Semaglutide is a Promising Drug Treatment for Chronic Weight Management

According to the CDC, the prevalence of obesity among US adults has increased from 35% in 2017 to 2018 to 42.4% in 1999 to 2000.1 This is of particular concern to health care professionals as obesity is associated with multiple serious conditions and comorbidities, such as diabetes mellitus, cardiovascular diseases, osteoarthritis, and certain types of cancer.²

On June 4, 2021, the FDA granted semaglutide (Wegovy; Novo Nordisk) approval for the treatment of chronic weight management in adults.³ Semaglutide, available in 0.25, 0.5, 1.0, 1.7, and 2.4 mg strengths for titration purposes, is a once weekly subcutaneous injection authorized for use in adults with obesity or overweight with at least one other weight related-condition—such as type 2 diabetes mellitus, hypertension, or dyslipidemia—alongside recommended lifestyle interventions.³ Such interventions include a reduced calorie diet, such as establishing a 500 kcal deficit per day, and average physical activity of 150 minutes per week.⁴

In 2017, semaglutide (Ozempic; Novo Nordisk) at doses of up to 1 mg subcutaneously once weekly was approved by the FDA for the treatment of type 2 diabetes mellitus.⁵ A glucagon-like peptide-1 receptor agonist (GLP-1 RA), semaglutide was evaluated in the Semaglutide Treatment Efficacy in People with Obesity (STEP) trials at a maintenance dose of 2.4 mg subcutaneously once weekly.⁴

The double-blind STEP 1 trial enrolled 1961 adults with a body mass index (BMI) of 30 kg/m2 or greater or a BMI of 27 kg/m2 or greater, with at least 1 weight related condition and without type 2 diabetes mellitus. The study participants were 74% females with an average age of 46 years and an average body weight of 105 kg.

During the study, participants were assigned to receive either a semaglutide 2.4 mg weekly injection or placebo for 68 weeks in addition to lifestyle interventions. Participants who received the semaglutide therapy showed an average weight loss of 14.9% from baseline compared to 2.4% in the placebo group.⁴

The phase 3 STEP 2 trial also investigated the efficacy and safety of semaglutide in adults with obesity or overweight with at least 1 weight-related condition, but included patients with diabetes.⁵ Participants during the study had average hemoglobin A1c levels of 7% to 10% and an average body weight of 99 kg. At week 68, the weight reduction was 9.6% with semaglutide at 2.4 mg weekly injection versus 3.4% with the placebo.⁶

During the STEP 3 trial, investigators specifically examined the effect of semaglutide at 2.4 mg once weekly injection alongside intensive behavioral therapy and an initial low-calorie diet in patients with obesity or overweight. In the STEP 3 trial, participants attended 30 counseling visits versus 18 counseling visits in the STEP 1 trial. At week 68, patients in the semaglutide group in the STEP 3 trial attained a 16% weight loss versus 5.7% in the placebo group.⁷

During the STEP 4 trial, the investigators examined the effects of long-term treatment. Patients received semaglutide at 2.4 mg once weekly for the first 20 weeks, achieving a mean weight loss of 10.6%, and were randomly assigned to continue treatment or receive placebo for the next 48 weeks. Participants who continued to be administered semaglutide lost an additional 7.9% of bodyweight versus the placebo group who regained 6.9% of their body weight on average.⁸

The most common adverse effects (AEs) reported in both trials were relatively similar and mostly gastrointestinal related, such as nausea, vomiting, diarrhea, and constipation.^4,6 AEs occurred more in the semaglutide group compared to the placebo group, at 74.2% versus 47.9%, respectively.⁴

For the STEP 1 trial, the investigators explained that the majority of the gastrointestinal AEs were mild to moderate in severity and ended up resolving without requiring the discontinuation of therapy.⁴ Additionally, in terms of safety, semaglutide demonstrated it has been safe as it has been used in patients with type 2 diabetes under the trade name Ozempic since 2017.

