Semaglutides
Trial evidence

What Semaglutide Clinical Trial Results Actually Show

Across the main trials, semaglutide produced 14.9% mean weight loss over 68 weeks without diabetes, cut HbA1c by 1.45–1.55% at 30 weeks, and lowered major cardiovascular events (HR 0.86 in SOUL). Main harms: gastrointestinal events and a retinopathy-complication signal (HR 1.76) in SUSTAIN 6.

Last checked ·19 sources cited
Clay still life of a central injection pen surrounded by smaller pens and a rising graph-like ridge, symbolizing clinical trial data.

Semaglutides.org provides information only, not medical advice. Talk to a licensed provider about your own care before making changes. Some telehealth links are affiliate links and are labeled where they appear.

The clinical trials of semaglutide show large weight loss, meaningful blood sugar reduction, and a real but modest reduction in heart attacks and strokes in people with type 2 diabetes. In the main obesity trial (STEP 1), adults without diabetes lost an average of 14.9% of body weight over 68 weeks, compared with 2.4% on placebo [5]. In SUSTAIN 1, a phase 3a trial of injected semaglutide alone versus placebo in type 2 diabetes managed with diet and exercise, HbA1c fell by 1.45% and 1.55% at 30 weeks on the two tested weekly doses, versus essentially no change on placebo [1]. The main harms were gastrointestinal — nausea, diarrhea, and treatment discontinuation because of them [1][5][6][7] — along with a significantly higher rate of retinopathy complications in one cardiovascular trial [2].

These results come from three families of phase 3 trials. SUSTAIN tested once-weekly injected semaglutide in type 2 diabetes [1][2]. PIONEER tested once-daily oral semaglutide in type 2 diabetes, with PIONEER 6 as its cardiovascular safety trial [3]. STEP tested once-weekly injected semaglutide at 2.4 mg for weight management [5][6][7]. A newer trial, SOUL, tested oral semaglutide for cardiovascular benefit in 2025 [4]. Semaglutide is a glucagon-like peptide-1 (GLP-1) analog with a half-life of about one week [2]. All of these trials were funded by Novo Nordisk, the maker of the drug, and in STEP 1 the sponsor also designed the trial and performed the analysis [1][2][3][4][5][6][7].

Which trials exist, and what did each one test?

The SUSTAIN program was the phase 3a program for once-weekly subcutaneous (injected) semaglutide in type 2 diabetes [1][2]. SUSTAIN 1 tested 0.5 mg and 1.0 mg weekly against volume-matched placebo in people whose type 2 diabetes was managed by diet and exercise alone, with no other diabetes medication [1].

The PIONEER program tested once-daily oral semaglutide in type 2 diabetes; PIONEER 6 was its cardiovascular safety trial [3]. SOUL, reported in 2025, was a separate trial testing oral semaglutide (up to 14 mg) for cardiovascular superiority [4].

The STEP program tested once-weekly subcutaneous semaglutide at 2.4 mg for weight management in people with overweight or obesity [5][6][7]. STEP 1 enrolled people without diabetes [5], STEP 2 enrolled people with type 2 diabetes [6], and STEP 3 added intensive behavioral therapy [7].

How much did blood sugar improve in the SUSTAIN 1 trial?

SUSTAIN 1 randomized 388 participants at 72 sites in 8 countries; 387 received at least one dose (128 at 0.5 mg, 130 at 1.0 mg, 129 placebo) [1]. To enter, participants had to be 18 or older, have type 2 diabetes managed with diet and exercise alone for at least 30 days, and have a baseline HbA1c between 7.0% and 10.0% [1]. The trial ran 30 weeks, and the mean baseline HbA1c was 8.05% [1].

At week 30, HbA1c fell by 1.45% on the 0.5 mg dose and 1.55% on the 1.0 mg dose, while placebo changed by a non-significant 0.02% [1]. The estimated treatment differences versus placebo were −1.43% and −1.53%, both with p<0.0001 [1].

