Physicians' Academy for Cardiovascular Education

Meta-analysis reassuring about cardiovascular safety DPP-4 inhibitors

Abbas AS et al. Diabetes Obes Metab. 2015


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

1. Mozaffarian D, Benjamin EJ, Go AS et al. Heart disease and stroke statistics-2015 update: a report from the American Heart Association. Circulation 2015;131: e29–e322.
2. Bianchi C, Miccoli R, Daniele G et al. Is there evidence that oral hypoglycemic agents reduce cardiovascular morbidity/mortality? Yes. Diabetes Care 2009; 32(Suppl. 2): S342–S348.
3. Ray KK, Seshasai SR, Wijesuriya S et al. Effect of intensive control of glucose on cardiovascular outcomes and death in patients with diabetes mellitus: a meta-analysis of randomised controlled trials. Lancet 2009; 373: 1765–1772.
4. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research. Guidance for industry: diabetes mellitus — evaluating cardiovascular risk in new antidiabetic therapies to treat type 2 diabetes. December 2008. Available from URL: http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm071627.pdf. Accessed 6 October 2015.
5. Karagiannis T, Paschos P, Paletas K et al. Dipeptidyl peptidase-4 inhibitors for treatment of type 2 diabetes mellitus in the clinical setting: systematic review and meta-analysis. BMJ 2012; 344: e1369.
6. Gerrald KR, Van Scoyoc E, Wines RC et al. Saxagliptin and sitagliptin in adult patients with type 2 diabetes: a systematic review and meta-analysis. Diabetes Obes Metab 2012; 14: 481–492.
7. Monami M, Ahrén B, Dicembrini I,Mannucci E. Dipeptidyl peptidase-4 inhibitors and cardiovascular risk: a meta-analysis of randomized clinical trials. Diabetes Obes Metab 2013; 15: 112–120.
8. Patil HR, Al Badarin FJ, Al Shami HA et al. Meta-analysis of effect of dipeptidyl peptidase-4 inhibitors on cardiovascular risk in type 2 diabetes mellitus. Am J Cardiol 2012; 110: 826–833.
9. Scirica BM, Bhatt DL, Braunwald E et al. Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus. N Engl J Med 2013; 369: 1317–1326.
10. White WB, Cannon CP, Heller SR et al. Alogliptin after acute coronary syndrome in patients with type 2 diabetes. N Engl J Med 2013; 369: 1327–1335.
11. Green JB, Bethel MA, Armstrong P et al. Effect of sitagliptin on cardiovascular outcomes in type 2 diabetes. N Engl J Med 2015; 373: 232–242.

 

Find this article online on Pubmed