Semaglutide (WEGOVY) for Weight Loss: Substantial Risks, Including Weight Regain

Semaglutide (WEGOVY), an injectable glucagon-like peptide-1 (GLP-1) receptor agonist (activator), is having its moment as a drug for weight loss. In May 2023, the manufacturer, Novo Nordisk, announced that it was pausing direct-to-consumer advertising because of difficulties keeping up with demand for the drug.[1]

In 2017, the Food and Drug Administration (FDA) approved semaglutide (OZEMPIC) as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes. The drug was subsequently approved to reduce the risk of major adverse cardiovascular events in adults with type 2 diabetes and established cardiovascular disease.[2] In 2019, the FDA approved an oral formulation of semaglutide (RYBELSUS) for treatment of type 2 diabetes. Although not approved for this indication, Ozempic and Rybelsus have been used off-label as weight-loss drugs.[3],[4]

In 2021, the FDA approved semaglutide under the brand name Wegovy for chronic weight management in adults with or without type 2 diabetes who have a body mass index (BMI) of 30 kilograms per square meter (kg/m²) or greater (obesity), or 27 kg/m² or greater (overweight) with at least one additional weight-related condition such as hypertension (high blood pressure), type 2 diabetes or dyslipidemia (high fat levels in the blood).[5] A BMI of 27 kg/m² corresponds to an adult who is 5 feet 8 inches tall and weighs approximately 178 pounds, and a BMI of 30 kg/m² corresponds to the same-height adult weighing 197 pounds.[6]

Liraglutide (SAXENDA), another GLP-1 receptor agonist, is also approved as an adjunct therapy for chronic weight management.[7]

Worst Pills, Best Pills News has previously classified all GLP-1 receptor agonists, including semaglutide, as Do Not Use for type 2 diabetes because of the limited benefits of the drug class and the serious adverse effects that include cardiovascular risk, pancreatitis (inflammation of the pancreas), and pancreas and thyroid cancers.[8]

Most commercial insurers and Medicare cover semaglutide for the treatment of type 2 diabetes.[9] Without coverage, semaglutide can cost patients thousands of dollars a year. Although Medicare Part D (that program’s prescription drug component) is banned from covering weight-loss drugs, the manufacturer has hired a lobbying firm to push for semaglutide coverage. If Medicare were to cover semaglutide and other similar weight-loss drugs, the annual costs could be in the tens of billions of dollars. Based on a hypothetical scenario in which all Medicare beneficiaries with obesity used semaglutide for weight loss, those costs would exceed the entire Part D budget (and this estimated cost does not include other indications for use of the drug).[10]

What is semaglutide?

Semaglutide is a GLP-1 analogue, similar in structure to the natural molecule that occurs in humans. GLP-1 analogues bind to and stimulate receptors in the brain that influence appetite and caloric intake.[11] The injectable forms of semaglutide (Ozempic, Wegovy) are administered subcutaneously (below the skin) once a week. Typical injection sites are the abdomen, thigh or upper arm. For type 2 diabetes, the approved starting dosage is 0.25 mg once weekly, with gradual dose increases if needed. The dosage is usually not more than 2 mg once a week. For weight loss, the approved starting dosage is also 0.25 mg once weekly, and the usual maintenance dosage is higher — 2.4 mg once weekly. It is important to emphasize that these treatments are labeled by the FDA as regimens that should be “adjunct to” (only additions to) a reduced caloric diet and increased physical activity.

Evidence for the effectiveness of semaglutide for chronic weight management

Semaglutide and other new-generation anti-obesity medications are an advance on previous-generation medications because they have produced weight loss of 15% to more than 20% in clinical trials. Lifetime use, however, may be required to prevent weight regain.[12]

In approving the Wegovy-branded semaglutide for weight management, the FDA mainly considered data from four studies of adults.[13]

Three randomized, double-blinded trials compared semaglutide with a placebo. All involved 68-week treatment periods beginning with 16 weeks of gradually increasing the semaglutide dosage to 2.4 mg per day. Subjects either were obese or were overweight with another medical condition (such as diabetes or hypertension). Average age was 48 years, and average starting weight was over 220 pounds. The trials involved a total of 2,117 adults on semaglutide and 1,262 on placebo. Collectively, these studies found significant 68-week weight loss, averaging 10% to 16% of starting body weight in the semaglutide group and 2% to 6% in the placebo group. These three studies (and the fourth study, described below) were designed such that semaglutide or placebo treatment were an adjunct to specific diet and exercise interventions.

