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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.

69 publications regarding Metabolism
  • 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; Pfeilschiffer 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)
  • 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 47, 1-11 Article in Press (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 Article in Press (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)
  • Author:
    Haak T; Meinicke T; Jones R; Weber S; Eynatten MV; Woerle HJ
    Title:
    Initial combination of linagliptn and metformin improveas 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; Retich 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)
  • 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 effi cacy 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:
    Owens DR; Swallow R; Dugi KA; Worle HJ
    Title:
    Efficacy and safety of linagliptin in persons with type 2 diabetes inadequately controlled by a combination of metformin and sulphonylurea: a 24-week randomized study.
    Source:
    Diabetic Med 28 (11), 1352-1361 (2011)
  • 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:
    Owens DR; Swallow R; Dugi KA; Woerle HJ
    Title:
    Efficacy and safety of linagliptin in persons with type 2 diabetes inadequately controlled by a combination of metformin and sulphonylurea: a 24-week randomized study(1).
    Source:
    Diabetic Med 28 (11), 1352-1361 (2011)
  • 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:
    Lee CA; Bentz J; O´Connor M; Palm J; Ellens H; Heredi-Szabo K; Bednarczyk D; Taub M; Perloff ES; Funk Ch; Balimane P; Salphati L; Guo A; Podila L; Hanna I; Xia C; Li L; Xiao G; Wortelboer HM; Weitz D; Pak YA; Reyner E; Taur J; Chu X; Gradhand U; Warren M; Rajaraman G; Zhang L
    Title:
    Application of receiver operating characteristics to assess digoxin drug interaction potential.
    Source:
    Drug Metab Rev 43 (Supp.2), 190-191 (2011)
  • Author:
    Chan TS; Khetani S; Moore A; Yu H
    Title:
    Accurate prediction of hepatic clearance for low-clearance compounds using micropatterned hepatocyte-stromal cell co-cultures (HepatoPac (R)).
    Source:
    17th North American Regional International Society for the Study of Xenobiotics (ISSX) Meeting, Atlanta (United States), Oct 16-20, 2011.Drug Metab Rev 43 (Suppl.2), 48 (2011)
  • Author:
    Barzilay JI; Gao P; Ryden L; Schumacher H; Probstfield J; Commerford P; Dans A; Ferreira R; Keltai M; Paolasso E; Yusuf S; Teo K
    Title:
    Effects of telmisartan on glucose levels in people at high risk for cardiovascular disease but free from diabetes the transcend study.
    Source:
    Diabetes Care 34 (9), 1902-1907 (2011)
    Abstract:
    OBJECTIVE-Several large clinical trials suggest that ACE inhibitors may reduce the incidence of diabetes. Less is known about the effects of angiotensin receptor blockers (ARBs) on reducing incident diabetes or leading to regression of impaired fasting glucose (IFG) or impaired glucose tolerance (IGT) to normoglycemia. RESEARCH DESIGN AND METHODS-Participants were 3,488 adults at high risk for cardiovascular disease but free from diabetes (mean age 67 years; 61% male) in the Telmisartan Randomized Assessment Study in ACE Intolerant Subjects With Cardiovascular Disease (TRANSCEND) study. The participants were randomized to the ARB telmisartan 80 mg (n = 1,726) or placebo (n = 1,762) in addition to usual care. RESULTS-During a median 56 months, 21.8% of participants treated with telmisartan and 22.4% of those on placebo developed diabetes (relative ratio 0.95 [95% CI 0.83-1.10]; P = 0.51). Participants originally diagnosed with IFG and/or IGT were equally likely to regress to normoglycemia (26.9 vs. 24.5%) or to progress to incident diabetes (20.1 vs. 21.1%; P = 0.59) on telmisartan or placebo. CONCLUSIONS-There was no evidence that addition of the ARB telmisartan to usual care prevents incident diabetes or leads to regression of IFG or IGT in people at high risk for cardiovascular disease but free from diabetes.
  • Author:
    Guthrie RM; Dahloef B; Jamerson KA; Olvera R; Seeber M; Schumacher H; Oigman W
    Title:
    Efficacy and tolerability of telmisartan plus amlodipine in added-risk hypertensive patients.
    Source:
    Curr Med Res Opin 27 (10), 1995-2008 (2011)
    Abstract:
    Objectives: Added-risk hypertensive patients with co-morbidities such as diabetes and metabolic syndrome often require two or more antihypertensives to achieve blood pressure (BP) targets. The aim of this sub-analysis was to determine the efficacy and safety of telmisartan 40 or 80mg plus amlodipine 5 or 10mg in patients with hypertension, stratified according to certain criteria such as type 2 diabetes mellitus and metabolic syndrome. Methods: Patients were treated for 8 weeks with telmisartan 2080mg plus amlodipine 2.510mg. This post-hoc analysis included patients treated with higher doses, and stratified according to a number of sub-populations (age, race, diabetes, obesity, metabolic syndrome, elevated baseline systolic BP (SBP), renal impairment). Results: Eight weeks' treatment with telmisartan plus amlodipine combinations provided consistent reductions in mean SBP/diastolic BP (DBP) across the different sub-populations, similar to the overall population. SBP/DBP reductions ranged from-13.5 to-34.7/-12.6 to-26.1mmHg and BP goal rates (<140/90mmHg) ranged from 29.8100% for the four key dose combinations of telmisartan plus amlodipine. For the highest dose combination of telmisartan 80mg plus amlodipine 10mg, SBP/DBP reduction ranged from-19.1 to-34.7/-16.4 to-22.8mmHg and goal attainment rate from 66.7% to 87.0%. Across the sub-populations, high SBP and DBP response rates were seen with combination treatment (83.397.7% and 75.095.7%, respectively, with telmisartan 80mg plus amlodipine 10mg). The combination was safe and well tolerated across all sub-populations and the incidence of peripheral oedema with telmisartan 4080mg plus amlodipine 10mg was generally lower than with A10 monotherapy. Conclusions: Despite small patient numbers in some sub-populations and the post-hoc nature of the analysis, this does show that the combination of telmisartan plus amlodipine provides an effective, safe and well-tolerated antihypertensive treatment for added-risk hypertensive patients. - Derwent Abstract - This study evaluated the efficacy and tolerability of telmisartan + amlodipine in 1461 added-risk hypertensive patients. 8 Wk treatment with telmisartan (20-80 mg) + amlodipine (2.5-10 mg) combinations provided consistent reductions in mean systolic B.P. (SBP)/diastolic B.P. (DBP) across the different sub-populations similar to the overall population. Across the sub-populations, high SBP and DBP response rates were seen with combination treatment. The combination was safe and well tolerated across all sub-populations and the incidence of peripheral edema with telmisartan + amlodipine was generally low. Thus, the combination of telmisartan + amlodipine provides an effective safe and well-tolerated antihypertensive treatment for added-risk hypertensive patients.
  • Author:
    Friedrich Ch; Glund St; Lionetti D; Kissling J; Righetti J; Patel S
    Title:
    Pharmacokinetics and pharmacodynamics evaluation of linagliptin in african american patients with type 2 diabetes.
    Source:
    40th Annual Meeting of the American College of Clinical Pharmacology, Chicago (United States), Sep 11-13, 2011.J Clin Pharmacol 51 (9), 1336 (2011)
    Abstract:
    This open label, phase-I study evaluated the safety, pharmacokinetics and pharmacodynamics (PK/PD) linagliptin (p.o.) in 41 patients with type 2 diabetes (T2D). No safety concerns were identified. No clinically meaningful differences in the PK/PD properties of linagliptin in African American patients were observed compared to those previously seen in Caucasian and Asian subjects. In conclusion, these findings support the 5 mg dose as the recommended dose for controlling blood glucose levels in African American patients with T2D. Methods 41 African American patients (22 men, mean age 51 yr) with T2D were treated daily with linagliptin (5 mg tablets, p.o.) for 7 days; full PK profiles were obtained on days 1 and 7. Results Linagliptin was rapidly absorbed with median time to maximum concentration (Tmax) values of 1.5 hr (day 1 and steady state). Single dose Cmax and AUC were 10.9 nmol/L and 137 nmol/L*hr. AUC at steady stale was 194 nmol/L*hr (26%) with a Cmax of 16.4 nmol/L (41%) and a terminal half-life of 119 hr. However, accumulation factors for AUC and Cmax were only 1.40 and 1.49. The accumulation half-life was calculated to be 13.1 hr. Linagliptin urinary excretion was low (0.5% mid 4.4% of the dose excreted over 24 hr, days 1 and 7). Dipeptidyl peptidase (DPP)-4 trough inhibition at steady state was 84.2%. Steady state exposure was within the range observed in Caucasian, Japanese and Chinese healthy subjects, though somewhat increased compared to Caucasian T2D patients. Multiple dosing of 5 mg linagliptin led to >80% (DPP)-4 inhibition at trough, comparable to that in Japanese healthy subjects and Caucasian T2D patients.
  • Author:
    Friedrich Ch; Shi X-J; Zeng P; Ring A; Woerle H-J; Patel S
    Title:
    Pharmacokinetic of single and multiple oral doses of 5 mg linagliptin in healthy chinese volunteers.
