The glucagon-like peptide 1 (GLP-1) receptor agonist semaglutide( Wegovy, Ozempic) reduced cardiovascular events and reduced the risk of progression to diabetes by 73% in people with established cardiovascular disease and obesitycompared with placebo, regardless of baseline A1clevels, according to two new analyses of the SELECT trial.

In the first of the two studies, presented at the American Diabetes Association (ADA) 84th Scientific Sessions and published online in the journal Diabetes Care, researchers looked at the effect of semaglutide on the progression of glycemia in people with cardiovascular issues and overweight or obesity, who did not have diabetes.

Among those who took semaglutide, a smaller number with pre-diabetes at baseline progressed to diabetes, and a greater proportion regressed to normal A1c levels than those taking placebo, said lead author Steven E. Kahn, MBChB, professor of medicine at the University of Washington in Seattle. 

Overall, "semaglutide improved glycemic control in people at high risk of cardiovascular disease," he told ADA attendees.

However, despite the increase in regression to normal glycemic levels, semaglutide did not slow glycemic progression over time, he reported. 

The original SELECT trial evaluated the effect of semaglutide on patients with overweight or obesity and atherosclerotic cardiovascular diseaseon major adverse cardiovascular events (MACE). As previously reportedby Medscape Medical News, the anti-obesity drug reduced MACE by around 20% vs placebo in this high-risk population. 

In this prespecified secondary analysis of the SELECT trial, Kahn and colleagues looked at glycemia through 156 weeks (3 years) of once-weekly treatment with either semaglutide (n = 8803) or placebo (n = 8801). 

At baseline, 33.5% of all participants had a normal glycemic level, defined as A1c of less than 5.7%. About two thirds had pre-diabetes (A1c of 5.7% to < 6%), and the remainder had an A1c of 6% to < 6.5%. 

At three years, 69.5% of study participants taking semaglutide had a normal glycemic level, compared with 35.8% of those taking placebo (P< .0001). Among those with a normal A1c level at baseline, 9 of 1676 participants (0.5%) receiving semaglutide developed diabetes (compared with 18 of 1690 placebo recipients). For those in the intermediate glycemia group, 0.8% of those taking semaglutide developed diabetes compared with 3.5% of those taking placebo. In the highest-level glycemic group, 3.5% of those taking semaglutide developed diabetes compared with 17% of those receiving placebo.

After 20 weeks, the A1c levels increased similarly in the placebo and semaglutide arms, but those taking semaglutide had smaller increases.

The rate of glycemic deterioration was greatest in those who started with the highest A1c levels at baseline, "an observation likely due to less residual beta-cell function in this group," write the authors.

In an accompanying editoriali n Diabetes Care, Shivani Misra, MD, PhD, from Imperial College London, UK, said, "There was a clear effect of semaglutide to lower glycemia, but importantly A1c increased over time at a similar rate in both semaglutide and placebo arms, indicating a clear progressive loss of beta-cell function."

Kahn noted that SELECT researchers did not measure insulin sensitivity or beta-cell function.

CV Risk Reduction for All A1c Levels

In a separate study, Ildiko Lingvay, MD, MPH, MSCS, professor in the Department of Internal Medicine at the University of Texas Southwestern Medical Center in Dallas, and colleagues showed that semaglutide's ability to reduce cardiovascular events seen in the primary results from SELECT held up even for those who had normal A1c levels at baseline.

The new analysis first looked at MACE, its individual components, expanded MACE (cardiovascular mortality, nonfatal myocardial infarction, or stroke; coronary revascularization; or hospitalization for unstable angina), a heart failurecomposite (heart failure hospitalization or urgent medical visit or cardiovascular mortality), coronary revascularization, and all-cause mortality by baseline A1c subgroup and categories of A1c change.

The researchers found the reduction in these events was similar to the initial results of the SELECT trial and independent of baseline A1c. 

Cardiovascular outcomes were "also consistent across subgroups of A1c change," they reported.

The analysis shows that "these beneficial effects of semaglutide will be anticipated across the glycemic continuum," said Lingvay at the ADA meeting. 

"Even if a patient has a completely normal A1c they would still benefit from semaglutide for cardiovascular risk reduction," she said. "And even if there's no improvement in A1c, we will still see the benefits."

Caution Warranted?

The positive results of these analyses may encourage greater use of semaglutide, which was approved by the US Food and Drug Administration for cardiovascular risk reduction earlier this year. 

Following the approval, the Centers for Medicare & Medicaid Services told health plans that it would cover 2.4 mg semaglutide injection for overweight or obesei ndividuals with preexisting cardiovascular disease, reversing some 40 years of noncoverage of weight loss drugs. 

Commenting at the meeting, editorialist Misra said, "I'm very excited by all of these new agents, but I believe some caution is also needed." 

Although, as she noted in her editorial, the role of GLP-1 receptor agonists is quickly expanding to include cardiovascular risk management, and perhaps prevention of type-2 diabetes, many questions remain, she said. 

She called for a mediation analysis to account for changes in body weight, cholesterol, blood pressure, C-reactive protein, and renal function, in part to fully understand the effects of semaglutide.

"Another elephant in the room is that we need to equitably deploy these agents," said Misra, speaking at ADA. 

Four out of five people with type 2 diabetesr eside in low- and middle-income countries, she noted. "If we really want to get these agents to the right people, we need to develop stratification approaches to identify those most likely to benefit and approaches that will be cost-effective for the global population."

Misra is also interested in how the drugs will be used in younger adults with type 2 diabetes who are increasingly at risk for later cardiovascular consequences.

SELECT and the two new trials are sponsored by Novo Nordisk, the company that markets semaglutide (Wegovy). All authors received some compensation from Novo Nordisk during SELECT, and all authors reported lengthy disclosures. Kahn reports advisory board/consulting fees from AltPep, Bayer, Boehringer Ingelheim, Casma Therapeutics, Eli Lilly, Intarcia, Merck, Novo Nordisk, Oramed Pharmaceuticals, Pfizer, and Third Rock Ventures. He is also editor-in-chief of Diabetes Care but was not involved in any decisions regarding review of either manuscript or acceptance. 




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