What is the role of oral semaglutide (Wegovy) in weight loss for patients who are overweight or obese?

Introduction
Obesity is a complex, chronic, progressive, heterogeneous, and neuroendocrine disease influenced by genetic predisposition and environmental factors, leading to excessive or abnormal fat accumulation that negatively impacts health.^1-3 It is closely linked to numerous complications and, when left untreated, leads to significant adverse health outcomes.^1-4 In the United States, obesity affects approximately 40.3% of adults aged 20 years and older and 22.9% of adolescents aged 12 to 19 years.⁵ These data underscore obesity as a significant and increasingly prevalent public health concern.

Historically, management of obesity has emphasized lifestyle interventions, including dietary modification, physical activity, and behavioral therapy.^1,3,6 Pharmacologic therapies, such as orlistat, phentermine-topiramate, and naltrexone-bupropion, have been reserved for patients who do not achieve adequate weight loss through lifestyle measures alone.⁴ However, these traditional agents often demonstrate only modest efficacy and may be limited by side effects or tolerability concerns. In recent years, glucagon-like peptide-1 (GLP-1) receptor agonists have emerged as a highly effective treatment option, providing substantial and sustained weight reduction while improving glycemic control and other cardiometabolic risk factors.^1,2,4 These agents represent a significant advancement in obesity care, particularly for patients with moderate to severe obesity or those with obesity-related complications. The emergence of GLP-1 receptor agonists has changed how obesity is treated, supporting a more comprehensive approach that integrates pharmacologic treatment with lifestyle strategies. In December 2025, an oral formulation of semaglutide was approved for weight loss, making it the first oral option among the GLP-1 receptor agonists approved for this indication. The purpose of this frequently asked question (FAQ) summary is to review guideline recommendations pertaining to the GLP-1 receptor agonists and to review literature on the efficacy of the new oral formulation of semaglutide for weight loss.

Standard of Care
Obesity screening is primarily conducted using body mass index (BMI), while diagnosis incorporates both anthropometric and clinical components.^1,4 Anthropometric assessment involves evaluating BMI, classified as overweight (25-29.9 kg/m²), class I obesity (30-34.9 kg/m²), class II obesity (35-39.9 kg/m²), and class III obesity ( ≥40 kg/m²), with lower thresholds sometimes applied for populations residing in the Asia-Pacific region. The waist circumference and waist-to-height ratio are also measured and assessed to determine risk for both males and females across different ethnic groups.¹ Clinical evaluation of obesity involves staging of adiposity-based chronic diseases (ABCD) based on the severity of obesity-related complications and diseases (ORCD). When evaluating ABCD, ORCD may include obesity complications (eg, osteoarthritis, obstructive sleep apnea, chronic kidney disease, and thromboembolism) and obesity-related diseases (eg, type 2 diabetes, metabolic dysfunction-associated steatohepatitis, heart failure with reduced ejection fraction, atrial fibrillation, and certain cancers). Staging of ABCD is based on ORCD, as follows:

• Stage 1: defined by excess adiposity without established ORCD; individuals remain at elevated risk for future ORCD
• Stage 2: includes the presence of at least 1 mild to moderate ORCD
• Stage 3: characterized by at least 1 severe or multiple ORCD

The overarching goals of obesity treatment across all stages are to achieve and maintain weight reduction, improve weight-related health conditions, and prevent the development of future chronic diseases.^2,4 Management should be individualized and comprehensive, addressing both weight and its associated health consequences. Initial treatment strategies are non-pharmacologic lifestyle interventions such as setting realistic weight management goals, optimizing nutrition, increasing physical activity, improving sleep, and engaging in behavioral therapy.^1,3,6 Pharmacologic therapy may be added when lifestyle measures alone are insufficient or when weight-related complications warrant medical treatment. If a surgical option is preferred, then one can also discuss metabolic or bariatric surgery or devices with their medical team when appropriate.