    Source:
    40th Annual Meeting of the Amerian College of Clinical Pharmacology, Chicago (United States), Sep 11-13, 2011.J Clin Pharmacol 51 (9), 1336-1337 ( 2011)
    Abstract:
    This phase I, single-center, open-label study evaluated the single and multiple dose pharmacokinelics (PK) and safety of linagliptin in 12 healthy volunteers. Single and multiple daily p.o. doses of linagliptin were safe and well tolerated. In conclusion, these findings support the 5 mg dose as the recommended dose him controlling blood glucose levels in Chinese patients with type 2 diabetes mellitus. Methods 12 Healthy subjects (6 men, age 18-45 yr, mean age 24 yr) received a single 5 mg dose of linagliptin on day 1, followed by a 7-day washout, then 6 consecutive days of once-daily administration. Results Linagliptin was rapidly absorbed with median. Tmax values of 1.75 hr (single dose) and 1.5 hr (steady state). Geometric mean area under the concentration curve (AUC) at steady state was 204 nM*hr and the maximum plasma concentration (Cmax) was 14.1 nM (49.4%). Single dose exposure was 10.4 nM (Cmax) and 658 nM*hr (AUC). A long terminal half-life of 82-103 hr was observed after the first and the last dose, which did not change over time. However, this did not represent the accumulation hall-life, since low accumulation factors of 1.35 were observed for both AUC and Cmax. An accumulation half-life of 11.5 hr was calculated. The renal excretion of linagliptin was low and accounted for <8% of the administered dose at steady state (<2% at day 1). No adverse events (AEs), clinically significant changes in laboratory tests, vital signs, or physical examination were reported. The rate and extent of steady state exposure observed in this study was similar to data previously observed in Caucasian, black/African American, and Japanese subjects.
  • 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 51 (9), 1336-1337 (2011)
  • Author:
    Yamada A; Maeda K; Ishiguro N; Tsuda Y; Igarashi T; Ebner Th; Roth W; Ikushiro S; Sugiyama Y
    Title:
    The impact of pharmacogenetics of metabolic enzymes and transporters on the pharmacokinetics of telmisartan in healthy volunteers.
    Source:
    Pharmacogenet Genomics 21 (9), 523-530 (2011)
    Abstract:
    OBJECTIVE: Telmisartan is mainly taken up into the liver by organic anion transporting polypeptide (OATP) 1B3, conjugated with glucuronate, and excreted into the bile. We investigated the relationship between genotypes of metabolizing enzymes and transporters and pharmacokinetics of telmisartan in clinical study. We also checked which enzymes are responsible for telmisartan glucuronidation. MATERIALS AND METHODS: We collected blood samples from 57 healthy volunteers who had participated in a clinical trial of telmisartan and examined the relationship between 14 mutations in six transporters/metabolic enzymes and pharmacokinetics of telmisartan. We also performed an in-vitro glucuronidation assay with recombinant uridine 5'-diphospho-glucuronosyltransferases isoforms and human liver microsomes. RESULTS: In the clinical study, area under the plasma concentration-time curve value from time zero to infinity, of telmisartan in heterozygotes of SLCO1B3 (encoding protein: OATP1B3) rs11045585 tended to be larger than that in homozygotes of wild-type alleles. Unexpectedly, 19 heterozygotes of UGT1A1*28, whose function was decreased, significantly increased its oral clearance compared with homozygotes of UGT1A1*1 alleles (1090.+-.690 vs. 620.+-.430 ml/min/body). Metabolic clearance of telmisartan in human liver microsomes obtained from individuals with UGT1A1*28/*28 was higher compared with that of UGT1A1*1/*1 (168.+-.33 vs. 93.3.+-.27.3 .mu.l/min/mg protein). Although telmisartan was metabolized by multiple UGT isoforms, in-vitro experiments revealed that UGT1A3 was estimated to be predominantly involved in telmisartan glucuronidation in human hepatocytes. CONCLUSION: UGT1A1*28 was thought to enhance the protein expression of UGT1A3 as reported most recently (Riedmaier et al. Clin Pharmacol Ther 2010; 87:65-73) and thereby increase glucuronidation activity of telmisartan and decrease the plasma concentration of telmisartan.
  • Author:
    Friedrich Ch; Port A; Ring A; Graefe-Mody U; Giessmann Th; Iovino M; Woerle H-J
    Title:
    Effect of multiple oral doses of linagliptin on the steady-state pharmacokinetics of a combination oral contraceptive in healthy female adults: an open-label, two-period, fixed-sequence, multiple-dose study.
    Source:
    Clin Drug Invest 31 (9), 643-653 (2011)
    Abstract:
    Background: Linagliptin is an oral dipeptidyl peptidase (DPP)-4 inhibitor that has been recently approved for the treatment of type 2 diabetes mellitus. Microgynon.RTM. 30 is a combined oral contraceptive pill containing both ethinylestradiol 30 .mu.g and levonorgestrel 150 .mu.g (EE 30 .mu.g/LNG 150 .mu.g). Objective: The objective of this study was to determine the effect of multiple doses of linagliptin (5 mg once daily) on the steady-state pharmacokinetics of EE and LNG following once-daily doses of EE 30 .mu.g/LNG 150 .mu.g. Methods: This was an open-label, two-period, fixed-sequence, multiple-dose study, consisting of a run-in period, a 14-day reference treatment period and a 7-day test treatment period. The study recruited 18 healthy pre-menopausal female subjects aged 18-40 years with a body mass index of 18.5-27.0 kg/m2. Only women with regular menstrual cycles were included in this study. The treatment sequence was divided into three steps: an individually tailored run-in period with EE 30 .mu.g/LNG 150 .mu.g to synchronize the menstrual cycles of the subjects followed by a washout period of 7 days; the reference treatment period, during which EE 30 .mu.g/LNG 150 .mu.g alone was taken on days 1-14; and the test treatment period, during which EE 30 .mu.g/LNG 150 .mu.g plus linagliptin were taken on days 15-21. The pharmacokinetic parameters measured were maximum steady-state plasma concentration during a dosage interval (C(max,ss)), time to reach maximum plasma concentration following administration at steady state (t(max,ss)) and area under the plasma concentration-time curve during a dosage interval (.tau.) at steady state (AUC(.tau.,ss)). Results: The AUC(.tau.,ss) and C(max,ss) of EE and LNG were comparable when EE 30 .mu.g/LNG 150 .mu.g was given alone or combined with linagliptin. The adjusted geometric mean ratios for AUC(.tau.,ss) and C(max,ss) of EE following EE 30 .mu.g/LNG 150 .mu.g plus linagliptin versus EE 30 .mu.g/LNG 150 .mu.g alone were 101.4 (90% CI 97.2, 105.8) and 107.8 (90% CI 99.7, 116.6), respectively. The adjusted geometric mean ratios for AUC(.tau.,ss) and C(max,ss) of LNG following EE 30 .mu.g/LNG 150 .mu.g plus linagliptin versus EE 30 .mu.g/LNG 150 .mu.g alone were 108.8 (90% CI 104.5, 113.3) and 113.5 (90% CI 106.1, 121.3), respectively. The combination was well tolerated. Conclusion: Linagliptin had no clinically relevant effect on the steady-state pharmacokinetics of EE and LNG in healthy female subjects, and the combination of EE 30 .mu.g/LNG 150 .mu.g and linagliptin was well tolerated in this study. Therefore, linagliptin has the potential to be used in the treatment of female patients with type 2 diabetes in combination with oral contraceptives containing these components, such as EE 30 .mu.g/LNG 150 .mu.g. Trial registration: The EudraCT number for this study is 2008-000953-37. - DERWENT Abstract - This open-label, 2-period, fixed-sequence, multiple-dose study evaluated the effects of linagliptin (LP; Boehr. Ingelheim) on the steady-state pharmacokinetics of ethinylestradiol (EE) and levonorgestrel (LG; both Microgynon, Bayer, all p.o.) in 18 healthy adults. Area under the plasma concentration-time curve during a dosage interval at steady state (AUCtauss) and maximum steady-state plasma concentration during a dosage interval (Cmax,ss) of EE and LG were comparable when EE/LG was given alone or combined with LP. Adjusted geometric mean ratios for AUCtauss and Cmax,ss of EE following EE/LG + LP vs. EE/LG alone were 101.4 and 107.8. The adjusted geometric mean ratios for AUCtauss and Cmax,ss of LG following EE/LG + LP vs. EE/LG alone were 108.8 and 113.5. LP has the potential to be used in the treatment of female patients with type 2 diabetes in combination with EE and LG. Methods 18 Healthy female adults (mean age 29.3 yr) were treated with EE (30 ug) + LG (150 ug) on days 1-21 followed by LP (5 mg/day; all p.o.) on days 15-21. Results Following administration of EE + LG alone, plasma concentrations of EE and LG increased rapidly, with a median time to reach maximum plasma concentration following administration at steady state (tmax,ss) of 1.00 hr for both EE and LG analytes. Co-administration with LP did not affect median tmax,ss for LG and slightly delayed tmax,ss for EE with a median value of 1.25 hr on day 21. Following maximum plasma concentration, EE showed bi-exponential elimination profiles with a rapid disposition phase until about 6 hr after drug administration, followed by a 2nd slower disposition phase. The plasma concentration-time profiles for both EE and LG were similar, regardless of whether EE/LG was administered alone or combined with LP. The geometric mean AUCtauss and Cmax,ss of LG were slightly higher when EE/LG and LP were co-administered for 7 days vs. EE/LG alone. However, the 90% CI for each pharmacokinetic parameter comparison of both EE and LG analytes were within the limits of 80-125%, which were considered as acceptance limits for bioequivalence. Geometric mean plasma concentrations of LP at trough on days 18, 19, 20 and 21 were 4.3, 4.3, 4.2 and 3.8 nM, respectively, and the geometric mean plasma concentrations at 1, 1.5 and 2 hr after drug administration on day 21 were 8.9, 7.9 and 7.9 nM, respectively. EE + LG + LP were well tolerated. The most commonly reported drug-related adverse event was headache. Other adverse events were vomiting, pruritus, dry eyes, nausea and metrorrhagia.
