SOURCE: Holman RR, Bethel MA, Mentz RJ, et al. N Engl J Med 2017;377:1228-1239.

Only in the last several years have randomized, clinical trials confirmed a cardiovascular (CV) benefit from glycemic control. To date, sodium-glucose cotransporter 2 (SGLT-2) inhibitors (canagliflozin, empagliflozin), glucagon-like peptide-1 receptor agonist (GLP-1RA; liraglutide, semaglutide), and bromocriptine have demonstrated CV risk reduction convincingly.

Among the SGLT-2 inhibitor and GLP-1RA classes of pharmacotherapy, there appears to be much more similarity than not. Should clinicians consider these salubrious CV effects a class effect? That is, should all members of the class be anticipated to experience similarly favorable CV outcomes?

The authors of the Exenatide Study of Cardiovascular Event Lowering (EXSCEL) trial randomized type 2 diabetics (n = 14,752) to either 2 mg of the GLP-1RA exenatide or placebo added to whatever ongoing diabetes regimen they already were receiving. The mean baseline A1c was 8.0%, and > 70% of participants presented with pre-existing CV disease.

After 3.2 years (mean) of intervention, exenatide failed to demonstrate a statistically significant improvement in the composite CV endpoint vs. placebo. Although all the answers are not known, the EXSCEL trial suggests there might be important differences among the class of GLP-1RA in reference to cardiovascular outcomes. Is it a class effect? Maybe not.