Wolfgang Kothny

Assessing the cardio-cerebrovascular safety of vildagliptin: meta-analysis of adjudicated events from a large Phase III type 2 diabetes population.

Aim: To assess the cardiovascular and cerebrovascular (CCV) safety of the dipeptidyl peptidase‐IV inhibitor vildagliptin.

Safety and efficacy of vildagliptin versus placebo in patients with type 2 diabetes and moderate or severe renal impairment: a prospective 24‐week randomized placebo‐controlled trial

Aim: Assess safety/tolerability and efficacy of the DPP‐4 inhibitor vildagliptin in 515 patients with type 2 diabetes mellitus (T2DM) and moderate or severe renal impairment (RI).

An assessment of adverse effects of vildagliptin versus comparators on the liver, the pancreas, the immune system, the skin and in patients with impaired renal function from a large pooled database of Phase II and III clinical trials

Aim: To assess the safety of vildagliptin versus all comparators (ACs) with regard to organs, systems or tissues of particular interest in type 2 diabetes (T2DM) and areas of potential concern with dipeptidyl peptidase‐IV (DPP‐4) inhibitors.

Individualised treatment targets for elderly patients with type 2 diabetes using vildagliptin add-on or lone therapy (INTERVAL): a 24 week, randomised, double-blind, placebo-controlled study

BACKGROUND Guidelines suggest setting individualised targets for glycaemic control in elderly patients with type 2 diabetes, despite no evidence. We aimed to assess the feasibility of setting and achieving individualised targets over 24 weeks along with conventional HbA1c reduction using vildagliptin versus placebo. METHODS In this multinational, double-blind, 24 week study, we enrolled drug-naive or inadequately controlled (glycosylated haemoglobin A1c [HbA1c] ≥7·0% to ≤10·0%) patients with type 2 diabetes aged 70 years or older from 45 outpatient centres in Europe. Investigators set individualised treatment targets on the basis of age, baseline HbA1c, comorbidities, and frailty status before a validated automated system randomly assigned patients (1:1) to vildagliptin (50 mg once or twice daily as per label) or placebo. Coprimary efficacy endpoints were proportion of patients reaching their investigator-defined HbA1c target and HbA1c reduction from baseline to study end. The study is registered with ClinicalTrials.gov, number NCT01257451, and European Union Drug Regulating Authorities Clinical Trials database, number 2010-022658-18. FINDINGS Between Dec 22, 2010, and March 14, 2012, we randomly assigned 139 patients each to the vildagliptin and placebo groups. 37 (27%) of 137 patients in the placebo group achieved their individualised targets by education and interactions with the study team alone and 72 (52·6%) of 137 patients achieved their target in the vildagliptin group (adjusted odds ratio 3·16, 96·2% CI 1·81-5·52; p<0·0001). This finding was accompanied by a clinically relevant 0·9% reduction in HbA1c from a baseline of 7·9% with vildagliptin and a between-group difference of -0·6% (98·8% CI -0·81 to -0·33; p<0·0001). The overall safety and tolerability was similar in the vildagliptin and placebo groups, with low incidence of hypoglycaemia and no emergence of new safety signals. INTERPRETATION This study is the first to introduce and show the feasibility of using individualised HbA1c targets as an endpoint in any type 2 diabetes population. Individualised glycaemic target levels are achievable with vildagliptin without any tolerability issues in the elderly type 2 diabetes population. FUNDING Novartis Pharma AG.

Clinical experience with vildagliptin in the management of type 2 diabetes in a patient population ≥75 years: a pooled analysis from a database of clinical trials

Aim: To report the experience with vildagliptin in a patient population with type 2 diabetes mellitus (T2DM) ≥75 years.

One-year safety, tolerability and efficacy of vildagliptin in patients with type 2 diabetes and moderate or severe renal impairment.

Assess long‐term safety and efficacy of the dipeptidlyl peptidase-4 (DPP‐4) inhibitor vildagliptin in 369 patients with type 2 diabetes mellitus (T2DM) and moderate or severe renal impairment (RI).

Improved glycaemic control with vildagliptin added to insulin, with or without metformin, in patients with type 2 diabetes mellitus

The aim of this study is to assess the efficacy and safety of vildagliptin 50 mg bid as add‐on therapy to insulin in type 2 diabetes mellitus (T2DM).

