A Watershed Moment for Weight Loss

The rates of obesity worldwide are expected to reach nearly 50% by the year 2035, which is catastrophic when considering that obesity contributes substantially to the risk of common killers like cardiovascular disease and malignancy.

Reducing cardiovascular risk has traditionally focused on interventions aimed at controlling hypertension, hyperlipidemia, and diabetes. Prior pharmacologic interventions for weight loss have been marginally effective, leaving obesity as a relatively unchecked and ongoing cardiovascular risk factor for many patients.

The GLP-1 agonists have proven very effective in helping patients with obesity lose substantial weight, and they can also reduce the risk of cardiovascular disease when given to patients with diabetes. Whether this weight loss can translate into a reduction in cardiovascular risk in patients without diabetes remains to be proven. In this week’s issue of Talking Therapeutics, we cover a new study that sought to address this gap in the evidence.

Point 1: Another Huge Win for GLP-1 Agonists

In the SELECT Trial, more than 17,000 adult patients 45 years of age or older had preexisting cardiovascular disease and a body-mass index of 27 or greater but no history of diabetes. Patients were randomly assigned in a 1:1 ratio to receive once-weekly subcutaneous semaglutide 2.4 mg or placebo and were studied for an average of just over 39 months. The primary cardiovascular end point was a composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke.

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 (HR, 0.80; 95% CI, 0.72 to 0.90; P<0.001).

Point 2: Important Safety Signals Noted

Treatment-related adverse events leading to permanent discontinuation of semaglutide or placebo occurred in 16.6% in the semaglutide group and 8.2% in the placebo group (P<0.001). These differences were primarily driven by a higher rate of gastrointestinal disorders (10.0%) in the semaglutide group versus 2.0% in the placebo group and gallbladder-related disorders. Importantly, rates of pancreatitis were not different between groups.

These side effects track with what is known about the GLP-1 agonists, and they are relevant given that some of these adverse events can be severe (eg, bowel obstruction). It’s important for pharmacists to counsel patients on both the risks and benefits of SGLT2 inhibitors when dispensing these medications for weight loss.