Los Angeles, CA—A new meta-analysis suggests that the use of dipeptidyl peptidase (DPP)-4 inhibitors to achieve glucose control in patients with type 2 diabetes may be cardioprotective.
“It is extremely unlikely that DPP-4 inhibitors increase cardiovascular adverse events,” said Kari A.O. Tikkinen, MD, PhD, Senior Researcher, McMaster University, Ontario, Canada, and a coinvestigator of the meta-analysis. “The results suggest the possibility of substantial relative risk reduction in cardiovascular events, particularly myocardial infarction, with DPP-4 inhibitors.” The data were released at the 2012 American Heart Association meeting.
DPP-4 inhibitors enhance incretin action and improve glucose control by inhibiting glucagon-like peptide (GLP)-1 and glucose-dependent insulinotropic peptide. Because of the low cardiovascular (CV) event rates in randomized controlled trials of DPP-4 inhibitors, information on CV risk is limited. Using a prespecified protocol, Dr Tikkinen and colleagues performed a systematic review and meta-analysis of randomized clinical trials of DPP-4 inhibitors with follow-up of at least 12 weeks.
To identify the randomized controlled trials, they searched MEDLINE, EMBASE, the Cochrane Library, clini caltrials.gov, published systematic reviews/health technology assessment reports, and abstracts accepted for presentation at the American Diabetes Association and the European Association for the Study of Diabetes meetings. Eligible trials included a comparison of an incretin agent with a placebo, usual care, or other active agents for patients with type 2 diabetes and for which prespecified CV outcomes were reported.
A total of 55 studies were eligible—42 studies of DPP-4 inhibitors and 13 of GLP-1 agonists. Of the 42 DPP-4 inhibitors trials, 19 investigated sitagliptin; 10, saxagliptin; 7, vildagliptin; and 6, alogliptin. The length of follow-up was 12 to 104 weeks; 10 of the trials followed patients for more than 24 weeks; 93% of the trials had a low risk for bias.
Some 110 major adverse cardiovascular events (MACE) were recorded in 24,215 trial participants. DPP-4 inhibitors reduced the risk of MACE by 49% (P = .004) and the risk of myocardial infarction by 72% (relative risk, 0.09-0.94). A 50% reduction in all-cause mortality with DPP-4 inhibitors was not significant, said Dr Tikkinen.
A difference in the effect of DPP-4 inhibitors was found between monotherapy, in which the risk of MACE was reduced by a nonsignificant 7%, and as add-on therapy, in which the risk of MACE was reduced by 54% (relative risk, 0.36-0.59).
There was no difference in treatment effects between study groups based on the duration of the trials, the type of control (active vs placebo), the risk of bias (low vs moderate vs high risk), or the type of DPP-4 inhibitor.
The number of events per study was too low to examine publication bias, he said. Only 4 of the studies adjudicated CV outcomes; in most of the studies, MACE were reported as adverse events.
The data are encouraging, said Dr Tikkinen, but confirmatory studies are necessary before DPP-4 inhibitors can be prescribed specifically to reduce the risk of CV events. Four large-scale randomized controlled outcomes trials with DPP-4 inhibitors are ongoing, he said.