  • Author:
    Troost J; Tatami Sh; Tsuda Y; Mattheus M; Mehlburger L; Wein M; Michel MC
    Title:
    Effects of strong CYP2D6 and 3A4 inhibitors, paroxetine and ketoconazole, on the pharmacokinetics and cardiovascular safety of tamsulosin.
    Source:
    Br J Clin Pharmacol 72 (2), 247-256 (2011)
    Abstract:
    WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT .bul. Tamsulosin metabolism involves both CYP2D6 and 3A4. However, data on potential drug-drug interactions between tamsulosin and inhibitors of CYP2D6 and 3A4 are limited and information on potential pharmacodynamic consequences of such pharmacokinetic interactions is missing. WHAT THIS STUDY ADDS .bul. This study provides information on the drug-drug interactions of tamsulosin with strong CYP2D6 and strong CYP3A4 inhibitors after single dose administration in healthy subjects. AIM To determine the effect of the strong CYP2D6 inhibitor paroxetine and strong CYP3A4 inhibitor ketoconazole on the pharmacokinetics and safety (orthostatic challenge) of tamsulosin. METHODS Two open-label, randomized, two-way crossover studies were conducted in healthy male volunteers (extensive CYP2D6 metabolizers). RESULTS Co-administration of multiple oral doses of 20 mg paroxetine once daily with a single oral dose of the 0.4 mg tamsulosin HCl capsule increased the adjusted geometric mean (gMean) values of C(max) and AUC(0,.infin.) of tamsulosin by factors of 1.34 (90% CI 1.21, 1.49) and 1.64 (90% CI 1.44, 1.85), respectively, and increased the terminal half-life (t(1/2) ) of tamsulosin HCl from 11.4 h to 15.3 h. Co-administration of multiple oral doses of 400 mg ketoconazole once dailywith a single oral dose of the 0.4 mg tamsulosin increased the gMean values of C(max) and AUC(0,.infin.) of tamsulosin by a factor of 2.20 (90% CI 1.96, 2.45) and 2.80 (90% CI 2.56, 3.07), respectively. The terminal half-life was slightly increased from 10.5 h to 11.8 h. These pharmacokinetic changes were not accompanied by clinically significant alterations of haemodynamic responses during orthostatic stress testing. CONCLUSION The exposure to tamsulosin is increased upon co-administration of strong CYP2D6 inhibitors and even more so of strong 3A4 inhibitors, but neither PK alteration was accompanied by clinically significant haemodynamic changes during orthostatic stress testing. - DERWENT Abstract - To determine the effect of the strong CYP2D6 inhibitor paroxetine and strong CYP3A4 inhibitor ketoconazole on the pharmacokinetics and safety (orthostatic challenge) of tamsulosin. METHODS Two open-label, randomized, two-way crossover studies were conducted in healthy male volunteers (extensive CYP2D6 metabolizers). RESULTS Co-administration of multiple oral doses of 20 mg paroxetine once daily with a single oral dose of the 0.4 mg tamsulosin HCl capsule increased the adjusted geometric mean (gMean) values of C-max and AUC(0,infinity) of tamsulosin by factors of 1.34 (90% CI 1.21, 1.49) and 1.64 (90% CI 1.44, 1.85), respectively, and increased the terminal half-life (t(1/2)) of tamsulosin HCl from 11.4 h to 15.3 h. Co-administration of multiple oral doses of 400 mg ketoconazole once dailywith a single oral dose of the 0.4 mg tamsulosin increased the gMean values of C-max and AUC(0,infinity) of tamsulosin by a factor of 2.20 (90% CI 1.96, 2.45) and 2.80 (90% CI 2.56, 3.07), respectively. The terminal half-life was slightly increased from 10.5 h to 11.8 h. These pharmacokinetic changes were not accompanied by clinically significant alterations of haemodynamic responses during orthostatic stress testing. CONCLUSION The exposure to tamsulosin is increased upon co-administration of strong CYP2D6 inhibitors and even more so of strong 3A4 inhibitors, but neither PK alteration was accompanied by clinically significant haemodynamic changes during orthostatic stress testing. - DERWENT Abstract - AIMTo determine the effect of the strong CYP2D6 inhibitor paroxetine and strong CYP3A4 inhibitor ketoconazole on the pharmacokinetics and safety (orthostatic challenge) of tamsulosin.METHODSTwo open-label, randomized, two-way crossover studies were conducted in healthy male volunteers (extensive CYP2D6 metabolizers).RESULTSCo-administration of multiple oral doses of 20 mg paroxetine once daily with a single oral dose of the 0.4 mg tamsulosin HCl capsule increased the adjusted geometric mean (gMean) values of C-max and AUC(0,infinity) of tamsulosin by factors of 1.34 (90% CI 1.21, 1.49) and 1.64 (90% CI 1.44, 1.85), respectively, and increased the terminal half-life (t(1/2)) of tamsulosin HCl from 11.4 h to 15.3 h. Co-administration of multiple oral doses of 400 mg ketoconazole once dailywith a single oral dose of the 0.4 mg tamsulosin increased the gMean values of C-max and AUC(0,infinity) of tamsulosin by a factor of 2.20 (90% CI 1.96, 2.45) and 2.80 (90% CI 2.56, 3.07), respectively. The terminal half-life was slightly increased from 10.5 h to 11.8 h. These pharmacokinetic changes were not accompanied by clinically significant alterations of haemodynamic responses during orthostatic stress testing.CONCLUSIONThe exposure to tamsulosin is increased upon co-administration of strong CYP2D6 inhibitors and even more so of strong 3A4 inhibitors, but neither PK alteration was accompanied by clinically significant haemodynamic changes during orthostatic stress testing. - DERWENT Abstract - Tamsulosin metabolism involves both CYP2D6 and 3A4. However, data on potential drug-drug interactions between tamsulosin and inhibitors of CYP2D6 and 3A4 are limited and information on potential pharmacodynamic consequences of such pharmacokinetic interactions is missing. This paper presented 2 open-label, randomized, crossover studies that determined the effect of the strong CYP2D6 inhibitor paroxetine p.o. (Seroxat, GlaxoSmithKline) and strong CYP3A4 inhibitor ketoconazole on the pharmacokinetics and safety (orthostatic challenge) of p.o. tamsulosin HCl (Alna, BI Austria) in 24 healthy subjects. The exposure to tamsulosin was increased upon co-administration of strong CYP2D6 inhibitors and even more so of strong 3A4 inhibitors, but neither PK alteration was accompanied by clinically significant hemodynamic changes during orthostatic stress testing. Methods 24 Healthy male volunteers were studied. Treatment A of both studies consisted of a single p.o. dose of 0.4 mg tamsulosin. Treatment B in the paroxetine study consisted of 10 mg paroxetine once daily for 3 days, the 20 mg paroxetine once daily for 9 days to achieve steady state and full CYP2D6 inhibitions and finally 10 mg paroxetine once daily for 3 days as taper out regimen. Results Co-administration of multiple p.o. doses of 20 mg paroxetine once daily with a single p.o. dose of the 0.4 mg tamsulosin HCl capsule increased the adjusted geometric mean (gMean) values of Cmax and AUC(0,infinity) of tamsulosin by factors of 1.34 and 1.64, respectively, and increased the terminal half-life of tamsulosin HCl from 11.4 hr to 15.3 hr. Co-administration of multiple p.o. doses of 400 mg ketoconazole once daily with a single p.o. dose of the 0.4 mg tamsulosin increased the gMean values of Cmax and AUC(0,infinity) of tamsulosin by a factor of 2.20 and 2.80, respectively. The terminal half-life was slightly increased from 10.5 hr to 11.8 hr. These pharmacokinetic changes were not accompanied by clinically significant alterations of hemodynamic responses during orthostatic stress testing. There were no serious or severe adverse events reported.
  • Author:
    Ring A; Port A; Graefe-Mody EU; Revollo I; Iovino M; Dugi KA
    Title:
    The DPP-4 inhibitor linagliptin does not prolong the QT interval at therapeutic and supratherapeutic doses.
