Semaglutide Weight Loss Trials: STEP Study Breakdown
The STEP (Semaglutide Treatment Effect in People with obesity) program is one of the largest clinical trial programs ever conducted for an anti-obesity medication.
The STEP (Semaglutide Treatment Effect in People with obesity) program is one of the largest clinical trial programs ever conducted for an anti-obesity medication. Spanning more than a dozen trials and thousands of participants, it built the evidence base that transformed semaglutide from a diabetes drug into one of the most prescribed weight-loss medications in the world.
This article breaks down each major STEP trial individually --- study design, participant populations, weight-loss outcomes, safety signals, and what the data actually shows when you look beyond the headlines.
Table of Contents
- How the STEP Program Works
- STEP 1: The Landmark Trial
- STEP 2: Weight Loss in Type 2 Diabetes
- STEP 3: Adding Intensive Behavioral Therapy
- STEP 4: What Happens When You Stop
- STEP 5: Two-Year Durability Data
- STEP 8: Head-to-Head Against Liraglutide
- STEP UP: The Higher Dose
- The SELECT Trial: Cardiovascular Outcomes
- Side-by-Side Comparison of All STEP Trials
- Limitations and Things the Headlines Miss
- FAQ
- The Bottom Line
- References
How the STEP Program Works
Every trial in the STEP program tested subcutaneous semaglutide 2.4 mg (the dose marketed as Wegovy) administered once weekly. The newer STEP UP trial also tested a higher 7.2 mg dose. Each trial addressed a different clinical question: Does semaglutide work in people without diabetes? With diabetes? Alongside intensive therapy? What happens when you discontinue it? How does it compare to other GLP-1 drugs?
All trials were sponsored by Novo Nordisk, the manufacturer of semaglutide. All included some form of lifestyle intervention alongside the drug. And all used similar endpoints: percentage change in body weight from baseline and proportion of participants achieving at least 5% weight loss.
Understanding this shared framework matters because it lets you compare results across trials while accounting for the differences in populations and designs.
STEP 1: The Landmark Trial
STEP 1 was the trial that put semaglutide on the weight-loss map. Published in the New England Journal of Medicine in February 2021, it provided the primary efficacy data that led to FDA approval of Wegovy [1].
Study Design
- Population: 1,961 adults with BMI of 30 or greater (or 27+ with at least one weight-related condition) without diabetes
- Randomization: 2:1 ratio to semaglutide 2.4 mg or placebo
- Duration: 68 weeks
- Lifestyle intervention: Counseling on diet (500 kcal/day deficit) and physical activity (150 min/week)
- Primary endpoints: Percentage change in body weight; proportion achieving at least 5% weight loss
Results
The numbers were striking by the standards of obesity pharmacotherapy:
| Outcome | Semaglutide 2.4 mg | Placebo |
|---|---|---|
| Mean weight loss | -14.9% | -2.4% |
| Absolute weight loss | -15.3 kg (33.7 lb) | -2.6 kg (5.7 lb) |
| Achieved 5%+ loss | 86.4% | 31.5% |
| Achieved 10%+ loss | 69.1% | 12.0% |
| Achieved 15%+ loss | 50.5% | 4.9% |
The estimated treatment difference was -12.4 percentage points (95% CI, -13.4 to -11.5; P<0.001).
Safety
Gastrointestinal side effects were the most common issue. Nausea affected 44.2% of the semaglutide group versus 17.4% on placebo. Diarrhea hit 31.5% versus 15.9%. These events were mostly mild to moderate and tended to occur during the dose-escalation phase. About 4.5% of semaglutide participants discontinued due to GI side effects, compared to 0.8% on placebo [1].
What This Means
STEP 1 established that semaglutide 2.4 mg could produce weight loss in the range of 15% --- a figure that had previously been achievable only through bariatric surgery. But the participants were carefully selected: no diabetes, mostly women (74%), mostly white (75%), and motivated enough to enroll in a clinical trial with regular follow-up visits. Real-world results may differ.
STEP 2: Weight Loss in Type 2 Diabetes
People with type 2 diabetes typically lose less weight on any intervention compared to those without diabetes. STEP 2 was designed to quantify semaglutide's effect in this harder-to-treat population [2].
