Takeda announces post hoc analysis of data from EXAMINE cardiovascular safety outcomes trial

In patients with type 2 diabetes and recent acute coronary syndrome (ACS), dipeptidyl peptidase 4 (DPP-4) inhibitor alogliptin compared to placebo did not increase the risk of heart failure (HF) outcomes, according to data published in The Lancet.

Post-hoc analysis of data from the global EXAMINE (EXamination of CArdiovascular OutcoMes: AlogliptIN vs. Standard of CarE in Patients with Type 2 Diabetes Mellitus and Acute Coronary Syndrome) cardiovascular (CV) safety outcomes trial showed that alogliptin was non inferior to placebo on the primary end point of CV death, myocardial infarction, or stroke compared with placebo.

Dr Zannad

“In this report, we investigated heart failure outcomes in this high-CV risk population, including assessments by baseline history of HF and levels of brain natriuretic peptide [BNP], as well as assessments of changes of N-Terminal proBNP from baseline to 6 months,” said Faiez Zannad, MD, professor of therapeutics and cardiology, Institut Lorrain du Coeur et des Vaisseaux, Centre d’Investigation Clinique Inserm, in France.

EXAMINE studied 5,380 patients in 49 countries with type 2 diabetes with an acute coronary syndrome (ACS) within the previous 15 to 90 days. Patients were randomly assigned to receive alogliptin or placebo added to existing anti-hyperglycemic and cardiovascular drug therapy. Mortality and hospitalized heart failure (HHF) were adjudicated prospectively by an independent committee and evaluated by treatment group and by history of HF and brain natriuretic peptide (BNP) levels at baseline. The researchers evaluated pre-specified and post hoc analyses of heart failure hospitalization in EXAMINE.

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Alogliptin had no effect on the primary end point of major cardiovascular events (MACE) as reported in the primary NEJM paper in 2013. In this report in The Lancet, it is shown that alogliptin had no effect on the extended exploratory post hoc composite end point of CV death and HHF (HR=1.00, 95% CI, 0.82, 1.21). Patients with a history of HF prior to randomization had a higher risk of HF outcomes in EXAMINE. The sub-analysis showed that the risk of the composite of CV death and HHF was not increased with alogliptin (n=107, 13.9%) compared with placebo (n=120, 15.7%) (HR=0.90, 95% CI, 0.70, 1.17). In patients without a history of HF at baseline, there was also no increased risk of the composite endpoint of CV death and HHF for alogliptin (HR=1.14 [95% CI, 0.85-1.54]; P=.337) versus placebo

“Alogliptin did not increase the risk of heart failure outcomes that included cardiovascular death and heart failure hospitalization,” Dr Zannad said. “This reassuring result was further confirmed by similar reductions in NT-pro-BNP as well as with similar use of diuretics-both thiazide and loop-with alogliptin as compared to placebo.”

DPP-4 inhibitors are new additions to the therapy of type 2 diabetes, according to Dr Zannad.

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“Concern was raised about the CV safety of newer diabetes drugs, but not specifically about DPP-4 inhibitors,” he said. “However the FDA mandated that CV safety trials are undertaken with new treatments for diabetes type 2. So far we have the results of the 2 first such trials, which showed that saxagliptin and alogliptin respectively, are safe on major cardiovascular events.”

However, contrary to EXAMINE, SAVOR (Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus-TIMI 53) trial, showed that more cases of heart failure occurred with saxagliptin, compared to placebo.

“Although this is puzzling and one cannot reasonably explain the difference (no mechanistic plausibility), we believe that the preferred DPP-4 inhibitor, so far, in patients at risk of heart failure is alogliptin,” Dr Zannad said.

The results of the Sitagliptin Cardiovascular Outcome Study (TECOS), a cardiovascular-outcomes trial with sitagliptin, will be presented at the American Diabetes Association meeting in June.

According to Dr Zannad, TECOS is eagerly awaited and “we shall see where it would topple the balance.”

“Meanwhile, the results of EXAMINE are reassuring, and if my patients need a DPP-4 inhibitor, I would get them on alogliptin,” he said.

Heart disease, or cardiovascular disease (CVD), is the leading cause of morbidity and mortality in patients with type 2 diabetes, and is responsible for between 50% and 80% of deaths in people with diabetes.

Alogliptin is approved as a monotherapy for the treatment of type 2 diabetes in adults as adjuncts to diet and exercise. These therapies are not for treatment of type 1 diabetes or diabetic ketoacidosis.

Takeda sponsored the EXAMINE trial.