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

Abbas AS, Dehbi HM, Ray KK.
Diabetes Obes Metab. 2015 Oct 29. doi: 10.1111/dom.12595. [Epub ahead of print]

Background

Cardiovascular disease accounts for the majority of deaths in patients with type 2 diabetes mellitus [1]. The evidence on whether tight glycaemic control with several classes of oral
hypoglycaemic agents leads to improved CV outcomes is still diverse [2,3]. Because of the side effects of existing therapies, the search for novel treatments is necessary.
In 2008, the US Food and Drug Administration (FDA) required that all new diabetes drugs must
demonstrate CV safety with an upper boundary of risk of <1.3 for the composite endpoint of CV-specific death, non-fatal myocardial infarction (MI) and non-fatal stroke [4]. Dipeptidyl peptidase-4 (DPP-4) inhibitors are the first class of drugs for which prospective trial data have been reported since this guidance. DPP-4 inhibitors have advantages over existing therapies, such as a once-daily preparation, weight neutrality and glucose-dependent release of insulin [5,6]. DPP-4 inhibitors may offer considerable CV benefit [7,8], but long-term CV outcome trial data are lacking.
Several randomized trials with long-term follow-up have recently been completed, meeting the FDA requirement for safety for the composite endpoint [9–11]. However, there remains uncertainty with respect to the effect of DDP-4 inhibition on the individual components.
This meta-analysis of all prospective CV outcome trials assessing DPP-4 inhibitors aimed to provide more reliable data, regarding not only the overall CV safety but also the effect of DPP-4 inhibitors on specific CV and important non-CV endpoints.

Three randomized controlled trials with formal and prospectively assessed endpoints were included in the final meta-analysis: the SAVOR [9], EXAMINE [10] and TECOS [11] trials.

Main results

• During 86 716 person-years of follow-up, 36 543 patients with T2DM experienced 3334 CV events.
• 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 any individual component by >30%, in line with the FDA licensing guidelines.
• Relative risks (RRs) were 0.99 (CI 0.93–1.06) for CV-specific death, non-fatal 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 elevated (RR 1.79; CI 1.13–2.81), associated with 5.5 extra cases per 10 000 patients/year (weighted mean) and a number needed to harm of 1940/year.
• The risk of any hypoglycaemic episode was also elevated (RR 1.12, CI 1.05–1.20) with a number needed to harm of 234/year, but serious hypoglycaemia was not (CI 0.95–1.38).
• A signal for protection against pancreatic cancer was observed,  which may warrant further study (RR 0.55; CI 0.29–1.03).
• There was no statistically significant heterogeneity among the studies for any endpoint, supporting a class effect for benefit and harm.

Conclusion

This meta-analysis provides reassurance about the CV safety of DPP-4 inhibitors with regard to individual atherothrombotic events. Further investigation into identifying those most at risk of rare but potentially serious acute pancreatitis secondary to DPP-4 inhibition may be useful for prescribers.

References

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