A higher semaglutide dose meant more weight loss in STEP UP, but tripling the dose didn't triple the result. The STEP UP trial results showed average losses of 18.7% with 7.2 mg, 15.6% with 2.4 mg, and 3.9% with placebo over 72 weeks.
That extra weight loss came with more stomach symptoms and unusual skin sensations. These are group averages, not a forecast for one person.
What STEP UP asked, and who joined
The question was straightforward: would weekly semaglutide 7.2 mg produce more weight loss than 2.4 mg, and how would side effects compare?
The 2025 paper in The Lancet Diabetes & Endocrinology enrolled 1,407 adults with obesity and without diabetes. Participants were at least 18. Their average age was 47, and about three-quarters were women.
Eligibility required a BMI of at least 30. BMI is a measure based on height and weight; the group's average was 39.9. Participants also reported an earlier unsuccessful attempt to lose weight through diet.
The trial registry, NCT05646706, lists the eligibility rules. These excluded diabetes, recent glucose-lowering medicines, and a weight change greater than 5 kg during the preceding 90 days.
Researchers assigned people by chance: 1,005 to 7.2 mg, 201 to 2.4 mg, and 201 to placebo, an injection without active medicine. Neither participants nor study staff knew the assignments.
Treatment lasted 72 weeks. Doses rose over 20 weeks; the higher-dose group moved directly from 2.4 mg to 7.2 mg. All groups received food and activity counseling. This wasn't specifically a study of people whose weight loss had stalled on 2.4 mg.
What the researchers measured
The primary endpoints, meaning the main outcomes chosen beforehand, were percentage weight change and the share losing at least 5%. Researchers compared 7.2 mg with placebo for both. Comparing weight change between the two active doses was another planned test.
The paper used two estimands: two precisely defined versions of the treatment question.
- Treatment policy estimand: What happened after assignment, including people who stopped treatment, reduced their dose, or used another weight-management treatment?
- Trial product estimand: What would happen if everyone stayed on the assigned treatment without another weight-management treatment?
The second answer is a statistical estimate under those assumptions. It isn't simply an average of the people who finished. Missing measurements also required statistical estimates.
The estimand explainer shows why these questions can produce different headlines from the same trial.
STEP UP trial results at 72 weeks
The main analysis found 18.7% average weight loss with 7.2 mg, compared with 3.9% with placebo. The higher dose added 3.1 percentage points of loss compared with 2.4 mg.
A percentage point is the gap between two percentages. Here, it describes the difference between group averages, rather than a prediction of extra loss after switching doses.
| Analysis | Semaglutide 7.2 mg | Semaglutide 2.4 mg | Placebo |
|---|---|---|---|
| Treatment policy estimand | −18.7% | −15.6% | −3.9% |
| Trial product estimand | −20.7% | −17.5% | −2.4% |
Minus signs mean weight decreased. Each result measures change from the person's starting weight.
About half of the higher-dose group with a week-72 measurement lost at least one-fifth of their starting weight. The paper's Table 2 reports these proportions:
| Weight lost by week 72 | 7.2 mg | 2.4 mg | Placebo |
|---|---|---|---|
| At least 5% | 90.7% | 89.9% | 36.8% |
| At least 10% | 82.4% | 75.1% | 20.5% |
| At least 15% | 66.5% | 54.5% | 7.6% |
| At least 20% | 47.7% | 33.3% | 2.9% |
| At least 25% | 31.2% | 15.3% | 0.0% |
These are observed proportions among 950, 189, and 171 people with measurements, respectively. They include measurements after treatment stopped. They aren't percentages of all 1,407 originally assigned participants.
The earlier STEP 1 results provide the background for the 2.4 mg dose.
Side effects at the higher dose
Stomach and bowel problems affected about seven in ten people on 7.2 mg. Gastrointestinal, or GI, means involving the stomach and intestines. Nausea, vomiting, diarrhea, and constipation were common examples.
Dysaesthesia means unusual skin sensations, such as sensitivity, tingling, or burning. About one in four people on 7.2 mg reported these symptoms, compared with about one in seventeen on 2.4 mg.
The paper's Table 3 reports:
| Recorded health event | 7.2 mg | 2.4 mg | Placebo |
|---|---|---|---|
| GI problems | 70.8% | 61.2% | 42.8% |
| Dysaesthesia | 22.9% | 6.0% | 0.5% |
| Serious adverse events | 6.8% | 10.9% | 5.5% |
| Events causing permanent treatment discontinuation | 5.4% | 4.0% | 1.0% |
An adverse event is a health problem recorded during a study, whether or not the medicine caused it. Serious events include problems requiring hospitalization. Safety calculations used 1,004 people on 7.2 mg and 201 in each other group.
Most GI symptoms were mild or moderate and temporary. Most skin-sensation events were mild, none were serious, and most affected participants recovered by the trial's end.
What critics and later analyses add
Novo Nordisk funded the trial. Its size and random assignment help answer the weight-loss question, but 72 weeks cannot settle every long-term outcome.
In an accompanying commentary, Naveed Sattar and Michael Lean questioned whether higher-dose semaglutide would add protection against heart disease. Greater weight loss alone doesn't establish that benefit.
As of September 30, 2026, the day this article was written, a September 29 conference presentation had examined blood pressure. This was a post hoc analysis, meaning an additional analysis beyond the original trial plan. Assuming continued treatment, the top blood-pressure number fell an estimated 10.9 points with 7.2 mg, 9.4 with 2.4 mg, and 4.1 with placebo. The difference between the active doses remained uncertain. These readings don't establish fewer heart attacks or strokes.
Where tirzepatide fits
Tirzepatide is another weight-management medicine, but STEP UP didn't compare it with semaglutide. The direct SURMOUNT-5 trial, published in the New England Journal of Medicine in 2025, used semaglutide doses up to 2.4 mg, not 7.2 mg.
As of September 30, 2026, the day this article was written, Lilly had released a comparison using separate trials. Our Zepbound versus Wegovy HD explainer walks through that September 29 analysis.
What this means for a prescription
As of September 30, 2026, the day this article was written, the FDA's March 19, 2026 decision had added Wegovy HD, a 7.2 mg injection, for adult weight management.
The current Wegovy prescribing information says “Revised: 6/2026.” For adults needing further weight reduction, it allows a maximum of 7.2 mg injected under the skin once weekly. That option follows at least four weeks tolerating 2.4 mg and requires a clinical reason for additional weight reduction. The prescriber sets the actual dose.
STEP UP studied the trial's semaglutide product. It cannot establish the same results for a compounded version, a medicine prepared by a pharmacy for an individual prescription.
Semaglutide prescribed through Promise is dispensed by a licensed U.S. compounding pharmacy as a compounded medication, which is different from an FDA-approved product: the formulation offered here is not FDA-approved. The FDA explains that compounded drugs do not undergo its review before marketing.
A licensed provider may still prescribe a compounded formulation; that decision is between the patient and the doctor. At Promise, a licensed provider reviews every request, and not everyone qualifies.
