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- In this international placebo-controlled trial involving 17,604 patients with established cardiovascular disease and a BMI of 27 kg/m2 or greater but without diabetes, once-weekly treatment with semaglutide (2.4 mg) was associated with a 20% reduction in the risk of the composite endpoint of cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke. Additional benefits in terms of HbA1c and hs-CRP levels, body weight, waist circumference, cardiometabolic endpoints, and health status were also observed, without an excess risk of serious adverse events.
- These findings highlight the role of 2.4 mg of semaglutide atop standard of care in the secondary prevention of cardiovascular outcomes among patients with pre-existing cardiovascular disease and overweight or obesity.
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The results of the SELECT trial, which demonstrated that the glucagon-like peptide-1 receptor agonist (GLP1RA) semaglutide 2.4 mg reduced the risk of cardiovascular events compared with placebo, should change the paradigm of how we reduce cardiovascular risk in patients with obesity. This is the first time any therapy targeting weight reduction has demonstrated clear evidence of a reduction in the risk of cardiac events.
In 17,604 patients with overweight and obesity as well as established atherosclerotic cardiovascular disease but without diabetes, semaglutide reduced the risk of major adverse cardiovascular events (cardiovascular death, myocardial infarction, or stroke) by 20% (HR, 0.80; 95% CI, 0.72–0.90; P < .001), myocardial infarction alone by 28% (HR, 0.72; 95% CI, 0.61–0.85), and all-cause mortality by 19% (HR, 0.81; 95% CI, 0.71–0.93) over a mean follow-up period of 3.3 years. On average, semaglutide resulted in an 8.5-kg weight loss compared with placebo, with favorable reductions in the levels of cardiovascular risk factors like systolic blood pressure, diastolic blood pressure, LDL-C, triglycerides, and hs-CRP. There were no important safety concerns such as pancreatitis or cancer, and over 75% of the subjects reached the highest semaglutide dose (2.4 mg).
There is over a decade of experience with GLP1RAs in patients with diabetes where they are now first-line agents for glucose control and, after a series of cardiovascular outcomes trials, with several different GLP1RAs proven to reduce cardiovascular events. The more potent GLP1RAs like semaglutide 2.4 mg have been shown to reduce weight by over 15% in healthier patients with obesity. The SELECT trial, the largest completed randomized controlled trial in diabetes or obesity, is the first to show the benefit of this class of drugs in patients with obesity without diabetes.
The implications of these results are enormous. A large proportion of patients with atherosclerotic cardiovascular disease are obese or overweight (BMI, ≥27 kg/m2) and are, thus, potentially eligible for treatment. The implementation barriers — such as whether cardiologists are going to “own” GLP1RAs, like statins, for cardiovascular risk reduction — and the costs of GLP1RAs, which are already straining budgets, may slow the adoption of GLP1RAs. Obesity should be considered a modifiable cardiovascular risk factor. Amidst all the debates, it should not be forgotten that this is the first therapy for obesity ever proven to make people live longer and have fewer cardiovascular events.
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BACKGROUND
Semaglutide, a glucagon-like peptide-1 receptor agonist, has been shown to reduce the risk of adverse cardiovascular events in patients with diabetes. Whether semaglutide can reduce cardiovascular risk associated with overweight and obesity in the absence of diabetes is unknown.
METHODS
In a multicenter, double-blind, randomized, placebo-controlled, event-driven superiority trial, we enrolled patients 45 years of age or older who had preexisting cardiovascular disease and a body-mass index (the weight in kilograms divided by the square of the height in meters) of 27 or greater but no history of diabetes. Patients were randomly assigned in a 1:1 ratio to receive once-weekly subcutaneous semaglutide at a dose of 2.4 mg or placebo. The primary cardiovascular end point was a composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke in a time-to-first-event analysis. Safety was also assessed.
RESULTS
A total of 17,604 patients were enrolled; 8803 were assigned to receive semaglutide and 8801 to receive placebo. The mean (±SD) duration of exposure to semaglutide or placebo was 34.2±13.7 months, and the mean duration of follow-up was 39.8±9.4 months. A primary cardiovascular end-point event occurred in 569 of the 8803 patients (6.5%) in the semaglutide group and in 701 of the 8801 patients (8.0%) in the placebo group (hazard ratio, 0.80; 95% confidence interval, 0.72 to 0.90; P<0.001). Adverse events leading to permanent discontinuation of the trial product occurred in 1461 patients (16.6%) in the semaglutide group and 718 patients (8.2%) in the placebo group (P<0.001).
CONCLUSIONS
In patients with preexisting cardiovascular disease and overweight or obesity but without diabetes, weekly subcutaneous semaglutide at a dose of 2.4 mg was superior to placebo in reducing the incidence of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke at a mean follow-up of 39.8 months. (Funded by Novo Nordisk; SELECT ClinicalTrials.gov number, NCT03574597.).