GLP-1 agents have reshaped the management of obesity, and the market continues to accelerate as new agents and indications emerge. On December 22, 2025, the FDA approved the first oral GLP-1 for weight loss and reduction of major adverse cardiovascular events (MACE), Novo Nordisk’s Wegovy1. A second oral GLP-1 approval is anticipated in the first half of 2026 from Eli Lilly with orforglipron2. The introduction of effective oral options lowers barriers to use for patients, which is likely to accelerate demand, pushing this already high-cost category into a new phase of coverage complexity.
Oral vs. Injectable GLP-1s: Key Differences at a Glance
Novo Nordisk has reached the market first with an oral GLP-1 option for obesity, while Eli Lilly’s orforglipron is expected to follow in 2026. Orforglipron is a small-molecule GLP-1, allowing it to be dosed without regard to meals, an attribute that may offer a competitive advantage in this category2.
While oral formulations offer a new level of convenience, both oral Wegovy and orforglipron require once-daily dosing. In contrast, subcutaneous options such as Wegovy and Zepbound are administered once weekly for a different form of convenience.
Injectable Wegovy can be used in a wider population, with approval for use in patients 12 years of age and older for weight loss, and an additional indication for metabolic dysfunction-associated steatohepatitis (MASH) in adults. It is also indicated to treat major adverse cardiovascular events (MACE) in adults. Zepbound similarly holds an additional indication for obstructive sleep apnea.
| Brand Name | Generic Name/Route | Mechanism | Dosage Forms and Strengths | Dosing | Age** | Expanded Indications | Approval Year6 |
| TBD3 | orforglipron | Small molecule GLP-1 receptor agonist | Tablet: 12 mg, 24 mg, 36 mg | Once daily without regard to meals | 18+ | N/A | TBD |
| Wegovy4 | semaglutide, oral | GLP-1 receptor agonist | Tablet: 1.5 mg, 4 mg, 9 mg and 25 mg | Once daily with 4 oz of water 30 minutes prior to eating | 18+ | MACE with established CV disease in adults | 2025 |
| Wegovy4 | semaglutide, subcutaneous | GLP-1 receptor agonist | Injection: 0.25 mg, 0.5 mg, 1 mg, 1.7 mg or 2.4 mg | Once weekly | 12+ | In adults: MACE with established CV disease and MASH | 2021 |
| Zepbound5 | tirzepatide, subcutaneous | Dual GIP*/GLP-1 receptor agonist | Injection: 2.5 mg, 5 mg, 7.5 mg, 10 mg, 12.5 mg, or 15 mg | Once weekly | 18 + | Obstructive sleep apnea in adults | 2023 |
*GIP= glucose-dependent insulinotropic polypeptide / ** FDA approved age for weight loss indication
Efficacy Comparison
While the GLP-1s agents in the table below were not evaluated in head-to-head clinical trials, their studies were conducted over similar durations (64–72 weeks) and enrolled comparable patient populations, allowing for cross-trial comparisons. Across these studies, oral and subcutaneous formulations of Wegovy and orforglipron demonstrated generally similar weight-loss outcomes.
For patients unwilling or unable to self-inject, oral GLP-1 options offer a viable alternative. However, as shown below, Zepbound demonstrated a notably greater mean percentage reduction in body weight, approximately 21%, compared to 11.2% to 14.9% for the others.
| Orforglipron7, 9 | Wegovy, oral8 | Wegovy, subq4 | Zepbound5 | |
| Trial | ATTAIN-1 (NCT05869903): Phase 3, 72-week, randomized, double-blind, placebo-controlled trial | OASIS-4 (NCT05564117): Phase 3, 64-week, randomized, double-blind, placebo-controlled trial | STEP 1 (NCT03548935): Phase 3, 68-week, randomized, double-blind, placebo-controlled trial | SURMOUNT-1 (NCT04184622): Phase 3, 72-week, randomized, double-blind, placebo-controlled trial |
| Population | Adults with obesity (BMI ≥30 kg/m2) or overweight (BMI 27 to <30 kg/m2) with a weight-related problem without diabetes | |||
| Intervention | Orforglipron vs placebo | Semaglutide 25 mg daily vs placebo | Semaglutide vs placebo | Tirzepatide weekly vs placebo |
| Primary Endpoint | Percentage change in body weight | |||
| Efficacy | Lowered weight by an average of 11.2% compared to 2.1% with placebo | Lowered weight by an average of 13.6% compared to 2.4% with placebo | Lowered weight by an average of 14.9% compared to 2.4% with placebo | Lowered weight by an average of 20.9% compared to 3.1% with placebo g |
Adverse Events and Treatment Discontinuation
With GLP-1s, side effects are a common and expected consideration and can influence whether patients remain on treatment. The most commonly reported adverse drug reactions (ADRs) associated with GLP-1 therapies are gastrointestinal, including nausea, diarrhea, constipation, and vomiting. These effects can drive treatment discontinuation, particularly during an increase in dosage.
