SELECT Trial: Semaglutide Lowers CVD Risk in Patients with Obesity

The Semaglutide Effects on Cardiovascular Outcomes in People with Overweight or Obesity (SELECT) trial was a significant clinical study designed to evaluate the efficacy of semaglutide 2.4 milligrams in reducing the risk of major adverse cardiovascular events (MACE) in adults who were overweight or had obesity without a prior history of diabetes. The trial is considered a landmark study and the results are expected to significantly impact the treatment of obesity and the prevention of cardiovascular events.

SELECT was conducted by an international network of research institutions and was a randomized, double-blind, parallel-group, placebo-controlled trial that enrolled 17,604 adults in 41 countries at more than 800 investigator sites starting in 2018. All participants were aged 45 or older, had a body mass index (BMI) of 27 kilograms per square meter or higher, and over 70 percent had a BMI of 30 or above, which indicates obesity. At the time of enrollment in the study, none of the participants had Type 1 or Type 2 diabetes, but roughly two-thirds had prediabetes defined as an A1C level between 5.7 percent to 6.4 percent. All enrolled individuals had a history of cardiovascular disease, such as a previous heart attack, stroke, or peripheral artery disease.

Additional trial details include:

• The SELECT trial utilized a dosage of semaglutide at 2.4 milligrams subcutaneously once weekly. This dosage was compared to a placebo as an adjunct to standard care for preventing major adverse cardiovascular events (MACE) in patients with established cardiovascular disease and overweight or obesity but without diabetes.
• The study's primary endpoint was the composite outcome of the first occurrence of MACE, defined as cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for unstable angina.
• The trial demonstrated a statistically significant and superior reduction in MACE of 20 percent for individuals treated with semaglutide 2.4 milligrams compared to placebo, indicating the potential of this dosage to reduce the risk of cardiovascular events in the studied population.
• Participants treated with semaglutide also experienced a significant reduction in body weight, losing an average of 9.4 percent.
• Adverse events leading to trial drug discontinuation were higher in the semaglutide group at 16.6 percent compared to 8.2 percent in the placebo group. Additionally, gastrointestinal complications were reported at a higher rate in the semaglutide group at 10.0 percent compared to two percent in the placebo group. However, other serious adverse effects were largely similar or less frequent with semaglutide.
• The trial also reported that acute pancreatitis occurred at a rate of 0.2 percent in the semaglutide group compared to 0.3 percent in the placebo group, and acute kidney failure occurred at a rate of 1.9 percent in the semaglutide group compared to 2.3 percent in the placebo group. These findings indicate that while there were adverse events associated with semaglutide, the overall safety profile of the medication was generally consistent with or less frequent than the placebo group.

It's important to note that this was not a primary cardiovascular prevention trial, meaning it did not investigate the prevention of cardiovascular disease in individuals without a history of heart attack, stroke or peripheral artery disease. This limitation affects the extrapolation of the results to individuals with obesity who do not have a history of cardiovascular disease. Lack of diversity and gender representations were also limitations in this study. The trial predominantly included White, non-Hispanic men, with only 12.5 percent of participants being Black. There was also a lower proportion of female participants at 28 percent, which may not be proportionate to the number of women with cardiovascular disease and overweight or obesity in the general population. These limited representations of diverse populations may impact the generalizability of the trial's findings.

The findings from the SELECT trial indicate the potential of semaglutide to address both obesity and cardiovascular risk factors, particularly in individuals with established cardiovascular disease and overweight or obesity but without diabetes. The trial's findings have been described as a turning point in the treatment of obesity and a call to action, highlighting the need to address obesity to improve health outcomes in people with cardiovascular disease. Further research and primary cardiovascular prevention trials in individuals with obesity without diabetes are needed to fully understand the potential benefits of semaglutide in this population.

References:

Alana Hippensteele ME. Select trial data show benefit of SEMAGLUTIDE in patients with obesity. Pharmacy Times. November 13, 2023. Accessed November 15, 2023. https://www.pharmacytimes.com/view/select-trial-data-show-benefit-of-semaglutide-in-patients-with-obesity.

EA; K. Selenium and vitamin E cancer prevention trial. Annals of the New York Academy of Sciences. Accessed November 15, 2023. https://pubmed.ncbi.nlm.nih.gov/15753149/.

Select-life: A research study looking at long-term effects of semaglutide in people who took part in the Select Cardiovascular Outcomes Trial. SELECT-LIFE: A research study looking at long-term effects of semaglutide in people who took part in the SELECT cardiovascular outcomes trial. Accessed November 15, 2023. https://www.novotrials.com/trials-conditions/all-trials/EX9536-4750.html.

Major CVD event risk cut by 20% in adults without diabetes, with overweight or obesity. American Heart Association. Accessed November 15, 2023. https://newsroom.heart.org/news/major-cvd-event-risk-cut-by-20-in-adults-without-diabetes-with-overweight-or-obesity.

Wheeler T. International clinical trial finds that semaglutide reduced cardiovascular events by 20% in adults with overweight or obesity who don’t have diabetes . Cleveland Clinic Newsroom. November 14, 2023. Accessed November 15, 2023. https://newsroom.clevelandclinic.org/2023/11/11/international-clinical-trial-finds-that-semaglutide-reduced-cardiovascular-events-by-20-in-adults-with-overweight-or-obesity-who-dont-have-diabetes/.

Campbell P. Select trial shows semaglutide 2.4 mg could reduce cardiovascular risk. HCP Live. November 11, 2023. Accessed November 15, 2023. https://www.hcplive.com/view/select-trial-shows-semaglutide-2-4-mg-could-reduce-cardiovascular-risk.

Ryan DH;Lingvay I;Colhoun HM;Deanfield J;Emerson SS;Kahn SE;Kushner RF;Marso S;Plutzky J;Brown-Frandsen K;Gronning MOL;Hovingh GK;Holst AG;Ravn H;Lincoff AM; SEMAGLUTIDE effects on cardiovascular outcomes in people with overweight or obesity (select) rationale and design. American heart journal. Accessed November 15, 2023. https://pubmed.ncbi.nlm.nih.gov/32916609/.