Efficacy and safety of linagliptin in subjects with type 2 diabetes mellitus and poor glycemic control: Pooled analysis of data from three placebo-controlled phase III trials.

AIMS: To evaluate the efficacy/safety of dipeptidyl peptidase-4 inhibitor, linagliptin, in subjects with insufficiently controlled type 2 diabetes mellitus (T2DM), and factors influencing treatment response. METHODS: Pooled analysis of data from 2258 subjects in three 24-week phase III, randomized, placebo-controlled, parallel-group studies, who received oral linagliptin (5mg/day) or placebo as monotherapy, added-on to metformin, or added-on to metformin plus sulfonylurea was performed. RESULTS: Among 388 subjects with HbA1c ≥9.0%, adjusted mean baseline HbA1c (9.4% both groups) declined to 8.3% in linagliptin group and 9.1% in placebo group at 24weeks (P<.0001) and adjusted mean change from baseline was 1.2% (vs. 0.4%, placebo). Linagliptin significantly lowered fasting plasma glucose levels vs. placebo (1.6mmol/l vs. 0.4mmol/l); treatment difference, 1.1mmol/l (95% CI, -1.7 to -0.5). Treatment and washout of previous oral antidiabetes drugs were the only factors to independently affect HbA1c change at week 24. Adverse event rates were similar for linagliptin (61.9%) and placebo (62.7%). Hypoglycemia was rare with linagliptin monotherapy/add-on to metformin (≤1%) and increased when linagliptin was added to metformin plus sulfonylurea (linagliptin, 17.9% vs. placebo, 8.3%). CONCLUSIONS: Linagliptin was an effective, well-tolerated treatment in subjects with T2DM and insufficient glycemic control, both as monotherapy or added-on to metformin/metformin plus sulfonylurea

Linagliptin treatment in subjects with type 2 diabetes with and without mild-to-moderate renal impairment

Aims: Renal disease is a frequent comorbidity of type 2 diabetes mellitus (T2DM) and an important factor complicating the choice of glucose-lowering drugs. The aim of this analysis was to evaluate the efficacy and safety of the dipeptidyl peptidase (DPP)-4 inhibitor linagliptin (5mg/day) in mono, dual or triple oral glucose-lowering regimens in subjects with T2DM and mild or moderate renal impairment (RI). Methods: In this pooled analysis of three 24-week, placebo-controlled, phase 3 trials, subjects with mild (estimated glomerular filtration rate (eGFR) 60-<90ml/min/1.73m2, n=838) or moderate RI (30-<60ml/min/1.73m2, n=93) were compared with subjects with normal renal function (≥90ml/min/1.73m2, n=1212). Results: Subjects with RI were older, had longer duration of diabetes, and increased prevalence of diabetes-related comorbidities. After 24weeks, linagliptin achieved consistent placebo-corrected mean glycated haemoglobin (HbA1c) changes across the three renal function categories: normal (-0.63%; p<0.0001), mild RI (-0.67%; p<0.0001) and moderate RI (-0.53%; p<0.01), with no inter-group difference (p=0.74). Renal function with linagliptin remained stable across all categories. In linagliptin-treated subjects, overall adverse event (AE) rates and serious AE rates were similar to placebo. The incidence of hypoglycaemia with linagliptin and placebo was 11.1 versus 6.9%, 11.9 versus 9.0% and 15.9 versus 12.0% in the normal, mild RI and moderate RI categories, respectively. Conclusions: This pooled analysis provides evidence that linagliptin is an effective, well-tolerated and convenient treatment in subjects with T2DM and mild or moderate RI. © 2014 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd

The effect of empagliflozin on muscle sympathetic nerve activity in patients with type 2 Diabetes mellitus

Inhibition of sodium glucose cotransporter 2 with empagliflozin results in caloric loss by increasing urinary glucose excretion and has a mild diuretic effect. Diuretic effects are usually associated with reflex-mediated increases in sympathetic tone, whereas caloric loss is associated with decreased sympathetic tone. In an open-label trial, muscle sympathetic nerve activity (MSNA) (burst frequency, burst incidence, and total MSNA) was assessed using microneurography performed off-treatment and on day 4 of treatment with empagliflozin 25 mg once daily in 22 metformin-treated patients with type II diabetes (mean [range] age 54 [40–65] years). Systolic and diastolic blood pressure (BP), heart rate, urine volume, and body weight were assessed before and on day 4 (BP, heart rate), day 5 (urine volume), or day 6 (body weight) of treatment with empagliflozin. After 4 days of treatment with empagliflozin, no significant changes in MSNA were apparent despite a numerical increase in urine volume, numerical reductions in BP, and significant weight loss. There were no clinically relevant changes in heart rate