More From EXAMINE: CV Events Predispose Diabetics to Death

June 12, 2016

NEW ORLEANS — A post hoc analysis of the Examination of Cardiovascular Outcomes With Alogliptin versus Standard of Care (EXAMINE) trial with the type 2 diabetes drug alogliptin (Nesina, Takeda), an oral dipeptidyl peptidase–4 (DPP-4) inhibitor, has shown that the risk of cardiovascular death was higher if patients in the trial had first experienced a nonfatal cardiovascular event.

This was particularly true of hospitalization for heart failure (HF) — those patients were almost five times more likely to subsequently die (hazard ratio [HR], 4.96; P < .0001); of interest, there was no difference in this outcome between those randomized to alogliptin and those taking placebo (22.7% of patients taking alogliptin compared with 34.1% of those taking placebo were hospitalized for heart failure, HR, 1.02; 95% CI 0.51–2.02).

The findings therefore indicate how powerful an indicator of mortality HF is in patients with type 2 diabetes and coronary heart disease, say the investigators, led by William B White, MD, of University of Connecticut School of Medicine, Farmington, Connecticut.

Prof Simon Heller

"The potential to reduce mortality through aggressive use of evidence-based secondary-prevention strategies" in this patient population, therefore "remains substantial," they note.

The new findings were presented here at the American Diabetes Association (ADA) 2016 Scientific Sessions by coauthor Prof Simon Heller, professor of clinical diabetes, University of Sheffield, United Kingdom, and were also simultaneously published online in Diabetes Care.

In a press conference discussing these latest findings, moderator Robert Eckel, MD, of the University of Colorado, Denver, said: "A third of the patients in this trial died; let's prevent cardiovascular disease" in this patient population.

Should FDA Now Rethink HF Warning on Alogliptin Label?

These results also appear to exonerate alogliptin with regard to its association with an increased risk of heart failure; the US Food and Drug Administration (FDA) said earlier this year that the drug would require a warning added to the label to indicate an increased risk for heart failure, due to a signal to this effect in the overall EXAMINE trial, which was first reported in September 2013.

In the ADA press conference, Dr Eckel noted: "There is the caution [for HF in the US label] — is it going to be relaxed now, based on the fact that alogliptin did not increase heart-failure hospitalizations?"

Asked this same question by Medscape Medical News, Dr Heller said: "It's difficult for a European to comment [on what the FDA should do], and in Europe there isn't a warning about heart failure [on the alogliptin label] and it's used with greater impunity, so I can't speak for the FDA."

However, there wasn't a statistically significant increase in HF hospitalizations in those taking alogliptin in EXAMINE, he stressed, "so these are reassuring data, and I think there is a case for [the FDA] to look at the label again."

Takeda has always insisted that alogliptin is not associated with an increased risk of heart failure. A prior analysis of EXAMINE published in March 2015 in the Lancet showed no difference between those taking alogliptin and those on placebo in terms of either hospital admission for heart failure or the composite end point of cardiovascular death and hospital admission for heart failure.

Latest Post Hoc Analysis of EXAMINE

EXAMINE, one of the FDA-mandated cardiovascular-outcomes trials for new agents for type 2 diabetes, randomized 5380 patients with type 2 diabetes at very high cardiovascular risk (having had an ACS within the last 90 days) to standard of care for diabetes plus alogliptin 25 mg once daily or placebo for up to 3.3 years.

In the overall study, alogliptin was shown to be safe in cardiovascular terms, other than the concern about the possible HF signal — and that was the intention of trials such as this.

In this latest post hoc analysis, the aim was to evaluate the risk of a cardiovascular death in all EXAMINE study participants and in those who experienced an "on-study" major nonfatal cardiovascular event, explained Dr Heller.

Patients were monitored until censoring or death, regardless of a prior postrandomized nonfatal CV event. The risk of death in the absence of or after each nonfatal event was estimated.

Rates of cardiovascular death were 4.1% among those who took alogliptin in EXAMINE vs 4.9% in those who took placebo (HR 0.85; 95% CI 0.66–1.10).

There were 736 patients (13.7%) in the study population who experienced a first nonfatal cardiovascular event (5.9% myocardial infarction [MI], 1.0% stroke, 3.3% hospitalization for heart failure, and 3.8% unstable angina).

Compared with patients not experiencing a nonfatal CV event, the adjusted HR for death was 3.12 after MI (< .0001), 4.96 after HF (P < .0001), 3.08 after stroke (P = .011) and 0.81 after unstable angina (P = .164).

Mortality rates after a nonfatal event were comparable for alogliptin and placebo.

The results therefore indicate that "heart failure is a powerful predictor of mortality in patients with both type 2 diabetes and coronary heart disease," Dr White stated in an ADA press release.

"This study suggests that we have an important opportunity to evaluate and understand the factors underlying incident heart failure to improve prevention strategies," he added.

And these findings "emphasize how critical it is to aggressively make use of evidence-based, secondary-prevention therapies, which should be considered a standard in the clinical management of patients with type 2 diabetes who are at high risk for cardiovascular disease," he concluded.

Dr Heller has done advisory work for Novo Nordisk, Eli Lilly, and Sanofi and given talks for all three companies. He has also received consulting fees or honoraria from Takeda, MSD, AstraZeneca, Johnson & Johnson, and Boehringer Ingelheim. Disclosures for the coauthors are listed in the conference abstract . Medtronic supplied the pumps for the trial but had no influence over study design, analysis of the results, or the presentation or upcoming paper.

Follow Lisa Nainggolan on Twitter: @LisaNainggolan1. For more diabetes and endocrinology news, follow us on Twitter and on Facebook.

Diabetes Care. Published online June 11, 2016. Abstract

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