    Source:
    Br J Clin Pharmacol 72 (1), 39-50 (2011)
    Abstract:
    WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT .bul. Linagliptin (BI 1356) is an oral, highly selective dipeptidyl peptidase-4 inhibitor which is under development for the treatment of type 2 diabetes mellitus and for which the pivotal phase III programme has recently been completed. .bul. There have been no observed electrocardiogram changes in a linagliptin single rising dose study with up to 600 mg, and no preclinical signals for QT liability. WHAT THIS STUDY ADDS .bul. This manuscript describes the findings of a thorough QT study for linagliptin conducted according to the ICH E14 guideline, with a therapeutic dose (5 mg) and a 20-fold therapeutic dose (100 mg). .bul. Linagliptin does not cause clinically relevant changes of the corrected QT interval with a therapeutic dose and a 20-fold therapeutic dose. .bul. The 20-fold therapeutic dose of linagliptin was safe and well tolerated. AIM To evaluate the potential effects of therapeutic and supratherapeutic doses of linagliptin (BI 1356) on the QT/QT(c) interval in healthy subjects. METHODS The study was a randomized, double-blind, placebo-controlled, four-period crossover study using single oral doses of linagliptin (5 mg and 100 mg), moxifloxacin (400 mg) and placebo. Electrocardiogram (ECG) profiles using triplicates of 12-lead 10-s ECGs were digitally recorded pre-dose and after drug administration. The mean change from baseline (MCfB) of the individually heart rate corrected QT interval (QT(c) I) between 1 and 4 h postdrug administration was the primary end point. Blood samples to measure plasma concentrations of linagliptin and its main metabolite were also obtained. RESULTS Forty-four Caucasian subjects (26 male) entered the study and 43 subjects completed the study as planned in the protocol. Linagliptin was not associated with an increase in the baseline-adjusted mean QT(c) I, at any time point. The placebo-corrected MCfB of QT(c) I was -1.1 (90% CI -2.7, 0.5) ms and -2.5 (-4.1, -0.9) ms for linagliptin 5 mg and 100 mg, respectively, thus within the non-inferiority margin of 10 ms according to ICH E14. Linagliptin was well tolerated; the assessment of ECGs and other safety parameters gave no clinically relevant findings at either dose tested. Maximum plasma concentrations after administration of 100-mg linagliptin were .apprx.24-fold higher than those observed previously for chronic treatment with the therapeutic 5-mg dose. Assay sensitivity was confirmed by a placebo-corrected MCfB of QT(c) I with moxifloxacin of 6.9 (90% CI 5.4, 8.5) ms. CONCLUSIONS Therapeutic and significantly supratherapeutic exposure to linagliptin is not associated with QT interval prolongation. - DERWENT Abstract - The Authors evaluated the potential effects of therapeutic and supratherapeutic single p.o. doses of DPP-4 inhibitor linagliptin (BI-1356) on the QT/QT interval in a randomized, double-blind, placebo-controlled, 4-period crossover, thorough QT study of 44 healthy Caucasian subjects. Therapeutic (5 mg) and 20-fold supratherapeutic exposure (100 mg) to linagliptin was not associated with QT interval prolongation. The 20-fold therapeutic dose of linagliptin was safe and well tolerated. This thorough QT study, designed and carried out in accordance with the guidance ICH E14, shows that linagliptin administered at therapeutic and 20-fold supratherapeutic doses does not prolong QT interval duration. Results support the favorable safety and tolerability profile of linagliptin observed to date. Methods 44 Healthy Caucasian subjects (aged 22-48 yr, mean 36.4 yr, 26 male) received single p.o. doses of linagliptin (5 mg and 100 mg), moxifloxacin (400 mg), or placebo. Electrocardiogram (ECG) profiles using triplicates of 12-lead 10-sec ECG were digitally recorded predose and after drug administration. The mean change from baseline (MCfB) of the individually HR-corrected QT interval (QTcI) between 1 and 4 hr postdrug administration was the primary end point. Blood samples to measure plasma concentrations of linagliptin and its main metabolite were also obtained. Results 43 Subjects completed the study as planned in the protocol. Linagliptin was not associated with an increase in the baseline-adjusted mean QTcI at any time point. The placebo-corrected MCfB of QTcI was -1.1 msec and -2.5 msec for linagliptin 5 mg and 100 mg, respectively, thus within the noninferiority margin of 10 msec according to ICH E14. Linagliptin was well tolerated; the assessment of ECG and other safety parameters gave no clinically relevant findings at either dose tested. Maximum plasma concentrations after administration of 100-mg linagliptin were about 24-fold higher than those observed previously for chronic treatment with the therapeutic 5-mg dose. Assay sensitivity was confirmed by a placebo-corrected MCfB of QTcI with moxifioxacin of 6.9 msec.
  • Author:
    Meyers JL; Candrilli SD; Kovacs B
    Title:
    Type 2 diabetes mellitus and renal impairment in a large outpatient electronic medical records database: Rates of diagnosis and antihyperglycemic medication dose adjustment.
    Source:
    Postgrad Med 123 (3), 133-143 (2011)
    Abstract:
    Objective: To assess rates of diagnosis and antihyperglycemic dose adjustment in patients with moderate to end-stage renal impairment (RI) and type 2 diabetes mellitus (T2DM). Methods: Retrospective database analysis using GE Centricity Outpatient Electronic Medical Records. Patients aged ? 18 years with evidence of T2DM (International Classification of Diseases, Ninth Edition, Clinical Modification codes 250.x0 and 250.x2) between January 1, 2000 and June 30, 2009, and ? 12 months of data after identification were selected. Moderate to end-stageRI was evaluated using a formula-derived estimated glomerular filtration rate (eGFR) based on serum creatinine (SCr). Patients were classified as moderate (eGFR, 30-59 mL/min/1.73 m2), severe (eGFR, 15-29 mL/min/1.73 m2), or end-stage (eGFR, &lt; 15 mL/min/1.73 m2), per the National Kidney Foundation guidelines, based on the first-observed SCr test. Among patients with a physician diagnosis, the time to diagnosis was reported. Dose adjustment was reported for patients receiving metformin and sitagliptin. Predictors of progression to end-stage RI based on logistic regressions were examined. Results: 35.2% of patients with T2DM had evidence ofmoderate to end-stage RI. Of these patients, 20% had a chart-documented physician diagnosis (range, 16% [moderate RI] to 66% [end-stage RI]). Patients with moderate or severe RI had a physician diagnosis mean of 253.4 (standard deviation [SD], 584.5) and 86.9 (SD, 417.4) days, respectively, after the eGFR calculation indicating RI. Patients with end-stage RI had a physiciandiagnosis mean of 83.6 (SD, 399.2) days before the eGFR calculation. After the eGFR calculation, 15.1% and 0.1% of patients with orders for sitagliptin and metformin, respectively, receiveddoses of the drug appropriate for their degree of RI. Among patients with moderate or severeRI, appropriate diagnosis of RI was associated with significantly lower odds of progressing toend-stage RI (odds ratio, 0.200; 95% confidence interval, 0.188-0.213). Conclusions: Renal impairment is common but often undetected in patients with T2DM. Patients with a documented RI diagnosis have lower odds of progression to end-stage RI. Metformin and sitagliptin are frequently used at inappropriate doses in patients with RI. Further analyses to understand the clinical and economic consequences of these findings are needed.
  • Author:
    Gomis R; Espadero R-M; Jones R; Woerele H-J; Dugi KA
    Title:
    Efficacy and safety of initial combination therapy with linagliptin and pioglitazone in patients with inadequately controlled type 2 diabetes: A randomized, double-blind, placebo-controlled study.
    Source:
    Diabetes Obes Metab 13 (7), 653-661 (2011)
    Abstract:
    Aims: To compare the efficacy, safety and tolerability of linagliptin or placebo administered for 24 weeks in combination with pioglitazone in patients with type 2 diabetes mellitus (T2DM) exhibiting insufficient glycaemic control (HbA1c 7.5-11.0%). Methods: Patients were randomized to receive the initial combination of 30 mg pioglitazone plus 5 mg linagliptin (n = 259) or pioglitazone plus placebo (n = 130), all once daily. The primary endpoint was change from baseline in HbA1c after 24 weeks of treatment, adjusted for baseline HbA1c and prior antidiabetes medication. Results: After 24 weeks of treatment, the adjusted mean change (.+-.s.e.) in HbA1c with the initial combination of linagliptin plus pioglitazone was -1.06% (.+-.0.06), compared with -0.56% (.+-.0.09) for placebo plus pioglitazone. The difference in adjusted mean HbA1c in the linagliptin group compared with placebo was -0.51% (95% confidence interval [CI] -0.71, -0.30; p < 0.0001). Reductions in fasting plasma glucose (FPG) were significantly greater for linagliptin plus pioglitazone than with placebo plus pioglitazone; -1.8 and -1.0 mmol/l, respectively, equating to a treatment difference of -0.8 mmol/l (95% CI -1.2, -0.4; p < 0.0001). Patients taking linagliptin plus pioglitazone, compared with those receiving placebo plus pioglitazone, were more likely to achieve HbA1c of <7.0% (42.9 vs. 30.5%, respectively; p = 0.0051) and reduction in HbA1c of .gtoreq.0.5% (75.0 vs. 50.8%, respectively; p < 0.0001). .beta.-cell function, exemplified by the ratio of relative change in adjusted mean HOMA-IR and disposition index, improved. The proportion of patients that experienced at least one adverse event was similar for both groups. Hypoglycaemic episodes (all mild) occurred in 1.2% of the linagliptin plus pioglitazone patients and none in the placebo plus pioglitazone group. Conclusion: Initial combination therapy with linagliptin plus pioglitazone was well tolerated and produced significant and clinically meaningful improvements in glycaemic control. This combination may offer a valuable additive initial treatment option for T2DM, particularly where metformin either is not well tolerated or is contraindicated, such as in patients with renal impairment. - DERWENT Abstract - This randomized, double-blind, placebo-controlled study evaluated the efficacy, safety, and tolerability of initial combination therapy with linagliptin (LIN) and pioglitazone (PIO) in 389 patients with inadequately controlled type 2 diabetes. After 24 wk of treatment, the adjusted mean change in HbA1c with the initial combination of LIN (5 mg) + PIO (30 mg) was -1.06% compared with -0.56% for placebo + PIO. Reductions in fasting plasma glucose were greater for LIN + PIO than with placebo + PIO. Beta-cell function improved. The proportion of patients that experienced at least 1 adverse event was similar for both groups. Hypoglycemic episodes occurred in 1.2% of the LIN + PIO patients and none in the placebo + PIO group. Thus, initial combination therapy with LIN + PIO was well tolerated and produced meaningful improvements in glycemic control.
