The GLP-1 Receptor Agonist Semaglutide for Diabetes or Weight Management

Semaglutide is in a class of medications known as glucagon-like peptide-1 (GLP-1) receptor agonists that were originally developed for the management of type 2 diabetes. GLP-1 drugs mimic the effects of a hormone that stimulates insulin secretion and helps control blood sugar levels.[1] Use of semaglutide is associated with reduced food cravings and an increased likelihood of feeling full after food is consumed, which is likely related to slower emptying of the stomach.

The Food and Drug Administration (FDA) has approved several formulations of brand-name semaglutide, as shown in Table 1 (below); there are no FDA-approved generic versions. For all formulations and indications, including type 2 diabetes and weight management, the FDA approved semaglutide as an adjunct to a reduced-calorie diet and increased physical activity.

Although there is robust evidence to support the FDA-approved indications, the beneficial effects of semaglutide require continued and sustained use. There are also important adverse events, as discussed in more detail below.

The other FDA-approved GLP-1 receptor agonist drugs are not the subject of this article.

Management of type 2 diabetes

The FDA first approved semaglutide (OZEMPIC) in 2017 as a once-weekly subcutaneous (under-the-skin) injection to improve glycemic control in adults with type 2 diabetes.[2] Subsequently, Ozempic was approved to reduce the risk of major adverse cardiovascular events (including cardiovascular death, as well as nonfatal heart attacks or strokes) in adults with type 2 diabetes and cardiovascular disease, and in adults with type 2 diabetes and chronic kidney disease to reduce the risk of progression of chronic kidney disease, end-stage kidney disease and cardiovascular death.

In 2019 the FDA approved a once-daily oral formulation of semaglutide (RYBELSUS) for the management of type 2 diabetes.[3]

Obesity or overweight

In 2021 subcutaneous semaglutide was approved under the brand name WEGOVY for obesity or overweight with comorbid conditions.[4],[5]

Overweight is defined as a body mass index (BMI) of 27 kilograms per square meter (kg/m) or greater, and obesity is defined as a BMI of 30 kg/m or greater.

Since December 2025 Wegovy also has been available as a once-daily oral tablet; as of March 2026 Wegovy was the only oral GLP-1 drug approved for these indications.

The injection and tablet forms of Wegovy are indicated to reduce the risk of major adverse cardiovascular events in adults with cardiovascular disease and either obesity or overweight. They are also approved for the reduction of body weight and maintenance of weight reduction in obese adults, and in overweight adults with at least one weight-related comorbid condition, such as hypertension or abnormal levels of lipids (fats) in the blood.

The Wegovy injection, but not the tablet, also is indicated to reduce excess body weight and maintain weight loss long term in obese youths aged 12 years and older, and for the treatment of noncirrhotic metabolic dysfunction-associated steatohepatitis (MASH), as discussed in a separate article in this issue.
 

Table 1. Dosages and Strengths of Brand-Name Semaglutide

The efficacy of semaglutide

In industry-sponsored clinical trials with participants who were obese, overweight or had type 2 diabetes, semaglutide, coupled with diet and exercise, consistently significantly reduced body weight (up to 16%) and waist circumference compared with placebo, resulting in improved outcomes for cardiovascular disease and blood glucose control. It also led to a reduced risk of worsening kidney disease and kidney failure.[6],[7],[8]

GLP-1 drugs, especially semaglutide and tirzepatide (MOUNJARO, ZEPBOUND; reviewed in another article in this issue), are being studied for other conditions. For example, a 2025 analysis using a Department of Veterans Affairs database and including over 200,000 participants with diabetes identified substance use, psychotic disorders, coagulation diseases and respiratory ailments for further study.[9] There also have been reports of GLP-1 drugs for alcohol use disorder,[10] age-related cataracts,[11] pain related to knee osteoarthritis,[12] and colon cancer.[13] The FDA has not approved semaglutide or other GLP-1 drugs for any of these conditions.

