Effect of renal impairment and haemodialysis on the pharmacokinetics of gemigliptin (LC15‐0444)

This study evaluated the effects of renal impairment (RI) and haemodialysis (HD) on the pharmacokinetics of gemigliptin, a novel dipeptidyl peptidase‐4 (DPP‐4) inhibitor. After a 100 mg administration to subjects with normal renal function (n = 23) or RI (n = 24), plasma, urine or dialysate samples were analysed. Control subjects were matched to patients based on age, gender and body mass index. Patients with mild, moderate, severe RI and end‐stage renal disease (ESRD) showed 1.20, 2.04, 1.50 and 1.66‐fold (1.10, 1.49, 1.22 and 1.21‐fold) increase of mean area under the time‐plasma concentration curve from 0 to infinity (AUC_inf) [maximum plasma concentration (C_max)] of gemigliptin, respectively. Pharmacokinetics of gemigliptin was comparable between HD and non‐HD periods in ESRD patients. Less than 4% of the dose was removed by 4 h HD. RI appeared to have modest effect on the gemigliptin disposition. No dose adjustment in patients with RI is proposed on the basis of exposure–response relationship. Impact of HD on the removal of gemigliptin was negligible.     

Saxagliptin improves glycaemic control and is well tolerated in patients with type 2 diabetes mellitus and renal impairment

Aim: To evaluate the efficacy and safety of saxagliptin vs. placebo in patients with type 2 diabetes mellitus (T2DM) and renal impairment. Methods: In this multicentre, randomized, parallel‐group, double‐blind, placebo‐controlled study, patients with glycated haemoglobin (HbA1c) 7–11% and creatinine clearance <50 ml/min were stratified by baseline renal impairment (moderate, severe or end‐stage on haemodialysis), and randomized (1 : 1) to saxagliptin 2.5 mg once daily or placebo for 12 weeks. Oral antihyperglycaemic drugs and insulin therapy present at enrolment were continued throughout the study. The absolute change in HbA1c from baseline to week 12 (primary efficacy end‐point) was analysed using an analysis of covariance model with last observation carried forward methodology. Results: A total of 170 patients were randomized and treated. The adjusted mean decrease from baseline to week 12 in HbA1c was statistically significantly greater in the saxagliptin group than in the placebo group; the difference between treatments was ?0.42% (95% confidence interval: ?0.71 to ?0.12%, p = 0.007). Adjusted mean HbA1c decreases from baseline to week 12 were numerically greater with saxagliptin than with placebo in the subgroups of patients with moderate (?0.64 vs. ?0.05%) and severe (?0.95 vs. ?0.50%) renal impairment. HbA1c reductions were similar between saxagliptin and placebo in the subgroup with end‐stage renal disease on haemodialysis (?0.84 vs. ?0.87%). Saxagliptin was generally well tolerated; incidences of adverse events and hypoglycaemic events were similar to placebo. Conclusions: Saxagliptin 2.5 mg once daily is a well‐tolerated treatment option for patients with inadequately controlled T2DM and renal impairment.     

The oral DPP-4 inhibitor linagliptin significantly lowers HbA1c after 4 weeks of treatment in patients with type 2 diabetes mellitus

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.     

Mechanisms of action of the dipeptidyl peptidase-4 inhibitor vildagliptin in humans

Inhibition of dipeptidyl peptidase-4 (DPP-4) by vildagliptin prevents degradation of glucagon-like peptide-1 (GLP-1) and reduces glycaemia in patients with type 2 diabetes mellitus, with low risk for hypoglycaemia and no weight gain. Vildagliptin binds covalently to the catalytic site of DPP-4, eliciting prolonged enzyme inhibition. This raises intact GLP-1 levels, both after meal ingestion and in the fasting state. Vildagliptin has been shown to stimulate insulin secretion and inhibit glucagon secretion in a glucose-dependent manner. At hypoglycaemic levels, the counterregulatory glucagon response is enhanced relative to baseline by vildagliptin. Vildagliptin also inhibits hepatic glucose production, mainly through changes in islet hormone secretion, and improves insulin sensitivity, as determined with a variety of methods. These effects underlie the improved glycaemia with low risk for hypoglycaemia. Vildagliptin also suppresses postprandial triglyceride (TG)-rich lipoprotein levels after ingestion of a fat-rich meal and reduces fasting lipolysis, suggesting inhibition of fat absorption and reduced TG stores in non-fat tissues. The large body of knowledge on vildagliptin regarding enzyme binding, incretin and islet hormone secretion and glucose and lipid metabolism is summarized, with discussion of the integrated mechanisms and comparison with other DPP-4 inhibitors and GLP-1 receptor activators, where appropriate.     

The dipeptidyl peptidase-4 inhibitor PHX1149 improves blood glucose control in patients with type 2 diabetes mellitus