  • Author:
    Schneider M; Haeck HJ
    Title:
    Screening for colorectal cancer: A cost benefit analysis on a health prevetion programme at the Boehringer-Ingelheim company.
    Source:
    Dtsch Med Wochenschr 136 (20), 1047-1052 (2011)
    Abstract:
    Background and objective: In Germany, approximately 70.000 people are diagnosed with colorectal cancer every year. With early diagnosis the recovery rates are over 90% and early intervention can significantly reduce the costs of medical treatment as well as the economic losses from worker productivity. We here present the organisational procedure for bowel cancer screening and have weighed the costs against benefits to employees, the company and the healthcare system. The screening costs are compared with economic benefits. Methods: The target group for the study consisted of all 11.536 employees at the companys site in Germany. Volunteers were given a standardized questionnaire about the risk factors for colorectal cancers and an immunological fecal occult blood test (IFOBT). If risk factors for development of colorectal cancer were present or if the test result was positive, a colonoscopy was recommended in accordance with DGVS guidelines (German Society of Digestive and Metabolic diseases). Results: A total of 4.287 employees (37.2%) indicated an interest in undergoing screening; at the end of the period 3.958 complete datasets (2.296 men and 1.662 women, mean age 51.2 years) were available for evaluation. A colonoscopy was performed on 114 persons. Six cases of overt cancer were detected with three in the 3650 age group and three in the 5165 age group. Five of the six cases were stage T1 or T2. Adenomatous polyps were found and removed in 29 persons. The calculated cost benefit ratio was 1:2 for the company and 1:35 for the public health system. Conclusion: Using the example of colorectal screening, this study represents a cost benefit analysis of this preventative health measure in a company environment. The results show that even while taking into account the financial and personal commitment required, the cost benefit ratio is positive both for the company and for the healthcare system.
  • Author:
    Graefe-Mody EU; Brand T; Ring A; Withopf B; Stangier J; Iovino M; Woerle H-J
    Title:
    Effect of linagliptin on the pharmacokinetics and pharmacodynamics of warfarin in healthy volunteers.
    Source:
    Int J Clin Pharmacol Ther 49 (5), 300-310 (2011)
    Abstract:
    Objective: To investigate the effect of the estimated highest therapeutic dose of linagliptin (5 mg) on the pharmacokinetics and pharmacodynamics of warfarin, a CYP2C9 substrate. Subjects and methods: This open-label, 2-period, fixed-sequence trial enrolled 18 healthy male volunteers, 17 of whom were homozygous for CYP2C9*1/*1. Subjects received a single oral dose of warfarin (10 mg) followed by a washout period of at least 14 days. Subjects then received oral linagliptin 5 mg once daily for 12 days (i.e. steady state) with a single dose of warfarin (10 mg) on Day 6. R(+) warfarin, S(-) warfarin, prothrombin time (PT) and international normalized ratio (INR) were assayed pre-dose and up to 168 h post-dose. Results: The geometric mean ratios (GMRs) (90% confidence interval (CI)) of AUC0-.infin. and Cmax for (linagliptin + warfarin)/warfarin were 98.5 (95.7 - 101.5) and 99.7 (94.7 - 104.9), respectively, for R-warfarin; 103.0 (99.1 - 107.0) and 100.9 (93.7 - 108.6), respectively, for S-warfarin. Concomitant administration of linagliptin and warfarin had o clinically relevant effect on the AUC0-168 for INR or PT. The GMRs (90% CI) of INR nd PT AUC0-168 for (linagliptin + warfarin)/ warfarin were 93.4 (86.2 - 101.1) and 103.2 (95.4 - 111.6), respectively. The corresponding Eax values for both INR and PT were slightly increased after co-administration of linagliptin and warfarin compared with warfarin alone, being 104.3 (85.2 - 127.6) and 15.1 (94.3 -140.6), respectively, reflecting the higher variability of these endpoints. Co-administration of linagliptin and warfarin was well tolerated. Conclusions: Coadministration of linagliptin did not alter the pharmacokinetics or pharmacodynamics of R- or S-warfarin, indicating that no dosage adjustment for warfarin is necessary when co-administered with linagliptin. - DERWENT Abstract - This open-label, 2-period study investigated the effect of the estimated highest therapeutic dose of linagliptin (5 mg) on the pharmacokinetics and pharmacodynamics of warfarin in 18 healthy volunteers. The corresponding Emax values for both INR and PT were slightly increased after co-administration of linagliptin and warfarin compared with warfarin alone, being 104.3 and 115.1, respectively, reflecting the higher variability of these endpoints. Co-administration of linagliptin and warfarin was well tolerated. Coadministration of linagliptin did not alter the pharmacokinetics or pharmacodynamics of R- or S-warfarin, indicating that no dosage adjustment for warfarin is necessary when co-administered with linagliptin. Methods 18 Healthy volunteers who received single p.o. dose of warfarin (10 mg) followed by a washout period of at least 14 days were evaluated. Results The geometric mean ratios (GMR) of AUC and Cmax for (linagliptin + warfarin)/warfarin were 98.5 and 99.7, respectively, for R-warfarin; 103.0 and 100.9, respectively, for S-warfarin. Concomitant administration of linagliptin and warfarin had no clinically relevant effect on the AUC0-168 for INR or PT. The GMR of INR and PT AUC0-168 for (linagliptin + warfarin)/warfarin were 93.4 and 103.2, respectively. The corresponding Emax values for both INR and PT were slightly increased after co-administration of linagliptin and warfarin compared with warfarin alone, being 104.3 and 115.1, respectively, reflecting the higher variability of these endpoints. Co-administration of linagliptin and warfarin was well tolerated.
  • Author:
    Owens DR; Swallow R; Jones P; Woerle H-J; Tocque-le-Gousse E; Dugi KA
    Title:
    The linagliptine improves glycemic control in type 2 diabetics inadequately controlled by metformin over sulfonylureas, without weight gain or hypoglucemia.
    Source:
    Diabetes Metab 37 (Sp.iss.1), A4 (2011)
  • Author:
    Forst T; Uhlig-Laske B; Ring A; Ritzhaupt A; Graefe-Mody U; Dugi KA
    Title:
    The oral DPP-4 inhibitor linagliptin significantly lowers HbA1C after 4 weeks of treatment in patients with type 2 diabetes mellitus.
