbA 1c (baseline 7·69% [SE 0·03] in both groups) were similar in the linagliptin (-0·16% [SE 0·03]) and glimepiride groups (-0·36% [0·03]; diff erence 0·20%, 97·5% CI 0·09-0·30), meeting the predefi ned non-inferiority criterion of 0·35%. Fewer participants had hypoglycaemia (58 [7%] of 776 vs 280 [36%] of 775 patients, p&lt;0·0001) or severe hypoglycaemia (1 [&lt;1%] vs 12 [2%]) with linagliptin compared with glimepiride. Linagliptin was associated with signifi cantly fewer cardiovascular events (12 vs 26 patients; relative risk 0·46, 95% CI 0·23-0·91, p=0·0213). Interpretation The results of this long-term randomised active-controlled trial advance the clinical evidence and comparative eff ectiveness bases for treatment options available to patients with type 2 diabetes mellitus. The fi ndings could improve decision making for clinical treatment when metformin alone is insuffi cient.
  • Author:
    Mease K; Sane R; Podila L; Taub ME
    Title:
    Differential selectivity of efflux transporter inhibitors in Caco-2 and MDCK-MDR1 monolayers: A strategy to assess the interaction of a new chemical entity with P-go, BCRP and MRP2.
    Source:
    J Pharm Sci Article in Press (2012)
  • Author:
    Luippold G; Klein T; Mark M; Grempler R
    Title:
    Empagliflozin, a novel potent and selective SGLT-2 inhibitor, improves glycaemic control alone and in combination with insulin in streptozotocin-induced diabetic rats, a model of type 1 diabetes melitus.
    Source:
    Diabetes Obes Metab 14 (7), 601-607 (2012)
    Abstract:
    Aim: Sodium glucose cotransporter-2 (SGLT-2) is key to reabsorption of glucose in the kidney. SGLT-2 inhibitors are in clinical development for treatment of type 2 diabetes mellitus (T2DM). The mechanism may be of value also in the treatment of type 1 diabetes mellitus (T1DM). This study investigated effects of the SGLT-2 inhibitor, empagliflozin, alone and in combination with insulin, on glucose homeostasis in an animal model of T1DM. Methods: Sprague-Dawley rats were administered a single intraperitoneal injection of streptozotocin (STZ; 60 mg/kg). Acutely, STZ rats received two doses of insulin glargine with or without empagliflozin, and blood glucose was measured. In a subchronic study, STZ rats received empagliflozin alone, one or two insulin-releasing implants or a combination of one implant and empagliflozin over 28 days; blood glucose and HbA 1c were measured. Results: In the acute setting, empagliflozin in combination with 1.5 IU insulin induced a similar glucose-lowering effect as 6 IU insulin. Both interventions were more efficacious than monotherapy with 1.5 IU insulin. In the subchronic study, 12-h blood glucose profile on day 28 in the combination group was lower than with one implant, and similar to two implants. Plasma HbA 1c was improved in the combination group and in animals with two implants. Conclusions: Empagliflozin reduced blood glucose levels in a T1DM animal model. Empagliflozin combined with low-dose insulin showed comparable glucose-lowering efficacy to treatment with high-dose insulin. Our data suggest that empagliflozin is an efficacious adjunctive-to-insulin therapy with the clinical potential for the treatment of T1DM. © 2012 Blackwell Publishing Ltd. Reaxys Database Information
  • Author:
    Lynch CJ; Zhou Q; Shyng SL; Heal DJ; Cheetham SC; Dickinson K; Gregory P; Fimges M; Nordheim U; Goshorn S; Reiche D; Turski L; Antel J
    Title:
    Some cannabinoid receptor ligands and their distomers are direct-acting openers of SUR1 K ATP channels.
    Source:
    Am J Physiol 302 (5), E540-E541 (2012)
  • Author:
    Mease K; Sane R; Podila L; Taub M E
    Title:
    Differential selectivity of efflux transporter inhibitors in Caco-2 and MDCK-MDR1 monolayers: a strategy to assess the interaction of a new chemical entity with P-gp, BCRP, and MRP2.
