What the STEP Trials Showed About Semaglutide and Weight Loss
A plain-language look at what the STEP trials — and the SELECT heart study — actually found about semaglutide (Wegovy) for weight loss: how much people lost, what happens when they stop, and where the evidence stops short.
By Wellness Wire Editorial
Over the past few years, a once-weekly injection called semaglutide has changed how doctors and patients talk about treating obesity. Most of what we know about it for weight loss comes from a family of clinical trials known as STEP — short for Semaglutide Treatment Effect in People with obesity — together with a large heart-health study called SELECT. Here is what that evidence actually shows, and where it stops short.
The higher-dose version studied for weight, semaglutide 2.4 mg, is sold as Wegovy. The U.S. Food and Drug Administration approved it for chronic weight management on June 4, 2021 — the first new obesity drug cleared since 2014 — for adults with a body mass index (BMI) of at least 30, or at least 27 alongside a weight-related condition such as high blood pressure, type 2 diabetes, or high cholesterol. It is meant to be used together with a reduced-calorie diet and increased physical activity.
What the STEP trials tested
The STEP program was a series of large clinical trials, each asking a slightly different question. One point matters for reading all of them: every STEP trial paired the drug with lifestyle changes, and so did the comparison groups. People assigned to placebo also received diet and activity support. So the results describe drug-plus-lifestyle versus placebo-plus-lifestyle — not the medication working in isolation. It is also worth knowing that nearly all of these trials, and SELECT, were funded by Novo Nordisk, the drug's manufacturer. That is standard for large phase 3 programs, but it is a relevant disclosure.
How much weight people lost
The flagship trial, STEP 1, enrolled 1,961 adults with overweight or obesity but without diabetes. After 68 weeks, the semaglutide group lost an average of 14.9% of their body weight, compared with 2.4% on placebo — a gap of about 12.4 percentage points. Put another way, 86.4% of people on the drug lost at least 5% of their weight (versus 31.5% on placebo), and roughly half reached 15% or more.
Results were even stronger when the drug was paired with intensive counseling. In STEP 3, 611 adults received a low-calorie diet plus about 30 counseling visits; the semaglutide group lost an average of 16.0% versus 5.7% on placebo, and more than a third (36.7%) lost at least 20% of their body weight, compared with under 4% on placebo. STEP 5 then followed 304 people for two full years and found the effect held up: an average loss of 15.2% versus 2.6% on placebo at 104 weeks.
The picture is more modest for people with type 2 diabetes. In STEP 2, which enrolled 1,210 such adults, semaglutide 2.4 mg reduced weight by an average of 9.6%, compared with 7.0% for a lower 1.0 mg dose and 3.4% for placebo. Weight loss tends to run somewhat smaller in people with diabetes than in those without — a consistent pattern across the research.
- STEP 1 (no diabetes)about 14.9% average weight loss versus 2.4% on placebo, over 68 weeks.
- STEP 2 (type 2 diabetes)about 9.6% versus 3.4% on placebo.
- STEP 3 (plus intensive counseling)about 16.0% versus 5.7% on placebo.
- STEP 5 (two years)about 15.2% versus 2.6% on placebo.
- STEP 8 (versus an older drug, liraglutide)about 15.8% versus 6.4%.
Why staying on it matters
One trial was designed specifically to see what happens when treatment stops. In STEP 4, everyone first took semaglutide for 20 weeks. Then 535 people continued the drug and 268 switched to placebo. Over the following weeks, those who stayed on it lost a further 7.9% of their weight, while those switched to placebo regained 6.9% — a difference of nearly 15 percentage points. The lesson researchers drew is that obesity behaves like a chronic condition: the medication manages it rather than curing it, and weight tends to return when the drug is stopped.
When treatment stopped, much of the lost weight came back — a sign that obesity behaves like a chronic condition rather than something a course of medicine cures.
