Treatment with semaglutide is associated with lower rates of all-cause death, including from cardiovascular disease and infections, according to study results presented at the European Society of Cardiology Congress 2024 and published in the Journal of the American College of Cardiology.1
“These results are surprising,” said corresponding author Benjamin M. Scirica, MD, MPH, director of quality initiatives at Brigham and Women’s Hospital’s Cardiovascular Division and professor of medicine at Harvard Medical School in Boston, Massachusetts, in a news release.2 “It is rare for a cardiometabolic drug to modify non-cardiovascular outcomes. The fact that semaglutide reduced non-cardiovascular death, and in particular COVID-19–related deaths, was surprising. It opens up new avenues for exploring how this class of drugs may benefit patients.”
Using data from the SELECT clinical trial (NCT03574597)—which began in 2018 and ran through 2023, including the worst periods of the COVID-19 pandemic—researchers evaluated the effect of semaglutide 2.4 mg therapy on all-cause, cardiovascular, and non-cardiovascular deaths to determine if semaglutide therapy modified those risks.
READ MORE: Understanding the Role of Tirzepatide, Semaglutide in Cardiovascular Disease
Following the onset of the pandemic, researchers initiated modifications to study protocol in order to document COVID-19 cases among participants, associated adverse events, and to adjudicate COVID-19–related deaths. For the current analysis, all deaths were reviewed by an independent clinical events committee who were blinded to trial group assignment (semaglutide or placebo), who then determined the cause of death—cardiovascular or non-cardiovascular—as well as the subcategory of death, such as sudden cardiac death, myocardial infarction, infectious, or malignancy, if possible.
About SELECT
Trial Name: Semaglutide Effects on Heart Disease and Stroke in Patients With Overweight or Obesity
ClinicalTrials.gov Identifier: NCT03574597
Sponsor: Novo Nordisk
Summary: An evaluation of whether semaglutide reduces the risk of cardiovascular events in patients with overweight or obesity and prior cardiovascular disease, without diabetes
In the SELECT clinical trial, investigators compared outcomes of once-weekly administration of semaglutide 2.4 mg in adults aged 45 years or older with preexisting cardiovascular disease and BMI of 27 or higher but no history of diabetes vs placebo across a primary endpoint of composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke. Results of that study—published in November 2023 in the New England Journal of Medicine and presented at the American Heart Association 2023 Scientific Sessions—demonstrated that treatment with semaglutide was associated with a significant, 20% risk reduction in cardiovascular outcomes.3
Over a median follow-up period of 3.3 years, 833 deaths were recorded among SELECT trial participants, 48% and 42% of which were cardiovascular and non-cardiovascular deaths, respectively. Compared with the placebo group, patients in the semaglutide group had lower rates of all-cause death (4.3% vs 5.2%; HR, 0.81; 95% CI, 0.71-0.83), cardiovascular death (2.5% vs 3.0%; HR, 0.85; 95% CI, 0.71-1.01), and non-cardiovascular death (1.7% vs 2.2%; HR, 0.77; 95% CI, 0.62-0.95).
Rates of death across all 3 categories were consistently lower in the semaglutide group vs the placebo group across major subgrous, such as age, sex, race, region, atherosclerotic disease areas, renal function, or heart failure. Investigators also noted “a trend toward a greater treatment effect with semaglutide compared to placebo” in patients with HbA1c levels higher than 6% for all-cause and non-cardiovascular death.
Numerically, the most common causes of cardiovascular death were sudden cardiac death (98 vs 109 in the semaglutide vs placebo groups, respectively), and deaths with insufficient data for adjudication (77 vs 90). The most common causes of non-cardiovascular death included infections (62 vs 87) and malignancies (55 vs 60).
In total, 24.2% of the study cohort reported a diagnosis of COVID-19. Median time from random assignment to the first COVID-19 event was 752 days in both arms (interquartile range [IQR], 511-999 days in the semagtlutide group and 499-1000 days in the placebo group). Although semaglutide therapy did not reduce the number of patients who recorded COVID-19 diagnoses, fewer patients in this group experienced serious COVID-19–related adverse events (2.6% vs 3.1%). Among patients who died due to COVID-19, there was a –6.4 kg change in weight in the semaglutide group and a –0.9% kg change in the placebo group; among those who did not die, weight changes were –8.4 kg and –1.25 kg, respectively.
According to researchers, patients with COVID-19 were more likely to die from non-cardiovascular causes than from cardiovascular causes (74.5% vs 25.5% non-cardiovascular vs cardiovascular deaths); that relationship was inverse in patients who did not report a diagnosis of COVID-19. In the semaglutide group, fewer deaths were adjudicated to be directly related to COVID-19 than in the placebo group (43 vs 65; HR, 0.66; 95% CI, 0.44-0.96), with the rate of all-cause death concurrent with COVID-19 serious adverse events similarly lower (46 vs 69; HR, 0.66; 95% CI, 0.45-0.96).
The analysis did have several limitations, including challenges in adjudication deaths due to limited medical information and the role of the pandemic on the effect of non-cardiovascular death.
Editors at the Journal of the American College of Cardiology also praised the study.4 “This groundbreaking study demonstrates that semaglutide, perhaps by improving cardiometabolic health, has far-reaching benefits beyond what we initially imagined,” said Harlan M. Krumholz, MD, FACC, editor-in-chief and the Harold H. Hines, Jr. Professor at the Yale School of Medicine. “The ability of semaglutide to significantly lower cardiovascular and COVID-19 related adverse events underscores the transformative potential of targeting obesity and improving cardiometabolic health as a strategy to protect against a broad spectrum of human health threats.”
READ MORE: Obesity Management Resource Center
References
Scirica BM, Lincoff AM, Lingvay I, et al. The effect of semaglutide on mortality and COVID-19–related deaths: an analysis from the SELECT trial. J Am Coll Cardiol. 2024 Aug 27:S0735-1097(24)08156-7. Doi: 10.1016/j.jacc.2024.08.007
