A Major Breakthrough In Obesity Treatment

The SELECT trial of semaglutide in patients with obesity and pre-existing heart disease marks a before and after moment in cardiology.

When the primary investigator showed the main results slide of the SELECT trial here at the American Heart Association meeting, there was applause.

I am not sure how I feel about clinicians clapping for positive results, but the fact remains that the SELECT trial is a big deal.

In SELECT, the injectable glucagon-like peptide 1 (GLP-1) agonist semaglutide was studied against placebo in more than 17,000 obese or overweight patients who had atherosclerotic disease. (Meaning this was a secondary prevention study.)

We call the primary endpoint of SELECT—CV death, MI or stroke—a hard cardiovascular endpoint.

Patients in the trial were in their low sixties. The average BMI was 33 and patients weighed about 96 kilograms.

In the trial, 6.5% of patients experienced a first primary outcome event in the semaglutide arm vs 8.0% in the placebo arm. That 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.

The Kaplan-Meier curves for outcomes began separating early and continued over 3-4 years.

There were other positive results as well.

Semaglutide resulted in weight loss—8.5% more than the placebo arm. Each component of the primary outcome was lower. Overall death was nearly 1% lower in the semaglutide arm. And the onset of pre-diabetes was reduced by 75% in the semaglutide arm vs the placebo arm.

The only clinically significant downside was higher rates of termination of the drug for GI side effects. There were no serious medical issues identified.

Comments:

This is a breakthrough. For many reasons.

One is the prevalence of obesity. I need not put numbers on this. All you have to do is look around. SELECT studied semaglutide as a secondary prevention drug (patients had heart disease), but many millions of people fall into this category. Given that semaglutide reduces cardiac events in patients with diabetes, it is likely that the drug class will improve outcomes in obese patients without heart disease. (Studies pending).

SELECT may also induce a change in the social framing of obesity. For too long, societal norms took a tolerant stance to obesity. Think body-positivity. But this study shows that a weight lost drug (perhaps through other mechanisms as well) reduces hard cardiac outcomes.

Thinking backwards from the study’s results leads to the conclusion that obesity itself causes premature cardiac events. We’ve known that from observational studies, but few clinicians and professional societies, have emphasized it.

I wrote a summary piece for theheart.org | Medscape Cardiology and wondered about this:

It [obesity] 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.

Another issue worth noting are the benefits of profit motive. This newsletter often criticizes industry and biased researches. But it is also true that profit-motive can lead to substantial societal benefit. The makers of GLP-1 agonists drugs (there are others) will win. But so will society.

Which leads me to a major headwind for this class of drugs—cost and access. Right now, and surely in the near-term, the drugs will be costly and difficult to get. Policy makers will have to find solutions to improving access.

Let’s finish with a bit of philosophy. The fundamental truth is that we would be better off not needing this class of drugs. You can look at the upward slope of obesity incidence since the 1950s and conclude that obesity can be prevented by lifestyle.

When I visited Oslo, I saw almost no obesity. Clearly how we live has contributed to the rise in rates of obesity. I get that. But I don’t see Western society changing that fast, or at all. Kentucky cannot become Oslo.

Pragmatic thinking: GLP-1 agonists drugs work. They help people with a serious health condition. How people got that health condition does not bear on the fact that we now have a beneficial drug that was proven effective in multiple randomized controlled trials.

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