Thorough QT study of the effects of vildagliptin, a dipeptidyl peptidase IV inhibitor, on cardiac repolarization and conduction in healthy volunteers

Abstract

Objective:

This randomized, double-blind study evaluated the effects of vildagliptin, a dipeptidyl peptidase IV inhibitor for treating type 2 diabetes, on cardiac repolarization and conduction.

Methods:

Healthy volunteers (n = 101) were randomized (1:1:1:1 ratio) to vildagliptin 100 or 400 mg, moxifloxacin 400 mg (active control), or placebo once daily for 5 days. Electrocardiograms were recorded at baseline and day 5 for 24 hours post-dose. Placebo-adjusted mean change from baseline in QT interval, heart-rate-corrected QT intervals by Fridericia's (QTcF) or Bazett's (QTcB) formula, and PR and QRS intervals were compared at each time-point (time-matched analysis) and for values averaged across the dosing period (time-averaged analysis).

Results:

For time-matched analysis, mean changes in QTcF with vildagliptin were below predefined limits for QTc prolongation (mean increase <5 ms; upper 90% confidence interval [CI] < 10 ms), except for vildagliptin 100 mg at 1 and 8 hours post-dose (upper 90% CI > 10 ms). With moxifloxacin, significant QTcF prolongation occurred at most time-points, demonstrating assay sensitivity. No vildagliptin- or placebo-treated volunteer had QTcF > 450 ms. Incidences of QTcF increases ≥30 ms with vildagliptin (100 and 400 mg) and placebo were similar (4–8%) and were much lower than with moxifloxacin (39%). No QTcF increase ≥60 ms was observed with vildagliptin or placebo (versus one with moxifloxacin). Time-averaged, time-matched, and categorical analyses of QT/QTcF/QTcB showed similar results. Drug exposure analysis showed no correlation between vildagliptin plasma levels and QTc changes. Vildagliptin had no effect on PR or QRS intervals. Although this study, completed before publication of current ICH E14 guidelines, was underpowered for time-matched analysis, the results are consistent with lack of effect of vildagliptin on QTc.

Conclusion:

Vildagliptin did not prolong QT interval or affect cardiac conduction at the highest daily therapeutic dose or a fourfold higher dose.

Key words::

• Cardiac repolarization
• Diabetes
• Moxifloxacin
• QT interval
• Vildagliptin

Transparency

Declaration of funding

This study was funded by Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA. Novartis were involved in the design, collection and analysis of the data. All authors had access to all data, participated in the development of the manuscript and approved the final version for submission.

Declaration of financial/other relationships

All authors are employees of either Novartis Pharmaceuticals Corporation or Novartis Institutes for BioMedical Research Inc., and are therefore eligible for Novartis stock and stock options.

Acknowledgments

The authors thank Dr Joelle Campestrini for the bioanalytical support of measuring the plasma concentration of vildagliptin, and Dr Jenny Handford (Oxford PharmaGenesis™ Ltd) for medical writing support, editorial assistance and collation and incorporation of comments from all authors. This support was funded by Novartis Pharmaceuticals Corporation (East Hanover, NJ, USA).