Weight also fell. From a mean baseline body weight of 91.93 kg, participants lost 3.73 kg on 0.5 mg and 4.53 kg on 1.0 mg, versus 0.98 kg on placebo [1]. No deaths occurred in any group, and most adverse events were mild or moderate [1].

What did SUSTAIN 6 find about the heart — and about the eyes?

SUSTAIN 6 randomized 3,297 patients with type 2 diabetes on standard care to once-weekly semaglutide (0.5 mg or 1.0 mg) or placebo for 104 weeks [2]. Most participants — 2,735 of them, or 83.0% — already had established cardiovascular disease, chronic kidney disease, or both at the start [2].

The primary composite outcome (cardiovascular death, nonfatal heart attack, or nonfatal stroke) occurred in 6.6% of the semaglutide group (108 of 1,648) versus 8.9% of the placebo group (146 of 1,649), a hazard ratio of 0.74 with a 95% confidence interval of 0.58 to 0.95 [2]. Nonfatal stroke was lower with semaglutide (1.6% vs 2.7%, hazard ratio 0.61, P=0.04), while nonfatal heart attack did not reach significance (2.9% vs 3.9%, hazard ratio 0.74, P=0.12), and cardiovascular death rates were similar in the two groups [2].

An important caveat: SUSTAIN 6 was designed as a noninferiority trial with a margin of 1.8 — its formal conclusion was that semaglutide did not carry excess cardiovascular risk, not that it was proven superior [2]. It also found a significantly higher rate of retinopathy complications (vitreous hemorrhage, blindness, or conditions requiring treatment with an intravitreal agent or photocoagulation): hazard ratio 1.76, 95% CI 1.11 to 2.78, P=0.02 [2]. Rates of new or worsening nephropathy were lower with semaglutide, and there were fewer serious adverse events overall, though more patients stopped treatment because of adverse events, mainly gastrointestinal ones [2].

What did the oral semaglutide trials show?

PIONEER 6 randomized 3,183 patients (mean age 66) and followed them for a median of 15.9 months [3]. Entry required age 50 or older with established cardiovascular or chronic kidney disease, or age 60 or older with cardiovascular risk factors only [3]. Major adverse cardiovascular events occurred in 3.8% on oral semaglutide versus 4.8% on placebo (hazard ratio 0.79, 95% CI 0.57 to 1.11) [3]. Death from any cause was 1.4% versus 2.8% (hazard ratio 0.51, 95% CI 0.31 to 0.84), and cardiovascular death was 0.9% versus 1.9% (hazard ratio 0.49) [3]. But PIONEER 6 was designed to rule out 80% excess cardiovascular risk, not to prove benefit — its formal conclusion was noninferiority [3].

SOUL, reported in 2025, was the trial built to prove benefit. It randomized 9,650 participants aged 50 or older with type 2 diabetes (HbA1c 6.5–10.0%) and atherosclerotic cardiovascular disease, chronic kidney disease, or both, to oral semaglutide (maximal dose 14 mg) or placebo [4]. Follow-up averaged 47.5 months, with a median of 49.5 months [4].

SOUL met its primary endpoint: major adverse cardiovascular events occurred in 12.0% of the oral semaglutide group (579 of 4,825) versus 13.8% on placebo (668 of 4,825), a hazard ratio of 0.86 with a 95% confidence interval of 0.77 to 0.96, P=0.006 [4]. That works out to 3.1 versus 3.7 events per 100 person-years [4]. However, the confirmatory secondary outcomes — including a five-point composite of major kidney disease events — did not differ significantly between the groups [4]. Serious adverse events occurred in 47.9% versus 50.3%, and gastrointestinal disorders in 5.0% versus 4.4% [4].

How much weight did people lose in the STEP 1 obesity trial?

