Semaglutide vs Tirzepatide, SURMOUNT-5 Weight-Loss Data

In the SURMOUNT-5 phase 3b trial, tirzepatide produced a mean -20.2% weight change at 72 weeks, compared with -13.7% for semaglutide, roughly 47% more mean weight loss from the head-to-head.¹ That is a real efficacy gap. It is not the only factor that matters, which is why this comparison covers cost, dose ladders, side effects, and the post-2025 compounded status of each drug alongside the efficacy numbers.

We cover both FDA-approved branded versions (Wegovy and Zepbound for weight management, Ozempic and Mounjaro for Type 2 diabetes) and compounded forms. Our editorial position is neutral, compounded semaglutide and compounded tirzepatide are legitimate options that many of our readers are using or considering, and we cover their current regulatory status rather than steering readers away from them. For prescribing decisions, work with a licensed clinician. For a broader comparison that includes Saxenda (liraglutide) and the off-label-for-weight-loss use of Ozempic and Mounjaro, see our guide to the best injection for weight loss in 2026.

What are semaglutide and tirzepatide?

Semaglutide and tirzepatide are both peptide therapeutics that mimic naturally occurring gut hormones. The similarity is strong enough that the two drugs are often discussed interchangeably. The mechanistic difference is real, and it is the main reason the head-to-head efficacy numbers land where they do.

Semaglutide is a GLP-1 receptor agonist

Semaglutide, developed by Novo Nordisk, binds the glucagon-like peptide-1 (GLP-1) receptor. GLP-1 is an incretin hormone released by the gut in response to food; it triggers insulin secretion, slows gastric emptying, and signals satiety to the brain. Semaglutide has been FDA-approved in multiple formats: Ozempic (injectable, for Type 2 diabetes, approved 2017), Rybelsus (oral tablet, for Type 2 diabetes, 2019), and Wegovy (injectable, for chronic weight management, 2021). Wegovy was updated in 2025 to add a 7.2 mg high-dose option and in 2025-2026 to add an oral tablet (25 mg maintenance) for cardiovascular risk reduction and weight reduction.²

Tirzepatide is a dual GLP-1 / GIP receptor agonist

Tirzepatide, developed by Eli Lilly and Company, binds both the GLP-1 receptor and the glucose-dependent insulinotropic polypeptide (GIP) receptor. GIP is a second incretin hormone with overlapping and complementary effects on insulin, appetite, and energy balance. The dual-receptor agonism is the mechanistic differentiator from semaglutide. Tirzepatide is FDA-approved as Mounjaro (for Type 2 diabetes, 2022) and Zepbound (for chronic weight management and moderate-to-severe obstructive sleep apnea in adults with obesity, 2023).³

How do semaglutide and tirzepatide compare in the SURMOUNT-5 trial?

For several years, comparisons between the two drugs had to rely on cross-trial analyses, comparing the STEP-1 semaglutide trial against the SURMOUNT-1 tirzepatide trial, which enrolled different populations and used different protocols. That changed in 2025 with the publication of SURMOUNT-5, the first large phase 3 trial to directly compare the two molecules head-to-head for weight management.

SURMOUNT-5 was a phase 3b open-label trial that randomized 751 adults with obesity (and without Type 2 diabetes) in a 1:1 ratio to the maximum tolerated dose of tirzepatide (10 mg or 15 mg) or the maximum tolerated dose of semaglutide (1.7 mg or 2.4 mg), with both administered subcutaneously once weekly for 72 weeks.¹

Results at Week 72

Source: Aronne LJ et al. SURMOUNT-5 phase 3b trial, New England Journal of Medicine 2025.¹ Least-squares mean values, intention-to-treat population, treatment-regimen estimand. ClinicalTrials.gov NCT05822830.

A few observations worth sitting with. First, the 6.5-percentage-point gap between tirzepatide and semaglutide in SURMOUNT-5 is statistically significant and clinically meaningful, but it is also a gap between two genuinely effective drugs. Semaglutide's 13.7% mean weight loss is itself far above what any non-bariatric intervention achieved before this drug class. Second, response is individual. Some patients respond better to semaglutide than tirzepatide, for reasons that are not fully predictable in advance. Third, SURMOUNT-5 was funded by Eli Lilly (which manufactures tirzepatide). That is not a reason to discount the result: phase 3 trials are run under strict protocols, and NEJM peer review is substantive. But it is a routine disclosure to note.

How do the semaglutide and tirzepatide dose ladders compare?

Both drugs use a structured dose-escalation schedule to blunt gastrointestinal side effects, which concentrate during escalation rather than after a patient reaches steady state. The ladders are different, and the maintenance options are different.

