ArticlesHeart failure and mortality outcomes in patients with type 2 diabetes taking alogliptin versus placebo in EXAMINE: a multicentre, randomised, double-blind trial
Introduction
Congestive heart failure is increasing in incidence due to reduced mortality from myocardial infarction and the ageing of the population worldwide. Type 2 diabetes mellitus increases the likelihood of developing heart failure1—almost half of patients develop heart failure2, 3—and adversely affects the outcomes of patients with established heart failure.4, 5, 6 The effects of treatment for type 2 diabetes on heart failure outcomes, however, has not been adequately addressed in trials, but potential cardiovascular harm has been suggested with several glucose-lowering medications.7
Two randomised controlled trials focusing on major cardiovascular outcomes in patients with type 2 diabetes assessed treatment with DPP-4 inhibitors. In the SAVOR TIMI 53 trial,8, 9 which enrolled 16 492 patients with type 2 diabetes and a history or risk of cardiovascular events, saxagliptin had no effect on the composite outcome of cardiovascular death, myocardial infarction, or ischaemic stroke. However, the rate of hospital admission for heart failure was higher with saxagliptin than with placebo (3·5% vs 2·8%, hazard ratio [HR] 1·27, 95% CI 1·07–1·51, p=0·007). In the EXAMINE trial,10 which enrolled 5380 patients with type 2 diabetes and a recent acute coronary syndrome event, alogliptin was non-inferior to placebo in lowering the risk of the composite primary endpoint of cardiovascular death, myocardial infarction, or stroke (11·3% vs 11·8%, HR 0·96, upper boundary of the one-sided 95% CI 1·16). As part of EXAMINE, we investigated heart failure outcomes in patients with a history or high risk of cardiovascular disease in a prespecified exploratory analysis and in post-hoc analyses. We also assessed changes in N-terminal pro-BNP (NT-pro-BNP) from baseline to 6 months.
Section snippets
Study design
Details of the EXAMINE study design are published elsewhere.10 The study was a multicentre, randomised, double-blind trial, into which patients were enrolled from 898 centres in 49 countries between October, 2009, and March, 2013. The EXAMINE trial was overseen by a steering committee, data safety monitoring committee, and cardiovascular endpoints committee. The data safety monitoring committee was independent and had ongoing access to the unmasked data to advise the funder and steering
Results
5380 patients were enrolled, of whom 2701 received alogliptin and 2679 received placebo (figure 1). Approximately 60% of the patients with heart failure at baseline had a history of heart failure before the index acute coronary syndrome event. Patients with history of heart failure at baseline were older, more frequently women, and had higher baseline BNP concentrations and lower eGFR values, than patients with no history of heart failure (table 1). Otherwise, baseline characteristics were
Discussion
The EXAMINE trial showed that treatment with the DPP-4 inhibitor alogliptin had similar outcomes for heart failure to placebo in patients with type 2 diabetes and a recent acute coronary syndrome event (panel). Subgroup analyses by history of heart failure at baseline showed that alogliptin did not lead to more new hospital admissions for heart failure or worse outcomes for existing heart failure outcomes in patients with the comorbidity of heart failure. Previously, we had reported that the
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