STEP 1 enrolled 1,961 adults at 129 sites in 16 countries, with a BMI of 30 or more (or 27 or more with at least one weight-related condition), and without diabetes [5]. Participants were randomized 2:1 to once-weekly semaglutide or placebo for 68 weeks [5]. The trial started semaglutide at 0.25 mg weekly and increased the dose every 4 weeks to reach 2.4 mg by week 16, with lower maintenance doses permitted for side effects [5]. Both groups got the same lifestyle program: a 500-calorie-per-day deficit, 150 minutes per week of physical activity, and counseling every 4 weeks [5].

At week 68, mean body weight fell 14.9% with semaglutide versus 2.4% with placebo — a treatment difference of 12.4 percentage points (95% CI −13.4 to −11.5, P<0.001) [5]. In absolute terms, that was −15.3 kg versus −2.6 kg, a difference of 12.7 kg [5].

The responder rates show how wide the spread was [5]:

Weight loss goalSemaglutidePlacebo
5% or more86.4%31.5%
10% or more69.1%12.0%
15% or more50.5%4.9%

That 86.4% figure has a flip side: roughly 1 in 7 people on semaglutide did not reach even 5% weight loss [5]. People with diabetes, HbA1c of 6.5% or higher, a history of chronic pancreatitis, pancreatitis within 180 days, prior bariatric surgery, or anti-obesity drug use within 90 days were excluded [5].

Does having diabetes change the weight loss results?

Yes. STEP 2 enrolled 1,210 adults with a BMI of 27 or more and type 2 diabetes (HbA1c 7–10%), randomized 1:1:1 to semaglutide 2.4 mg, semaglutide 1.0 mg, or placebo for 68 weeks at 149 clinics in 12 countries [6]. Mean weight change at week 68 was −9.6% on 2.4 mg versus −3.4% on placebo, a difference of 6.2 percentage points (95% CI −7.3 to −5.2, p<0.0001) [6]. 68.8% of the 2.4 mg group lost at least 5% of body weight versus 28.5% on placebo (odds ratio 4.88) [6].

STEP 3 showed the other direction: adding intensive behavioral support raises results. It enrolled 611 US adults without diabetes at 41 sites, randomized 2:1 for 68 weeks; both the semaglutide and placebo groups received an initial 8-week low-calorie diet and 30 counseling visits of intensive behavioral therapy [7]. Mean weight change was −16.0% with semaglutide versus −5.7% with placebo, a difference of 10.3 percentage points (95% CI −12.0 to −8.6, P<0.001) [7]. Responders reaching 5%, 10%, and 15% loss were 86.6%, 75.3%, and 55.8% on semaglutide versus 47.6%, 27.0%, and 13.2% on placebo [7]. The population averaged age 46, was 81.0% women, and had a mean weight of 105.8 kg and mean BMI of 38.0 [7].

Note what the placebo arms show: STEP 3’s placebo group lost 5.7% versus 2.4% in STEP 1, because the intensive behavioral program lifted both arms [5][7].

TrialPopulationSemaglutide resultPlacebo result
STEP 1 [5]No diabetes, lifestyle counseling−14.9%−2.4%
STEP 2 [6]Type 2 diabetes−9.6%−3.4%
STEP 3 [7]No diabetes, intensive behavioral therapy−16.0%−5.7%

How common were side effects, and how many people quit?

Gastrointestinal effects were the dominant harm across all the trials. In SUSTAIN 1, nausea was reported by 20% of the 0.5 mg group and 24% of the 1.0 mg group versus 8% on placebo; diarrhea was reported by 13% and 11% versus 2% on placebo [1]. Discontinuation rates were 13% and 12% versus 11% on placebo, with gastrointestinal events the main reason [1].

In STEP 1, nausea and diarrhea were the most common adverse events; they were typically transient, mild-to-moderate, and subsided with time [5]. Discontinuation because of gastrointestinal events occurred in 4.5% of the semaglutide group (59 participants) versus 0.8% on placebo (5 participants) [5].

