Positive Results From SELECT Begins a New Era in Cardiology

The positive press release regarding the performance of the glucagon-like peptide 1 (GLP-1) agonist semaglutide in the SELECT trial did not exaggerate.

SELECT Trial Results

In this multicenter, placebo-controlled trial of more than 17,000 patients with overweight/obesity and established atherosclerotic disease, semaglutide reduced a composite endpoint of cardiovascular death, myocardial infarction (MI), and stroke.

In the semaglutide arm, 6.5% of patients experienced a first primary outcome event vs 8.0% in the placebo arm. This 1.5% absolute risk reduction translates to a 20% relative risk reduction (hazard ratio = 0.80; 95% CI, 0.72 - 0.90; P < .001). Adverse events leading to stopping the drug occurred in 16.6% of those taking semaglutide (weekly dose of 2.4 mg) vs 8.2% on placebo.

There were many other notable and positive findings for semaglutide:

• Patients lost about 8.5% more body weight than those in the placebo arm.

• The Kaplan-Meier curves for the primary endpoint began to separate early, well before weight loss took effect, suggesting multiple ways the drug may confer its benefit.

• Each component of the primary endpoint was lower.

• Overall death was nearly 1% lower.

• These positive findings occurred in the setting of robust baseline care, including statins and antiplatelet agents in approximately 90% of patients.

• The onset of prediabetes was reduced by 75% and levels of C-reactive protein and systolic blood pressure were lowered.

Progress in cardiology, especially preventive cardiology, has been held back by such good standards of care. New advances have been mostly incremental.

Semaglutide as a secondary prevention agent for patients with obesity is different. This is a big effect, a statin-like effect. I don't know how else to feel other than hugely positive. These patients were a mean 62 years old; prevention of an MI, stroke, or death at that age is a big deal.

At the American Heart Association Scientific Sessions there was much discussion about mechanism. My take is that it doesn't matter. That's why I love trials. Trials bypass the mechanism step and simply tell us what works and what does not. I remind you that we don't know how SGLT2 inhibitors work.

Another notable discussion point from the meeting was that obesity is a disease. This, I think, could be a major positive externality of the trial.

Changing Norms on Obesity

I speculate, but one of the many reasons obesity has become so prevalent, at least in the US, is our norms. Being obese is no longer exceptional. It starts in school-age children. Social forces have even emphasized a body-positivity frame. The medical establishment hasn't pushed back against this.

Now, though, with a trial that clearly shows a weight-loss drug reduces serious cardiac events — in the absence of diabetes — perhaps a new frame will take hold. A norm where obesity is not okay. It is a disease that should be approached in ways we approach any disease. Imagine the societal benefit if professional societies applied the vigor of its antismoking messages to obesity.

Finally, I conclude with cost and access. Semaglutide will clearly gain approval for this indication. There are millions of people with heart disease and overweight/obesity. Healthcare costs are already high. Adding a costly drug to many millions of patients will surely expand healthcare budgets.

The legendary economist Thomas Sowell famously said there are no solutions, only tradeoffs. Policymakers will have to figure out which tradeoffs they are willing to make to achieve equitable access to this new breakthrough drug.

My simple mind can't help thinking that if we spent less on low-value care, we'd have more for proven therapies, such as semaglutide as a preventive drug.

John Mandrola practices cardiac electrophysiology in Louisville, Kentucky, and is a writer and podcaster for Medscape. He espouses a conservative approach to medical practice. He participates in clinical research and writes often about the state of medical evidence. Mandrola has disclosed no relevant financial relationships.