Semaglutide reduced a composite of CV events at two years in patients with type 2 diabetes and high CV risk

Semaglutide, a new once-weekly glucagon-like peptide-1 (GLP-1) analogue, reduced cardiovascular (CV) events compared to placebo, according to a manufacturer-sponsored study. The trial included 3,297 patients with type 2 diabetes and elevated CV risk—83% had established CV disease, chronic kidney disease, or both. Exclusion criteria included use of dipeptidyl peptidase-4 (DPP-4) inhibitors in the past 30 days; acute coronary or cerebrovascular event or use of GLP-1 agonist or insulin other than basal or premixed in the past 90 days; long-term dialysis; or planned revascularization of a coronary, carotid, or peripheral artery.

The study was published in the Nov. 10, 2016, New England Journal of Medicine and summarized in the October ACP Diabetes Monthly. The following commentary by Anthony A. Donato, MD, MHPE, FACP, was published in the ACP Journal Club section of the Jan. 17 Annals of Internal Medicine.

For patients who have incomplete glycemic control after lifestyle interventions and metformin, the 2016 American Diabetes Association guidelines suggest adding 1 of 5 classes of medications (sulfonylureas, DPP4 inhibitors, sodium-glucose cotransporter 2 [SGLT2] inhibitors, GLP-1 agonists, or basal insulin). Few studies have directly compared these second-line agents, but new US Food and Drug Administration requirements for companies to study CV safety of these agents may provide data to guide physicians' selections.

The industry-sponsored SUSTAIN-6 examined the benefits of the long-acting GLP-1 agonist semaglutide (not yet available in the USA) in older patients at high CV risk. Semaglutide improved composite CV outcomes, HbA1c, and weight, with no difference in hospitalization for heart failure or in total mortality, and an increase in adverse effects, including retinopathy.

Premature discontinuation for gastrointestinal side effects occurred in 5.7% and 9.4% of the 0.5 mg and 1.0 mg groups, respectively; this is a common side effect of this drug class, which slows gastric emptying in 10% to 50% of patients. No differences were found for acute pancreatitis or medullary thyroid or pancreatic cancer, but there was a nonsignificant increase in breast cancer with semaglutide (0.8% vs 0.2%, HR 1.73, 95% CI 0.41 to 7.29), a finding seen in a recent trial of liraglutide that is worthy of further observation.

Clinicians who are disappointed with the lack of CV benefit of the short-acting GLP-1 agonist lixisenatide will now have the option of adding the once-weekly, long-acting semaglutide to liraglutide and the SGLT2 inhibitor empagliflozin as medications that are probably safe add-ons in patients with CV disease and poor diabetes control.