STEP 2 reported any adverse event in 87.6% of the 2.4 mg group, 81.8% of the 1.0 mg group, and 76.9% of the placebo group; gastrointestinal adverse events, mostly mild to moderate, occurred in 63.5%, 57.5%, and 34.3% respectively [6]. In STEP 3, gastrointestinal adverse events occurred in 82.8% of the semaglutide group versus 63.2% on placebo, and 3.4% versus 0% stopped treatment because of them [7]. Retention in STEP 3 was high: 92.8% completed the trial and 82.7% were still on treatment at the end [7].

How should you read these numbers without being misled?

A few design details matter. First, the “estimand”: STEP 1’s primary estimand was a prespecified description of the treatment effect that counted results regardless of whether participants stopped the drug or needed rescue therapy [5]. Second, efficacy was analyzed in the full analysis or intention-to-treat population, while safety was analyzed in everyone who received at least one dose [5][6]. SUSTAIN 1 used a modified intention-to-treat population (everyone exposed to at least one dose) and pooled its two placebo groups [1].

Third, noninferiority and superiority are different claims. SUSTAIN 6 and PIONEER 6 were noninferiority trials — designed to show semaglutide was not worse than placebo by more than a set margin — while SOUL was an event-driven superiority trial that did prove a benefit [2][3][4].

Fourth, the percent-change figures depend on who was in the trial: 14.9% without diabetes, 9.6% with diabetes, and 16.0% with added intensive behavioral therapy [5][6][7]. These are trial results under structured conditions — free drug, scheduled counseling visits, and close follow-up — not a prediction of what any individual will experience outside a trial [5][6][7].

What are the limits of this evidence?

The longest randomized follow-up among these trials is SOUL’s mean of 47.5 months, about 4 years, and it tested oral semaglutide in people with type 2 diabetes and cardiovascular or kidney disease — not weight loss [4]. The obesity trials ran 68 weeks and excluded people with diabetes (STEP 1 and STEP 3) [5][7].

STEP 1 also included a 7-week off-treatment period after week 68, meaning the drug effect was measured only while people were on treatment [5]. SOUL did not show significant benefit on its confirmatory secondary kidney composite [4]. And the retinopathy complication excess in SUSTAIN 6 remains an unexplained safety finding [2]. Whether these findings apply to compounded semaglutide is not something these trials address.

Sources

  1. PubMed. Efficacy and safety of once-weekly semaglutide monotherapy versus placebo in patients with type 2 diabetes (SUSTAIN 1): a double-blind, randomised, placebo-controlled, parallel-group, multinational, multicentre phase 3a trial.
  2. PubMed. Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes.
  3. PubMed. Oral Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes.
  4. PubMed. Oral Semaglutide and Cardiovascular Outcomes in High-Risk Type 2 Diabetes.
  5. New England Journal of Medicine. Once-Weekly Semaglutide in Adults with Overweight or Obesity.
  6. PubMed. Semaglutide 2·4 mg once a week in adults with overweight or obesity, and type 2 diabetes (STEP 2): a randomised, double-blind, double-dummy, placebo-controlled, phase 3 trial.
  7. PubMed. 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.
  8. Nature Medicine. Two-year effects of semaglutide in adults with overweight or obesity: the STEP 5 trial.
  9. The Lancet Diabetes & Endocrinology. Once-weekly semaglutide 7·2 mg in adults with obesity (STEP UP): a randomised, controlled, phase 3b trial.
  10. New England Journal of Medicine. Semaglutide and Cardiovascular Outcomes in Obesity without Diabetes.
  11. PubMed. Effects of Semaglutide on Chronic Kidney Disease in Patients with Type 2 Diabetes.
  12. PubMed. Phase 3 Trial of Semaglutide in Metabolic Dysfunction-Associated Steatohepatitis.
  13. PubMed. Semaglutide and walking capacity in people with symptomatic peripheral artery disease and type 2 diabetes (STRIDE): a phase 3b, double-blind, randomised, placebo-controlled trial.
  14. PubMed. Once-Weekly Semaglutide in Persons with Obesity and Knee Osteoarthritis.
  15. PubMed. Efficacy and safety of once-weekly semaglutide 2·4 mg versus placebo in people with obesity and prediabetes (STEP 10): a randomised, double-blind, placebo-controlled, multicentre phase 3 trial.
  16. PubMed. Efficacy and safety of oral semaglutide 14 mg (flexible dose) in early-stage symptomatic Alzheimer’s disease (evoke and evoke+): two phase 3, randomised, placebo-controlled trials.
  17. PubMed. Changes in weight and glycemic control following obesity treatment with semaglutide or tirzepatide by discontinuation status.
  18. PubMed Central. Impact of Semaglutide on Body Composition in Adults With Overweight or Obesity: Exploratory Analysis of the STEP 1 Study.
  19. PubMed. A systematic review and meta-analysis of the efficacy and safety of pharmacological treatments for obesity in adults.

