GLP-1 Weight-Loss Evidence: What the Clinical Trials Actually Show (2026)

Almost every page that sells you a GLP-1 quotes a single number — “lose up to 22.5% of your body weight” — and stops there. That number is real, but it comes from one dose, in one trial, measured one specific way, in people who were not buying a compounded copy online. This guide is the version with the footnotes left in: what the major trials measured, how big the effects actually were, where the evidence is strong, and where it genuinely runs out. Every figure below is attributed to its primary source so you can check it yourself.

The quick answer

In head-to-head and placebo-controlled trials, tirzepatide produced larger average weight loss than semaglutide. At their top studied doses over roughly 17 months, tirzepatide drove average reductions in the low-20% range and semaglutide in the mid-teens. Those results come from the branded molecules (Zepbound, Wegovy, Mounjaro, Ozempic) studied under FDA trial conditions. Compounded semaglutide and tirzepatide have never been tested in their own clinical trials — the pharmacology is the same molecule, but the finished compounded product’s potency, purity, and consistency are not what the trials measured. That distinction is the single most important thing on this page.

What the pivotal obesity trials measured

SURMOUNT-1 — tirzepatide

The trial behind the “22.5%” headline is SURMOUNT-1, published in The New England Journal of Medicine in 2022 (Jastreboff et al.). It randomized 2,539 adults with obesity, or overweight with a weight-related complication and without type 2 diabetes, to once-weekly tirzepatide at 5 mg, 10 mg, or 15 mg, or placebo, for 72 weeks.

By the efficacy estimand — the analysis that estimates the effect if people stay on the drug as directed — average weight reductions were 16.0% at 5 mg, 21.4% at 10 mg, and 22.5% at 15 mg, versus 2.4% on placebo. In pounds, that is roughly 35, 49, and 52 lb at the three doses. By the more conservative treatment-regimen estimand, which counts people who stopped the drug or used rescue therapy, the 15 mg figure was about 20.9%. Both numbers are correct; they answer slightly different questions. The trial also reported that about 40% of people on 15 mg lost at least a quarter of their body weight, and that fat mass fell roughly three times more than lean mass.

STEP-1 — semaglutide

The comparable semaglutide trial is STEP-1 (Wilding et al., NEJM 2021). Once-weekly semaglutide 2.4 mg produced an average weight reduction of 14.9% over 68 weeks in adults with obesity or overweight without diabetes, against about 2.4% on placebo. This is the trial that earned Wegovy its obesity indication, and 14.9% is the number to anchor on for semaglutide monotherapy.

SURPASS-2 — the diabetes comparison

In type 2 diabetes, SURPASS-2 (Frías et al., NEJM 2021) compared tirzepatide against semaglutide 1 mg — note, the diabetes dose of semaglutide, not the 2.4 mg obesity dose — and found greater A1C and weight reduction with tirzepatide. It is frequently miscited as a clean obesity head-to-head. It is not; the semaglutide arm was dosed for glycemic control, and the population had diabetes.

The head-to-head that settled the comparison: SURMOUNT-5

For years the tirzepatide-versus-semaglutide question was answered by comparing separate trials, which is statistically shaky. SURMOUNT-5 (Aronne et al., NEJM, May 2025) was the first direct, randomized comparison in obesity. It enrolled 751 adults with obesity or overweight-plus-a-comorbidity and without diabetes, and ran each drug to its maximum tolerated dose (tirzepatide 10 or 15 mg; semaglutide 1.7 or 2.4 mg) for 72 weeks.

The result: average weight reduction of 20.2% with tirzepatide versus 13.7% with semaglutide by the treatment-regimen estimand — a 47% greater relative weight loss. About 31.6% of the tirzepatide group lost at least a quarter of their body weight, versus 16.1% of the semaglutide group. Safety profiles were consistent with prior trials, with gastrointestinal effects the most common adverse events for both. The Weill Cornell investigators noted the outcome nearly matched what the independent trials had each shown years earlier — a reassuring sign that the separate-trial comparisons had been roughly right.

The practical reading: tirzepatide tends to deliver more weight loss on average, but semaglutide’s mid-teens result is still a large, clinically meaningful effect, and individual response varies widely. “More average weight loss” is not the same as “the right drug for you.”

Does the weight stay off?

The honest answer is: only while the underlying treatment and habits continue. A three-year analysis of SURMOUNT-1 presented at the 2025 European Congress on Obesity reported that roughly two-thirds of participants had regained 5% or less of their lowest (“nadir”) weight at three years on continued tirzepatide. Separately, withdrawal trials of both molecules have consistently shown that a substantial share of lost weight returns over the year after stopping. GLP-1 therapy behaves like a treatment for a chronic condition, not a time-limited course — a fact with obvious cost consequences, since “for as long as it works” can mean years.

