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)

Should We Be Excited About a New Medication (Liraglutide) for Obesity?

Thus far, “the benefits of medications to treat obesity remain limited because of side effects and inadequate efficacy, especially in the long term.” This is part of an editorial (Siraj ES, Williams J. NEJM 2015; 373: 82-3) that explains a recent study (Pi-Sunyer X, et al. NEJM 2015; 373: 11-22). However, there is a huge need for a cost-effective medication because bariatric surgery is not feasible for 400 million obese persons worldwide.

Liraglutide (marketed as Victoza) has been approved by the FDA for weight loss in adults based on this published study and two other trials.  Liraglutide is a glucagon-like peptide-1 (GLP-1) mimetic.  The authors conducted a 56-week, double-blind trial with 3731 non-diabetic patients. In a 2:1 design, most patients received a once-daily subcutaneous 3.0 mg injection of liraglutide; some received placebo.  Both groups received lifestyle counseling.

Key finding:

  • At week 56, the treatment group had lost a mean of 8.4 kg compared with the placebo group which lost 2.8 kg.

There were similar rates of adverse events (mildly increased in treatment group); the rate of new diagnoses of diabetes was less than one-eighth that in the placebo group.  A 2-year extension trial is being analyzed to further pursue this finding.  Also, the authors note that 4 cases of breast cancer (0.2%) were detected in the treatment group compared with 1 (0.1%) in the placebo group.  This finding could have been due to easier exam following weight loss.  It is noted that the labeling for liraglutide has a black box warning regarding thyroid c-cell tumor risk which have occurred in rodents at clinically relevant doses.

A fairly good 2 minute summary: NEJM Short Take on Liraglutide

Despite the weight loss, the editorial has a cautious tone.

  • “There were statistically significant, although sometimes quantitatively modest, improvements in secondary end points, which included glycemic control, fasting insulin concentrations, cardiometabolic markers, and quality-of-life measures.”
  • “Most obese participants stayed obese, reversal of the metabolic syndrome was not quantified, and liraglutide may be required indefinitely, like statins, but with delivery by injection and at a nontrivial cost.”  According to http://www.goodrx.com, the approximate retail price is $596.01 for 18 mg. For type 2 diabetes, the dosage varies from 1.2 to 1.8 mg per day, after the first week which is dosed at 0.6 mg.

Take-home point: This new medication may help with modest weight loss but at a very significant cost.  In addition, long-term data are lacking. Thus, right now, this medication does not provide the cost-effective option to bariatric surgery.

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