Shelley Wood

September 20, 2011

September 19, 2011 (Updated September 21, 2011) (Lisbon, Portugal) — Offering a rare glimmer of good cardiovascular-disease news for a diabetes drug, a new meta-analysis suggests that dipeptidyl peptidase-4 (DPP-4) inhibitors, at worst, do not increase the risk of cardiovascular events and, at best, may even have a protective effect [1].

Dr Edoardo Mannucci (Careggi Teaching Hospital, Florence, Italy) presented the results of the study last week at the European Association for the Study of Diabetes (EASD) 2011 Meeting.

To heartwire , Mannucci explained that his group decided to do the meta-analysis after a July publication by Elashoff and colleagues reported a significant increase in pancreatitis and pancreatic cancer among patients taking sitagliptin [2]. Back in 2009, the FDA announced that it would be revising prescribing information for both sitagliptin (Januvia, Merck) and sitagliptin/metformin (Janumet, Merck) after cases of acute pancreatitis, some severe, surfaced in postmarketing reports, as reported by heartwire .

"We wanted to verify this very unexpected and worrying result on available randomized clinical trials," Mannucci said, "[and] in the process of retrieving all trials, we also collected information on CV safety, which is a major concern for regulatory bodies."

Gliptin Class and CV Events

Mannucci, with first author Dr Caterina Lamanna (Careggi Teaching Hospital), combined data from a total of 53 clinical trials of "gliptin" drugs (alogliptin, dutogliptin, linagliptin, saxagliptin, sitagliptin, and vildagliptin) that included information on metabolic outcomes and cardiovascular events. Ultimately, the meta-analysis included 33 000 patients with type 2 diabetes randomized to a DPP-4 inhibitor, another diabetes drug, or placebo. All trials included a minimum duration of 24 weeks.

In all, 257 major adverse cardiovascular events occurred in the trials over a mean of 10 months: 137 in patients taking a DPP-4 inhibitor and 120 in patients taking either placebo or another diabetes agent.

In an intention-to-treat analysis, which excluded trials with zero events, the odds ratio for a major adverse cardiovascular event was 0.69 (p=0.006) for patients treated with a DPP-4 inhibitor, as compared with placebo or another diabetes agent.

Looking only at placebo-controlled trials, Mannucci et al found an odds ratio of 0.71 (p= 0.045). "We also performed analyses for each class of active comparators, but the number of trials available for each one of those was very small, so that the results cannot be considered reliable," he told heartwire . Overall, however, "in active-comparator trials, the risk reduction is similar to that observed in placebo-controlled trials."

Investigators also looked at CV outcomes based on trial duration: in trials with follow-up ranging from 24 to 51 weeks, use of DPP-4 inhibitors was associated with a significant reduction in events. For trials that were 52 weeks in duration or longer, the findings were not statistically significant. "However, this was only the effect of the sample size," since there were fewer studies of longer duration, Mannucci speculated for heartwire. Of note, the point estimate for the odds ratio was similar, around 0.7, for both shorter- and longer-term trials, he noted.

Patient-level information, he added, is owned by the sponsoring companies of each trial and was not available for the analysis.

In a separate poster presentation also at the EASD meeting, Dr Matteo Monami (University of Florence, Italy) presented the cancer results from the meta-analysis. In that, the odds ratio for all malignancies was 1.020 (95% CI 0.742–1.402, p=0.904) [3]. "We did not see any signal of any harm," Mannucci said.

"Reassuring," at Least for Now

"I think that this meta-analysis clearly shows that the cardiovascular safety of DPP-4 inhibitors is completely reassuring in the short and medium term," Mannucci told heartwire . "Obviously, we still need the specific trials on cardiovascular outcomes in order to have complete information on the effect of long-term exposure."

But it should be remembered, he added, that "we do not have such information for some of the older and widely used drugs, such as sulfonylureas, which were never tested with specific and appropriately powered trials on cardiovascular outcomes, despite some problematic epidemiologic data suggesting that they could worsen the prognosis of myocardial ischemia."

Mannucci disclosed receiving research grants from AstraZeneca, Novartis, Merck Sharp & Dohme, Novo Nordisk, and Sanofi-Aventis and consultancy and/or speaking fees from Bristol-Myers Squibb, Boehringer Ingelheim, Eli Lilly, Novartis, Merck Sharp & Dohme, Takeda, GlaxoSmithKline, Merck-Serono, and Novo Nordisk.