Frequently asked questions

How much weight did people lose in the main semaglutide obesity trial, and over how long?

In STEP 1, 1,961 adults without diabetes took once-weekly semaglutide 2.4 mg or placebo for 68 weeks. Mean weight change was −14.9% versus −2.4% with placebo, or −15.3 kg versus −2.6 kg. Half the semaglutide group (50.5%) lost 15% or more of their body weight.

Is weight loss smaller in people who have type 2 diabetes?

In the trials, yes. STEP 2 tested the same 2.4 mg weekly dose in adults with type 2 diabetes and found −9.6% mean weight loss versus −3.4% on placebo over 68 weeks, compared with −14.9% in the non-diabetes STEP 1 population. The trials show the difference between these populations but do not explain the cause.

Does semaglutide actually reduce heart attacks and strokes, or just risk markers?

SOUL, a superiority trial of oral semaglutide in 9,650 people with type 2 diabetes and cardiovascular or kidney disease, found major adverse cardiovascular events in 12.0% versus 13.8% on placebo (HR 0.86, 95% CI 0.77–0.96, P=0.006) over a median 49.5 months. SUSTAIN 6 found HR 0.74 but was designed only to rule out excess risk.

Is the pill version proven to help heart outcomes?

Yes, in SOUL. Oral semaglutide (maximal dose 14 mg) lowered major adverse cardiovascular events versus placebo with HR 0.86 over about 4 years. Earlier, PIONEER 6 had only established safety (HR 0.79, noninferiority), not benefit.

What percentage of trial participants fail to lose 5% of their weight?

In STEP 1, 86.4% of the semaglutide group lost at least 5% of body weight, which means roughly 1 in 7 did not reach that threshold. In STEP 2, in people with type 2 diabetes, 68.8% reached 5%.

How common were nausea and diarrhea, and how many people quit because of them?

In SUSTAIN 1, nausea occurred in 20–24% on semaglutide versus 8% on placebo, and diarrhea in 11–13% versus 2%. In STEP 1, 4.5% stopped treatment because of gastrointestinal events versus 0.8% on placebo; events were typically mild to moderate and transient.

What is the eye/retinopathy warning about, and which trial found it?

SUSTAIN 6 found significantly higher rates of retinopathy complications — vitreous hemorrhage, blindness, or conditions needing intravitreal treatment or photocoagulation — with semaglutide: HR 1.76, 95% CI 1.11–2.78, P=0.02. The finding remains unexplained in that trial report.

How long is the longest randomized evidence for semaglutide?

Among these trials, SOUL has the longest follow-up: mean 47.5 months (median 49.5 months) in 9,650 participants. The obesity trials ran 68 weeks, and STEP 1 measured the drug effect only while people were on treatment.

This article summarizes FDA labeling, published research and company information current as of September 14, 2026. It is not medical advice and does not replace a conversation with your own healthcare provider. How we research and verify.