For individuals with stage 1 or stage 2 ABCD, first-generation anti-obesity medications (AOMs) may be considered, with an expected weight loss of approximately 5% to ≥15%.¹ These include phentermine, phentermine/topiramate extended-release, naltrexone/bupropion extended-release, and liraglutide.^1,4,6 In stage 3 ABCD, second-generation medications are strongly preferred due to their greater efficacy, with expected weight loss of 15% or more; these include semaglutide and tirzepatide.^1,3,4,6 Current guidelines from the American Association of Clinical Endocrinology (AACE) recommend individualizing weight loss treatment to target specific ORCD; Table 1 below summarizes specific hierarchies recommended by the AACE for complication-centric care of people with ABCD. Of note, while the guideline does not specify a particular formulation of semaglutide, the oral formulation was not yet approved for weight loss at the time the guideline was published.

Drug Overview
Semaglutide is a glucagon-like peptide-1 (GLP-1) receptor agonist available as both a subcutaneous injection and an oral tablet, indicated for chronic weight management in adults with obesity or in those who are overweight with at least 1 weight-related comorbidity, such as hypertension, dyslipidemia, or type 2 diabetes.^7-9 It promotes clinically meaningful weight loss by increasing satiety and reducing appetite, particularly when combined with a reduced-calorie diet and increased physical activity. Both formulations share the same mechanism of action and major safety considerations, including a boxed warning for potential thyroid C-cell tumors based on animal data and other warnings for potential development of pancreatitis, gallbladder disease, acute kidney injury, hypoglycemia when used with insulin or insulin secretagogues, and gastrointestinal adverse reactions. Key differences relate to route and frequency of administration, which may impact patient preference, adherence, and tolerability. Additional comparative details are summarized in the accompanying table.

Literature Overview
A targeted literature review was conducted to identify studies evaluating oral semaglutide for weight management in adults without type 2 diabetes who are overweight with ≥1 weight-related complication or comorbidity or obese. The review focused on randomized controlled trials that enrolled non-diabetic participants or reported outcomes separately for individuals without diabetes.

OASIS 1 trial
OASIS 1 is a phase 3 randomized, double-blind, placebo-controlled trial that evaluated once-daily oral semaglutide 50 mg or placebo, administered in a 1:1 allocation ratio in adults who are overweight with ≥1 weight-related complication or comorbidity or obese.¹⁰ The study was conducted over 68 weeks and included lifestyle counseling in both treatment arms. The coprimary endpoints assessed at week 68 were the percentage change in body weight from baseline and the proportion of participants achieving at least 5% weight loss. A total of 334 participants were assigned to oral semaglutide and 333 participants to placebo. Baseline characteristics were comparable across treatment groups. The population had a mean age of 50 years, mean body weight of 105.4 kg, mean BMI of 37.5 kg/m², and mean waist circumference of 113.6 cm. Most participants were White (74%) and female (73%). The majority (92%; n=613) had a BMI ≥ 30 kg/m², while 54 participants (8%) had a BMI of 27 to $\lt$30 kg/m² with at least one weight‑related comorbidity. By design, all individuals presented with at least one weight‑related comorbidity, most commonly hypertension (46%), dyslipidemia (40%), or obstructive sleep apnea (14%).

At week 68, participants receiving oral semaglutide experienced a mean body-weight reduction of approximately 15.1%, compared with 2.4% in the placebo group (estimated treatment difference, -12.7; 95% CI, -14.2 to -11.3; p$\lt$0.0001).¹⁰ A substantially higher proportion of participants in the semaglutide group achieved clinically meaningful weight-loss thresholds of ≥5% compared to those treated with placebo (85% vs. 26%, respectively; odds ratio [OR], 12.6; 95% CI, 8.5 to 18.7; p$\lt$0.0001). Secondary endpoints also showed significantly higher proportions of patients achieving weight-loss thresholds of ≥10%, ≥15%, and ≥20% with oral semaglutide versus placebo (p$\lt$0.0001 for all comparisons). When compared with placebo, oral semaglutide was also associated with improvements in multiple cardiometabolic risk factors such as reductions in blood pressure, low-density lipoprotein cholesterol, and triglycerides, with an increase in high-density lipoprotein cholesterol. Adverse events were reported more frequently among participants receiving oral semaglutide than among those receiving placebo (92% vs. 86%). Gastrointestinal adverse events, including nausea, vomiting, diarrhea, and constipation were most commonly reported, generally of mild to moderate severity, and occurred more frequently in the semaglutide group than in the placebo group (80% vs. 46%).