    Source:
    Diabetes Obes Metab 13 (6), 542-550 (2011)
    Abstract:
    Aim: To investigate the safety, tolerability, pharmacokinetics and pharmacodynamics of linagliptin in patients with type 2 diabetes mellitus (T2DM). Methods: After screening and a 14-day washout, subjects received linagliptin 2.5, 5 or 10 mg or placebo once-daily for 28 days in this randomized, double-blind, parallel, placebo-controlled within-dose groups study. Results: Seventy-seven patients entered the study (linagliptin: 61; placebo: 16). Four patients withdrew prematurely. There was little evidence of linagliptin accumulation. Exposure, maximum and trough plasma concentrations of linagliptin increased less than dose-proportionally. Rapid and sustained inhibition of dipeptidyl peptidase-4 reached 91-93% across linagliptin doses at steady state. At the end of the 24-h dosing interval, inhibition was still high (82-90%). There were marked increases in plasma glucagon-like peptide-1 after 28 days of dosing. Compared to placebo, all linagliptin doses resulted in statistically significant decreases of the area under the glucose curve following a meal tolerance test on day 29, that is, 24 h after the last study drug intake. After 28 days of treatment with linagliptin the placebo-corrected mean change in haemoglobin A1c (HbA1c) (median baseline 7.0%) was -0.31% (2.5-mg dose), -0.37% (5-mg dose) and -0.28% (10-mg dose). The frequency of adverse events was similar for linagliptin (31%) and placebo (34%). There were no notable safety concerns. Conclusions: Linagliptin administration led to attenuation of postprandial glucose excursions and, despite a low HbA1c at baseline, statistically significant reductions in HbA1c after only 4 weeks of treatment. Linagliptin had a safety and tolerability profile similar to placebo in T2DM patients. - DERWENT Abstract - Methods: After screening and a 14-day washout, subjects received linagliptin 2.5, 5 or 10 mg or placebo once-daily for 28 days in this randomized, double-blind, parallel, placebo-controlled within-dose groups study. Results: Seventy-seven patients entered the study (linagliptin: 61; placebo: 16). Four patients withdrew prematurely. There was little evidence of linagliptin accumulation. Exposure, maximum and trough plasma concentrations of linagliptin increased less than dose-proportionally. Rapid and sustained inhibition of dipeptidyl peptidase-4 reached 91-93% across linagliptin doses at steady state. At the end of the 24-h dosing interval, inhibition was still high (82-90%). There were marked increases in plasma glucagon-like peptide-1 after 28 days of dosing. Compared to placebo, all linagliptin doses resulted in statistically significant decreases of the area under the glucose curve following a meal tolerance test on day 29, that is, 24 h after the last study drug intake. After 28 days of treatment with linagliptin the placebo-corrected mean change in haemoglobin A1c (HbA1c) (median baseline 7.0%) was -0.31% (2.5-mg dose), -0.37% (5-mg dose) and -0.28% (10-mg dose). The frequency of adverse events was similar for linagliptin (31%) and placebo (34%). There were no notable safety concerns. Conclusions: Linagliptin administration led to attenuation of postprandial glucose excursions and, despite a low HbA1c at baseline, statistically significant reductions in HbA1c after only 4 weeks of treatment. Linagliptin had a safety and tolerability profile similar to placebo in T2DM patients. - DERWENT Abstract - This phase IIa, randomized, double-blind, parallel-group, placebo (PL)-controlled study evaluated the safety, tolerability, pharmacokinetics and pharmacodynamics of p.o. linagliptin (LN) in 77 type 2 diabetes mellitus patients. There was little evidence of LN accumulation. Exposure, maximum and trough plasma levels of LN raised less than dose-proportionally. Rapid and sustained inhibition of dipeptidyl peptidase (DP)-4 reached 91-93% across LN doses (2.5, 5 and 10 mg) at steady state. At 24 hr dosing interval, inhibition of DP-4 was still high (82-90%). There were increases in plasma glucagon-like peptide-1 after 28 days of dosing. All LN doses resulted in decreases of AUC of glucose following a meal tolerance test on day 29. LN therapy leads to attenuation of postprandial glucose excursions and, despite a low HbA1c at baseline, reductions in HbA1c after only 4 wk of therapy. Methods 77 Type 2 diabetes mellitus patients were randomized to receive p.o. LN at 2.5 mg/day (n = 26, 22 male, median age 62 yr, range 40-68 yr), 5 mg/day (n = 16, 15 male, median age 64 yr, range 48-69 yr) or 10 mg/day (n = 19, 19 male, median age 62 yr, range 40-68 yr), or PL (n = 16, 16 male, median age 62 yr, range 49-69 yr) for 28 days. Results Adverse events were MI, nasopharyngitis, back pain, elevations in aspartate transaminase levels, and weight decrease. Following p.o. LN dosing, LN was rapidly absorbed and showed nonlinear pharmacokinetics over 2.5, 5 and 10 mg of LN doses, with a less than dose-proportional increase in systemic exposure in terms of Cmax and AUC. Exposure, maximum and trough plasma levels of LN increased less than dose-proportionally. Rapid and sustained inhibition of DP-4 was noted after the 1st dose of LN. Mean maximum inhibition of DP-4 was about 91-93% across all LN doses (2.5, 5 and 10 mg). Mean plasma levels of active glucagon like peptide-1 measured 30 min after an meal tolerance test showed marked increases after 28 days for all LN doses. Fasting plasma glucose levels reduced at day 29 for all LN doses vs. day -1. At day 29, reduction of 7-point glucose for all LN doses was significant vs. PL; the greatest reduction in plasma glucose levels at day 29 was noted in the 5 mg dose arm, followed by the 2.5 mg arm. Patients with LN therapy showed a small reduction in peak plasma glucose level on days 1 and 29 vs. day -1. Significant decreases from baseline in mean HbA1c were noted on day 29 for all LN doses vs. PL. After 28 days of dosing, there were no changes in plasma fructosamine levels between LN and PL arms.
  • Author:
    Graefe-Mody U; Rose P; Ring A; Zander K; Iovino M; Woerle H-J
    Title:
    Assessment of the pharmacokinetic interaction between the novel DPP-4 inhibitor linagliptin in a sulfonylurea, glyburide, in healthy subjects.
    Source:
    Drug Metab Pharmacokinet 26 (2), 123-129 (2011)
    Abstract:
    The aim of this study was to investigate the effect of the dipeptidyl peptidase-4 inhibitor linagliptin on the pharmacokinetics of glyburide (a CYP2C9 and CYP3A4 substrate) and vice versa. This randomized, open-label, three-period, two-way crossover study examined the effects of co-administration of multiple oral doses of linagliptin (5 mg/day .times. 6 days) and single doses of glyburide (1.75 mg/day .times. 1 day) on the relative bioavailability of either compound in healthy subjects (n = 20, age 18-55 years). Coadministration of glyburide did not alter the steady-state pharmacokinetics of linagliptin. Geometric mean ratios (GMRs) [90% CI] for (linagliptin + glyburide)/linagliptin AUC(.tau.,ss) and C(max,ss) were 101.7% [97.7-105.8%] and 100.8% [89.0-114.3%], respectively. For glyburide, there was a slight reduction in exposure of .apprx.14% when coadministered with linagliptin (GMRs [90% CI] for (glyburide + linagliptin)/glyburide AUC(0-.infin.) and C(max) were 85.7% [79.8-92.1%] and 86.2% [79.6-93.3%], respectively). However, this was not seen as clinically relevant due to the absence of a reliable dose-response relationship and the known large pharmacokinetic interindividual variability of glyburide. These results further support the assumption that linagliptin is not a clinically relevant inhibitor of CYP2C9 or CYP3A4 in vivo. Coadministration of linagliptin and glyburide had no clinically relevant effect on the pharmacokinetics of linagliptin or glyburide. Both agents were well tolerated and can be administered together without the need for dosage adjustments.
  • Author:
    Park BK; Goldring ChEP; Laverty HG; Maisbitt DJ; Williams DP; Boobis A; Clarke St; Jones D; Kenna JG; Lambert C; Baillie ThA; Nicoll-Griffith DA; Obach RS; Routledge Ph; Smith DA; Tweedie DJ; Vermeulen N; Wilson ID
    Title:
    Managing the challenge of chemically reactive metabolites in drug development.
    Source:
    Nat Rev Drug Discov 10 (4), 292-306 (2011)
    Abstract:
    The normal metabolism of drugs can generate metabolites that have intrinsic chemical reactivity towards cellular molecules, and therefore have the potential to alter biological function and initiate serious adverse drug reactions. Here, we present an assessment of the current approaches used for the evaluation of chemically reactive metabolites. We also describe how these approaches are being used within the pharmaceutical industry to assess and minimize the potential of drug candidates to cause toxicity. At early stages of drug discovery, iteration between medicinal chemistry and drug metabolism can eliminate perceived reactive metabolite-mediated chemical liabilities without compromising pharmacological activity or the need for extensive safety evaluation beyond standard practices. In the future, reactive metabolite evaluation may also be useful during clinical development for improving clinical risk assessment and risk management. Currently, there remains a huge gap in our understanding of the basic mechanisms that underlie chemical stress-mediated adverse reactions in humans. This Review summarizes our views on this complex topic, and includes insights into practices considered by the pharmaceutical industry.
  • Author:
    Stopfer P; Rathgen K; Bischoff D; Ludtke S; Marzin K; Kaiser R; Wagner K; Ebner Th
    Title:
    Pharmacokinetics and metabolism of BIBF 1120 after oral dosing to healthy male volunteers.