    Source:
    J Pharm Sci 101 (5), 1888-1897 (2012)
    Abstract:
    Determining the interaction of a molecule with membrane transporters is challenging because of overlapping substrate and inhibitor specificities and coexpression of multiple transporters. Caco-2 and MDCK-MDR1 cells were used to evaluate the selectivity of zosuquidar (LY335979), fumitremorgin C (FTC), and MK571 as inhibitors of P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), and multidrug resistance-associated protein 2 (MRP2), respectively. Although these compounds are commonly used as transporter inhibitors, the concentrations at which they selectively inhibit P-gp, BCRP, and MRP2 have not been definitively assessed. In Caco-2 cells, which express P-gp, BCRP, and MRP2, FTC (1 ?M) selectively inhibited the efflux of BCRP substrates estrone-3-sulfate and genistein; however, at 10 ?M, FTC partially inhibited the efflux of P-gp substrates paclitaxel and digoxin. MK571 (50 ?M), commonly used to inhibit MRP2, inhibited the efflux of P-gp and BCRP probe substrates in Caco-2 cells. In MDCK-MDR1 cells, which express human P-gp but not BCRP or MRP2, MK571 (50 ?M) and FTC (10 ?M) did not inhibit paclitaxel and digoxin efflux. Using Caco-2 cell monolayers, selected probe substrates, and optimized concentrations of LY335979 (3 ?M) and FTC (1 ?M), we propose a strategy to evaluate the interaction of a molecule with P-gp, BCRP, and MRP2. Copyright © 2012 Wiley Periodicals, Inc.
  • Author:
    Khawam A
    Title:
    Reply to "Filling hard gelatin capsules by the dosator nozzle system - Is it possible to predict where the powder goes?"
    Source:
    Int J Pharm Article in Press (2012)
  • Author:
    Schadt S; Kallbach S; Almeida R; Sandel J
    Title:
    Investigation of figopitant and its metabolites in rat tissue by combining whole-body autoradiography with liquid extraction surface analysis mass specrometry.
    Source:
    Drug Metab Dispos 40 (3), 419-429 (2012)
  • Author:
    Scott-Moncrieff JCR; Moore GE; Coe J; Lynn RC; Gwin W; Petzold R
    Title:
    Characteristics of commercally manufactured and compounded protamine zinc insulin.
    Source:
    J Am Vet Med Assoc 240 (5), 600-605 (2012)
  • Author:
    Kawamori R; Inagaki N; Araki E; Watada H; Hayashi N; Horie Y; Sarashina A; Gong Y; von Eynatten M; Woerle HJ; Dugi KA
    Title:
    Linagliptin monotherapy provides superior glycaemic control versus placebo or voglibose with comparable safety in Japanese patiens with type 2 diabetes: A randomized placebo and active comparator-controlled double-blind study.
    Source:
    Diabetes Obes Metab 14 (4), 348-357 (2012)
  • Author:
    Neldam S; Edwards C; Lang M; Jones R
    Title:
    Long-term tolerability and efficacy of single-pill combinations of telmisartan 40-80 mg plus amlodipine 5 or 10 mg in patients whose blood pressure was not initially controlled by amlodipine 5-10 mg: Open-label, long-term follow-ups of the TEAMSTA-5 and TEAMSTA-10 studies.