Safety concerns

Examples of serious adverse events and possible adverse events from GLP-1 drugs are shown in Table 2 below. Across the clinical trials for FDA approval, participants taking semaglutide had substantially more gastrointestinal adverse events, including severe events, than those taking placebo. These adverse events included nausea, vomiting, diarrhea, constipation and abdominal pain. Although gastrointestinal adverse events were typically dose dependent, mild to moderate, and self-limiting, they were also the main reason for discontinuing the drug.[14],[15] As discussed in another article in this issue, semaglutide’s gastrointestinal effects appear to be similar to those of other GLP-1 medications.[16]

Other adverse events more frequently reported in semaglutide users than in placebo recipients include gallbladder-related disorders (cholelithiasis or cholecystitis), headache, fatigue, dyspepsia (impaired digestion) and dizziness.[17],[18],[19]

Semaglutide should not be used during pregnancy because of the risk of fetal harm. The prescribing information also includes a boxed warning — the FDA’s strongest warning — for thyroid C-cell tumors, a warning that is based on studies in rodents, not humans. GLP-1 drugs are contraindicated in people with a personal or family history of multiple endocrine neoplasia syndrome type 2.

Table 2. Examples of Serious Adverse Events and Possible Adverse Events From GLP-1 Drugs

†Brand-name combination products were excluded.
*Designated as Limited Use
**Designated as Do Not Use
***The 80-milligram dose of simvastatin is designated as Do Not Use.

Drug discontinuation

The benefits associated with GLP-1 drugs require continued long-term treatment. When treatment is discontinued, patients generally regain weight and lose health benefits, such as lower blood pressure, lower lipid levels, and glycemic control.[21] For example, patients who stopped their GLP-1 treatment returned to their original weight after 1.7 years, according to a 2026 systematic review of 37 studies including over 9,000 participants.[22] Patients discontinuing GLP-1 drugs also regained their weight more rapidly than those who had lost weight through diet and physical activity. Similarly, all cardiometabolic improvements returned to pretreatment levels within 1.4 years.

Up to 60% of people in the United States taking GLP-1 medications discontinue their treatment within 12 months, especially patients without diabetes and those older than 65 years.[23],[24] Although gastrointestinal adverse events are a key reason for treatment interruptions or stopping treatment, costs, supply shortages and unwillingness to take these drugs continuously are contributing factors.[25]

What You Can Do

GLP-1 drugs are a new class of medications; the long-term benefits and risks of these drugs, including in adults 65 years of age and older, require additional study.[26] The drugs require continued use and there are safety concerns. Only consider treatment with semaglutide for an FDA-approved indication and in conjunction with a reduced-calorie diet and increased physical activity.
 

References

[1] Tan HC, Dampil OA, Marquez MM. Efficacy and safety of semaglutide for weight loss in obesity without diabetes: A systematic review and meta-analysis. J ASEAN Fed Endocr Soc. 2022;37(2):65-72.

[2] Novo Nordisk. Label: semaglutide (OZEMPIC). October 2025. https://www.accessdata.fda.gov/drugsatfda_docs/label/2025/209637s035,209637s037lbl.pdf. Accessed February 2, 2026.

[3] Novo Nordisk. Label: semaglutide (RYBELSUS). October 2025. https://www.accessdata.fda.gov/drugsatfda_docs/label/2025/213051s024,s028s029lbl.pdf. Accessed February 2, 2026.

[4] Novo Nordisk. Label: semaglutide (WEGOVY). October 2025. https://www.accessdata.fda.gov/drugsatfda_docs/label/2025/218316Orig1s000lbl.pdf. Accessed February 2, 2026.

[5] Semaglutide (WEGOVY) for weight loss: Substantial risks, including weight regain. Worst Pills, Best Pills News. August 2023. https://www.worstpills.org/newsletters/view/1545. Accessed February, 2026.

[6] Cleto AS, Schirlo JM, Beltrame M, et al. Semaglutide effects on safety and cardiovascular outcomes in patients with overweight or obesity: a systematic review and meta-analysis. Int J Obes (Lond). 2025 Jan;49(1):21-30.

[7] Celletti F, Branca F, Farrar J. Obesity and glucagon-like peptide-1 receptor agonists. JAMA. 2025 Feb 18;333(7):561-562.