    Source:
    Xenobiotica 41 (4), 297-311 (2011)
    Abstract:
    The pharmacokinetics and metabolism of BIBF 1120, an oral triple angiokinase inhibitor targeting vascular endothelial growth factor receptor (VEGFR), platelet-derived growth factor receptor (PDGFR), and fibroblast growth factor receptor (FGFR), were studied in healthy male volunteers (n = 8) who had received a single oral dose of 100 mg [(14)C]-radiolabelled BIBF 1120 administered as solution. BIBF 1120 was well-tolerated and rapidly absorbed; median time to reach maximum plasma concentrations was 1.3 h and gMean terminal half-life was 13.7 h. A relatively high apparent total body clearance and volume of distribution possibly indicated a high tissue distribution. Plasma concentrations of BIBF 1120 plus carboxylate metabolite BIBF 1202 were lower than the total [(14)C]-radioactivity in plasma, indicating presence of additional metabolites. Total recovery in excreta was 94.7% 1 week post-dose; mass balance was considered complete after 96 h. BIBF 1120 and metabolites were mainly excreted via faeces. The major metabolic pathway for BIBF 1120 was methyl ester cleavage to BIBF 1202. Subsequently, the free carboxyl group of BIBF 1202 was glucuronidated to 1-O-acylglucuronide. Pathways of minor importance were oxidative N-demethylation to yield BIBF 1053, and oxidation of the piperazine moiety and conjugation. Glucuronidation of the parent drug and formylation of the secondary aliphatic amine of the piperazine ring played a minor role. - DERWENT Abstract - The Authors studied the pharmacokinetics and metaboism of BIBF-1120, a p.o. triple angiokinase inhibitor targeting VEGF, PDGF, and fibroblast growth factor receptors in 8 healthy male volunteers who had received a single p.o. dose 14C-radiolabelled BIBF-1120 administered as solution. BIBF-1120 was well-tolerated and rapidly absorbed. Cmax of BIBF-1120 + carboxylate metabolite BIBF-1202 were lower than total 14C-radioactivity in plasma, indicating presence of additional metabolites. BIBF-1202 (m1) and its acylglucuronide (m2, including isomeric acylglucuronide) were the predominant circulating molecular entities beside the parent compound. Results suggest that BIBF-1120 was safe and has favorable pharmacokinetics and excretion profile with almost no elimination via urine, as well as metabolic characteristics that are independent of cytochrome P450-catalyzed metabolic pathways. Method 8 Healthy male volunteers (aged 23-53 yr-old, mean age 32.3 yr-old) received a single p.o. dose 14C-radiolabelled BIBF-1120 administered as solution. Results BIBF-1120 was rapidly absorbed with maximum BIBF-1120 Cmax occurring at 1.3 hr after dosing (median tmax value). The gMean half-life for BIBF-1120 was 13.7 hr. The gMean total body clearance (CL/F) for BIBF-1120 was 16300 ml/min. BIBF-1120 exhibited a high gMean apparent Vd (Vz/F; gMean of 19300 l) during the terminal phase. BIBF-1202 plasma concentrations were detected 15 min after administration and BIBF-1202 maximum plasma concentrations were reached 2.5 hr after dosing. Almost all 14C-radioactivity concentrations (single time points) in the whole blood were below the limit of quantification. The total exposures (AUC0-12) of the parent compounds BIBF-1120 (gMean 61.3 ng.hr/ml) and BIBF-1202 (gMean 347 ng eq.hr/ml). The 14C-radioactivty excretion via the urine within the 1st 24 hr was approximately 0.526% of the dose. As radioactivity in feces samples were still above the defined threshold after 120 hr, measurements in feces samples were prolonged in all participants up to 168 hr. BIBF-1202 (m1) and its acylglucuronide (m2, including isomeric acylglucuronide) were the predominant circulating molecular entities beside the parent compound. In addition to the parent drug and 4 principal metabolites m1, m2, m3 and m4, all other minor metabolites in urine samples were present in very small amounts, none exceeding 0.2% of the administered dose. The 1-O-acylglucoronide of BIBF-1202 (m2) exhibited isomerization in aqueous solution that was due to acyl migration.
  • Author:
    Friedrich C; Ring A; Brand T; Sennewald R; Graefe-Mody EU; Woerle H-J
    Title:
    Evaluation of the pharmacokinetic interaction after multiple oral doses of linagliptin and digoxin in healthy volunteers.
    Source:
    Eur J Drug Metab Pharmacokinet 36 (1), 17-24 (2011)
    Abstract:
    The aim of this study was to investigate whether multiple doses of the oral and highly selective dipeptidyl peptidase-4 inhibitor linagliptin affect the steady-state pharmacokinetics of the P-glycoprotein substrate digoxin. This single-center, open-label, two-period cross-over study involved healthy subjects (n = 20), randomized to treatment sequence AB or BA, where A comprised 0.25 mg digoxin qd for 5 days, then 0.25 mg digoxin qd plus 5 mg linagliptin qd for 6 days, and B comprised 0.25 mg digoxin qd for 11 days. A treatment-free period (?35 days for AB and 14 days for BA) separated each treatment in both sequences. There were no clinically significant changes in steady-state pharmacokinetic parameters of digoxin when it was co-administered with linagliptin. The ratio of the adjusted-by-treatment geometric mean ratios and associated 90% confidence intervals for the AUC?,ss, Cmax,ss and renal clearance (CLR,0 -24,ss) of digoxin were all within the bioequivalence range 80-125%, which is important as digoxin has a narrow therapeutic range. There was a low incidence of adverse events, which were randomly distributed between treatment groups. In conclusion, linagliptin did not alter the pharmacokinetics of digoxin in this study, indicating that linagliptin does not inhibit P-glycoprotein or other transporters relevant for digoxin pharmacokinetics. These results suggest that linagliptin and digoxin can be co-administered without dose adjustment. Administration of digoxin alone and with linagliptin was well tolerated. - DERWENT Abstract - This single-center, randomized, open-label, two-period crossover study investigated whether multiple doses of the p.o. and highly selective dipeptidyl peptidase-4 inhibitor linagliptin (Boehr.Ingelheim) affect the steady-state pharmacokinetics of the P-glycoprotein substrate digoxin (Teofarma Srl) in 20 healthy subjects. Linagliptin did not alter the pharmacokinetic parameters of digoxin. The ratio of the adjusted-by-treatment geometric mean ratios and associated 90% confidence intervals for the AUCtau,ss, Cmax,ss and renal clearance of digoxin were all within the bioequivalence range. There was a low incidence of adverse events (AE). Administration of digoxin alone or in combination with linagliptin was safe and well tolerated. Thus, linagliptin and digoxin can be co-administered without dose adjustment. Administration of digoxin alone and with linagliptin was well tolerated. Methods 20 Healthy subjects (aged 23-49 yr, 9 male) were randomized to treatment sequence AB (n=10, 4 male) or BA (n=10, 5 male), where A comprised 0.25 mg digoxin qd for 5 days, then 0.25 mg digoxin qd + 5 mg linagliptin qd for 6 days, and B comprised 0.25 mg digoxin qd for 11 days. A treatment-free period (35 days or more for AB and 14 days for BA) separated each treatment in both sequences. Results Digoxin reached a steady-state on day 8 of both treatments. Steady-state plasma concentrations increased rapidly after drug administration in both treatments, reaching a maximum concentration after approximately 1 hr. Following maximum concentration, bi-exponential elimination profiles of digoxin were seen, with a rapid disposition phase until about 6 hr after drug administration followed by a slower disposition phase for both treatments. The GMR between the 2 treatment periods and the corresponding 90% CI were within the bioequivalence acceptance range 80%-125%. The Cmax,ss and AUCtau,ss values were comparable for digoxin administered alone or in combination with linagliptin. Renal clearance in the dosing interval was 130 ml/min for both digoxin administered alone and for digoxin coadministered with linagliptin. Adequate exposure of linagliptin was achieved following multiple administration of a 5-mg dose. Digoxin was well tolerated, both when given alone or in combination with linagliptin. AE were headache, nausea, fatigue. All AE resolved completely and there were no discontinuations due to AE.