Study Design
- Population: 1,210 adults with BMI of 27+ and type 2 diabetes (HbA1c 7--10%)
- Randomization: 1:1:1 to semaglutide 2.4 mg, semaglutide 1.0 mg (the standard diabetes dose), or placebo
- Duration: 68 weeks
- Sites: 149 outpatient clinics across 12 countries
Results
| Outcome | Semaglutide 2.4 mg | Semaglutide 1.0 mg | Placebo |
|---|---|---|---|
| Mean weight loss (ITT) | -9.6% | -7.0% | -3.4% |
| Mean weight loss (per-protocol) | -10.6% | -7.5% | -3.1% |
| Achieved 5%+ loss | 68.8% | 57.1% | 28.5% |
The treatment difference for the 2.4 mg dose versus placebo was -6.2 percentage points (95% CI, -7.3 to -5.2; P<0.0001).
Safety
GI adverse events occurred in 63.5% of the 2.4 mg group, 57.5% of the 1.0 mg group, and 34.3% of the placebo group. These were mostly mild to moderate [2].
What This Means
Weight loss of 9.6% in people with type 2 diabetes is significant --- it exceeds what most other anti-obesity medications achieve in this population. But it's notably lower than the 14.9% seen in STEP 1 participants without diabetes. This gap is consistent with what researchers see across all obesity treatments: the metabolic changes associated with type 2 diabetes make weight loss harder. The 2.4 mg dose did outperform the 1.0 mg diabetes dose, supporting the higher dose for weight management in this group.
STEP 3: Adding Intensive Behavioral Therapy
A natural question: does pairing semaglutide with a more aggressive lifestyle program produce even better results? STEP 3 tested exactly that [3].
Study Design
- Population: 611 adults with BMI of 30+ (or 27+ with comorbidities), without diabetes
- Randomization: 2:1 to semaglutide 2.4 mg or placebo
- Duration: 68 weeks
- Lifestyle intervention: Low-calorie diet (1,000--1,200 kcal/day using meal replacements) for the first 8 weeks, plus 30 behavioral counseling sessions over 68 weeks
- Key difference from other STEP trials: Much more intensive behavioral support
Results
| Outcome | Semaglutide 2.4 mg | Placebo |
|---|---|---|
| Mean weight loss | -16.0% | -5.7% |
| Achieved 5%+ loss | 86.6% | 47.6% |
| Achieved 10%+ loss | 75.3% | 27.0% |
| Achieved 15%+ loss | 55.8% | 13.2% |
The treatment difference was -10.3 percentage points (P<0.001). GI adverse events were reported in 82.8% of semaglutide participants versus 63.2% on placebo [3].
What This Means
The semaglutide group lost slightly more weight here (16.0%) than in STEP 1 (14.9%), but the placebo group also lost more (5.7% versus 2.4%), reflecting the intensive behavioral component. The net drug effect --- the difference between semaglutide and placebo --- was actually smaller in STEP 3 (10.3 points) than in STEP 1 (12.4 points). This suggests that intensive behavioral therapy adds some benefit but doesn't dramatically amplify what the drug does on its own. For most people, the standard lifestyle counseling paired with semaglutide gets you most of the way there.
STEP 4: What Happens When You Stop
This was arguably the most clinically important trial in the program. STEP 4 used a withdrawal design to answer the question everyone wanted answered: does the weight come back when you stop the drug [4]?
Study Design
- Population: 902 adults with BMI of 30+ (or 27+ with comorbidities), without diabetes
- Phase 1 (run-in): All participants received semaglutide 2.4 mg for 20 weeks
- Phase 2 (randomization): 803 completers were randomized 1:1 to continue semaglutide or switch to placebo for 48 more weeks
- Total duration: 68 weeks
Results
During the 20-week run-in, participants achieved a mean weight loss of -10.6%. After randomization:
| Outcome (Weeks 20--68) | Continued Semaglutide | Switched to Placebo |
|---|---|---|
| Further weight change | -7.9% (additional loss) | +6.9% (regain) |
| Total weight loss at week 68 | -17.4% | -5.0% (net, after regain) |
The difference between groups from randomization to week 68 was -14.8 percentage points (95% CI, -16.0 to -13.5; P<0.001) [4].
The STEP 1 Extension Data
A follow-up extension of STEP 1 tracked participants for one year after stopping treatment. The findings were sobering: participants regained approximately two-thirds of the weight they had lost. At week 120 (one year after treatment ended), only 48.2% still maintained at least 5% weight loss from baseline, down from 86.4% at the end of active treatment [5].
What This Means
STEP 4 provided the clearest evidence that semaglutide-driven weight loss requires continued treatment. This is consistent with how obesity works as a chronic condition --- stopping medication leads to weight regain, similar to how stopping blood pressure medication leads to blood pressure rising again. The trial didn't test whether a lower maintenance dose could sustain results, which remains an open question.
