Full SELECT Results Affirm CV Risk Reduction With Semaglutide in Nondiabetics

PHILADELPHIA, PA—Mirroring results in patients with type 2 diabetes, semaglutide (Wegovy; Novo Nordisk) reduces cardiovascular events in patients with overweight or obesity and preexisting CVD who are not diabetic, according to full results of the SELECT trial.

Top-line results released over the summer indicated a 20% relative reduction in risk of MACE with semaglutide versus placebo on top of standard care. That stems from a 1.5% absolute reduction, from 8.0% in placebo-treated patients to 6.5% in those taking the glucagon-like peptide-1 (GLP-1) receptor agonist, A. Michael Lincoff, MD (Cleveland Clinic, OH), reported here at the American Heart Association 2023 Scientific Sessions.

There were no unexpected safety findings, although well-known GI side effects drove a higher rate of permanent treatment discontinuation in the semaglutide arm (16.6% vs 8.2%; P < 0.001).

Semaglutide “is the first weight management therapy which is proven in a rigorous randomized controlled trial to reduce the risk of cardiovascular events, which establishes overweight and obesity as a modifiable risk factor for cardiovascular disease,” Lincoff said during a press conference. This makes the drug “a treatment that could well be applied much more broadly to the expanding population of patients with overweight and obesity and cardiovascular disease.”

Commenting for TCTMD, Cynthia Jackevicius, PharmD (Western University of Health Sciences, Pomona, California), said the findings, published simultaneously online in the New England Journal of Medicine, confirm “what we really thought might happen, but it’s so important to see it in a cardiovascular outcomes trial.”

The magnitude of the absolute MACE reduction translates into a number needed to treat of 67, which is a “pretty good number,” she said. On the flip side, there are adverse events—primarily GI-related—that might be a deterrent for some patients taking GLP-1 receptor agonists and could affect adherence. “Patients could lose the benefits if they can’t tolerate this medication.”

Other issues to consider are cost and accessibility. Not all payers cover GLP-1 receptor agonists and if patients have to cover the cost—around $1,300 a month—out of pocket, it not only presents a barrier to treatment but also can exacerbate healthcare disparities between those who can versus cannot afford the medications.

Nonetheless, use of semaglutide could help address CVD, which remains the leading cause of mortality around the world, and obesity, which is still an epidemic, Jackevicius said.  “This can apply to so many patients across the US or across the world really,” she added. “This could have a huge population impact in terms of reducing morbidity and mortality from cardiovascular disease.”

What’s impressive about the risk reduction seen with semaglutide is that trial participants were reasonably well-treated for CVD, Martha Gulati, MD (Smidt Heart Institute at Cedars-Sinai, Los Angeles, CA), president of the American Society for Preventive Cardiology, commented to TCTMD via email.

“It means we should consider the use of this GLP-1 receptor agonist in patients without diabetes who have CVD and are overweight or obese,” she said, adding that she hopes these findings will lead to regulatory approval for this indication.

But challenges remain, Gulati indicated. “We have had limited access to these medications due to coverage (by insurance), high copays when insurance covers, and no coverage by Medicare at all,” she said. Moreover, there have been medication shortages due to the growing popularity of the GLP-1 receptor agonists for weight loss. Many are hoping the approval of tirzepatide (Zepbound; Eli Lilly) earlier this week will help to ease access and ultimately drive down costs.

“Hopefully these challenges will disappear so we can help our patients,” Gulati said. “Patients have been told to lose weight unsuccessfully because obesity is a chronic disease without an effective therapy, until now. Now, we have new drugs that can complement lifestyle changes and also reduce cardiovascular events, as proven by SELECT.”

The SELECT Trial

The World Obesity Federation projects that by 2035 more than half of the world’s population will have overweight or obesity, Lincoff said, noting that one study attributed about 4 million deaths around the world in 2015 to a high body mass index (BMI). Two-thirds of those deaths were related to cardiovascular disease. “And yet no lifestyle or pharmacologic weight management strategy has been shown to reduce the excess cardiovascular risk associated with overweight and obesity,” he said.

GLP-1 receptor agonists have been proven to reduce body weight and lessen CV risk in patients with type 2 diabetes, but—until now—they had not been shown to improve cardiovascular outcomes in patients with a high BMI but no diabetes.

The SELECT trial, conducted at 804 sites across 41 countries, was designed to answer that question. It included patients ages 45 or older who had preexisting CVD, a BMI of at least 27 kg/m², and no history of diabetes. They were randomized to once-weekly, subcutaneous semaglutide—uptitrated to a target dose of 2.4 mg—or placebo, both on top of standard CVD care.

There was a total of 17,604 patients (mean age 61.6; 72.3% men), who had a mean BMI of 33.3 kg/m²; 71.5% had obesity (BMI 30.0 kg/m² or higher). Mean glycated hemoglobin was 5.8%, with two-thirds of patients meeting criteria for prediabetes (5.7% to 6.4%).

Overall, participants were well treated for their underlying CVD, with 90.1% of patients taking lipid-lowering medications, 86.2% antiplatelets, 70.2% beta-blockers, 45.0% ACE inhibitors, and 29.5% ARBs.

Permanent premature discontinuation of the study drug was observed in 26.7% of semaglutide-treated patients and 23.6% of placebo-treated patients. By 2 years, 77% of patients in the active treatment group were taking the 2.4-mg target dose.

