And for Wegovy’s Next Trick, Full-Blown Cardiovascular Benefit Outside Diabetes

PHILADELPHIA — An enormous swath of Americans can be expected to get secondary cardiovascular prevention benefits from weekly semaglutide (Wegovy) injections based on the SELECT trial.

Even in the absence of diabetes, overweight and obese people with pre-existing cardiovascular disease had the advantage of a substantially lower incidence of combined death from cardiovascular causes, myocardial infarction, or stroke more than 3 years after starting semaglutide treatment in lieu of placebo (6.5% vs 8.0%, HR 0.80, 95% CI 0.72-0.90), reported A. Michael Lincoff, MD, of Cleveland Clinic, at the American Heart Association (AHA) annual meeting.

Importantly, event curves separated as early as the first few months — well before patients reached maximum weight loss with semaglutide. The cardiovascular protection was consistent across subgroups, including by degree of obesity, Lincoff said.

“Semaglutide 2.4 mg is the first weight management therapy proven in a rigorous randomized trial to reduce the risk of cardiovascular events, which establishes overweight or obesity as a modifiable risk factor for cardiovascular disease,” he told the AHA audience. SELECT results were simultaneously published in the New England Journal of Medicine (NEJM). The top-line results of the trial had been released by Novo Nordisk this summer.

The implication is the GLP-1 receptor agonist’s new position as a treatment for the ever-broadening population of patients with overweight and obesity and cardiovascular disease, most of whom do not have diabetes. A recent estimate has 6.6 million Americans being SELECT-like enough for semaglutide treatment, according to AHA session discussant Ania Jastreboff, MD, PhD, of Yale School of Medicine in New Haven, Connecticut.

“It’s really important to remember that in the SELECT population, these patients were extremely well treated. They received all the best evidence based treatment that we have, and this was reflected in various cardiometabolic measures such as LDL and blood pressure. So the therapeutic impact of semaglutide is on top of optimized evidence-based treatment that we have today. This is critical,” Jastreboff said at an AHA press conference.

Lincoff and fellow panelists acknowledged the challenge of teasing out the mechanisms behind the cardiovascular protection from GLP-1 receptor agonist therapy. It likely comes down to a combination of factors such as weight loss itself and changes in inflammation and eating patterns, Jastreboff said.

Semaglutide had previously shown its ability to prevent adverse cardiovascular events in patients with diabetes.

Separately, it proved its weight loss effects in the STEP 1 study in which half of participants were able to lose at least 15% of initial body weight and a third lost at least 20%. The pricey drug has been in demand since it got 2021 FDA approval for long-term weight management in people with overweight or obesity.

Not all people benefit from treatment, however, as some may not respond and others may be overwhelmed by gastrointestinal side effects.

Lincoff noted that in SELECT, adverse events (AE) leading to permanent discontinuation were more frequent among semaglutide users than controls in the study (16.6% vs 8.2%, P<0.001). As anticipated based on the previous literature, these safety events were mainly driven by GI side effects (10.2% vs 2.0%, P<0.0001), with some excess gallbladder-related events as well (2.8% vs 2.3%, P=0.04).

Providing some reassurance was the finding that serious AEs did not suggest disproportionate harm, and in fact favored the semaglutide group (33.4% vs 36.4%, P<0.001).

“We know what the most common side effects are. They’re gastrointestinal, they are transient, and the most commonly occur during dose escalation. And the best way we have to mitigate them is slow uptitration. So we start low and we go slow,” Jastreboff said.

Also important are the concepts of ensuring that people have access to obesity treatment and preventing obesity in the first place, suggested press conference moderator Amit Khera, MD, of University of Texas Southwestern Medical Center in Dallas.

“Along the obesity treatment continuum, intensive lifestyle interventions and bariatric surgery remain effective but underutilized options, particularly for underresourced populations that are disproportionately affected by obesity,” wrote Khera alongside Tiffany Powell‑Wiley, MD, MPH, of the NIH in Bethesda, Maryland, in an accompanying NEJM editorial.

SELECT was a multicenter trial that had participants randomized to subcutaneous injections of semaglutide or placebo from 2018 to 2021. These were 17,604 people ages 45 or older who had pre-existing atherosclerotic cardiovascular disease and a BMI ≥27 but no history of diabetes.

Mean age of the patients was 61.6, and 72.3% were men, while 84% white. A history of coronary artery disease was noted in 82%. The mean glycated hemoglobin level was 5.8%, and 71% of individuals were obese rather than overweight.

Patients averaged 34.2 months of exposure to their assigned therapies. The semaglutide arm had had initial doses escalated up to once weekly 2.4 mg. By week 104, 77% of patients were at this target dose and the mean weight loss was 9.4%.

Follow-up reached 39.8 months in the SELECT cohort. Secondary endpoints supported the GLP-1 receptor agonist’s cardiovascular benefits to different extents over placebo, some reaching statistical significance:

• Cardiovascular death: 2.5% vs 3.0% (HR 0.85, 95% CI 0.71-1.01)
• Heart failure composite: 3.4% vs 4.1% (HR 0.82, 95% CI 0.71-0.96)
• All-cause death: 4.3% vs 5.2% (HR 0.81, 95% CI 0.71-0.93)

SELECT was limited by its relatively non-diverse cohort of largely white men. It was also limited to a secondary prevention cohort, leaving room for future high-risk primary prevention trials.

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