Beyond the scale: heart health
Weight is not the only thing that changed. The SELECT trial tested whether semaglutide could help prevent serious heart problems. It enrolled 17,604 adults who had established cardiovascular disease and overweight or obesity but not diabetes. Over an average of about 39.8 months, major adverse cardiovascular events — defined as cardiovascular death, a nonfatal heart attack, or a nonfatal stroke — occurred in 6.5% of the semaglutide group versus 8.0% on placebo. That works out to roughly a 20% reduction in relative risk. On the strength of these results, the FDA added a cardiovascular risk-reduction indication in March 2024.
Two cautions apply. This benefit was shown specifically in people who already had heart disease along with excess weight; it does not prove the same protection for lower-risk groups. And because the drug does several things at once, the trial cannot fully separate how much of the heart benefit came from weight loss versus other effects of the medication.
Side effects and limits
The most common side effects across the STEP trials were gastrointestinal — nausea, diarrhea, vomiting, and constipation. These were generally mild to moderate and tended to fade over time, but they were far from rare: in STEP 1, about 44% of people on semaglutide reported nausea, compared with about 17% on placebo.
A few other limits are worth keeping in mind. One head-to-head trial, STEP 8, compared semaglutide with an older GLP-1 drug, liraglutide 3.0 mg, in 338 adults; semaglutide produced greater weight loss (about 15.8% versus 6.4%), and far more people reached the 15% threshold (55.6% versus 12.0%). But unlike STEP 1 through 5, STEP 8 was open-label, meaning participants and investigators knew which drug was being given — something that can influence behavior-dependent outcomes such as eating and activity. And across all of these studies, the headline numbers are averages; individual results vary widely, with some people responding far more or far less than the typical figure.
Taken together, the STEP and SELECT trials make a fairly consistent case: at the 2.4 mg dose, semaglutide plus lifestyle changes produced substantial, sustained weight loss for many people, and lowered cardiovascular risk in a specific high-risk group. The evidence also comes with honest limits — smaller effects in people with diabetes, weight regain after stopping, common digestive side effects, and manufacturer funding across the board. Those trade-offs are exactly the kind of thing worth talking through with a professional who knows your health.
- 01 STEP 1 — Wilding et al., NEJM, 2021 nejm.org ↗68-week trial in 1,961 adults with overweight/obesity without diabetes; ~14.9% mean weight loss.
- 02 STEP 2 — Davies et al., The Lancet, 2021 thelancet.com ↗68-week trial in 1,210 adults with type 2 diabetes; ~9.6% mean weight loss.
- 03 STEP 3 — Wadden et al., JAMA, 2021 jamanetwork.com ↗68-week trial adding intensive behavioral therapy in 611 adults; ~16.0% mean weight loss; 35.7% vs 3.7% reached >=20%.
- 04 STEP 4 — Rubino et al., JAMA, 2021 jamanetwork.com ↗Withdrawal-design trial (803 randomized) showing weight regain after stopping treatment.
- 05 STEP 5 — Garvey et al., Nature Medicine, 2022 pmc.ncbi.nlm.nih.gov ↗104-week trial in 304 adults; weight loss sustained (~15.2%) to two years.
- 06 STEP 8 — Rubino et al., JAMA, 2022 jamanetwork.com ↗Open-label head-to-head versus liraglutide 3.0 mg in 338 adults; semaglutide superior (~15.8% vs ~6.4%).
- 07 SELECT — Lincoff et al., NEJM, 2023 nejm.org ↗Cardiovascular outcomes trial in 17,604 adults; ~20% reduction in major adverse cardiovascular events (6.5% vs 8.0%).
- 08 FDA news release, 2021 content.govdelivery.com ↗Announcement of Wegovy (semaglutide 2.4 mg) approval for chronic weight management, first since 2014.
Wellness Wire Editorial
The Wellness Wire editorial team. Our explainers are researched from primary sources — clinical-trial reports and FDA labeling — and written for general education. They are not individually reviewed by a clinician and are not a substitute for medical advice.
