New analyses from the SELECT trial of glucagon-like peptide-1 (GLP-1) receptor agonist semaglutide showed a 73 percent reduction in progression to diabetes over four years regardless of baseline glycemia compared to placebo. About two-thirds of the 17,604 participants in the global trial had prediabetes at baseline and one-third had normoglycemia. All had established cardiovascular (CV) disease, and the mean body mass index (BMI) was 33.

“Regardless of body weight or BMI at baseline, semaglutide reduced progression to diabetes,” said Steven E. Kahn, MB, ChB, Professor of Metabolism, Endocrinology and Nutrition at the University of Washington (UW) and Veterans Affairs Puget Sound Health Care System, and Director of the UW Diabetes Research Center and the VA Puget Sound Diabetes Research Group. “The greatest effect was seen in those with normal glucose at baseline, but similar reductions in progression were seen after 20 weeks of treatment in those with normoglycemia and with prediabetes.”

Dr. Kahn presented the first detailed diabetes findings from the trial during SELECT Trial: New Looks at Glycemia, Inflammation, and Heart Failure on Saturday morning, June 22. The symposium can be viewed on-demand by registered meeting participants on the virtual meeting platform. If you haven’t registered for the 84^th Scientific Sessions, register today to access the valuable meeting content through Aug. 26.

The trial included 804 sites in 41 countries and regions and has a mean follow up of 40 months.

In addition to reducing progression to diabetes, semaglutide improved glycemia over time regardless of baseline A1C. The entire SELECT population had a baseline A1C of 5.8 percent, which fell to less than 5.5 percent at 20 weeks and increased slightly at week 208.

Among participants with normoglycemia at baseline, 80 percent still had normoglycemia at 20 weeks, and 75 percent had normoglycemia at week 156. Of participants with the highest A1C at baseline (6 percent–<6.5percent), half had normoglycemia at week 20 and about 45 percent at week 156.

Initial results from SELECT showed a 20 percent reduction in CV events in individuals with overweight or obesity who have existing CV disease without diabetes. Preplanned analyses presented on Saturday looked at progression to diabetes, the effects of weight and glycemia on CV events, heart failure (HF), and markers of inflammation.

Semaglutide is best known as a weight-loss drug, but SELECT was not a weight-loss study.

“SELECT was a secondary cardioprevention trial,” said Donna H. Ryan, MD, Professor Emerita, Pennington Biomedical Research Center.

The hypothesis was that CV risk can be mediated by a combination of weight loss and the pleiotropic effects of semaglutide, she explained. The primary endpoint was a composite of major cardiovascular events (MACE), including acute myocardial infarction, stroke, and CV failure.

A majority of SELECT participants (62 percent) had lost at least 5 percent of baseline body weight by week 20. But there was no significant difference in time to first MACE by weight loss in the first 20 weeks of the trial.

“It did not matter how much weight participants lost in the first 20 weeks,” said Ildiko Lingvay, MD, MPH, MSCS, Professor of Endocrinology, University of Texas Southwestern Medical Center. “The CV benefits of semaglutide were seen in all weight-loss classes and are not driven by weight loss.”

Changes in glycemic levels likewise had minimal impact on CV risk reduction. While semaglutide brought important reductions in CV events versus placebo, there were no significant differences in benefit by A1C at baseline or by A1C improvement over the course of the study.

“The CV benefits of semaglutide are due to pleiotropic factors besides its glucose-lowering effect,” Dr. Lingvay said.

A third pre-specified analysis explored HF and changes in inflammatory markers in SELECT. Semaglutide is similarly effective in those with and without HF and in both HF with preserved ejection fraction (HFpEF) and with reduced ejection fraction (HFrEF).

“The data support use of semaglutide to improve CV outcomes independent of HF history,” said Jorge Plutzky, MD, Director of Preventive Cardiology, Brigham and Women’s Hospital and Associate Professor of Medicine, Harvard Medical School.

Inflammatory markers, as measured by hsCRP, also fell in the semaglutide arm, a 39 percent decrease versus placebo, and semaglutide reduced the risk of MACE similarly across all hsCRP subgroups.

Greater weight loss was associated with greater hsCRP reduction, Dr. Plutzky said, but reductions were similar regardless of weight loss. Importantly, hsCRP fell sharply by week four, before significant weight loss had occurred.

Glycemia, CV, and heart failure and inflammatory marker results were published simultaneously online in Diabetes Care®.