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Diabetes Obes Metab. 2016 Mar;18(3):295-9. doi: 10.1111/dom.12595. Epub 2015 Dec 23.

Cardiovascular and non-cardiovascular safety of dipeptidyl peptidase-4 inhibition: a meta-analysis of randomized controlled cardiovascular outcome trials.

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Department of Primary Care and Public Health, School of Public Health, Imperial College London, London, UK.
Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK.


The full licensing of dipeptidyl peptidase-4 (DPP-4) inhibitors in the USA and Europe requires demonstration of cardiovascular (CV) safety with an upper boundary of harm of <30%. We report a total of 3334 CV events during 86,716 person-years of follow-up in 36,543 patients, when combining data from three trials with formal and prospectively assessed endpoints. Fixed-effect meta-analysis showed that, compared with placebo, DPP-4 inhibition did not increase the upper boundary of risk for the composite endpoint, nor for any individual component by >30%. Relative risks (RRs) were: 0.99 [confidence interval (CI) 0.93-1.06] for composite CV-specific death, non-fatal myocardial infarction (MI) and non-fatal stroke; 1.01 (CI 0.91-1.12) for CV-specific death; 0.98 (CI 0.89-1.09) for non-fatal MI; and 1.00 (CI 0.86-1.16) for non-fatal stroke. The risk of acute pancreatitis was increased (RR 1.79; CI 1.13-2.81), equating to 5.5 extra cases/10,000 patients/year (weighted mean) and a number needed to harm of 1940/year. These data provide reassurance about the safety of DPP-4 inhibitors with regard to individual atherothrombotic events and a safety signal for pancreatitis.


DPP-IV inhibitor; antidiabetic drug; cardiovascular disease; meta-analysis

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