Who Benefits Most From Semaglutide and How Long Will That Take?

A post hoc, time-to-event analysis of the SELECT trial of semaglutide suggests that 80 patients would need to be treated for 3 years for one person to avoid a cardiovascular event and that the survival time gained may be “relatively small.”

On that basis, write João Pedro Ferreira, MD, PhD (University of Porto, Portugal), and colleagues in the Journal of Cardiac Failure (JCF), taking a risk-based approach to semaglutide prescribing might be a better way of ensuring the drug has a meaningful impact on hard events.

A. Michael Lincoff, MD (Cleveland Clinic, OH), presented the SELECT trial results at the American Heart Association (AHA) 2023 Scientific Sessions, as reported by TCTMD; the results were simultaneously published in the New England Journal of Medicine. In SELECT, patients with overweight or obesity and preexisting CVD, but no diabetes, who were randomized to semaglutide (Wegovy; Novo Nordisk), had a 20% relative reduction (and a 1.5% absolute reduction) in MACE versus placebo over a mean follow-up of 39.8 months.

But as Ferreira et al note in their research letter, the aim of SELECT was to include patients with existing CVD, yet most patients (76%) were enrolled on the basis of a prior myocardial infarction, and the rest on the basis of a heart failure diagnosis. As such, the population as a whole could be considered to be at moderate—not high—risk of CV events, they write.

In this patient group, having a sense of the annualized absolute and time-specific risk, as well as the restricted mean survival time (RMST), would “add clinically relevant information,” they say.

Absolute Risks

In a time-to-event reconstruction, using data derived from the published Kaplan-Meier curves using published methods, Ferreira and colleagues calculated an annualized event rate for the primary endpoint (MI, stroke, or cardiovascular death) of 1.9 events per 100 person-years for patients taking semaglutide and 2.4 per 100 person-years for placebo-treated patients. Those numbers yielded a number needed to treat (NNT) of 200 patients.

The RMST, meanwhile, for primary-event-free survival was 0.5 months longer for semaglutide-treated patients. For the secondary endpoint of heart failure hospitalizations or death, the annualized event rate per 100 person-years was 1 for semaglutide-treated patients and 1.2 for placebo-treated patients, yielding an NNT of 500. For survival alone, the absolute risk reduction (ARR) at 36 months was -1.2, yielding an NNT of 83.

For the average SELECT patient, they conclude, the estimated lifetime gains over 48 months would be just 8 extra days alive.

“When you look at the relative risk reduction you can get impressive resulting numbers in terms of [the] hazard ratio, but when you look into absolute risk reduction, or survival time gains and those kinds of metrics, the results become less impressive because you have a few events,” Ferreira told TCTMD. “You need to treat a lot of people to avoid one event.”

It's easy to skip lifestyle interventions when you have a drug that can, in people's minds, be a replacement for lifestyle. João Pedro Ferreira

“In the ideal world, if everybody could take this drug for a very low cost with a good safety profile [then] why not?” he continued. “But the thing is that these treatments do have associated costs and they have some side effects, and you need . . . to treat many people to potentially avoid one major adverse cardiovascular event.”

In many parts of the world, he continued, there are “severe disruptions in the supply” of semaglutide, “so not even people with diabetes and morbid obesity, that would clearly have a clear indication for the drug—they cannot have the drug because it's not available. So I think there's more selection that needs to be done, at least until we have these treatments more available, or other options, and the costs are significantly lower.”

Only then, he said, should the drug be prescribed more widely in people at lower risk for cardiovascular events.

Contextualizing SELECT

Speaking with TCTMD, JCF deputy editor Anu Lala, MD (Icahn School of Medicine at Mount Sinai, New York, NY), said they were moved to fast-track this research letter through their “Ignite” pathway because it “contextualizes” what was presented at AHA. “We’re all thrilled by the [SELECT] results,” she said. “I do think the GLP-1 agonists are turning things on its head in terms of our understanding of cardiovascular disease along the continuum of heart failure.”

That said, she continued, patients are extremely eager to take these medications, which puts physicians under added pressure to understand and convey the risk-benefit trade-off. “I think there's a lot of hype,” she said, “but it's important to recognize that we'll have to be a little bit more thoughtful as to who's actually going to benefit from the drug.”

She herself is “excited” to have another diabetes medication demonstrate cardiovascular disease efficacy, she stressed. “I don't mean to be negative about it at all, but I also think that it's important to understand how cost-effectiveness will play into the rollout of this drug.”

It's important to recognize that we'll have to be a little bit more thoughtful as to who's actually going to benefit from the drug. Anu Lala

Also speaking with TCTMD, JCF editor-in-chief Robert Mentz, MD (Duke University Medical Center, Durham, NC), pointed out that the 2022 heart failure guidelines for the first time include “value statements” to make practitioners more aware of the costs their patients may be facing, and what benefit those therapies yield for that price. Recent estimates put the monthly cost of semaglutide at around $1,350, with most patients paying at least two-thirds of that price out of pocket.

Ferreira’s analysis “gives direct numbers that translate to patient benefit, and the timing for the amount of time that is needed to demonstrate that benefit,” Mentz said. For now, he believes the patients likely to benefit most in his clinic are the ones with heart failure with preserved ejection fraction, diabetes, and obesity. “That overlap is the group that we think really benefits both in terms of feeling and functioning better [based on STEP-HFpEF], and potentially [seeing] clinical outcome benefits.”

Risk Models Needed

Ferreira hopes the SELECT investigators will delve into patient subgroups to get a better understanding of which patients benefit most and use that information, in combination with biomarkers or other risk markers, to help clinicians direct these scarce and expensive drugs to the patients most likely to benefit.

“A patient [with] a 10% probability of having an event in 2 or 3 years—this patient might benefit over a relatively short term of the treatment,” he said. “And then, in the medium-risk category, you could say, ‘Okay, we don't know if this patient might or might not benefit, but you can consider treatment based on other factors.’” The patients at the lowest risk should then be steered first towards lifestyle changes, he said.

In fact, Ferreira said, lifestyle modification is “really important for all patients. I think that should be the primary aim. It's easy to skip lifestyle interventions when you have a drug that can, in people's minds, be a replacement for lifestyle. But one should not forget that lifestyle will have a wide range of benefits that you cannot achieve with a drug: musculoskeletal, peripheral, oxygen consumption, anxiety, sleeping,” and more, he said.

Contacted by TCTMD, SELECT’s Lincoff pointed out that the NEJM paper did not report ARR or NNT figures for anyone to dispute. “Those numbers are arbitrary, depending upon what time frame one uses for the calculation, and they apply only to an overall population, not individual patients at individual risk,” he said in an email. For those reasons, the authors intentionally “did not make any statements in the paper regarding ARR or NNT.”

“Clearly,” he continued, “absolute risk reduction and number needed to treat are more favorable in patients at higher baseline risk. Risk scores, equations, or models have proven to be unreliable to predict risk, however, in secondary prevention populations—those tested here.”