OASIS 4 trial
OASIS 4 is a phase 3 randomized, double-blind, placebo-controlled trial that evaluated once-daily oral semaglutide 25 mg or placebo, administered in a 2:1 allocation ratio in adults who were overweight with at least one obesity-related complication or obese.¹¹ The study was conducted over 71 weeks, comprising a 12-week dose titration phase, a 52-week maintenance phase, then a 7-week follow-up period, and incorporated concurrent lifestyle interventions. The coprimary endpoints assessed at week 64 were the percentage change in body weight from baseline and the proportion of participants achieving at least 5% weight loss. A total of 205 participants received oral semaglutide, and 102 received placebo. The study population was predominantly White (91.5%) and female (78.8%), with a mean body weight of 105.9 kg, mean BMI of 37.6 kg/m², and mean waist circumference of 113.9 cm.

At week 64, participants treated with oral semaglutide achieved a mean weight reduction of 13.6% from baseline, compared with 2.2% in the placebo group (estimated treatment difference, -11.4; 95% CI, -13.9 to -9; p$\lt$0.001).¹¹ Individuals receiving semaglutide were significantly more likely to reach weight-loss thresholds of ≥5% than those who received placebo (79.2% vs. 31.1%, respectively; OR, 7.3; 95% CI, 4.2 to 12.8; p$\lt$0.001). Secondary endpoints also showed significantly higher proportions of patients achieving weight-loss thresholds of ≥10%, ≥15%, and ≥20% with oral semaglutide versus placebo (p$\lt$0.001 for all comparisons). Greater improvements in physical function, assessed using the 20-item self-reported Impact of Weight on Quality of Life-Lite Clinical Trials Version (IWQOL-Lite-CT) score, as well as in various cardiometabolic risk factors, were also observed in the oral semaglutide group. Adverse events were reported more frequently among participants receiving oral semaglutide than among those receiving placebo (93.1% vs. 85.3%, respectively). Gastrointestinal adverse events were more common with semaglutide treatment compared with placebo (74% vs. 42.2%, respectively).

Discussion/Conclusion
Limitations of the OASIS trials include a predominance of women and White participants, which may limit the generalizability of the findings to more diverse, real-world populations.^10,11 The treatment duration was 68 to 71 weeks, restricting evaluation of long-term weight maintenance and safety. Oral semaglutide requires fasting administration with strict timing relative to food and other medications; adherence monitoring was limited in the trials, potentially leading to an overestimation of efficacy compared with real-world use. Although gastrointestinal adverse events were common and generally mild to moderate, with most resolving without permanent discontinuation of treatment, these effects may have a greater impact on tolerability and adherence outside of controlled trial settings. Finally, both trials lacked an active comparator.

