Less Is Certainly More: The Frontier of Weight Loss Pharmacotherapy

Volume 5, Issue 2

The last 50 years of human evolution has yielded many scientific breakthroughs—from space travel to the internet. However, for the first time in the history of our species, more people in the modern era are going to die from overeating as opposed to starvation.

Obesity is the second, only to smoking, leading cause of preventable death in this country and the situation is only growing more dire. Despite a multibillion-dollar weight loss industry, more than half of Americans will be considered obese by the end of this decade. In this week’s issue of Talking Therapeutics, we explore the latest data surrounding a promising new agent for weight loss.

Point 1: Semaglutide is a Game Changer

The handful of drugs currently approved for long-term treatment of obesity have a satisfactory safety profile and help people lose an average of about 5% to 10% of their body weight—a clinically meaningful amount but far from the results seen with bariatric surgery, the golden standard. Enter semaglutide.

In the STEP-3 trial, which assessed the additional contribution of semaglutide to intensive behavioral treatment in 611 adults with overweight/obesity, participants in the semaglutide group lost 16.8 kg (16.0% of initial body weight). This was 10.6 kg (10.3%) more weight loss than participants in the placebo group, with 55.8% of participants who received semaglutide (vs 13.2% who received placebo) losing at least 15% of their body weight.

In the follow up STEP-4 trial of 803 adults without diabetes, the effect of continued semaglutide, 2.4 mg, for 68 weeks was compared to a placebo switch at 20 weeks. This trial found an additional 7.9% weight loss among those who continued drug treatment, compared with a weight gain of 6.9% among those who switched to placebo, for a final placebo-subtracted weight loss of 14.8%. This study confirmed the necessity of continued anti-obesity pharmacotherapy for sustained benefit.

Adverse events with semaglutide were primarily gastrointestinal and similar to other GLP-1 receptor agonists.

Point 2: Alternative Therapies are Insufficient

As of June 2021, a total of 5 medications—orlistat, phentermine plus topiramate, naltrexone plus bupropion, liraglutide, and semaglutide—are currently approved by the US Food and Drug Administration for long-term weight management in adults with body mass index of at least 30 or body mass index of at least 27 and comorbid conditions. The mean placebo-subtracted 1-year weight loss for prescription medications for obesity approved before 2021 ranged from 3.4 kg to 8.9 kg, with the greatest weight loss associated with use of high-dose phentermine plus topiramate.

Semaglutide offers a clear and significant advantage over these agents in terms of both safety and efficacy. Ongoing cardiovascular outcomes trials should provide evidence for any salutary or adverse effects on cardiovascular outcomes in these high-risk patient populations.

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