Both labels require a minimum of 4 weeks on each dose before escalation. Reaching the recommended semaglutide maintenance dose (2.4 mg) takes 17 weeks; reaching the tirzepatide maximum (15 mg) takes 21 weeks. For the full tirzepatide dose ladder, see our tirzepatide dosing guide.

Both labels explicitly permit staying at a lower maintenance dose if weight-loss response is acceptable and tolerability is marginal at higher doses. For semaglutide, the label lists 1.7 mg and 2.4 mg as acceptable maintenance doses, with 2.4 mg as the recommended target. For tirzepatide, the label lists 5 mg, 10 mg, and 15 mg as acceptable maintenance doses, three defensible landing points rather than a single target.

How much do semaglutide and tirzepatide cost in 2026?

Retail list prices for the two branded weight-loss products are in the same general range, but the cash-pay and insurance pathways differ enough to matter.

Prices reflect April 2026 reporting from manufacturer direct-to-consumer channels and third-party pricing aggregators. Verify directly with the manufacturer or provider before enrolling.

Medicare Part D does not cover either drug for weight loss by statute (the Medicare Modernization Act excludes weight-loss prescriptions). Mounjaro and Ozempic, the Type 2 diabetes indications of the same molecules, may be covered by commercial insurance or Medicare Part D depending on plan formulary. For the full breakdown on tirzepatide cost paths, see our tirzepatide cost guide.

What are the side effects of semaglutide vs tirzepatide?

Both drugs share a side-effect profile that is dominated by gastrointestinal adverse events: nausea, diarrhea, vomiting, and constipation. These symptoms are most common during dose escalation and typically decrease once a patient reaches a stable maintenance dose. In SURMOUNT-5, gastrointestinal adverse events were the most common in both treatment groups, and most were mild to moderate in severity.¹ In the STEP-1 trial of semaglutide 2.4 mg versus placebo, nausea and diarrhea were the most common adverse events, and gastrointestinal events caused treatment discontinuation in 4.5% of semaglutide patients compared with 0.8% of placebo patients.⁵

Shared safety considerations across both molecules include:

• Pancreatitis: both labels carry warnings based on postmarketing reports.
• Gallbladder disease: rapid weight loss with either drug increases risk of gallstones.
• Delayed gastric emptying: both drugs slow gastric emptying, which has generated postmarketing reports of pulmonary aspiration during surgery requiring general anesthesia. Patients on either drug should disclose it to their surgical team before any procedure.
• Oral contraceptive interaction: delayed gastric emptying can reduce oral contraceptive absorption. The Zepbound label specifically instructs patients on oral hormonal contraceptives to add a non-oral method for 4 weeks after initiation and after each dose escalation. Semaglutide has a similar gastric-emptying effect.
• Thyroid C-cell tumor risk: both drugs carry boxed warnings based on rodent data; human data is inconclusive. Neither should be used in patients with personal or family history of medullary thyroid carcinoma or MEN 2.

Rates of treatment discontinuation due to adverse events in SURMOUNT-5 were comparable between the two drugs, which is part of why the efficacy gap, rather than a safety gap, is the main differentiator in the head-to-head data. For the full adverse-reaction rate tables from the FDA-approved labels, see our spoke articles on semaglutide side effects and tirzepatide side effects.

Is compounded semaglutide or tirzepatide still available in 2026?

Both drugs had extended FDA shortage periods that allowed licensed pharmacies to produce compounded copies under Section 503A and 503B of the Federal Food, Drug, and Cosmetic Act. Both shortages resolved, and both enforcement windows closed, at different times.

Tirzepatide

The FDA declared the tirzepatide shortage resolved on December 19, 2024. After a federal court denied a preliminary injunction on March 5, 2025, state-licensed 503A pharmacies could no longer compound copies of tirzepatide. Outsourcing facilities (503B) lost their window on March 19, 2025.⁶

Semaglutide

The FDA declared the semaglutide shortage resolved on February 21, 2025. The agency provided a grace period for compounders: 503A pharmacies could continue producing copies until April 22, 2025, and 503B outsourcing facilities until May 22, 2025.⁶

What still exists after the grace periods

Both 503A and 503B pharmacies retain authority to produce personalized formulations and combination products that have a clinical difference from the commercial drug, for instance, tirzepatide combined with vitamin B12, or a custom-concentration semaglutide formulation for a specific clinical need. These are permitted under the narrower compounding pathway that applies even when no shortage exists, provided a valid patient-specific prescription supports the compounded formulation.

For readers currently on or considering compounded versions of either drug, we cover the regulatory categories, how to evaluate a compounding pharmacy, and what has actually changed in our explainer on what compounded tirzepatide is. The same regulatory framework applies to compounded semaglutide.

Should you choose semaglutide or tirzepatide?