Among clinical trials assessing the efficacy and safety of injectable semaglutide for weight management, the STEP 1 trial represents the most appropriate comparator for OASIS 4. STEP 1 evaluated once-weekly injectable semaglutide at a dose of 2.4 mg in adults with overweight or obesity and at least one weight-related comorbidity.¹² Both OASIS 4 and STEP 1 assessed coprimary endpoints of percentage change in body weight and the proportion of participants achieving at least 5% weight loss.^11,12 In STEP 1, treatment with injectable semaglutide resulted in a mean body-weight reduction of 14.9%, which was similar to the 13.6% reduction in body weight reported in OASIS 4. In addition, both studies demonstrated a substantially higher proportion of participants achieving ≥5% weight loss with semaglutide compared to placebo. Overall adverse event rates in STEP 1 were similar between the semaglutide and placebo groups (89.7% vs 86.4%). Gastrointestinal adverse events occurred more frequently with semaglutide than placebo in STEP 1 (74.2% vs. 37.9%), a finding consistent with OASIS 4, in which gastrointestinal adverse events were reported in approximately 74% of participants treated with oral semaglutide.

Patient preferences play a key role in selecting pharmacotherapy for weight loss. Oral semaglutide provides several practical advantages, including avoidance of injections, which may enhance acceptance among individuals with needle aversion and eliminate the risk of injection-site reactions. Additionally, it does not require refrigeration, facilitating easier storage and travel, and its once-daily dosing may integrate smoothly into established medication routines. Conversely, injectable semaglutide is administered once weekly, reducing the dosing burden and offering greater flexibility in timing, as it is not meal-dependent. Considering this, integrating patient preferences and formulation factors into treatment selection can promote better adherence and clinical outcomes.

References

1. Nadolsky K, Garvey WT, Agarwal M, et al. American Association of Clinical Endocrinology consensus statement: algorithm for the evaluation and treatment of adults with obesity/adiposity-based chronic disease – 2025 update. Endocr Pract. 2025;31(11):1351-1394. doi:10.1016/j.eprac.2025.07.017
2. Obesity and overweight. World Health Organization. Updated December 8, 2025. Accessed January 14, 2026. https://www.who.int/news-room/fact-sheets/detail/obesity-and-overweight#:~:text=They%20recognized%20that%20accelerated%20global,as%20the%20complex%2C%20lifelong%20condition
3. WHO guideline on the use of glucagon-like peptide-1 (GLP-1) therapies for the treatment of obesity in adults. World Health Organization. Updated December 1, 2025. Accessed January 14, 2026. https://app.magicapp.org/#/guideline/LrRxrL
4. Fredrick TW, Camilleri M, Acosta A. Pharmacotherapy for obesity: recent updates. Clin Pharmacol. 2025;17:305-327. doi:10.2147/CPAA.S497904
5. Obesity and overweight. Centers for Disease Control and Prevention. Updated January 27, 2026. Accessed February 20, 2026. https://www.cdc.gov/nchs/fastats/obesity-overweight.htm
6. Chao AM, Paul A, Hodgkins JV, Wadden TA. A guideline-directed approach to obesity treatment. Diabetes Spectr. 2024;37(4):281-295. doi:10.2337/dsi24-0001
7. Micromedex. Merative US; 2026. Accessed January 21, 2026. https://www.micromedexsolutions.com
8. Clinical Pharmacology. Elsevier; 2026. Accessed January 21, 2026. https://www.clinicalkey.com
9. Wegovy. Package insert. Novo Nordisk; 2026.
10. Knop FK, Aroda VR, do Vale RD, et al. Oral semaglutide 50 mg taken once per day in adults with overweight or obesity (OASIS 1): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2023;402(10403):705-719. doi:10.1016/S0140-6736(23)01185-6
11. Wharton S, Lingvay I, Bogdanski P, et al. Oral semaglutide at a dose of 25 mg in adults with overweight or obesity. N Engl J Med. 2025;393(11):1077-1087. doi:10.1056/NEJMoa2500969
12. Wilding JPH, Batterham RL, Calanna S, et al. Once-weekly semaglutide in adults with overweight or obesity. N Engl J Med. 2021;384(11):989-1002. doi:10.1056/NEJMoa2032183

Prepared by:
Shirley Yang
PharmD Candidate Class of 2026
University of Illinois Chicago Retzky College of Pharmacy

March 2026

The information presented is current as of January 9, 2026. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.