Semaglutide Cuts Cardiovascular Events in Landmark Trial

The popular but expensive weight-loss drug, semaglutide (Wegovy), significantly reduced major adverse cardiovascular events (MACE) by 20% when given to patients, compared with those receiving placebo, in the pivotal SELECT trial, with more than 17,000 enrolled people with overweight or obesity and established cardiovascular disease (CVD), but no diabetes.

The finding should fuel improved patient access to this glucagon-like peptide-1 (GLP-1) agonist weight-loss agent that has historically been hindered by skepticism among US payers, many of whom have criticized the health benefits and cost effectiveness of this drug in people whose only indication for treatment is overweight or obesity.

According to top-line results from SELECT released by Novo Nordisk today, the people randomly assigned to receive weekly 2.4 mg subcutaneous injections of semaglutide showed a significant 20% reduction in their incidence of the combined endpoint of cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke. The announcement added that semaglutide treatment also significantly linked with a drop in the incidence of each of these individual three endpoints; the magnitude of these reductions, however, wasn’t specified, nor was the duration of treatment and follow-up.

The results also showed a level of safety and patient tolerance for weekly 2.4 mg injections of semaglutide that were consistent with prior reports on the agent. Semaglutide as Wegovy received marketing approval from the US Food and Drug Administration in 2021 for weight loss, and in 2017 for glucose control in people with type 2 diabetes, at a weekly maximum dose of 2.0 mg (for which it’s marketed as Ozempic).

SELECT began in 2018 and randomly assigned 17,604 adults age 45 years and older at more than 800 sites in 41 countries. The company’s announcement noted that the trial had accrued a total of 1270 study participants with a first MACE event but did not break this total down based on treatment received.

“A Good Result for Patients”

“The topline results from SELECT are exciting, as preventing heart attacks and stroke with a drug that also lowers weight is very important for many patients, especially if the data also show — as I suspect they will — a meaningful improvement of quality of life for patients due to associated weight loss,” commented Naveed Sattar, PhD, a professor of metabolic medicine at the University of Glasgow who was not involved with the study.

“This is a good result for patients,” added Sattar, who also noted that “we do not know to what extent the weight loss effects of semaglutide — as opposed to its other direct effects on blood vessels or the heart — account for the 20% reduction in cardiovascular events, and more data are needed to try to work this out.”

Despite this lack of current clarity over the role that weight loss by itself played in driving the observed result, the SELECT findings seem poised to reset a long-standing prejudice against the medical necessity and safety of weight-loss agents when used for the sole indication of helping people lose weight.

Changing How Obesity is Regarded

“To date, there are no approved weight management medications proven to deliver effective weight management while also reducing the risk of heart attack, stroke, or cardiovascular death,” said Martin Holst Lange, executive vice president for development at Novo Nordisk, in the company’s press release.

“SELECT is a landmark trial and has demonstrated that semaglutide 2.4 mg has the potential to change how obesity is regarded and treated.”

Several of the early medical options for aiding weight loss had substantial adverse effects, including increased MACE rates, a history that led to pervasive wariness among physicians over the safety of anti-obesity agents and the wisdom of using medically aided weight loss to produce health benefits.

This attitude also helped dampen health insurance coverage of weight-loss treatments. For example, Medicare has a long-standing policy against reimbursing the cost for medications that are used for the indication of weight loss, and a 2003 US law prohibited part D plans from providing this coverage.

Semaglutide belongs to the class of agents that mimic the action of the incretin GLP-1. The introduction of this class of GLP-1 agonists for weight loss began in 2014 with the FDA’s approval of liraglutide (Saxenda), a daily subcutaneous injection that marked the first step toward establishing the class as safe and effective for weight loss and launching a new era in weight-loss treatment.

According to the Novo Nordisk announcement, a full report on results from SELECT will occur “at a scientific meeting later in 2023.”

SELECT is sponsored by Novo Nordisk, the company that markets semaglutide (Wegovy). Sattar is a consultant to several companies that market GLP-1 receptor agonists, including Novo Nordisk and Lilly, but has had no involvement in SELECT.

Mitchel L. Zoler is a reporter with Medscape and MDedge based in the Philadelphia region. @mitchelzoler

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