The fourth study had a different design: It began with 20 weeks of open-label (unblinded) use of semaglutide in all 803 subjects (mean age, 46 years), followed by a phase lasting an additional 48 weeks in which 204 of those subjects were randomly switched to placebo; this part of the study was blinded. When patients stopped semaglutide, the researchers found a substantial rebound effect, meaning that those who had been taking the medicine regained much of the weight they had lost. The patients who continued semaglutide for 68 weeks had a 17% reduction in weight (from week 0 to 68), whereas the patients who switched to placebo after 20 weeks had a 5% reduction. Based on these data, FDA scientists concluded that “there does not appear to be a role for the short-term use of semaglutide (20 weeks or fewer) as an adjunct to a reduced calorie diet and exercise for chronic weight management.”

Safety issues

The first three randomized trials described above found numerous adverse effects related to semaglutide. For safety, subjects were followed from baseline through week seven after the last medication dose (75 weeks of follow-up). The most frequently observed adverse effects, all substantially greater with semaglutide than with placebo, were nausea, diarrhea, vomiting, constipation, abdominal pain, headache, fatigue, dyspepsia (impaired digestion) and dizziness. Most of the gastrointestinal events were characterized as mild or moderate and “self-limiting.” The FDA review noted that the median durations of nausea and constipation observed with semaglutide were 8 days and 47 days, respectively.

Studies in monkeys have shown that semaglutide-induced weight loss correlated with pregnancy loss and decreased infant weight. In rats, thyroid tumors also were noted as an adverse effect. These findings prompted the FDA to require post-marketing studies that will likely not be completed for years.

Less frequent adverse events associated with semaglutide include appendicitis, gallbladder disorders (gallstones), pancreatitis, hypoglycemia (low blood sugar) in individuals also using insulin, retinal disorders and rapid heart rate.

What You Can Do

For type 2 diabetes, Worst Pills, Best Pills News recommends that you Do Not Use semaglutide, because other drugs and strategies (especially diet and exercise) are effective and safer. If you are obese or overweight and considering using semaglutide for chronic weight management, consult with your doctor. The discussion should include consideration of the adverse effects of semaglutide, the potential for a substantial rebound in weight if the medication is stopped, and the advantages of losing weight primarily through a reduced caloric diet and increased physical activity. To prevent weight regain, lifetime use of semaglutide may be required. Also, be aware that semaglutide is a relatively new drug; as more people take the drug, and for longer periods of time, more will become known about adverse effects and drug interactions.
 

References

[1] Chen E. Novo Nordisk pauses ads for weight loss drug Wegovy as it struggles to meet demand. STAT+. May 19, 2023.

[2] Novo Nordisk. Label: semaglutide (Ozempic). October 2022. https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/209637s012lbl.pdf. Accessed June 5, 2023.

[3] Marcus R. Opinion: I lost 40 pounds on Ozempic. But I’m left with even more questions. Washington Post. June 6, 2023.

[4] Raman V, Gupta A, Ashraf AP, et al. Pharmacologic Weight Management in the Era of Adolescent Obesity. J Clin Endocrinol Metab. 2022;107(10):2716-2728.

[5] Novo Nordisk. Label: semaglutide (Wegovy). December 2022. https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/215256s005lbl.pdf. Accessed June 5, 2023.

[6] U.S. Center for Disease Prevention and Control. Adult body mass index calculator. https://www.cdc.gov/healthyweight/assessing/bmi/adult_bmi/english_bmi_calculator/bmi_calculator.html. Accessed May 25, 2023.

[7] Novo Nordisk. Label: liraglutide (Saxenda). April 2023. https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/206321s016lbl.pdf. Accessed June 26, 2023.

[8] Worst Pills Best Pills News. “Do Not Use” type 2 diabetes gliptin drugs also raise risk of gallbladder inflammation. March 2023. https://www.worstpills.org/newsletters/view/1521. Accessed June 6, 2023.

[9] Wilson MR. Ozempic, Wegovy-maker hires lobbying firm to push for Medicare coverage. Politico. June 16, 2023.

[10] Baig K, Dusetzina SB, Kim DD, Leech AA. Medicare Part D coverage of antiobesity medications - challenges and uncertainty ahead. N Engl J Med. 2023;388(11):961-963.

[11] Novo Nordisk. Label: semaglutide (Wegovy). December 2022. https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/215256s005lbl.pdf. Accessed June 5, 2023.

[12] Baig K, Dusetzina SB, Kim DD, Leech AA. Medicare Part D coverage of antiobesity medications - challenges and uncertainty ahead. N Engl J Med. 2023;388(11):961-963.

[13] Sharretts J. Center for Drug Evaluation and Research. Application Number: 215256Orig1s000. Summary Review. NDA 215256, Semaglutide (WEGOVY). PDUFA Goal Date: June 4, 2021. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2021/215256Orig1s000SumR.pdf. Accessed June 6, 2023.