Beyond the scale: cardiovascular and metabolic outcomes

Weight is a surrogate; what patients and clinicians ultimately care about is health outcomes. Here the branded semaglutide evidence is notably strong. The SELECT trial (Lincoff et al., NEJM 2023) followed more than 17,000 adults with cardiovascular disease and overweight or obesity, without diabetes, and found that semaglutide 2.4 mg reduced the risk of major adverse cardiovascular events — cardiovascular death, heart attack, or stroke — by about 20% versus placebo. That is an outcomes benefit, not just a weight benefit, and it is part of why these drugs are treated as cardiometabolic therapies rather than cosmetic ones. Tirzepatide’s dedicated cardiovascular-outcomes trial (SURMOUNT-MMO) is ongoing; its cardiometabolic risk-factor improvements (blood pressure, lipids, glycemia) are well documented, but the hard-outcome cardiovascular data are not yet mature.

What the trials say about side effects

Across SURMOUNT, STEP, and SURPASS, the dominant adverse events were gastrointestinal — nausea, diarrhea, vomiting, and constipation — usually mild to moderate, concentrated during dose escalation, and the leading reason people discontinued. Labeling for both molecules carries a boxed warning regarding thyroid C-cell tumors based on rodent studies, and contraindicates use in people with a personal or family history of medullary thyroid carcinoma or MEN 2. Pancreatitis, gallbladder events, and (with rapid loss) lean-mass reduction are recognized considerations. None of this is exotic, but “the molecule is well studied” should not be read as “risk-free.”

The part the sales pages skip: compounded versions were never in these trials

Every figure above comes from the FDA-approved branded products manufactured by Novo Nordisk and Eli Lilly under trial conditions. Compounded semaglutide and tirzepatide contain the same active molecule, so the pharmacology should be similar — but a compounded vial is a different finished product, and there are no Phase 3 trials of compounded formulations. The gaps that matter:

Potency and purity vary by pharmacy. The trials used a single, tightly controlled manufactured product. A compounded preparation’s actual delivered dose depends on the compounder’s processes.
Salt forms differ. Some compounders have used semaglutide salt forms (sodium, acetate) that are not the form in the approved drugs and whose safety and efficacy are not established.
Adverse events have been reported. As of early 2025, the FDA had logged more than 455 adverse-event reports tied to compounded semaglutide and more than 320 for compounded tirzepatide, with several involving dosing errors from self-measured multidose vials.

This does not make every compounded product unsafe, and many patients have used reputable 503A pharmacies without incident. It means the trial results are evidence about the molecule, and the quality of the specific product in front of you is a separate question you have to verify — pharmacy name and license, a named prescriber, third-party testing, and no “research use only” labeling. (See our provider verification checklist.)

The 2026 regulatory reality

The evidence discussion now sits inside a closing regulatory window. The FDA declared the tirzepatide shortage resolved in late 2024 and the semaglutide shortage resolved in February 2025, which ended the shortage-based pathway that had allowed widespread “essentially a copy” compounding. Then, on April 30, 2026, the FDA proposed excluding semaglutide, tirzepatide, and liraglutide from the 503B outsourcing-facility bulks list, finding no clinical need for large-scale bulk compounding when approved products are available (Federal Register, 91 Fed. Reg. 23431; public comment open through June 29, 2026). Patient-specific 503A compounding remains legally available but is narrower and constrained by the “essentially a copy” provision. The likely direction of travel is less mass-compounded supply, not more. Our 2026 legal-status explainer tracks the details.

How to read any GLP-1 claim you see online

Ask which drug and which dose. “Up to 22.5%” is tirzepatide 15 mg, not a generic GLP-1 result and not a semaglutide result.
Ask which estimand. Efficacy-estimand numbers run a couple of points higher than treatment-regimen numbers. Reputable sources say which they mean.
Ask whether it is the branded trial or the compounded product. The trials studied the brand. Your compounded vial was not in the study.
Ask about duration. Most loss accrues over 60–72 weeks of escalating dose, not in the first month, and reverses after stopping.
Separate average from individual. Trial averages hide a wide spread; some people lose far more, some far less.

Sources

Jastreboff AM, et al. Tirzepatide Once Weekly for the Treatment of Obesity (SURMOUNT-1). N Engl J Med. 2022.
Wilding JPH, et al. Once-Weekly Semaglutide in Adults with Overweight or Obesity (STEP-1). N Engl J Med. 2021.
Frías JP, et al. Tirzepatide versus Semaglutide Once Weekly in Type 2 Diabetes (SURPASS-2). N Engl J Med. 2021.
Aronne LJ, et al. Tirzepatide as Compared with Semaglutide for the Treatment of Obesity (SURMOUNT-5). N Engl J Med. 2025.
Lincoff AM, et al. Semaglutide and Cardiovascular Outcomes in Obesity without Diabetes (SELECT). N Engl J Med. 2023.
U.S. FDA. Proposal to exclude semaglutide, tirzepatide, and liraglutide from the 503B bulks list. Federal Register, 91 Fed. Reg. 23431 (May 1, 2026); comment period through June 29, 2026.

Educational content, not medical advice. Compounded semaglutide and tirzepatide are not FDA-approved and are not the same as Wegovy, Ozempic, Zepbound, or Mounjaro. Talk to a licensed clinician before starting, stopping, or changing any medication. Trial figures are reported as published; individual results vary.