The head-to-head data favors tirzepatide on mean weight loss, but "higher mean effect" does not automatically mean "better choice for you." A few practical framings:

• If efficacy is the priority and both drugs are accessible: SURMOUNT-5 supports tirzepatide as the higher-expected-value choice, with roughly 47% more mean weight loss at 72 weeks.
• If cost or insurance coverage differs: the cheaper accessible option is usually the right option. A drug that a patient can actually afford and refill consistently outperforms a marginally more effective drug that gets discontinued.
• If a patient has already tried one and tolerated it poorly: switching to the other is reasonable. Tolerability is not predictable from one drug to the other, and some patients do substantially better on the second drug they try.
• If a patient is considering a compounded version: the regulatory pathway is narrower for both drugs after 2025, but licensed pharmacies still produce personalized formulations. Evaluate the pharmacy's state license, 503B registration (if applicable), and pharmacist availability for questions before enrolling.
• If a patient has Type 2 diabetes as the primary indication: this article focuses on weight management; for diabetes, Ozempic and Mounjaro, the T2D-approved versions of the same molecules, are the relevant comparison. The head-to-head SURPASS-2 trial for diabetes is the equivalent of SURMOUNT-5 for weight loss.

Frequently Asked Questions

Is tirzepatide just a better version of semaglutide?

Not exactly. Tirzepatide is a structurally different molecule that agonizes a second receptor (GIP) in addition to GLP-1. In the SURMOUNT-5 head-to-head trial, it produced greater mean weight loss, but it is not a drop-in replacement. Individual response, tolerability, cost, and access all factor into the right choice for a given patient.

How long does it take to lose 20 lbs on tirzepatide versus semaglutide?

Neither drug is a rapid-loss medication. In SURMOUNT-5, the mean weight change at 72 weeks was -20.2% on tirzepatide and -13.7% on semaglutide. For a patient starting at 200 lbs, that maps to roughly 40 lbs lost on tirzepatide and 27 lbs on semaglutide over 72 weeks, with meaningful variation around the mean. Individual results vary.

Do you lose more muscle on semaglutide or tirzepatide?

Body-composition data from GLP-1 trials show that roughly 20-40% of total weight loss on either drug is lean mass, which is comparable to lean-mass losses seen in dietary weight-loss interventions. Head-to-head lean-mass comparisons between tirzepatide and semaglutide are limited. Resistance training and adequate protein intake during treatment support lean-mass retention on either drug.

Can I get compounded semaglutide or tirzepatide legally in 2026?

Direct copies of Wegovy, Ozempic, Zepbound, and Mounjaro are no longer broadly permitted after the 2025 FDA shortage resolutions. Licensed 503A and 503B pharmacies still produce personalized or combination formulations, for instance, tirzepatide with vitamin B12 or a custom-concentration semaglutide preparation, under a narrower regulatory pathway that applies even without a shortage.

Is the 7.2 mg Wegovy HD dose better than standard 2.4 mg?

The FDA approved Wegovy 7.2 mg HD in 2025 for additional weight reduction in patients who tolerate 2.4 mg for at least 4 weeks and need further reduction. Clinical studies (Studies 8 and 9 on the FDA label) showed statistically significant additional weight loss at 7.2 mg versus placebo and versus 2.4 mg over 72 weeks. The trade-off is higher exposure and a corresponding side-effect profile during the escalation to 7.2 mg.

Can I take Ozempic for weight loss instead of Wegovy?

Ozempic is FDA-approved only for Type 2 diabetes, not for weight management. Prescribing Ozempic off-label for weight loss happens clinically, but insurance typically will not cover Ozempic for a non-diabetic patient, and the Wegovy savings card does not apply to Ozempic. Wegovy is the on-label choice for weight management; Zepbound is the tirzepatide equivalent.

Is one drug safer than the other long-term?

Long-term safety data on both drugs continues to accumulate. Both share the same class-level safety signals: pancreatitis, gallbladder disease, delayed gastric emptying, and thyroid C-cell tumor warnings from rodent data. Neither drug has been in broad clinical use for long enough to fully characterize 10+ year outcomes. Routine monitoring with a prescriber is standard on either drug.

The Bottom Line

In the first published head-to-head trial, tirzepatide produced about 47% more mean weight loss than semaglutide at 72 weeks. That is a real and clinically meaningful advantage. It is not the only variable that matters, cost, insurance coverage, tolerability, availability of a compounded version, and whether the patient has already tried one drug and responded poorly all shape the right choice for a given person. For most weight-management patients who can access either drug equally, SURMOUNT-5 favors tirzepatide. For patients where access, cost, or tolerability differs, the answer is less clear-cut and should be worked out with a prescriber.

Before starting, switching, or stopping either drug, talk to a licensed clinician. For deeper coverage of each drug individually, see our tirzepatide hub and related articles on tirzepatide cost, tirzepatide dosing, and compounded tirzepatide.