Elsevier

The Lancet

Volume 385, Issue 9982, 23–29 May 2015, Pages 2067-2076
The Lancet

Articles
Heart failure and mortality outcomes in patients with type 2 diabetes taking alogliptin versus placebo in EXAMINE: a multicentre, randomised, double-blind trial

https://doi.org/10.1016/S0140-6736(14)62225-XGet rights and content

Summary

Background

The EXAMINE trial showed non-inferiority of the DPP-4 inhibitor alogliptin to placebo on major adverse cardiac event (MACE) rates in patients with type 2 diabetes and recent acute coronary syndromes. Concerns about excessive rates of in-hospital heart failure in another DPP-4 inhibitor trial have been reported. We therefore assessed hospital admission for heart failure in the EXAMINE trial.

Methods

Patients with type 2 diabetes and an acute coronary syndrome event in the previous 15–90 days were randomly assigned alogliptin or placebo plus standard treatment for diabetes and cardiovascular disease prevention. The prespecified exploratory extended MACE endpoint was all-cause mortality, non-fatal myocardial infarction, non-fatal stroke, urgent revascularisation due to unstable angina, and hospital admission for heart failure. The post-hoc analyses were of cardiovascular death and hospital admission for heart failure, assessed by history of heart failure and brain natriuretic peptide (BNP) concentration at baseline. We also assessed changes in N-terminal pro-BNP (NT-pro-BNP) from baseline to 6 months. This study is registered with ClinicalTrials.gov, number NCT00968708.

Findings

5380 patients were assigned to alogliptin (n=2701) or placebo (n=2679) and followed up for a median of 533 days (IQR 280–751). The exploratory extended MACE endpoint was seen in 433 (16·0%) patients assigned to alogliptin and in 441 (16·5%) assigned to placebo (hazard ratio [HR] 0·98, 95% CI 0·86–1·12). Hospital admission for heart failure was the first event in 85 (3·1%) patients taking alogliptin compared with 79 (2·9%) taking placebo (HR 1·07, 95% CI 0·79–1·46). Alogliptin had no effect on composite events of cardiovascular death and hospital admission for heart failure in the post hoc analysis (HR 1·00, 95% CI 0·82–1·21) and results did not differ by baseline BNP concentration. NT-pro-BNP concentrations decreased significantly and similarly in the two groups.

Interpretation

In patients with type 2 diabetes and recent acute coronary syndromes, alogliptin did not increase the risk of heart failure outcomes.

Funding

Takeda Development Center Americas.

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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