A recent study published in the Journal of the American College of Cardiology indicates that semaglutide, a GLP-1 agonist typically used for diabetes, may significantly reduce mortality rates in obese or overweight individuals without diabetes but with cardiovascular disease. The SELECT trial, funded by the makers of semaglutide, involved 17,604 participants and revealed promising results regarding the drug's potential beyond its established use in diabetes management.
SELECT Trial Details and Findings
The SELECT trial randomized participants to receive weekly injections of either semaglutide or a placebo over a three-year follow-up period. The primary aim was to assess the impact on deaths, heart attacks, and strokes. The study's findings, initially published in The New England Journal of Medicine in December 2023, highlighted a 19% reduction in cardiovascular mortality, heart attacks, and strokes in the semaglutide group. During the follow-up, 833 people (4.7%) died. Participants receiving semaglutide had lower death rates from all causes, including cardiovascular, non-cardiovascular, and COVID-19 deaths, compared to the placebo group.
Unexpected Early Reduction in Mortality
One of the surprising aspects of the study was the early reduction in deaths, which occurred even before significant weight loss was observed in participants. This observation challenges the conventional understanding that the health benefits of weight loss typically take longer to manifest. Unlike the Swedish bariatric surgery study by Sjöström et al., where death reduction occurred much later despite initial weight loss, the SELECT trial showed a more immediate impact.
Potential Mechanisms Beyond Diabetes Control
Since the study participants were not diabetic, the known anti-diabetic effects of GLP-1 agonists could not fully explain the reduced mortality. Additionally, the unexpected reduction in COVID-19 deaths raises further questions about the drug's mechanisms of action. The study did not specify participants' vaccination status, leaving uncertainties about how GLP-1 agonists might affect COVID-19 mortality.
Baseline Health Discrepancies
When unexpected benefits are observed in a clinical trial, it is crucial to examine whether the treatment and placebo groups had significant differences at baseline. While the SELECT trial minimized discrepancies through randomization, a closer look at the supplementary tables revealed a notable difference in the use of loop diuretic medicines. Among those who remained alive, only 11.7% were using loop diuretic drugs at the start of the trial, compared to 35.9% among those who later died of cardiovascular causes. This suggests that many participants who died during the trial may have had more advanced heart disease from the outset, as loop diuretics are commonly prescribed for advanced heart, liver, and kidney conditions.
Implications for Medical Practice
Despite the need for further research to fully understand the mechanisms behind these findings, the SELECT trial suggests that GLP-1 agonists like semaglutide may offer benefits to overweight and obese individuals without diabetes. These findings could have a significant impact on medical practice, particularly if further studies confirm these results and elucidate the underlying mechanisms.
