SELECT Trial Data Show Benefit of Semaglutide in Patients With Obesity

By 2030, the global prevalence of obesity is expected to reach 1 billion, explained Ania M. Jastreboff, MD, PhD, associate professor in medicine and pediatrics at Yale School of Medicine, during a session at the American Heart Association (AHA) Scientific Sessions 2023 in Philadelphia, Pennsylvania. Jastreboff explained that the lifetime risk of cardiovascular disease in individuals with obesity without diabetes is about 1 in 2 in women and 2 in 3 in men.

“Most people with cardiovascular disease do not have diabetes, yet that is where most of our evidence lies,” Jastreboff said. “But with obesity, we know that we are in the midst of a rapid transformation. We are literally leaping forward from the past to the future at a watershed brought on by the recent introduction of highly effective antiobesity medications.”

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Jastreboff explained that although there were medications available before, the introduction of semaglutide (Ozempic; Novo Nordisk) and tirzepatide (Zepbound; Lilly) have quickly changed the landscape of treatment for obesity. Currently, there are other antiobesity medications that are now in phase 2 and phase 3 of development, with many more in phase 1, according to Jastreboff.

“Of course, semaglutide was FDA approved for obesity treatment in 2021, and just 2 days ago [on November 8, 2023] tirzepatide was FDA-approved for the same indication,” Jastreboff said. “Now, of course, when we talk about weight reduction with these medications, they're reaching double digits. But we're thinking beyond weight reduction—we're thinking of treating obesity and improving health outcomes.”

Jastreboff explained that data from the SELECT trial (NCT03574597) are showing, for the first time, that treating cardiovascular disease in the setting of obesity without type 2 diabetes decreases major adverse cardiovascular events (MACEs) by 20%.

“When we think about the current treatment paradigm, there's the traditional cardiovascular risk reduction by targeting hypertension, hyperlipidemia, and type 2 diabetes,” Jastreboff said. “But imagine a future where we're treating obesity and in effect, treating these other obesity-related diseases, targeting each one of these factors in reducing risk in our patients with cardiovascular disease.”

When looking at the primary endpoint of the SELECT trial, data show absolute reduction was 1.5%, with number needed to treat at 67. According to Jastreboff, this is in line with what has been seen in patients with type 2 diabetes and number needed to treat of 65.

“Now additionally, there's this early separation in terms of the effect, and this is before significant weight reduction occurs, so we really need to investigate the physiology,” Jastreboff said. “It's [also] 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 [low-density lipoprotein] and blood pressure. So, the therapeutic impact of semaglutide is on top of optimized evidence-based treatment.”

In terms of who may benefit from this treatment, Jastreboff noted that when looking at subgroup analyses, the data are all trending in the right direction.

“We might wonder do patients with less severe obesity benefit? And the answer is yes—71% of the participants were categorized as having overweight or class 1 obesity,” Jastreboff said. “The message here is to treat early in the course of the disease.”

Additionally, Jastreboff explained that two-thirds of participants in the SELECT trial had prediabetes, and the progression of diabetes was significantly reduced by treatment with semaglutide. For safety and tolerability data, Jastreboff noted that these medications have been used for the treatment of type 2 diabetes for over 17 years. Real-world data have shown that the most common adverse effects (AEs) are gastrointestinal, and these are transient and most commonly occur during dose escalation.

“The best way we have to mitigate them is slow titration. So, we start low, and we go slow,” Jastreboff said. “Now in trials, we don't have the ability to do this in the same way. So, not surprisingly, the most common [AEs] were gastrointestinal, and [they] were the most common reason for treatment discontinuation. But as pointed out in terms of severe [AEs], they were not increased with semaglutide. In fact, there were more events in the placebo group.”

Jastreboff noted that limitations of the SELECT trial were that participants were mostly White non-Hispanic men with only 12.5% Black participants, which ultimately limits generalizability of the data.

“Overall, we need to strive to do better in all of our trials,” Jastreboff said.

Jastreboff noted that a cross-sectional analysis of enhanced data from the SELECT trial was also conducted, with the results showing that individuals meeting the main criteria of SELECT increased from 4.3 million to 6.6 million in just one decade. Additionally, 53% of eligible individuals were women.

“A previous study showed that minority populations are disproportionately eligible for obesity treatment with semaglutide,” Jastreboff said. “We must strive for all patients who need them to receive these medications, especially those who usually don't [receive them].”

An additional limitation of the SELECT trial was that it was not a primary cardiovascular prevention trial. For this reason, Jastreboff noted that results cannot be extrapolated to people with obesity who do not have a history of cardiovascular disease.

“We need primary cardiovascular prevention trials, and hopefully those are coming in people with obesity without diabetes,” Jastreboff said. “Now, what SELECT taught us is treating obesity clearly improves health outcomes. The SELECT trial is a turning point. Treatment with semaglutide demonstrates clear secondary cardiovascular benefit in people with obesity without diabetes.”

Jastreboff noted that the therapeutic impact of semaglutide builds on top of current optimized evidence-based therapies. Further, the SELECT trial expands on existing literature that have shown safety and cardiovascular benefit in people with diabetes to now also show benefit in people with obesity.

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

Reference

Jastreboff AM. AHA Scientific Sessions 2023 Late-Breaking Science. Presented at: AHA Scientific Sessions 2023; November 10, 2023.