Exenatide confers benefits for survival, first HF hospitalization in diabetic patients

A once-weekly exenatide regimen is safe and well tolerated in diabetic patients with or without heart failure (HF), although its beneficial effects on all-cause death and first HF hospitalization appear to be weakened in those without HF at baseline, according to the results of the EXSCEL* trial.

EXSCEL included 14,752 type 2 diabetes (T2D) patients, among whom the 2,389 (16.2 percent) who had HF at baseline were randomized to treatment with the glucagon-like peptide-1 receptor agonist (GLP-1 RA) exenatide (n=1,161) or placebo (n=1,228).

The GLP-1 RA demonstrated superiority over placebo in terms of all-cause death (hazard ratio [HR], 0.86, 95 percent CI, 0.77–0.97) and the composite outcome of all-cause death or HF hospitalization (HR, 0.89, 0.80–0.99). [Circulation 2019;doi:10.1161/CIRCULATIONAHA.119.041659]

When stratified by presence or absence of baseline HF, exenatide exerted no significant effect on the risk of all-cause death in the HF group (HR, 1.05, 0.85–1.29) but conferred substantial risk reduction in the no-HF group (HR, 0.79, 0.68–0.92; p-interaction=0.031).

Furthermore, the decrease in the risk of the composite outcome seen with glucose-lowering drug in the no-HF group (HR, 0.81, 0.71-0.93) was absent in the HF group (HR, 1.07, 0.89–1.29; p-interaction=0.015).

Patients with pre-existing HF were older (median age, 64 vs 62 years), tended to be male (64.5 percent vs 61.6 percent), and had a higher burden of other cardiovascular diseases such as coronary artery disease (72.5 percent vs 49.0 percent) and cerebrovascular disease (20.9 percent vs 16.3 percent).

In the entire cohort, exenatide produced an 18-percent lower risk of first plus recurrent HF hospitalization as compared with placebo (HR, 0.82, 0.68–0.99; p=0.038).

“Since HF is characterized by repeated hospitalizations, the analysis of all events is more likely to give a complete picture of treatment effect than the evaluation of the time to first event alone,” the investigators said.

“[T]he nonsignificant trend toward fewer HF events in the exenatide group strengthened further with the increased power in the prespecified first plus recurrent HF hospitalization analyses. Here [the GLP-1 RA] was associated with a significant reduction in the burden of HF rehospitalizations,” they explained.

The investigators added that the lack of therapeutic effect of exenatide or the class of GLP-1 RAs, despite some evidence of an attenuated effect, in patients with pre-existing HF remains speculative at this time and warrants dedicated HF-specific clinical trials.

In EXSCEL, the length of exposure to the study drug and medication adherence were modest and could have contributed to the weakened effect of exenatide in patients with HF, according to the investigators. It is also possible that the finding could have been the result of chance.

“Although the present [data] are hypothesis-generating, the analysis offers the largest HF-specific analysis of patients treated with a GLP-1 RA,” they said.

*Exenatide Study of Cardiovascular Event Lowering