medwireNews: The results of the Exenatide Study of Cardiovascular Event Lowering (EXSCEL) study show that the glucagon-like peptide (GLP)-1 receptor agonist has a neutral cardiovascular (CV) effect, the investigators have reported at the EASD annual meeting, in Lisbon, Portugal.
To date, the CV outcome trials for semaglutide and liraglutide have reported cardioprotective effects, whereas lixisenatide was neutral for this endpoint, and those for albiglutide, dulaglutide, and oral semaglutide are yet to complete.
Although exenatide did not achieve statistical superiority to placebo for CV prevention over a median follow-up of 3.2 years, it did appear to come close. The hazard ratio for the combined endpoint of CV death, nonfatal myocardial infarction, and nonfatal stroke was 0.91, with a 95% confidence interval of 0.83 to 1.00 and a p value of 0.06. The individual endpoints followed the same pattern, as did death from any cause, and in most prespecified subgroup analyses the hazard ratio was less than 1.0.
In the subgroup analyses, there was an interaction between treatment effect and age, such that patients aged 65 years or more appeared to derive more benefit than younger patients, reported Adrian Hernandez (Duke University School of Medicine, Durham, North Carolina, USA).
Of note, exenatide appeared to reduce the risk for death from any cause versus placebo in the overall population, with a hazard ratio of 0.86 and a confidence interval of 0.77–0.97. However, the hierarchical testing plan in the study protocol dictated that the team could not consider the significance of the individual endpoints if the primary endpoint was nonsignificant.
The investigators aimed to recruit patients with a broad range of CV risk; 73% had prior CV events and an additional 12% had stage 3 or above chronic kidney disease. During follow-up, 11.4% of the 7356 patients randomly assigned to receive weekly exenatide injections had a primary endpoint event, as did 12.2% of the 7396 patients in the placebo group, giving event rates of 3.7 and 4.0 per 100 person–years.
Exenatide treatment resulted in significantly reduced glycated hemoglobin levels relative to placebo, despite the site investigators being encouraged to employ other glucose-lowering medications to achieve target levels in all patients. It also resulted in the expected improvements in bodyweight and systolic blood pressure, versus placebo, and increased heart rate.
Two presenters – lead investigator Rury Holman (Diabetes Trials Unit, Oxford, UK) and independent commentator Francesco Giorgino (University of Bari Aldo Moro, Bari, Italy) – gave an overview of all the GLP-1 receptor agonist cardiovascular outcome trials published to date. They examined the differences in patient and trial characteristics, including baseline glycated hemoglobin levels and CV risk, and the length of follow-up and exposure to the study drug, which might have contributed to the conflicting study findings.
Holman showed a meta-analysis of the three GLP-1 trials that used a three-point MACE outcome (LEADER, SUSTAIN, and EXSCEL), which gave a significant hazard ratio of 0.88 for GLP-1 receptor agonists versus placebo for this outcome. And there was an identical outcome for all-cause mortality.
Giorgino addressed the issue of whether the medications themselves might differ, citing research that suggests that different residues of the GLP-1 receptor may bind different agonists.
Nevertheless, the different medications in the class appear to have very similar effects in patients, he said. “Therefore, I think this trial is really leading to more research that is needed to clarify these issues,” Giorgino concluded.
The EXSCEL findings were simultaneously published in The New England Journal of Medicine.
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