    Source:
    Curr Ther Res 73 (1-2), 65-84 (2012)
    Abstract:
    Background: Two 8-week, randomized, double-blind, controlled studies previously evaluated the efficacy and tolerability of single-pill combinations of telmisartan 40-80 mg/amlodipine 5-10 mg (T40-80/A5-10) in patients with hypertension not at diastolic blood pressure (DBP) goal (DBP <90 mm Hg) after 6 weeks of amlodipine 5 mg monotherapy (A5) (TEAMSTA-5) or amlodipine 10 mg monotherapy (A10) (TEAMSTA-10). The long-term (=6 months) tolerability and efficacy of single-pill combinations of T40-T80/A5-A10 have now been evaluated in 2 open-label studies in patients who had successfully completed either TEAMSTA-5 or TEAMSTA-10 (TEAMSTA-5 and TEAMSTA-10 Follow-Ups). Methods: In the TEAMSTA-5 Follow-Up, 976 patients whose blood pressure was not initially controlled by taking A5 received T40/A5 for 4 or 8 weeks, with consecutive uptitration to T80/A5 if DBP was =90 mm Hg. In TEAMSTA-10 Follow-Up, 838 patients not initially achieving blood pressure control using A10 received T40/A10 for 4 weeks before randomization to T40/A10 or T80/A10; after 4 weeks, patients randomized to T40/A10 with DBP =90 mm Hg were uptitrated to T80/A10. In both studies, add-on antihypertensive medication was allowed if DBP was not at goal. Results: Treatment compliance in both follow-up studies was =98.4%. Single-pill combinations of T40-T80/A5-A10 resulted in additional clinically relevant blood pressure reductions and 67% to 93% of patients achieved DBP goal (<90 mm Hg); only 1% to 19% of patients received additional medication for hypertension, of whom 29% to 76% achieved DBP goal. Long-term treatment with T40-T80/A5-A10 was well tolerated, with comparable adverse event profiles for all telmisartan/amlodipine combinations. The most common drug-related adverse events were peripheral edema (1.9%-3.9%) and dizziness (1.5% in the T80/A5 group only); these were consistent with the known tolerability profiles of telmisartan/amlodipine combinations. Overall treatment discontinuation rates due to adverse events were low (0.7%-1.5%). Conclusions: In patients not achieving DBP goal with either A5 or A10 monotherapy, the vast majority achieved DBP goal with single-pill combinations of T40-T80/A5-A10. Long-term treatment was well tolerated with high compliance, promoting treatment adherence regardless of telmisartan/amlodipine dose. . ClinicalTrials.gov identifiers: . NCT00614380 (TEAMSTA-5 Follow-up) and . NCT00624052 (TEAMSTA-10 Follow-up).
  • Author:
    Sharma AM; Bakris G; Neutel JM; Littlejohn TW; Kobe M; Ting N; Ley L
    Title:
    Single-pill combination of telmisartan/amlodipine versus amlodipine monotherapy in diabetic hypertensive patients. An 8-week randomized parallel-group, double-blind trial.
    Source:
    Clin Ther 34 (3), 537-551 (2012)
    Abstract:
    Background: Hypertensive patients with diabetes often require combination therapy to achieve a blood pressure (BP) goal, and evidence suggests that time to BP goal is crucial to decrease cardiovascular risk. Objective: The aim of the study was to investigate whether the single-pill combination of telmisartan and amlodipine was superior to amlodipine alone as initial antihypertensive therapy in patients with diabetes and hypertension. Methods: An 8-week, randomized, parallel-group, double-blind international trial comparing the once-daily single-pill combination of telmisartan 80 mg and amlodipine 10 mg (T/A; n = 352) with once-daily amlodipine 10 mg (A; n = 354) in patients with type 2 diabetes mellitus and stage 1 or 2 hypertension (systolic BP [SBP] >150 mm Hg). Results: Patient demographics were similar between treatment groups, with an mean (SD) age of 60.5 (10.1) years; 51.7% were male, the mean (SD) body mass index was 32.0 (6.1) and the mean (SD) duration of hypertension was 8.8 (7.9) years. After 8 weeks (primary end point) as well as after 1, 2, and 4 weeks (key secondary end points), significantly greater decreases in the in-clinic mean seated trough cuff SBP with T/A versus A were achieved (-29.0 mm Hg vs -22.9 mm Hg at 8 weeks; P < 0.0001). After 8 weeks, 71.4% versus 53.8% of patients achieved the BP goal (<140/90 mm Hg) with T/A versus A, with mean SBPs of 131.9 and 137.9 mm Hg, respectively. Similar results were observed in the obese (metabolic syndrome) subpopulation. The more stringent goal (<130/80 mm Hg) was achieved by 36.4% and 17.9% patients in the T/A and A groups, respectively. The most common adverse events were peripheral edema, headache, and dizziness. Conclusions: In this selected population of patients with diabetes and hypertension, T/A provided prompt and greater BP decreases compared with A monotherapy, with the majority of patients achieving the BP goal (<140/90 mm Hg).