Aim: To determine the efficacy and tolerability of PHX1149, a novel dipeptidyl peptidase‐4 (DPP4) inhibitor, in patients with type 2 diabetes. Methods: This is a multicentre, randomized, double‐blind, placebo‐controlled, 4‐week study in patients with type 2 diabetes with suboptimal metabolic control. Patients with a baseline haemoglobin A_1c (HbA_1c) of 7.3 to 11.0% were randomized 1 : 1 : 1 : 1 to receive once‐daily oral therapy with either PHX1149 (100, 200 or 400 mg) or placebo; patients were on a constant background therapy of either metformin alone or metformin plus a glitazone. Results: Treatment with 100, 200 or 400 mg of PHX1149 significantly decreased postprandial glucose area under the curve AUC_{0–2 h} by approximately 20% (+0.11 ± 0.50, ?2.08 ± 0.51, ?1.73 ± 0.49 and ?1.88 ± 0.48 mmol/l × h, respectively, for placebo and 100, 200 and 400 mg (p = 0.002, 0.008 and 0.004 vs. placebo). Postprandial AUC_{0–2 h} of intact glucagon‐like peptide‐1, the principal mediator of the biological effects of DPP4 inhibitors, was increased by 3.90 ± 2.83, 11.63 ± 2.86, 16.42 ± 2.72 and 15.75 ± 2.71 pmol/l × h, respectively, for placebo and 100, 200 and 400 mg (p = 0.053, 0.001 and 0.002 vs. placebo). Mean HbA_1c was lower in all dose groups; the placebo‐corrected change in the groups receiving 400 mg PHX1149 was ?0.28% (p = 0.02). DPP4 inhibition on day 28 was 53, 73 and 78% at 24 h postdose in the groups receiving 100, 200 and 400 mg PHX1149, respectively. There were no differences in adverse events between PHX1149‐treated and placebo subjects. Conclusions: Addition of the DPP4 inhibitor PHX1149 to a stable regimen of metformin or metformin plus a glitazone in patients with type 2 diabetes was well tolerated and improved blood glucose control.     

The dipeptidyl peptidase‐4 inhibitor linagliptin lowers postprandial glucose and improves measures of β‐cell function in type 2 diabetes

Progressive deterioration of pancreatic β‐cell function in patients with type 2 diabetes mellitus (T2DM) contributes to worsening of hyperglycaemia. To investigate the effects of the dipeptidyl peptidase‐4 inhibitor linagliptin on β‐cell function parameters, a pooled analysis of six randomized, 24‐week, placebo‐controlled, phase 3 trials of 5 mg of linagliptin daily was performed in 2701 patients with T2DM (linagliptin, n = 1905; placebo, n = 796). At week 24, observed improvements in HbA1c, fasting plasma glucose, and 2‐h postprandial glucose were significantly greater for linagliptin than placebo (all p < 0.0001). Homeostasis model assessment (HOMA)‐%β, as a surrogate marker of fasting β‐cell function, was significantly improved with linagliptin, and did not change with placebo (placebo‐adjusted mean ± s.e. change for linagliptin: 16.5 ± 4.6 (mU/l)/(mmol/l); p = 0.0003). Further study is required to determine if the significant improvement in HOMA‐%β with linagliptin will translate into long‐term improvements in β‐cell function.     

Renal outcomes with dipeptidyl peptidase-4 inhibitors

Dipeptidyl peptidase-4 inhibitors (DPP-4is) are increasingly being used in the management of type 2 diabetes (T2D). The present review summarizes the current knowledge of the effects of DPP-4is on renal outcomes by analyzing the experimental preclinical data, the effects of DPP-4is on urinary albumin–creatinine ratios (UACRs) and estimated glomerular filtration rates (eGFRs) from observational studies and clinical trials, and renal events (including kidney failure requiring renal replacement therapy) in recent large prospective cardiovascular outcome trials. Renal protection has been demonstrated in various animal models that have implicated different underlying mechanisms independent of glucose control, whereas prevention of new onset microalbuminuria and/or progression of albuminuria has been reported in some clinical studies, but with no significant effects on eGFR in most of them. The long-term clinical effects of DPP-4is on renal outcomes and the development of end-stage renal disease remain largely unknown and, thus, demand further investigations in prospective trials and long-term observational studies. In conclusion, despite promising results in animal models, data on surrogate biological markers of renal function and clinical renal outcomes remain rather scanty in patients with T2D, and mostly demonstrate the safety rather than true efficacy of DPP-4is.     

Pharmacokinetics, pharmacodynamics and tolerability of multiple oral doses of linagliptin, a dipeptidyl peptidase-4 inhibitor in male type 2 diabetes patients

Aims:  To investigate the safety, tolerability, pharmacokinetic and pharmacodynamic properties of multiple oral doses of the dipeptidyl peptidase-4 (DPP-4) inhibitor linagliptin (BI 1356) in patients with type 2 diabetes mellitus.
Methods:  Forty-seven male type 2 diabetic patients received linagliptin 1, 2.5, 5 or 10 mg, or placebo, once daily for 12 days.
Results:  Linagliptin exposure [area under the plasma concentration–time curve and maximum plasma concentration ( C _max)] increased less than proportionally with dose. Accumulation half-life was short (8.6–23.9 h), resulting in rapid attainment of steady state (2–5 days) and little accumulation (range: 1.18–2.03). The long terminal half-life (113–131 h) led to a sustained inhibition of DPP-4 activity. Renal excretion was below 1% on day 1 in all dose groups. Inhibition of plasma DPP-4 activity correlated well with linagliptin plasma concentrations, resulting in DPP-4 inhibition >90% in the two highest dose groups; even 24 h postdose, DPP-4 inhibition was >80%. Following an oral glucose tolerance test, 24 h after the last dose, statistically significant reductions of glucose excursions were observed with linagliptin (2.5, 5 and 10 mg doses) compared with placebo. Linagliptin was well tolerated. The frequency of adverse events (AEs) was not higher with linagliptin (54%) than with placebo (75%). No serious AEs and no episodes of hypoglycaemia were reported.
Conclusions:  In type 2 diabetic patients, multiple rising doses of linagliptin were well tolerated and resulted in significant improvements of glucose parameters. Together with the favourable pharmacokinetics, these results confirm the unique profile of linagliptin in the DPP-4 inhibitor class.