The reduction in MACE (CV death, nonfatal MI, or nonfatal stroke) with semaglutide was seen during a mean follow-up of 39.8 months. Each component of the composite numerically favored active treatment, although only the difference in nonfatal MI reached significance:

• CV death (2.5% vs 3.0%; HR 0.85; 95% CI 0.71-1.01)
• Nonfatal MI (2.7% vs 3.7%; HR 0.72; 95% CI 0.61-0.85)
• Nonfatal stroke (1.7% vs 1.9%; HR 0.93; 95% CI 0.74-1.15)

In terms of other secondary endpoints, semaglutide was associated with lower rates of heart failure events (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), and coronary revascularization (5.4% vs 6.9%; HR 0.77; 95% CI 0.68-0.87).

Moreover, patients receiving semaglutide were significantly less likely to progress to diabetes, defined as a glycated hemoglobin level of 6.5% or higher (3.5% vs 12.0%; HR 0.27; 95% CI 0.24-0.31).

These findings came in the context of significantly greater weight loss with semaglutide (9.4% vs 0.9%), and greater improvements in a variety of other cardiometabolic risk factors, including waist circumference, glycated hemoglobin level, systolic and diastolic blood pressure, high-sensitivity C-reactive protein, and lipids.

In terms of safety, overall serious adverse events were less frequent in the semaglutide group (33.4% vs 36.4%; P < 0.001). Still, patients on active treatment were more likely to discontinue treatment due to adverse events, mostly related to a higher rate of GI disorders (10.0% vs 2.0%; P < 0.001). Gallbladder-related disorders were slightly more frequent with semaglutide (2.8% vs 2.3%; P = 0.04), but other adverse events of special interest, including cancer, acute kidney failure, and acute pancreatitis, occurred at similar rates in the two groups.

Of note, amid reports of suicidal ideation linked to GLP-1 receptor agonists being tracked by regulators, psychiatric disorders were no higher in the semaglutide group (0.7% vs 0.6%), although Lincoff said there was no further breakdown of the events in that category.

Is It Weight Loss, Something Else, or Both?

Intriguingly, the MACE reduction with semaglutide occurred early, before substantial weight loss could be achieved, which raised questions about the mechanism of the cardiovascular benefit.

Ania Jastreboff, MD, PhD (Yale School of Medicine, New Haven, CT), the discussant for Lincoff’s presentation, said it will be important to investigate the physiology to get to the bottom of the finding, which could be related to effects on inflammation, endothelial function, or other factors. But it’s likely, she said, that the gains are due to a combination of the indirect effects of weight loss—which include improvements in hypertension, hyperlipidemia, and glycemic control—and direct effects of the drug.

Lincoff agreed that it’s probably not simply related to weight loss. “I think most of us believe that some of this is weight loss, but I think that oversimplifies a very complex molecule, a complex receptor on multiple tissues, and I don’t think it’s as simple as that,” he said

Chiadi Ndumele, MD, PhD (Johns Hopkins University, Baltimore, MD), a panelist at the press conference, noted that the experience with bariatric surgery for obesity could be informative. In those studies, there are improvements in insulin resistance and various metabolic risk factors—postulated to be possibly related to changes in GLP-1, in fact—before any substantial weight loss occurs. “I think it speaks to the fact that there is something going on, but the weight loss is also important,” he said, noting that despite those early benefits, the CV benefits continue to grow with greater weight loss. “I think we’re seeing something analogous here.”

One other variable that could come into play when looking at the early impact are changes in patient behavior, Jackevicius proposed. Although patients were blinded to treatment, the GI adverse events accompanying semaglutide could have hinted to patients receiving active treatment what group they were in. “The side effects of semaglutide are pretty noticeable, so patients might have known that they were taking it and that might have made them induce even more lifestyle modification.”

‘A Call to Arms’

Jastreboff noted that the global prevalence of obesity is expected to reach 1 billion by 2030. But at the same time, there is a rapid transformation taking place in the field of obesity treatment with the introduction of highly effective medications like the GLP-1 receptor agonists and tirzepatide, the first in a class of agents that acts on GLP-1 and glucose-dependent insulinotropic polypeptide (GIP). And there are many more drugs in the pipeline.

The traditional CVD treatment paradigm has physicians attacking various risk factors, but one can imagine a future in which physicians treat obesity, which in turn leads to improvements in conditions like hypertension, hyperlipidemia, and type 2 diabetes, Jastreboff said.

It’s important to remember, that in SELECT, all patients were very well treated for underlying CVD, she noted. “So the therapeutic impact of semaglutide is on top of optimized evidence-based treatment that we have today. This is critical.”

There are some limitations to what can be learned from SELECT, Jastreboff said, pointing to the fact that participants were disproportionately non-Hispanic white men. Thus, generalizability is limited for women and people of Hispanic/Latino ethnicity and of nonwhite race, which underscores the need to “do better” to ensure diverse trial populations.

Underscoring that point, she pointed to prior research showing that the number of Americans who would meet criteria for inclusion in the SELECT trial increased from about 4.3 million in 2011 to 6.6 million in 2020; 53% of those individuals were women. And another study demonstrated that individuals from minority populations are disproportionately eligible for obesity treatment with semaglutide. “We must strive for all patients to receive these medications who need them, especially those who usually don’t,” said Jastreboff.

Addressing the small percentage of women in the SELECT trial population, Gulati said, “I am disappointed in that because we have done better in enrolling women in weight loss trials. . . . We need adequate representation of women in trials and in 2023, we should demand this of our trials.”

These issues notwithstanding, the SELECT trial “is a turning point” by virtue of showing that “treating obesity clearly improves health outcomes,” Jastreboff said.

Obesity should be treated like any other complex, chronic disease, with interventions like medications and surgery complemented by guidance on improving diet and physical activity, managing stress, and getting adequate sleep, she added. “I think it’s this idea that it’s not only one thing. It’s everything together.”

Overall, SELECT “is really a call to action,” Jastreboff said. “Now is the time to treat obesity, improving health outcomes in people with cardiovascular disease.”