DPP-4 inhibitors and GLP-1 agonists in type 2 diabetes - early assessment of cardiovascular safety in a nationwide setting

Abstract

Background: Dipeptidyl peptidase-4 (DPP-4) inhibitors and Glucagon Like Peptide-1 (GLP-1) agonists have recently been introduced in the treatment of type 2 diabetes and are mainly used as add-on therapy to metformin, either alone or with additional sulfonylureas (SU) and/or insulin. Data regarding long-term cardiovascular safety are sparse. Methods: All Danish inhabitants without a history of myocardial infarction or stroke initiating combinations of 2 or 3 glucose lowering therapies between May 9, 2007 and December 31, 2011 were followed for the risk of myocardial infarction, stroke, or all-cause mortality as a combined cardiovascular disease/safety endpoint. The different combinations included are presented in Fig.1. Rate ratios (RR) were calculated using time-dependent multivariable Poisson regression analysis adjusting for age, diabetes duration, comorbidity, income, calendar year and cardiovascular drugs. Results: A total of 42,254 initiated combination therapy. Numbers and events in each combination are presented in Fig.1. The adjusted analysis showed that metformin combined with DPP-4 inhibitor or GLP-1 agonist was associated with a similar and compared with SU+metformin lower risk. Triple combinations of DPP-4 inhibitor or GLP-1 agonist as add-on to SU+metformin were associated with similar risks as metformin+SU. Insulin combinations were generally associated with increased risk. (Figure presented) Conclusion: Combination therapy with DDP-4 inhibitors and GLP-1 agonists was not associated with increased cardiovascular risk compared with other conventional combinations of glucose-lowering treatments. Randomized prospective studies are needed to establish whether incretin-based therapies may be associated with differential safety profiles compared with older classes of glucose lowering therapies.