STEP 5: Two-Year Durability Data
STEP 5 was the longest trial in the initial STEP program, running for a full 104 weeks (two years) to test whether weight loss holds up over time with continued treatment [6].
Study Design
- Population: 304 adults with BMI of 30+ (or 27+ with comorbidities), without diabetes
- Randomization: 1:1 to semaglutide 2.4 mg or placebo
- Duration: 104 weeks (2 years)
- Completion rate: 92.8%
Results
| Outcome at Week 104 | Semaglutide 2.4 mg | Placebo |
|---|---|---|
| Mean weight loss | -15.2% | -2.6% |
| Mean weight loss (on-treatment) | -16.7% | -0.6% |
| Achieved 5%+ loss | 77.1% | 34.4% |
The treatment difference was -12.6 percentage points (95% CI, -15.3 to -9.8; P<0.0001).
Notably, weight loss at week 52 (-15.6%) and week 104 (-15.2%) were nearly identical, showing minimal regain over the second year [6].
What This Means
STEP 5 delivered reassuring news about durability. With continued treatment, the weight loss achieved by one year was maintained through two years with only marginal drift. The -15.2% at two years was remarkably close to the -14.9% seen at 68 weeks in STEP 1. This supports the model of semaglutide as a long-term treatment --- not a short-term intervention.
STEP 8: Head-to-Head Against Liraglutide
Before semaglutide, liraglutide 3.0 mg (Saxenda) was the leading GLP-1 receptor agonist for weight management. STEP 8 was the first head-to-head comparison between these two drugs [7].
Study Design
- Population: 338 adults with BMI of 30+ (or 27+ with comorbidities), without diabetes
- Randomization: 3:1:3:1 to semaglutide 2.4 mg, semaglutide placebo, liraglutide 3.0 mg, or liraglutide placebo
- Duration: 68 weeks
- Design: Open-label between drugs (due to different dosing schedules), double-blinded within each drug versus its placebo
Results
| Outcome | Semaglutide 2.4 mg | Liraglutide 3.0 mg | Pooled Placebo |
|---|---|---|---|
| Mean weight loss | -15.8% | -6.4% | -1.9% |
| Achieved 10%+ loss | 70.9% | 25.6% | -- |
| Achieved 15%+ loss | 55.6% | 12.0% | -- |
| Achieved 20%+ loss | 38.5% | 6.0% | -- |
The difference between semaglutide and liraglutide was -9.4 percentage points (95% CI, -12.0 to -6.8; P<0.001). Semaglutide participants were 6 to 8 times more likely to achieve major weight-loss thresholds [7].
Safety
GI adverse events were similar between drugs (84.1% with semaglutide, 82.7% with liraglutide). However, more liraglutide participants discontinued treatment (27.6%) compared to semaglutide (13.5%), possibly due to liraglutide's daily injection requirement versus semaglutide's weekly dosing [7].
What This Means
STEP 8 settled the question of whether semaglutide represented a genuine advance over its predecessor. It did --- producing roughly 2.5 times the weight loss with a more convenient once-weekly dosing schedule and better adherence. This trial effectively established semaglutide as the new standard of care among GLP-1 therapies for weight management.
STEP UP: The Higher Dose
Published in The Lancet Diabetes & Endocrinology in September 2025, STEP UP tested whether a higher dose of semaglutide (7.2 mg) could push results further [8].
Study Design
- Population: 1,407 adults with BMI of 30+, without diabetes
- Randomization: 5:1:1 to semaglutide 7.2 mg, semaglutide 2.4 mg, or placebo
- Duration: 72 weeks
Results
| Outcome (On-Treatment) | Semaglutide 7.2 mg | Semaglutide 2.4 mg | Placebo |
|---|---|---|---|
| Mean weight loss | -20.7% | -17.5% | -2.4% |
| Achieved 10%+ loss | 86.0% | 77.6% | 20.0% |
| Achieved 15%+ loss | 70.4% | 57.5% | 7.9% |
| Achieved 20%+ loss | 50.9% | 35.1% | 2.9% |
| Achieved 25%+ loss | 33.2% | 16.7% | 0% |
On the intention-to-treat analysis (regardless of adherence), the 7.2 mg dose achieved -18.7% versus -15.6% for 2.4 mg and -3.9% for placebo [8].
Safety
GI-related discontinuation was low for both doses: 3.3% with 7.2 mg versus 2.0% with 2.4 mg. About 75% of participants in the 7.2 mg group reached the full target dose [8].