[8] Novo Nordisk. Label: semaglutide (OZEMPIC). October 2025. https://www.accessdata.fda.gov/drugsatfda_docs/label/2025/209637s035,209637s037lbl.pdf. Accessed January 27, 2026.

[9] Xie Y, Choi T, Al-Aly Z. Mapping the effectiveness and risks of GLP-1 receptor agonists. Nat Med. 2025 Mar;31(3):951-962.

[10] Wang W, Volkow ND, Berger NA, et al. Associations of semaglutide with incidence and recurrence of alcohol use disorder in real-world population. Nat Commun. 2024 May 28;15(1):4548.

[11] Ahuja AS, Paredes AA 3rd, Ahuja SA, et al. Glucagon-like peptide-1 receptor agonist use and risk of cataract development. Am J Ophthalmol. 2026 Jan;281:666-673.

[12] Bliddal H, Bays H, Czernichow S, et al. Once-weekly semaglutide in persons with obesity and knee osteoarthritis. N Engl J Med. 2024 Oct 31;391(17):1573-1583.

[13] Cuomo RE. The influence of GLP-1 receptor agonists on five-year mortality in colon cancer patients. Cancer Invest. 2025 Nov;43(10):982-991.

[14] Smits MM, Van Raalte DH. Safety of semaglutide. Front Endocrinol (Lausanne). 2021 Jul 7;12:645563.

[15] Tan HC, Dampil OA, Marquez MM. Efficacy and safety of semaglutide for weight loss in obesity without diabetes: A systematic review and meta-analysis. J ASEAN Fed Endocr Soc. 2022;37(2):65-72.

[16] Crisafulli S, Alkabbani W, Paik JM, et al. Comparative gastrointestinal safety of dulaglutide, semaglutide, and tirzepatide in adults with type 2 diabetes. Ann Intern Med. 2025 Nov 4:10.7326/ANNALS-25-01724.

[17] Novo Nordisk. Label: semaglutide (OZEMPIC). October 2025. https://www.accessdata.fda.gov/drugsatfda_docs/label/2025/209637s035,209637s037lbl.pdf. Accessed February 3, 2026.

[18] Novo Nordisk. Label: semaglutide (WEGOVY). October 2025. https://www.accessdata.fda.gov/drugsatfda_docs/label/2025/218316Orig1s000lbl.pdf. Accessed February 3, 2026.

[19] Smits MM, Van Raalte DH. Safety of semaglutide. Front Endocrinol (Lausanne). 2021 Jul 7;12:645563.

[20] Xie Y, Choi T, Al-Aly Z. Mapping the effectiveness and risks of GLP-1 receptor agonists. Nat Med. 2025 Mar;31(3):951-962.

[21] Wilding JPH, Batterham RL, Davies M, et al. Weight regain and cardiometabolic effects after withdrawal of semaglutide: The STEP 1 trial extension. Diabetes Obes Metab. 2022 Aug;24(8):1553-1564.

[22] West S, Scragg J, Aveyard P, et al. Weight regain after cessation of medication for weight management: systematic review and meta-analysis. BMJ. 2026 Jan 7;392:e085304.

[23] Inoue K, Decker SRR, Shi I, et al. Discontinuation of semaglutide among older adults with diabetes in the US and Japan. JAMA Cardiol. 2025 Nov 1;10(11):1222-1224.

[24] Rodriguez PJ, Zhang V, Gratzl S, et al. Discontinuation and reinitiation of dual-labeled GLP-1 receptor agonists among US adults with overweight or obesity. JAMA Netw Open. 2025 Jan 2;8(1):e2457349.

[25] McGowan C. I no longer think GLP-1s are the answer. MedPage. January 30, 2025. https://www.medpagetoday.com/opinion/second-opinions/114009. Accessed February 12, 2026.

[26] Rivera FB, Arias-Aguirre E, Aguirre Z, et al. Evaluating the safety profile of semaglutide: an updated meta-analysis. Curr Med Res Opin. 2024 Sep;40(9):1495-1514.