Compared to liraglutide (Saxenda; Novo Nordisk), a daily injectable GLP-1 RA approved for weight loss by the FDA in 2014, the safety profile was found to be similar to semaglutide; however, the mean weight loss reported in clinical trials was 8.4 ± 7.3 kg of body weight after 56 weeks in the liraglutide group versus 2.8 ± 6.5 kg in the placebo group.¹⁰

Additionally, a meta-analysis study found the risk of non-adherence was 11% higher with daily dosing compared to once weekly dosing.¹¹ This may indicate a greater number of patients are willing to adhere to weekly regimens versus daily, especially when it comes to an injectable medication.

Other FDA approved medications for obesity are dosed more frequently, such as bupropion/naltrexone (Contrave; Nalpropion Pharmaceuticals) at 2 times daily for a maintenance dose or orlistat (Xenical or Alli; CHEPLAPHARM and H2-Pharma) at up to 3 times daily. However, the more frequent dosing regimen with bupropion/naltrexone or orlistatmay limit patient adherence and acceptability. Orlistat also has undesirable AEs, including oily spotting, fecal urgency, fatty stool, and oily evacuation.^12,13

REFERENCES

1. Obesity is a Common, Serious, and Costly Disease [Internet]. Centers for Disease Control and Prevention. 2021 [cited 2021 Jul 15]. Available from: https://www.cdc.gov/obesity/data/adult.html
2. Obesity and overweight. World Health Organization. Internet. [cited 2021 Mar 29]. Available from: https://www.who.int/news-room/fact-sheets/detail/obesity-and-overweight
3. The FDA Approves New Drug Treatment for Chronic Weight Management , First Since 2014. [Internet]. FDA. FDA; 2021 [cited 2021 Jul 15]. Available from: https://www.fda.gov/news-events/press-announcements/fda-approves-new-drug-treatment-chronic-weight-management-first-2014
4. Wilding JPH, Batterham RL, Calanna S, Davies M, Van Gaal LF, Lingvay I, et al. Once-Weekly Semaglutide in Adults with Overweight or Obesity. N Engl J Med. 2021 Mar 18;384(11):989.
5. Ozempic [ package insert]. The Food and Drug Administration. Novo Nordisk Pharmaceuticals. 2017.
6. Davies M, Færch L, Jeppesen OK, Pakseresht A, Pedersen SD, Perreault L, et al. Semaglutide 2·4 mg once a week in adults with overweight or obesity, and type 2 diabetes (STEP 2): a randomized, double-blind, double-dummy, placebo-controlled, phase 3 trial. Lancet. 2021 Mar 13;397(10278):971–84.
7. Wadden TA, 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 Apr 13;325(14):1403-13.
8. Rubino D, Abrahamsson N, Davies M, et al. Effect of continued weekly subcutaneous semaglutide vs placebo on weight loss maintenance in adults with overweight or obesity. JAMA. 2021;325(14):1414-1425. doi:10.1001/jama.2021.3224
9. Wegovy. [Package insert]. The Food and Drug Administration. Novo Nordisk. 2021.
10. Pi-Sunyer X, Astrup A, Fujioka K, Greenway F, Halpern A, Krempf M, et al. A Randomized, Controlled Trial of 3.0 mg of Liraglutide in Weight Management. New England Journal of Medicine. 2015 Jul 2;373(1):11–22.
11. Weeda ER, Muraoka AK, Brock MD, Cannon JM. Medication adherence to injectable glucagon-like peptide-1 (GLP-1) receptor agonists dosed once weekly vs once daily in patients with type 2 diabetes: A meta-analysis. Int J Clin Pract. 2021 Feb 1; e14060.
12. Xenical. [package insert]. The Food and Drug Administration. Roche Laboratories Inc. 1999.
13. Bupropion/ naltrexone. In: Clinical Pharmacology powered by ClinicalKey [database on the Internet]. Tampa (FL): Elsevier; 2021 [updated 2020 Aug 7; 2021 Aug 7].