medwireNews: A meta-analysis published in The Lancet Diabetes & Endocrinology is suggestive of a class cardioprotective effect for the glucagon-like peptide (GLP)-1 receptor agonists.
The researchers, led by M Angelyn Bethel (Diabetes Trials Unit, Churchill Hospital, Oxford, UK), pooled the results of the EXSCEL, ELIXA, LEADER, and SUSTAIN 6 trials, giving a total of 33,457 patients with type 2 diabetes treated with a GLP-1 receptor agonist or placebo for a median of 2.1 to 3.8 years.
They found an overall significant 10% reduction in risk for the combined endpoint of nonfatal myocardial infarction, nonfatal stroke, and cardiovascular death with GLP-1 receptor agonist treatment versus placebo. There was also a significant 13% reduction in the risk for cardiovascular mortality and a 12% reduction all-cause mortality risk.
The reductions in fatal or nonfatal myocardial infarction and fatal or nonfatal stroke did not attain statistical significance. Heterogeneity was moderate for the combined endpoint and low or absent for the other endpoints.
However, the four included trials had very different results, with ELIXA (lixisenatide) being neutral, LEADER (liraglutide) and SUSTAIN-6 (semaglutide) reporting a cardioprotective effect, despite the latter being designed only as a noninferiority trial, and EXSCEL (exenatide) being a near miss, with the 95% confidence interval of 0.83–1.00 just encompassing a neutral effect.
In a linked commentary, Simeon Taylor (University of Maryland School of Medicine, Baltimore, USA) suggests that much of this variability could be attributed to the GLP-1 receptor agonist doses used. He notes that the dose selected for phase III trials is a trade-off between glucose-lowering efficacy and minimizing side effects.
“Some companies invest a substantial amount of time and money to select the optimal dose by doing large studies of multiple closely spaced doses,” he observes. “Other companies save money by doing smaller studies of widely spaced doses.
“This cost-saving approach runs the risk of not selecting the optimal dose and not achieving a best-in-class clinical profile.”
Taylor’s own analysis reveals “a remarkable degree of correlation” between the glucose-lowering efficacy of the individual GLP-1 receptor agonists and the extent to which they reduce cardiovascular risk, suggesting that the failure of lixisenatide and exenatide to demonstrate convincing cardioprotection could be the fault of a less than optimal dose.
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