Assessing the general safety and tolerability of vildagliptin: value of pooled analyses from a large safety database versus evaluation of individual studies.

Aim: Analyzing safety aspects of a drug from individual studies can lead to difficult-to-interpret results. The aim of this paper is therefore to assess the general safety and tolerability, including incidences of the most common adverse events (AEs), of vildagliptin based on a large pooled database of Phase II and III clinical trials. Methods: Safety data were pooled from 38 studies of ≥12 to ≥104 weeks’ duration. AE profiles of vildagliptin (50 mg bid; N = 6116) were evaluated relative to a pool of comparators (placebo and active comparators; N = 6210). Absolute incidence rates were calculated for all AEs, serious AEs (SAEs), discontinuations due to AEs, and deaths. Results: Overall AEs, SAEs, discontinuations due to AEs, and deaths were all reported with a similar frequency in patients receiving vildagliptin (69.1%, 8.9%, 5.7%, and 0.4%, respectively) and patients receiving comparators (69.0%, 9.0%, 6.4%, and 0.4%, respectively), whereas drug-related AEs were seen with a lower frequency in vildagliptin-treated patients (15.7% vs 21.7% with comparators). The incidences of the most commonly reported specific AEs were also similar between vildagliptin and comparators, except for increased incidences of hypoglycemia, tremor, and hyperhidrosis in the comparator group related to the use of sulfonylureas. Conclusions: The present pooled analysis shows that vildagliptin was overall well tolerated in clinical trials of up to >2 years in duration. The data further emphasize the value of a pooled analysis from a large safety database versus assessing safety and tolerability from individual studies.

Cardiovascular and heart failure safety profile of vildagliptin: a meta‐analysis of 17 000 patients

To report the cardiovascular (CV) safety profile and heart failure (HF) risk of vildagliptin from a large pool of studies, including trials in high‐risk patients with type 2 diabetes mellitus (T2DM), such as those with congestive HF and/or moderate/severe renal impairment.

Efficacy of vildagliptin in combination with insulin in patients with type 2 diabetes and severe renal impairment

Background The purpose of this study was to evaluate the efficacy of vildagliptin 50 mg once daily in patients with severe renal impairment (estimated glomerular filtration rate < 30 mL/min/1.73 m2) and longstanding type 2 diabetes not adequately controlled with insulin therapy, which is a difficult-to-treat population, with limited therapeutic options and a high susceptibility to hypoglycemia. Methods This was a post hoc subanalysis of data obtained during a previously described randomized, double-blind, parallel-group, 24-week study comparing the efficacy and safety of vildagliptin 50 mg once daily versus placebo in patients with type 2 diabetes and moderate or severe renal impairment. The present data derive from 178 patients with severe renal impairment (baseline estimated glomerular filtration rate approximately 21 mL/min/1.73 m2, 100 randomized to vildagliptin, 78 randomized to placebo), all of whom were receiving insulin therapy (alone or in combination with an oral antidiabetic agent) for longstanding type 2 diabetes (mean approximately 19 years). Results With vildagliptin in combination with insulin, the adjusted mean change (AMΔ) in HbA1c from baseline (7.7% ± 0.1%) was −0.9% ± 0.4% and the between-treatment difference (vildagliptin – placebo) was −0.6% ± 0.2% (P < 0.001). The percentage of patients achieving endpoint HbA1c < 7.0% was significantly higher with vildagliptin than placebo (45.2% versus 22.8%, P = 0.008). When added to insulin, vildagliptin and placebo had comparable hypoglycemic profiles and did not cause weight gain. Both treatments were similarly well tolerated, with comparable incidences of adverse events, serious adverse events, and deaths. Conclusion When added to insulin therapy in patients with severe renal impairment and longstanding type 2 diabetes, vildagliptin 50 mg once daily was efficacious, eliciting HbA1c reductions consistent with those previously reported for a patient population with much more recent onset of type 2 diabetes and normal renal function, and had a hypoglycemic profile comparable with placebo. Accordingly, vildagliptin is a suitable treatment option for patients with advanced type 2 diabetes and impaired renal function who require insulin therapy and present a serious therapeutic challenge in clinical practice.