SURMOUNT-5: What the Zepbound vs Wegovy Head-to-Head Trial Actually Means

SURMOUNT-5 was a Phase 3b randomized, open-label clinical trial that directly compared tirzepatide (Zepbound) and semaglutide (Wegovy) for chronic weight management in 751 adults with obesity but without type 2 diabetes. Published in the New England Journal of Medicine in 2025, it was the long-awaited answer to the question patients, doctors, and insurance companies had been asking since both drugs hit the market: which one actually works better when you put them side by side?

Participants were randomly assigned to receive either weekly tirzepatide (titrated to the maximum tolerated dose of 10 or 15 mg) or weekly semaglutide (titrated to the maximum tolerated dose of 1.7 or 2.4 mg). Both groups received the same lifestyle counseling and the trial ran for 72 weeks. Unlike earlier SURMOUNT and STEP trials, which compared each drug to placebo separately, SURMOUNT-5 was the first apples-to-apples comparison — and it settled the debate that our [tirzepatide vs semaglutide article](/blog/tirzepatide-vs-semaglutide-comparison-2026) had to estimate from indirect data.

Zepbound delivered an average weight loss of 20.2% of body weight, compared to 13.7% for Wegovy — a 47% relative difference and a 6.5 percentage-point absolute difference. For a 220-pound starting weight, that translates to roughly 44 pounds lost on Zepbound versus 30 pounds on Wegovy. The gap was consistent across age, sex, baseline BMI, and starting weight subgroups.

Where the difference becomes really striking is at the high end of response. 31.6% of Zepbound users lost 25% or more of body weight, compared to only 16.1% on Wegovy — nearly double the rate of dramatic responders. And 56.7% of Zepbound users hit the 20% weight loss threshold versus 36.5% on Wegovy. These are clinically meaningful differences: dropping from 25% to 20% body weight loss can mean the difference between resolving sleep apnea and just improving it, or going off blood pressure medication versus reducing the dose.

Side effect profiles were broadly similar between the two drugs, with gastrointestinal symptoms — nausea, diarrhea, constipation, vomiting — dominating both groups. Nausea occurred in 44% of Zepbound users vs 50% of Wegovy users, surprisingly slightly higher on semaglutide. Diarrhea affected 26% of Zepbound users vs 24% on Wegovy. Constipation was reported by 19% on Zepbound and 17% on Wegovy. Most events were mild to moderate, and serious adverse events were rare and balanced between groups.

Discontinuation rates due to adverse events were also similar: 6.1% on Zepbound and 8.0% on Wegovy stopped treatment because of side effects. So while many patients assume tirzepatide is rougher because the molecule hits two receptors, the data doesn't support that. If you're tolerating Wegovy poorly, a switch to Zepbound isn't automatically going to be worse — and the steeper weight loss curve may be worth trying. For specific symptom management, our guides on [GLP-1 constipation](/blog/glp1-constipation-what-actually-works) and [sulfur burps](/blog/glp1-sulfur-burps-rotten-egg-taste-causes-fixes) cover practical fixes for both drugs.

No — Wegovy still has important advantages that SURMOUNT-5 didn't address. Most importantly, Wegovy is the only GLP-1 with an FDA-approved cardiovascular risk reduction indication based on the SELECT trial (Lincoff et al., NEJM 2023), which showed a 20% reduction in major adverse cardiovascular events in adults with overweight or obesity and established cardiovascular disease. Zepbound's analogous trial (SURMOUNT-MMO) is still running. For patients with a history of heart attack or stroke, Wegovy has the harder data.

Wegovy also has more long-term safety data — semaglutide has been on the market since 2017 in its diabetes formulation (Ozempic), giving us nearly a decade of post-market safety signals. Tirzepatide was approved in 2022. And insurance coverage still differs: some employer plans cover one but not the other, and the [GLP-1 insurance landscape](/blog/glp-1-insurance-coverage-2026-complete-guide) changes constantly. Finally, semaglutide is currently available in an oral form (Rybelsus) for type 2 diabetes, and an oral weight-loss version is in trials — tirzepatide has no oral option yet.

If you're losing weight steadily on Wegovy and feeling well, there's usually no reason to switch. SURMOUNT-5's average numbers don't predict your personal trajectory — some Wegovy responders lose 25% or more, and some Zepbound users plateau early. The trial's power was in showing that, on average across hundreds of people, tirzepatide outperformed. It doesn't say tirzepatide will outperform for you specifically.

Consider switching if you've plateaued for more than 3 months on the maximum tolerated Wegovy dose, if you've hit less than 5% weight loss after 6 months at therapeutic dose, or if you have significant residual weight to lose and are tolerating Wegovy well (a switch is more likely to be tolerated). Our guide on [switching from Wegovy to Zepbound](/blog/switching-from-wegovy-to-zepbound-when-and-how) walks through the timing, dose conversion, and what to expect. Always make the decision with your prescriber — and remember that insurance coverage often dictates feasibility more than the science does.

SURMOUNT-5 didn't stratify results by menopausal status, but a growing body of [research on GLP-1 in menopause](/blog/hrt-and-glp-1-combination-therapy-menopause-weight-loss) suggests that women navigating perimenopause and postmenopause may need slightly more aggressive medication strategies because of the visceral fat redistribution, sarcopenia risk, and metabolic slowdown that accompany hormonal change. The Weill Cornell observational data showed that postmenopausal women on tirzepatide combined with HRT had the best body composition outcomes — preserving lean mass while losing fat at higher rates than either intervention alone.

If you're in midlife and considering between Zepbound and Wegovy, the tirzepatide edge in body weight loss could matter even more — but so does the lean-mass preservation question, which the SURMOUNT-5 trial measured only with DXA in a subset. Early signals suggest both drugs preserve similar lean mass percentages, but the higher absolute weight loss on Zepbound means more total lean mass at risk if you're not [training for muscle preservation](/blog/exercise-on-glp1-during-menopause-dual-loss-prevention) and [hitting protein targets in menopause](/blog/protein-needs-on-glp-1-during-menopause-sarcopenia-strategy).

SURMOUNT-5 changes the conversation but doesn't replace individualized care. Bring these questions to your next appointment: What's my realistic target weight loss range based on my starting weight and health history? Given my cardiovascular risk profile, does the SELECT trial data on Wegovy change your recommendation? If insurance only covers one drug, are there compounded or coupon pathways for the other? How will we monitor lean mass and bone density if I'm in perimenopause or postmenopause? What's the plan if I plateau before reaching my goal?

A prescriber who has been following the GLP-1 literature should be comfortable answering all of these. If yours isn't, that's a signal to consider a [telehealth provider that specializes in obesity medicine](/blog/glp-1-insurance-coverage-2026-complete-guide). The drugs are powerful tools, but they work best when they're chosen and titrated to your specific story.