  • Author:
    Del Prato S; Barnett AH; Huisman H; Neubacher D; Woerle H-J; Dugi KA
    Title:
    Effect of linagliptin monotherapy on glycaemic control and markers of beta-cell function in patients with inadequately controlled type 2 diabetes: A randomized controlled trial
    Source:
    Diabetes Obes Metab 13 (3), 258-267 (2011)
    Abstract:
    Aim: To assess the safety and efficacy of the potent and selective dipeptidyl peptidase-4 inhibitor linagliptin 5 mg when given for 24 weeks to patients with type 2 diabetes who were either treatment-naive or who had received one oral antidiabetes drug (OAD). Methods: This multicentre, randomized, parallel group, phase III study compared linagliptin treatment (5 mg once daily, n = 336) with placebo (n = 167) for 24 weeks in type 2 diabetes patients. Before randomization, patients pretreated with one OAD underwent a washout period of 6 weeks, which included a placebo run-in period during the last 2 weeks. Patients previously untreated with an OAD underwent a 2-week placebo run-in period. The primary endpoint was the change in HbA1c from baseline after 24 weeks of treatment. Results: Linagliptin treatment resulted in a placebo-corrected change in HbA1c from baseline of -0.69% (p < 0.0001) at 24 weeks. In patients with baseline HbA1c ? 9.0%, the adjusted reduction in HbA1c was 1.01% (p < 0.0001). Patients treated with linagliptin were more likely to achieve a reduction in HbA1c of ?0.5% at 24 weeks than those in the placebo arm (47.1 and 19.0%, respectively; odds ratio, OR = 4.2, p < 0.0001). Fasting plasma glucose improved by -1.3 mmol/l (p < 0.0001) with linagliptin vs. placebo, and linagliptin produced an adjusted mean reduction from baseline after 24 weeks in 2-h postprandial glucose of -3.2 mmol/l (p < 0.0001). Statistically significant and relevant treatment differences were observed for proinsulin/insulin ratio (p = 0.025), Homeostasis Model Assessment-%B (p = 0.049) and disposition index (p = 0.0005). There was no excess of hypoglycaemic episodes with linagliptin vs. placebo and no patient required third-party intervention. Mild or moderate renal impairment did not influence the trough plasma levels of linagliptin. Conclusions: Monotherapy with linagliptin produced a significant, clinically meaningful and sustained improvement in glycaemic control, accompanied by enhanced parameters of ?-cell function. The safety profile of linagliptin was comparable with that of placebo. - DERWENT Abstract - Methods: This multicentre, randomized, parallel group, phase III study compared linagliptin treatment (5 mg once daily, n = 336) with placebo (n = 167) for 24 weeks in type 2 diabetes patients. Before randomization, patients pretreated with one OAD underwent a washout period of 6 weeks, which included a placebo run-in period during the last 2 weeks. Patients previously untreated with an OAD underwent a 2-week placebo run-in period. The primary endpoint was the change in HbA1c from baseline after 24 weeks of treatment. Results: Linagliptin treatment resulted in a placebo-corrected change in HbA1c from baseline of -0.69% (p < 0.0001) at 24 weeks. In patients with baseline HbA1c >= 9.0%, the adjusted reduction in HbA1c was 1.01% (p < 0.0001). Patients treated with linagliptin were more likely to achieve a reduction in HbA1c of >= 0.5% at 24 weeks than those in the placebo arm (47.1 and 19.0%, respectively; odds ratio, OR = 4.2, p < 0.0001). Fasting plasma glucose improved by -1.3 mmol/l (p < 0.0001) with linagliptin vs. placebo, and linagliptin produced an adjusted mean reduction from baseline after 24 weeks in 2-h postprandial glucose of -3.2 mmol/l (p < 0.0001). Statistically significant and relevant treatment differences were observed for proinsulin/insulin ratio (p = 0.025), Homeostasis Model Assessment-%B (p = 0.049) and disposition index (p = 0.0005). There was no excess of hypoglycaemic episodes with linagliptin vs. placebo and no patient required third-party intervention. Mild or moderate renal impairment did not influence the trough plasma levels of linagliptin. Conclusions: Monotherapy with linagliptin produced a significant, clinically meaningful and sustained improvement in glycaemic control, accompanied by enhanced parameters of beta-cell function. The safety profile of linagliptin was comparable with that of placebo. - DERWENT Abstract - This multicenter, randomized, parallel group, phase III study assessed the safety and efficacy of the potent and selective dipeptidyl peptidase-4 inhibitor linagliptin 5 mg when given for 24 wk to 503 patients with type 2 diabetes who were either treatment-naive or who had received 1 p.o. antidiabetes drug (OAD). Linagliptin treatment resulted in a placebo-corrected change in HbA1c from baseline of -0.69% at 24 wk. There was no excess of hypoglycemic episodes with linagliptin vs. placebo and no patient required third-party intervention. Mild or moderate renal impairment did not influence the trough plasma levels of linagliptin. Thus, linagliptin monotherapy produced a significant, clinically meaningful and sustained improvement in glycemic control, accompanied by enhanced parameters of beta-cell function. The safety profile of linagliptin was comparable with that of placebo. Methods 503 Patients (mean age 55.7 yr, 243 male) with type 2 diabetes who were either treatment-naive or who had received 1 OAD were studied. Linagliptin treatment (5 mg once daily, n=336) was compared with placebo (n=167) for 24 wk in type 2 diabetes patients. Before randomization, patients pretreated with one OAD underwent a washout period of 6 wk, which included a placebo run-in period during the last 2 wk. Patients previously untreated with an OAD underwent a 2-wk placebo run-in period. The primary endpoint was the change in HbA1c from baseline after 24 wk of treatment. Results The geometric mean trough plasma concentrations of linagliptin remained constant over time: 6.4 and 6.5 nM at Wk 12 and 24, respectively. Linagliptin treatment resulted in a placebo-corrected change in HbA1c from baseline of -0.69% at 24 wk. In patients with baseline HbA1c at least 9.0%, the adjusted reduction in HbA1c was 1.01%. Patients treated with linagliptin were more likely to achieve a reduction in HbA1c of at least 0.5% at 24 wk than those in the placebo arm (47.1% and 19.0%, respectively). Fasting plasma glucose improved by -1.3 mM with linagliptin vs. placebo, and linagliptin produced an adjusted mean reduction from baseline after 24 wk in 2-h postprandial glucose of -3.2 mM. Statistically significant and relevant treatment differences were noted for proinsulin/insulin ratio, Homeostasis Model Assessment-%B and disposition index. There was no excess of hypoglycemic episodes with linagliptin vs. placebo and no patient required 3rd-party intervention. Mild or moderate renal impairment did not influence the trough plasma levels of linagliptin.
  • Author:
    da Silva Xavier G; Farhan H; Kim H; Caxaria S; Johnson P; Hughes S; Buglani M; Marselli L; Marchetti P; Birzele F; Sun G; Scharfmann R; Rutter I; Siniakowicz K; Weir G; Parker H; Reimann F; Gribble FM; Rutter GA
    Title:
    Per-arnt-sim (PAS) domain-containing protein kinase is downregulated islets in type 2 diabetes and regulates glucagon secretion.
    Source:
    Diabetologia 54 (4), 819-827 (2011)
    Abstract:
    We assessed whether per-arnt-sim (PAS) domain-containing protein kinase (PASK) is involved in the regulation of glucagon secretion. mRNA levels were measured in islets by quantitative PCR and in pancreatic beta cells obtained by laser capture microdissection. Glucose tolerance, plasma hormone levels and islet hormone secretion were analysed in C57BL/6 Pask homozygote knockout mice (Pask (-/-)) and control littermates. Alpha-TC1-9 cells, human islets or cultured E13.5 rat pancreatic epithelia were transduced with anti-Pask or control small interfering RNAs, or with adenoviruses encoding enhanced green fluorescent protein or PASK. PASK expression was significantly lower in islets from human type 2 diabetic than control participants. PASK mRNA was present in alpha and beta cells from mouse islets. In Pask (-/-) mice, fasted blood glucose and plasma glucagon levels were 25 +/- 5% and 50 +/- 8% (mean +/- SE) higher, respectively, than in control mice. At inhibitory glucose concentrations (10 mmol/l), islets from Pask (-/-) mice secreted 2.04 +/- 0.2-fold (p < 0.01) more glucagon and 2.63 +/- 0.3-fold (p < 0.01) less insulin than wild-type islets. Glucose failed to inhibit glucagon secretion from PASK-depleted alpha-TC1-9 cells, whereas PASK overexpression inhibited glucagon secretion from these cells and human islets. Extracellular insulin (20 nmol/l) inhibited glucagon secretion from control and PASK-deficient alpha-TC1-9 cells. PASK-depleted alpha-TC1-9 cells and pancreatic embryonic explants displayed increased expression of the preproglucagon (Gcg) and AMP-activated protein kinase (AMPK)-alpha2 (Prkaa2) genes, implying a possible role for AMPK-alpha2 downstream of PASK in the control of glucagon gene expression and release. PASK is involved in the regulation of glucagon secretion by glucose and may be a useful target for the treatment of type 2 diabetes.
  • Author:
    Taskinen M; Rosenstock J; Tamminen I; Kubiak R; Patel S; Woerle H; Dugi KA
    Title:
    Safety and efficacy of linagliptin as add-on therapy to metformin in patients with type 2 diabetes: A randomized, double-blind, placebo-controlled study.
    Source:
    Diabetes, Obes Metab 13 (1), 65-74 (2011)
    Abstract:
    Aim: To evaluate the efficacy and safety of the potent and selective dipeptidyl peptidase-4 (DPP-4) inhibitor linagliptin administered as add-on therapy to metformin in patients with type 2 diabetes with inadequate glycaemic control. Methods: This 24-week, randomized, placebo-controlled, double-blind, parallel-group study was carried out in 82 centres in 10 countries. Patients with HbA1c levels of 7.0-10.0% on metformin and a maximum of one additional antidiabetes medication, which was discontinued at screening, continued on metformin ?1500 mg/day for 6 weeks, including a placebo run-in period of 2 weeks, before being randomized to linagliptin 5 mg once daily (n = 524) or placebo (n = 177) add-on. The primary outcome was the change from baseline in HbA1c after 24 weeks of treatment, evaluated with an analysis of covariance (ANCOVA). Results: Mean baseline HbA1c and fasting plasma glucose (FPG) were 8.1% and 9.4 mmol/l, respectively. Linagliptin showed significant reductions vs. placebo in adjusted mean changes from baseline of HbA1c (-0.49 vs. 0.15%), FPG (-0.59 vs. 0.58 mmol/l) and 2hPPG (-2.7 vs. 1.0 mmol/l); all p < 0.0001. Hypoglycaemia was rare, occurring in three patients (0.6%) treated with linagliptin and five patients (2.8%) in the placebo group. Body weight did not change significantly from baseline in both groups (-0.5 kg placebo, -0.4 kg linagliptin). Conclusions: The addition of linagliptin 5 mg once daily in patients with type 2 diabetes inadequately controlled on metformin resulted in a significant and clinically meaningful improvement in glycaemic control without weight gain or increased risk of hypoglycaemia.
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