By William Elliott, MD, FACP, and James Chan, PharmD, PhD

Dr. Elliott is Assistant Clinical Professor of Medicine, University of California, San Francisco.
Dr. Chan is Associate Clinical Professor, School of Pharmacy, University of California, San Francisco.

The FDA has approved a new treatment for chronic weight management. Semaglutide is a glucagon-like peptide (GLP-1) receptor agonist initially approved in 2017 to treat type 2 diabetes mellitus at a lower dose (1.2 mg) as Ozempic and in 2019 as oral tablets (Rybelsus). Semaglutide for weight management is marketed as Wegovy.

INDICATIONS

Semaglutide can be prescribed as an adjunct to a low calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of ≥ 30 kg/m2 (obese) or ≥ 27 kg/m2 (overweight) in the presence of at least one weight-related comorbidity condition.1 These include hypertension, type 2 diabetes mellitus, and dyslipidemia.

DOSAGE

The recommended maintenance dose is 2.4 mg given subcutaneously once weekly on the same day each week without regard to meals.1 To alleviate gastrointestinal side effects, the recommended escalation schedule is 0.25 mg (weeks 1-4), 0.5 mg (weeks 5-8), 1 mg (weeks 9-12), 1.7 mg (weeks 13-16), and 2.4 mg (week 17 and beyond). Semaglutide is available as prefilled, single-dose pens of 0.25 mg, 0.5 mg, 1 mg, 1.7 mg, and 2.4 mg.

POTENTIAL ADVANTAGES

Semaglutide injection may be more effective in reducing weight than other FDA-approved drugs, such as naltrexone/bupropion, phentermine/topiramate, and liraglutide.

POTENTIAL DISADVANTAGES

As with other GLP-1 receptor agonists, semaglutide carries a warning for the risk of thyroid C cell tumors and is contraindicated in patients with a personal or family history of medullary thyroid carcinoma of multiple endocrine neoplasia syndrome type 2.1 Acute pancreatitis and acute gallbladder disease have been reported in clinical trials. Antidrug antibodies were observed in 2.9% semaglutide-treated subjects. The most frequently reported (≥ 20%) adverse reactions (vs. placebo) were nausea (44% vs. 16%), diarrhea (30% vs. 16%), vomiting (24% vs. 6%), constipation (24% vs. 11%), and abdominal pain (20% vs. 10%).1 In clinical trials, 6.8% of semaglutide-treated subjects discontinued the study drug because of adverse reactions vs. 3.2% for placebo-treated subjects.1 Based on animal data, semaglutide may carry risk for the fetus.1

COMMENTS

The safety and efficacy of semaglutide for reducing body weight were evaluated mainly in three 68-week, randomized, placebo-controlled trials.1-4 Trials 1 and 3 included subjects with BMI of ≥ 30 kg/m2 or overweight (27 kg/m2 to 29.9 kg/m2) with ≥ 1 weight-related coexisting conditions (but not diabetes). Trial 2 included subjects with BMI of ≥ 27 kg/m2 and type 2 diabetes (mean HbA1c = 8.1%). Subjects in trials 1 and 3 were randomized (2:1) to semaglutide 2.4 mg or placebo (n = 1,306/655; n = 407/204, respectively). Subjects in trial 2 were randomized 1:1:1 to semaglutide 2.4 mg, 1 mg, or placebo (404/403/403). Trials 1 and 2 participants received instructions for a reduced caloric meal diet and increased physical activity. Trial 3 participants received intensive behavioral therapy. The coprimary endpoints were the percent change in mean body weight from baseline and weight reduction of at least 5%. Secondary endpoints included achieving a 10% reduction in weight and various anthropometric and cardiometabolic parameters (e.g., waist circumference, SF-36 functioning score, BP, HbA1c, lipid profile).

At week 68, the percent weight changes from baseline (semaglutide/placebo) were -14.9/-2.4, -9.6/-3.4, and -16/-5.7 for the three trials. The percentage of patients losing ≥ 5% of body weight was 83.5/31.1, 67.4/30.1, and 84.8/47.8, respectively. The percentage achieving ≥ 10% weight reduction was 66.1/12.0, 44.5/10.2, and 73.0/27.1. Semaglutide generally improved anthropometric and cardiometabolic parameters.

CLINICAL IMPLICATIONS

Obesity is a common multifactorial condition that negatively affects mortality and morbidity. Approximately 70% of American adults are obese or overweight.5 Since 2012, the FDA has approved four medications to enhance weight loss along with diet and physical activity (lorcaserin, phentermine-topiramate, naltrexone-bupropion, and liraglutide). Lorcaserin has since been withdrawn because of cancer risk (2020).6 The drug combinations feature their own adverse reaction profiles and limitations (e.g., suicide ideation with bupropion, phentermine/topiramate is a schedule CIV drug). GLP-1 receptors are located in the central nervous system and are involved in appetite regulation,1 which is the likely mechanism of action of both GLP-1 receptor agonists, semaglutide and liraglutide. In terms of relative effectiveness, there are no published direct comparisons of the older drugs to semaglutide. Also, study duration was 68 weeks for semaglutide and one year for the others. In terms of percent difference between drug effect and placebo, indirect comparisons suggest semaglutide may be more effective. For example, in obese and overweight subjects, the percentage who experienced ≥ 5% body weight reduction on the study drug was 54.1% for semaglutide, 25% for naltrexone/bupropion, 39.8% for phentermine/topiramate, and 27.9% for liraglutide.1,7,8,9

Semaglutide offers a new and highly effective treatment option for treating obese and overweight adults with or without diabetes. It should be used as part of a structured multimodality weight management program. The cost for semaglutide as Wegovy is $1,349 for a four-week supply.

REFERENCES

  1. Novo Nordisk. Wegovy prescribing information. June 2021.
  2. Wilding JPH, Batterham RL, Calanna S, et al. Once-weekly semaglutide in adults with overweight or obesity. N Engl J Med 2021;384:989.
  3. Davies M, Færch L, Jeppesen OK, et al. Semaglutide 2·4 mg once a week in adults with overweight or obesity, and type 2 diabetes (STEP 2): A randomised, double-blind, double-dummy, placebo-controlled, phase 3 trial. Lancet 2021;397:971-984.
  4. Wadden TA, Bailey TS, Billings LK, et al. Effect of subcutaneous semaglutide vs placebo as an adjunct to intensive behavioral therapy on body weight in adults with overweight or obesity: The STEP 3 Randomized Clinical Trial. JAMA 2021;325:1403-1413.
  5. U.S. Food & Drug Administration. FDA approves new drug treatment for chronic weight management, first since 2014. June 4, 2021.
  6. U.S. Food & Drug Administration. FDA requests the withdrawal of the weight-loss drug Belviq, Belviq XR (lorcaserin) from the market. Feb. 13, 2020.
  7. Vivus. Qsymia prescribing information. October 2020.
  8. Nalpropion Pharmaceuticals LLC. Contrave extended-release prescribing information. August 2020.
  9. Novo Nordisk. FDA approves Saxenda for the treatment of obesity in adolescents aged 12-17. Dec. 4, 2020.