  • Author:
    Burke J; Kovacs B; Borton L; Sander S
    Title:
    Health care utilizaton and costs in type 2 diabetes melitus and their association with renal impairment.
    Source:
    Postgrad Med 124 (2), 77-89 (2012)
  • Author:
    Neldam S; Schumacher H; Guthrie R
    Title:
    Telmisartan 80 mg/Hydrochlorothiazide 25 mg provides clinically relevant blood pressure reductions across baseline blood pressures.
    Source:
    Adv Ther 29 (4), 327-338 (2012)
    Abstract:
    Introduction: Most patients with hypertension require combination therapy to achieve optimal reduction of blood pressure (BP). The angiotensin II receptor blocker, telmisartan, provides 24-hour BP-lowering efficacy and is proven to prevent cardiovascular morbidity in high-risk patients. Methods: Pooled data from seven randomized controlled trials (3,654 patients with stage 1-2 hypertension) were analyzed to investigate the BP-lowering efficacy of telmisartan 40 or 80 mg (T40 or T80) in combination with hydrochlorothiazide 12.5 or 25 mg (H12.5 or H25) when compared with either placebo or telmisartan monotherapy, relative to patients' baseline BP. BP-lowering efficacy was also assessed in subpopulations. The primary endpoint was the change from baseline in seated trough clinic systolic BP (SBP) and diastolic BP (DBP). Results: In the overall population and across all baseline BP categories, T40/H12.5, T80/H12.5, and T80/H25 resulted in additional BP reductions to those provided by telmisartan monotherapy. In patients with baseline SBP ? 170 mmHg, T80/H25 effected a mean SBP change of -39.2 mmHg compared with changes of -25.5 mmHg and -8.3 mmHg observed with T80 and placebo treatment, respectively. Mean DBP changes were -20.4 mmHg T80/H25, -12.2 T80 and -5.9 placebo in patients with baseline DBP ? 105 mmHg. T80/H25 also resulted in larger BP reductions than telmisartan monotherapy in black patients with hypertension, irrespective of baseline BP. In patients with hypertension with type 2 diabetes and in patients with moderate or severe renal impairment, both T80/H12.5 and T80/H25 were more effective than monotherapy in reducing BP in all baseline BP categories. Conclusion: Combination treatment of telmisartan and hydrochlorothiazide results in large and clinically relevant BP reductions additional to those provided by monotherapy.
  • Author:
    Chen S-Y; Siu K; Kovacs B; Stokes M; Rao P; Sander S; Boulanger L
    Title:
    Clinical and economic outcomes associated with national kidney foundation guideline-concordant oral antidiabetic drug treatment among type 2 diabetes patients with chronic kidney disease.
    Source:
    Curr Med Res Opin 28 (4), 493-501 (2012)
  • Author:
    Glund S; Schoelch C; Thomas L; Niessen HG; Stiller D; Roth GJ; Neubauer H
    Title:
    Inhibition of acetyl-CoA carboxylase 2 enhances skeletal muskle fatty acid oxidation and improves whole-body glucose homeostasis in db/db mice.
    Source:
    Diabetologia, 1-10 Article in Press (2012)
  • Author:
    Schernthaner G; Barnett AH; Emser A; Patel S; Troost J; Woerle H-J; von Eynatten M
    Title:
    Safety and tolerability of linagliptin: A pooled analysis of data from randomized controlled trials in 3572 patients with type 2 diabetes melitus.