As shown below, overall ADR rates are relatively consistent across all of these agents. Discontinuation rates at the highest approved doses are also similar among most products, with the exception of orforglipron.
Overall, Zepbound appears to be associated with a lower overall rate of reported adverse events while delivering greater average weight-loss efficacy. For plan sponsors, these differences highlight the importance of balancing efficacy with tolerability, as side-effects can directly influence adherence and total cost of therapy.
| Orforglipron 36 mg7, 9 | Wegovy, 25 mg oral4, 8,10 | Wegovy, 2.4 mg subq4 | Zepbound 155 mg | |
| Nausea | 34% | 47% | 44% | 28% |
| Diarrhea | 23% | 18% | 30% | 23% |
| Constipation | 25% | 20% | 24% | 11% |
| Vomiting | 24% | 31% | 24% | 13% |
| Discontinuation due to ADRs | 10.3% | 6.9% | 6.8% | 6.7% |
Looking Ahead
As dosage and drug options expand, GLP-1 coverage decisions are becoming less about selecting a single product and more about managing utilization across an increasingly complex class. For plan sponsors, the challenge is no longer whether GLP-1 demand will grow, but how to structure coverage, clinical criteria, and utilization controls in a way that supports access while keeping long-term costs sustainable.
The GLP-1 pipeline remains active, with seven or more additional approvals expected between 2026 and 2028.12 As competition increases, pricing dynamics may shift but benefit design, utilization management, and lifestyle modifications will remain essential tools for controlling spend.
SlateRx’s clinical team monitors the evolving pipeline, and our Pharmacy and Therapeutics (P&T) committee evaluates new therapies to guide formulary placement and utilization strategies. As GLP-1 choices multiply, the real differentiator for payers will not be access, but a thoughtful clinical strategy.
References
- Novo Nordisk. Wegovy® pill approved in the US as first oral GLP-1 for weight management. Press release. December 22, 2025. NovoNordisk.com. Accessed December 26, 2026. https://www.novonordisk.com/content/nncorp/global/en/news-and-media/news-and-ir-materials/news-details.html?id=916472.
- Eli Lilly and Company. What to know about Orforglipron oral GLP-1. Last updated December 2025. Accessed December 26, 2026. https://www.lilly.com/news/stories/what-to-know-about-orforglipron.
- Eli Lilly and Company. A Phase 2 Study of Once-Daily LY3502970 Compared With Placebo in Participants Who Have Obesity or Are Overweight With Weight-Related Comorbidities (ClinicalTrials.gov Identifier: NCT05051579). ClinicalTrials.gov. Updated 2025. Accessed December 26, 2026.
- Wegovy (semaglutide) [prescribing information]. Plainsboro, NJ: Novo Nordisk Inc; December 2025.
- Zepbound (tirzepatide) [prescribing information]. Indianapolis, IN: Lilly USA LLC; September 2025.
- U.S. Food and Drug Administration. Drugs@FDA: FDA-Approved Drugs. Accessed December 29, 2026. https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm.
- Eli Lilly and Company. Lilly’s oral GLP-1, orforglipron, delivers weight loss of up to an average of 27.3 lbs in first of two pivotal Phase 3 trials in adults with obesity. News release. August 7, 2025. Accessed December 26, 2026. https://investor.lilly.com/news-releases/news-release-details/lillys-oral-glp-1-orforglipron-delivers-weight-loss-average-273
- Wharton S, Lingvay I, Bogdanski P, et al; OASIS 4 Study Group. 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. Accessed December 29, 2026.
- Wharton S, Aronne LJ, Stefanski A, et al. Orforglipron, an oral small-molecule GLP-1 receptor agonist for obesity treatment. N Engl J Med. 2025;393(24):2368-2379. doi:10.1056/NEJMoa2511774. Accessed December 29, 2026.
- Lin GA, Lee W, Fahim SM, Richardson M, Phillips M, Raymond F, Rind DM. Semaglutide and Tirzepatide for Obesity: Effectiveness and Value; Draft Evidence Report. Institute for Clinical and Economic Review; September 9, 2025. Accessed December 29, 2026. https://icer.org/wp-content/uploads/2025/09/ICER_Obesity_Draft-Report_For-Publication_090925.pdf.
- Lin GA, Lee W, Fahim SM, Richardson M, Phillips M, Raymond F, Rind DM. Semaglutide and Tirzepatide for Obesity: Effectiveness and Value; Final Report. Institute for Clinical and Economic Review; December 16, 2025. Accessed December 29, 2026. https://icer.org/wp-content/uploads/2025/12/ICER_Obesity_Final-Report_For-Publication_121625-1.pdf.
- IPD Analytics. https://www.ipdanalytics.com/.