What This Means
STEP UP showed that a tripled dose of semaglutide produces incrementally better weight loss --- roughly 3 additional percentage points on treatment. This narrows the gap with tirzepatide, which achieved 20--22% weight loss in SURMOUNT-1 at its highest dose. The relatively modest increase in GI side effects at the higher dose suggests the 7.2 mg could become a practical option for people who plateau on 2.4 mg.
The SELECT Trial: Cardiovascular Outcomes
While not technically part of the STEP program, the SELECT trial deserves mention because it answered the bigger question: does semaglutide-driven weight loss actually reduce cardiovascular events [9]?
Study Design
- Population: 17,604 adults aged 45+ with BMI of 27+, established cardiovascular disease, and no diabetes
- Randomization: 1:1 to semaglutide 2.4 mg or placebo
- Duration: Mean follow-up of 39.8 months (over 3 years)
- Primary endpoint: Major adverse cardiovascular events (MACE) --- a composite of cardiovascular death, nonfatal heart attack, and nonfatal stroke
Results
| Outcome | Semaglutide 2.4 mg | Placebo |
|---|---|---|
| MACE (primary endpoint) | 6.5% | 8.0% |
| Hazard ratio | 0.80 (95% CI, 0.72--0.90; P<0.001) | -- |
That's a 20% relative risk reduction in major cardiovascular events. All three individual components of MACE trended in favor of semaglutide [9].
An important finding: approximately 80% of the cardiovascular benefit appeared to come from mechanisms beyond weight loss alone. This suggests semaglutide has direct cardiovascular-protective effects, potentially through anti-inflammatory pathways, reduced arterial plaque inflammation, or other mechanisms researchers are still working to understand [9].
Based on SELECT, the FDA approved semaglutide 2.4 mg in 2024 specifically for cardiovascular risk reduction in adults with overweight/obesity and established cardiovascular disease --- a separate indication from weight management.
Side-by-Side Comparison of All STEP Trials
| Trial | N | Population | Duration | Mean Weight Loss (Sema) | Mean Weight Loss (Control) | Treatment Difference |
|---|---|---|---|---|---|---|
| STEP 1 [1] | 1,961 | Obesity, no diabetes | 68 wk | -14.9% | -2.4% (placebo) | -12.4 pp |
| STEP 2 [2] | 1,210 | Obesity + T2D | 68 wk | -9.6% | -3.4% (placebo) | -6.2 pp |
| STEP 3 [3] | 611 | Obesity + IBT, no diabetes | 68 wk | -16.0% | -5.7% (placebo) | -10.3 pp |
| STEP 4 [4] | 803* | Obesity, no diabetes (withdrawal) | 48 wk** | -7.9% additional | +6.9% regain | -14.8 pp |
| STEP 5 [6] | 304 | Obesity, no diabetes | 104 wk | -15.2% | -2.6% (placebo) | -12.6 pp |
| STEP 8 [7] | 338 | Obesity, no diabetes | 68 wk | -15.8% | -6.4% (liraglutide) | -9.4 pp |
| STEP UP [8] | 1,407 | Obesity, no diabetes | 72 wk | -20.7% (7.2 mg) | -17.5% (2.4 mg) | -3.2 pp |
*Randomized after 20-week run-in. **Post-randomization period. pp = percentage points. IBT = intensive behavioral therapy. T2D = type 2 diabetes.
Limitations and Things the Headlines Miss
The STEP data is impressive, but a few points deserve honest attention:
Industry funding. Every STEP trial was funded by Novo Nordisk. This doesn't invalidate the results --- the trials were well-designed, independently analyzed, and published in top journals --- but it's worth noting that the funder had a commercial interest in positive outcomes.
Trial populations don't match real-world patients. Clinical trial participants are screened for motivation, compliance, and absence of certain comorbidities. Real-world studies of semaglutide typically show lower weight loss (around 5--10% in observational data), partly because of lower adherence, fewer follow-up visits, and broader patient populations.
The weight comes back. STEP 4 and the STEP 1 extension make clear that discontinuing semaglutide leads to substantial weight regain. This positions obesity treatment with semaglutide as an ongoing commitment, not a short course. That has cost and access implications worth considering.
GI side effects are common. Across trials, 60--85% of semaglutide participants reported GI symptoms. While most were mild to moderate, they affect quality of life and may limit tolerability for some people.
Less effective in type 2 diabetes. STEP 2 showed roughly 5 percentage points less weight loss in people with diabetes compared to those without. If you have type 2 diabetes and are considering peptides for diabetes management, the expected range is closer to 10% rather than 15%.