    Source:
    Diabetes Obes Metab 14 (5), 470-478 (2012)
    Abstract:
    Aims: To assess the safety and tolerability of the dipeptidyl peptidase-4 inhibitor linagliptin in patients with type 2 diabetes. Methods: Data were pooled from eight randomized, double-blind, placebo-controlled Phase III clinical trials lasting ?24 weeks. Incidences were calculated with descriptive statistics for the overall population and for subgroups of elderly and renally impaired patients. Results: A total of 2523 patients received linagliptin 5 mg once daily and 1049 patients received placebo. The overall incidence of adverse events (AEs) or serious AEs with linagliptin was similar to placebo (AEs 55.8% vs. 55.0%; serious AEs 2.8% vs. 2.7%). Overall aggregated infection incidence was 19.5% for linagliptin and 21.4% for placebo. Similar or reduced incidence of AEs versus placebo were seen with linagliptin for upper respiratory tract infection (3.3% vs. 4.9%), headache (2.9% vs. 3.1%), urinary tract infection (2.2% vs. 2.7%), blood and lymphatic disorders (1.0% vs. 1.2%), hypersensitivity (0.1% vs. 0.1%), hepatic enzyme increase (0.1% and 0.1%) and serum creatinine increase (0.0% and 0.1%). There was a slight increased frequency of nasopharyngitis (5.9% vs. 5.1%) and cough (1.7% vs. 1.0%) with linagliptin. Hypoglycaemia incidence was 8.2% for linagliptin and 5.1% for placebo; incidence was higher in patients with a background of sulphonylurea therapy (20.7% and 13.3%, respectively). In patients not receiving concomitant sulphonylurea, the hypoglycaemic incidence with linagliptin was very low in both the total population (<1%), and elderly and renally impaired patients (both <1%). Conclusions: This pooled analysis shows that linagliptin is well tolerated, with a low risk of hypoglycaemia.
  • Author:
    Detournay B; Simon D; Guillausseau P-J; Joly D; Verges B; Attali C; Clement O; Briand Y; Delaitre O
    Title:
    Chronic kidney disease in type 2 diabetes patients in France: Prevalence, influence of glycaemic control and implications for the pharmacological management of diabetes.
    Source:
    Diabetes Metab 38 (2), 102-112 (2012)
    Abstract:
    Aim: Type 2 diabetes mellitus (T2DM) is often associated with chronic kidney disease. For this reason, this article reviews the relationship between treatment of T2DM and renal disease. Method: The review presents the recent French data on the management of diabetes in patients with renal impairment, and discusses the implications of renal disease for the treatment of such patients. Prescribing data are presented for various antidiabetic treatments, and the use of the more commonly prescribed medications is discussed with reference to T2DM patients with renal disease. Results: In France, it is estimated that 4-5% of the general population has T2DM and that almost 40% of patients with end-stage renal failure have diabetes. Diabetes and renal disease are both risk factors for cardiovascular morbidity and mortality. Glycaemic control is pivotal in T2DM patients for minimizing the risk of vascular complications and hypoglycaemic episodes, particularly in patients with renal disease who also have a higher risk of hypoglycaemia. Whereas poorly controlled glycaemia increases the risk of renal disease and its progression, the risk is diminished in patients treated intensively for diabetes and in those who achieve stable glycaemic control. Intensive multitargeted treatment can also help to decrease cardiovascular morbidity and mortality, especially if started early in patients who have not yet developed macrovascular complications. Conclusion: In recent years, considerable improvement has been observed in France regarding the follow-up of diabetic patients. Less extensive, but nonetheless significant, improvement has also been observed in glycaemic control. However, even though treatment decisions generally take renal function into account, some at-risk treatments are often still being used in patients with renal insufficiency.
  • Author:
    Grempler R; Augustin R; Froehner S; Hildebrandt T; Simon E; Mark M; Eickelmann P
    Title:
    Functional characterization of human SGLT-5 as a novel kidney-specific sodium-dependent sugar transporter.
    Source:
    FEBS Lett 586 (3), 248-253 (2012)
    Abstract:
    Sodium-dependent sugar transporters (SGLT) actively catalyse carbohydrate transport across cellular membranes. Six of the 12 known SGLT family members have the capacity to bind and/or transport monosaccharides (SGLT-1 to 6); of these, all but SGLT-5 have been characterised. Here we demonstrate that human SGLT-5 is exclusively expressed in the kidney. Four splice variants were detected and the most abundant SGLT-5-mRNA was functionally characterised. SGLT-5 mediates sodium-dependent [ 14C]-?-methyl-d-glucose (AMG) transport that can be inhibited by mannose, fructose, glucose, and galactose. Uptake studies using demonstrated high capacity transport for mannose and fructose and, to a lesser extent, glucose, AMG, and galactose. The transport of mannose, fructose or AMG was inhibited by SGLT-2 inhibitors. In summary, we have characterised SGLT-5 as a kidney mannose transporter.
