Are We On the Verge of Pharmacologic Management of Obesity (Again)?

In the 1990s, the combination of fenfluramine/phentermine was popularized as a treatment for obesity. Fenfluarmine, though, was shown to cause potentially fatal pulmonary hypertension and heart valve problems, which eventually led to its withdrawal and legal damages of over $13 billion (per Wikipedia: fenfluramine/phentermine).

Now, glucagon-like peptide-1 (GLP-1) receptor agonists, like liraglutide, are showing promise as agents to promote weight loss, primarily by inhibiting appetite. JR Lundrgen et al (NEJM 2021; 384: 1719-1730. Healthy Weight Loss Maintenance with Exercise, Liraglutide, or Both Combined) show that liraglutide can promote weight loss, especially if combined with exercise.

Methods: After an 8-week low-calorie diet, participants were randomly assigned for 1 year to one of four strategies: a moderate-to-vigorous–intensity exercise program plus placebo (exercise group); treatment with liraglutide (3.0 mg per day-SC injection) plus usual activity (liraglutide group); exercise program plus liraglutide therapy (combination group); or placebo plus usual activity (placebo group)

Key findings:

  • After the 8-week low-calorie diet, 195 participants had a mean decrease in body weight of 13.1 kg.
  • At 1 year, all the active-treatment strategies led to greater weight loss than placebo: difference in the exercise group, −4.1 kg (95% confidence interval [CI], −7.8 to −0.4; P=0.03); in the liraglutide group, −6.8 kg (95% CI, −10.4 to −3.1; P<0.001); and in the combination group, −9.5 kg (95% CI, −13.1 to −5.9; P<0.001). The combination strategy led to greater weight loss than exercise (difference, −5.4 kg; 95% CI, −9.0 to −1.7; P=0.004) but not significantly more than monotherapy with liraglutide (−2.7 kg; 95% CI, −6.3 to 0.8; P=0.13)
  • The side effects of decreased appetite, dizziness, increased heart rate and palpitations were more common in those receiving liraglutide; palpitations were evident in 12% of the liraglutide monotherapy group and 4% of the combination (with exercise) group.

The details of the exercise program are detailed in the methods section; all participants were assigned an instructor and expected to do a minimum of 150 minutes per week of moderate-intensity aerobic physical activity or 75 minutes per week of vigorous-intensity aerobic physical activity.

These results are similar to the 15% weight loss noted at 68 weeks with the GLP-1 receptor agonist semaglutide.

My take: GLP-1 receptor agonists help individuals lose weight. However, we’ve seen the promise of medical therapy before so we will have to see how the story ends.

Related blog post: Semaglutide: Potential or Problematic New Treatment for Fatty Liver Disease/NASH

Briefly noted: YY Gibbens et al. American Journal of Gastroenterology 2021 April 22. Effects of Central Obesity on Esophageal Epithelial Barrier Function. Key finding:  Obesity+/GER- group demonstrated increased intercellular space, reduced desmosome density, and increased fluorescein leak compared with control subjects. Thus, obesity may worsen esophageal disease by  impairing the structural and functional integrity of the esophageal barrier independent of GER. (Thanks to Mike Hart for this reference)