Limited diversity. Most STEP trials enrolled predominantly white, female participants. More data is needed on how semaglutide performs across different racial and ethnic groups, ages, and BMI ranges.
FAQ
How much weight can I expect to lose on semaglutide?
In clinical trials, the average was about 15% of body weight over 68 weeks for people without diabetes, and about 10% for people with type 2 diabetes. Real-world results tend to be somewhat lower. Individual responses vary --- some people lose 20%+ while others lose under 5%.
What's the difference between semaglutide 2.4 mg and 7.2 mg?
The 7.2 mg dose tested in STEP UP produced about 3 additional percentage points of weight loss compared to 2.4 mg (20.7% versus 17.5%), with a modest increase in GI side effects. As of early 2026, the higher dose is not yet widely approved.
Do I need to stay on semaglutide forever?
The STEP 4 withdrawal data and STEP 1 extension both show significant weight regain after stopping. Current evidence supports continued treatment for maintaining results, much like how blood pressure or cholesterol medications work.
How does semaglutide compare to tirzepatide?
Head-to-head data from the SURMOUNT-5 trial showed tirzepatide produced greater weight loss than semaglutide 2.4 mg (20.2% versus 13.7%). However, the higher semaglutide 7.2 mg dose has not been directly compared to tirzepatide.
Does semaglutide reduce heart attack risk?
Yes. The SELECT trial showed a 20% reduction in major cardiovascular events (heart attack, stroke, cardiovascular death) in people with obesity and established heart disease. This led to an FDA-approved cardiovascular indication. For more on peptides and heart health, see our guide on peptides for cardiovascular health.
What are the most common side effects?
Nausea (20--44%), diarrhea (15--32%), vomiting, and constipation. These are most common during the dose-escalation period and tend to improve over time.
Can semaglutide be combined with other weight-loss peptides?
Combining GLP-1 receptor agonists with other peptides is an area of active research. CagriSema, which pairs semaglutide with cagrilintide (an amylin analog), has shown promising early results. However, combining obesity medications outside of clinical trials raises safety concerns. See our peptide stacking guide for more on this topic.
The Bottom Line
The STEP program built a remarkably consistent evidence base for semaglutide 2.4 mg as a weight-loss treatment. Across multiple trials, populations, and designs, the drug produced weight loss in the range of 10--17% --- a figure that had previously been in the territory of bariatric surgery alone.
The data also established clear boundaries. Weight loss is lower in people with type 2 diabetes. Weight regain happens when the drug is stopped. GI side effects are common, even if usually manageable. And the SELECT trial added a genuinely new dimension by showing that semaglutide reduces cardiovascular events --- a benefit that goes beyond the number on the scale.
For anyone evaluating semaglutide, the STEP trials provide the most rigorous evidence available. Understanding what each trial measured --- and what it didn't --- gives you a clearer picture than any marketing claim or social media testimonial can offer. Explore our broader guides on the best peptides for fat loss and peptides for obesity for context on how semaglutide fits into the wider treatment picture.
References
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Wadden TA, Bailey TS, Billings LK, et al. Effect of subcutaneous semaglutide vs placebo as an adjunct to intensive behavioral therapy on body weight in adults with overweight or obesity: the STEP 3 randomized clinical trial. JAMA. 2021;325(14):1403-1413. PubMed
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Wilding JPH, Batterham RL, Davies M, et al. Weight regain and cardiometabolic effects after withdrawal of semaglutide: the STEP 1 trial extension. Diabetes Obes Metab. 2022;24(8):1553-1564. PMC
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Garvey WT, Batterham RL, Bhatt DL, et al. Two-year effects of semaglutide in adults with overweight or obesity: the STEP 5 trial. Nat Med. 2022;28(10):2083-2091. PubMed
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Rubino DM, Greenway FL, Khalid U, et al. Effect of weekly subcutaneous semaglutide vs daily liraglutide on body weight in adults with overweight or obesity without diabetes: the STEP 8 randomized clinical trial. JAMA. 2022;327(2):138-150. PubMed
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Novo Nordisk. Once-weekly semaglutide 7.2 mg in adults with obesity (STEP UP): a randomised, controlled, phase 3b trial. Lancet Diabetes Endocrinol. 2025. PubMed
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Lincoff AM, Brown-Frandsen K, Colhoun HM, et al. Semaglutide and cardiovascular outcomes in obesity without diabetes. N Engl J Med. 2023;389(24):2221-2232. PubMed