  • Author:
    Stopfer P; Marzin K; Narjes H; Gansser D; Shahidi M; Uttenreuther-Fischer M; Ebner T
    Title:
    Afatinib pharmacokinetics and metabolism after oral administration to healthy male volunteers.
    Source:
    Cancer Chemother Pharmacol 69 (4), 1051-1061 (2012)
    Abstract:
    Purpose: To investigate the pharmacokinetics, metabolism and tolerability of afatinib (BIBW 2992), an oral irreversible ErbB family blocker, in healthy male volunteers. Methods: In this open-label, single-center study, 8 healthy male volunteers received a single oral dose of 15 mg [14C]-radiolabeled afatinib (equivalent to 22.2 mg of the dimaleinate salt) as a solution. Blood, urine and fecal samples were collected for at least 96 hours (h) after dosing. Plasma and urine concentrations of afatinib were analyzed using high-performance liquid chromatography-tandem mass spectrometry. [14C]-radioactivity levels in plasma, whole blood, urine and feces were measured by liquid scintillation counting methods. Metabolite patterns were assessed by high-performance liquid chromatography. Results: [14C]-radioactivity was mainly excreted via feces (85.4%). Overall recovery of [14C]-radioactivity was 89.5%, indicative of a complete mass balance. Afatinib was slowly absorbed, with maximum plasma concentrations achieved at a median of 6 h after dosing, declining thereafter in a biexponential manner. The geometric mean terminal half-life of afatinib was 33.9 h in plasma and longer for [14C]-radioactivity in plasma and whole blood. Apparent total body clearance for afatinib was high (geometric mean 1,530 mL/min). The high volume of distribution (4,500 L) in plasma may indicate a high tissue distribution. Afatinib was metabolized to only a minor extent, with the main metabolite afatinib covalently bound to plasma proteins. Oxidative metabolism mediated via cytochrome P-450 was of negligible importance for the elimination of afatinib. Afatinib was well tolerated. Conclusions: Afatinib displayed a complete mass balance with the main route of excretion via feces. Afatinib undergoes minimal metabolism.
  • Author:
    Thomas L; Grempler R; Eckhardt M; Himmelsbach F; Sauer A; Klein T; Eickelmann P; Mark M
    Title:
    Long-term treatment with empagliflozin, a novel, potent and selective SGLT-2 inhibitor, improves glycaemic control and features of metabolic syndrome in diabetic rats.
    Source:
    Diabetes Obes Metab 14 (1), 94-96 (2012)
    Abstract:
    Empagliflozin is a potent, selective sodium glucose co-transporter-2 inhibitor that is in development for the treatment of type 2 diabetes. This series of studies was conducted to assess the in vivo pharmacological effects of single or multiple doses of empagliflozin in Zucker diabetic fatty rats. Single doses of empagliflozin resulted in dose-dependent increases in urinary glucose excretion and reductions in blood glucose levels. After multiple doses (5 weeks), fasting blood glucose levels were reduced by 26 and 39% with 1 and 3 mg/kg empagliflozin, respectively, relative to vehicle. After 5 weeks, HbA1c levels were reduced (from a baseline of 7.9%) by 0.3 and 1.1% with 1 and 3 mg/kg empagliflozin, respectively, versus an increase of 1.1% with vehicle. Hyperinsulinaemic-euglycaemic clamp indicated improved insulin sensitivity with empagliflozin after multiple doses versus vehicle. These findings support the development of empagliflozin for the treatment of type 2 diabetes.
