SELECT Provides HOPE For People With Obesity And Heart Disease

On January 20, 2000, Salim Yusuf and colleagues published the seminal Heart Outcomes Prevention Evaluation (HOPE) Study in the New England Journal of Medicine. 

The HOPE Study included over 9,000 high-risk patients (55 years of age or older) who had evidence of vascular disease or diabetes plus one other cardiovascular risk factor and who were not known to have a low ejection fraction or heart failure, who were randomly assigned to receive ramipril (10 mg once per day orally) or matching placebo for a mean of five years. 

A total of 651 participants who were assigned to receive ramipril (14.0 percent) reached the primary end point, as compared with 826 patients who were assigned to receive placebo (17.8 percent) (relative risk, 0.78; 95 percent confidence interval, 0.70 to 0.86; P<0.001). 

Thus, the HOPE study established the benefits of angiotensin converting enzyme inhibition in the prevention of cardiovascular complications in high-risk individuals, which remains a leading principle for the treatment of such patients to this day.

Today (November 11, 2023), Michael Lincoff and colleagues presented the results of the long-awaited SELECT trial of the GLP-1 analogue semaglutide (2.4 mg) vs. placebo in over 17,000 participants 45 years of age or older who had preexisting cardiovascular disease and a BMI of 27 or greater but no history of diabetes. 

According to the results of SELECT, published in the New England Journal of Medicine, a primary cardiovascular end-point event occurred in 569 of the 8803 patients (6.5%) in the semaglutide group and in 701 of the 8801 patients (8.0%) in the placebo group (hazard ratio, 0.80; 95% confidence interval, 0.72 to 0.90; P<0.001).

Thus, SELECT shows a reduction in cardiovascular risk with semaglutide 2.4 mg, of a magnitude virtually identical to that reported for ramipril in the HOPE trial. 

It must, however be noted that the SELECT trial results are in fact far more impressive that those of the HOPE study. 

For one, while almost 40% of participants in HOPE had diabetes, the SELECT study specifically excluded people with diabetes.

Secondly, whereas the mean age of HOPE participants was 66 years, the SELECT population was five years younger. 

Thirdly, SELECT was conducted on participants receiving today’s standard of care, which includes routine use of ACE/ARBs, statins, anti-platelet agents and liberal use of revascularisation.

Notably, this being a study of an anti-obesity medication in people with obesity, the BMI of participants was 33, i.e. five points higher than that of the HOPE trial. 

It should perhaps also be mentioned here that participants on semaglutide lost about 10% of their body weight compared to less than 1% on placebo.

Incidentally, adverse effects, including those leading to discontinuation of semaglutide, were pretty much as expected given its mode of action (largely limited to GI side effects).

Within a few months of the publication of the HOPE trial, ACE inhibition pretty much became part of the global standard treatment for high-risk cardiovascular patients. 

Whether or not this will be the case for semaglutide, given the cost and limited availability remains to be seen. 

Nevertheless, SELECT will surely go down in the history of medicine (as did the HOPE trial) as the first randomised placebo-controlled trial documenting the beneficial effect of an anti-obesity medication (and intentional weight loss?) in individuals with obesity and established cardiovascular disease (without diabetes). 

Congratulations to everyone involved!

@DrSharma,
Berlin, D

Disclaimer: I have received honoraria as an independent medical, research and/or educational consultant from various companies including Aidhere, Allurion, Boehringer Ingelheim, Currax, Eli-Lilly, Johnson & Johnson, Medscape, MDBriefcase, Novo Nordisk, Oviva and Xenobiosciences.