  • Author:
    Grempler R; Thomas L; Eckhardt M; Himmelsbach F; Sauer A; Sharp DE; Bakker RA; Mark M; Klein T; Eickelmann P
    Title:
    Empagliflozin, a novel selective sodium glucose cotransporter-2 (SGLT-2) inhibitor: Characterisation and comparison with other SGLT-2 inhibitors.
    Source:
    Diabetes, Obes Metab 14 (1), 83-90 (2012)
    Abstract:
    Aims: Empagliflozin is a selective sodium glucose cotransporter-2 (SGLT-2) inhibitor in clinical development for the treatment of type 2 diabetes mellitus. This study assessed pharmacological properties of empagliflozin in vitro and pharmacokinetic properties in vivo and compared its potency and selectivity with other SGLT-2 inhibitors. Methods: [14C]-alpha-methyl glucopyranoside (AMG) uptake experiments were performed with stable cell lines over-expressing human (h) SGLT-1, 2 and 4. Two new cell lines over-expressing hSGLT-5 and hSGLT-6 were established and [14C]-mannose and [14C]-myo-inositol uptake assays developed. Binding kinetics were analysed using a radioligand binding assay with [3H]-labelled empagliflozin and HEK293-hSGLT-2 cell membranes. Acute in vivo assessment of pharmacokinetics was performed with normoglycaemic beagle dogs and Zucker diabetic fatty (ZDF) rats. Results: Empagliflozin has an IC50 of 3.1 nM for hSGLT-2. Its binding to SGLT-2 is competitive with glucose (half-life approximately 1 h). Compared with other SGLT-2 inhibitors, empagliflozin has a high degree of selectivity over SGLT-1, 4, 5 and 6. Species differences in SGLT-1 selectivity were identified. Empagliflozin pharmacokinetics in ZDF rats were characterised by moderate total plasma clearance (CL) and bioavailability (BA), while in beagle dogs CL was low and BA was high. Conclusions: Empagliflozin is a potent and competitive SGLT-2 inhibitor with an excellent selectivity profile and the highest selectivity window of the tested SGLT-2 inhibitors over hSGLT-1. Empagliflozin represents an innovative therapeutic approach to treat diabetes.
  • Author:
    Shi X-J; Zeng P; Patel S
    Title:
    Pharmacokinetics of single and multiple oral doses of 5 mg linagliptin in healthy chinese volunteers.
    Source:
    J Clin Pharmacol 50 (12), 889-895 (2012)
    Abstract:
    Abstract Objective: To investigate the pharmacokinetic and safety profile of linagliptin after single and multiple doses in healthy Chinese volunteers. Methods: Men and women (n = 12) aged 18-45 years with body mass index 19-24 kg/m 2 received a single 5-mg dose of linagliptin an Day 1, followed by 7-day washout and 6 consecutive days of once-daily administration. Vital signs, electrocardiogram, routine laboratory tests, urinalysis, and adverse events were recorded. Blood and urine analytes were measured by HPLC/MS/MS. Results: Linagliptin was rapidly absorbed; median time to maximum concentration was 1.75 h for single dose and 1.5 hours at steady-state. Maximum plasma drug concentration (C max) after single dose was 4.9 ng/ml (10.4 nM), with a geometric coefficient of variation (gCV) 46%. The corresponding geometric mean area under the plasma concentrationtime curve (AUC) was 71 ngxh ml -1 (150 nmolxh I -1, gCV 25%). At steady-state, C max and AUC were 6.7 ng/ml (14.1 nM, gCV 49%) and 96 nmolxh I -1 (204 nmolxh I -1, gCV 25%). An accumulation half-life of 1311.5 h (gCV 46.9%) was calculated. Renal excretion of linagliptin was low and &lt; 8% of administered dose at steady-state (&lt; 2% at Day 1). Single and multiple daily oral doses of 5 mg linagliptin were safe and well tolerated. No adverse events or clinically significant changes in laboratory tests, vital signs, or physical examination were reported. Conclusions: Linagliptin demonstrated a favorable safety profile in healthy Chinese volunteers, with a pharmacokinetic profile that was similar to that observed previously in subjects of Japanese, Caucasian, or African American origin. ©2012 Dustri-Verlag Dr. K. Feistle.