Semaglutide is a modified version of the gut hormone GLP-1. It is sold as Ozempic (type 2 diabetes), Wegovy (weight management and cardiovascular risk reduction) and as an oral tablet (Rybelsus). It is by far the best-evidenced peptide on this site.
What the studies found10 studies explained
The STEP programme of randomized trials tested it for obesity; SUSTAIN-6 tested cardiovascular safety in type 2 diabetes and found fewer major cardiovascular events than placebo; later trials looked at kidney and heart outcomes. Head-to-head, tirzepatide produced greater weight loss than semaglutide in the SURMOUNT-5 trial.
Wilding JPH, Batterham RL, Calanna S · N Engl J Med · 2021 · PMID 33567185
humanRandomized, double-blind, placebo-controlled phase 3 (STEP 1)
- Who / how many
- 1,961 adults with overweight or obesity, no diabetes
- What they found
- Mean weight change at 68 weeks was -14.9% with semaglutide 2.4 mg vs -2.4% with placebo. About 86% lost at least 5% of body weight vs 32% on placebo.
- Limitations
- Funded by the manufacturer; participants also received lifestyle intervention; 68-week duration, so long-term outcomes need other trials.
Marso SP, Bain SC, Consoli A · N Engl J Med · 2016 · PMID 27633186
humanRandomized, double-blind, placebo-controlled phase 3 (SUSTAIN-6)
- Who / how many
- 3,297 adults with type 2 diabetes, mostly with existing cardiovascular disease
- What they found
- Major cardiovascular events occurred in 6.6% on semaglutide vs 8.9% on placebo (hazard ratio 0.74).
- Limitations
- Designed mainly to show non-inferiority for safety; the population was high risk, and results do not apply to everyone.
Aronne LJ, Horn DB, le Roux CW · N Engl J Med · 2025 · PMID 40353578
humanOpen-label phase 3b head-to-head
- Who / how many
- 751 adults with obesity, no diabetes
- What they found
- At 72 weeks, tirzepatide produced -20.2% weight change vs -13.7% for semaglutide.
- Limitations
- Open-label (not blinded), maximum tolerated doses, and funded by the maker of tirzepatide.
Lincoff AM, Brown-Frandsen K, Colhoun HM · N Engl J Med · 2023 · PMID 37952131
humanRandomized, double-blind, placebo-controlled phase 3 (SELECT)
- Who / how many
- 17,604 adults aged 45+ with cardiovascular disease and overweight or obesity, no diabetes (8,803 semaglutide, 8,801 placebo)
- What they found
- Semaglutide 2.4 mg weekly was superior to placebo at reducing a composite of cardiovascular death, nonfatal heart attack or nonfatal stroke over a mean follow-up of about 40 months. A related report describes this as a 20% reduction in major cardiovascular events.
- Limitations
- Funded by Novo Nordisk. Participants already had cardiovascular disease, so the result may not apply to people without it.
Colhoun HM, Lingvay I, Brown PM · Nat Med · 2024 · PMID 38796653
humanPrespecified analysis of a randomized trial (SELECT kidney outcomes)
- Who / how many
- About 17,600 adults with overweight/obesity and cardiovascular disease, no diabetes
- What they found
- The main composite kidney endpoint occurred in 1.8% on semaglutide vs 2.2% on placebo (hazard ratio 0.78). Kidney function (eGFR) declined more slowly with semaglutide.
- Limitations
- Kidney outcomes were a secondary analysis, event rates were low, and the trial was manufacturer funded.
Wilding JPH, Batterham RL, Davies M · Diabetes Obes Metab · 2022 · PMID 35441470
humanExploratory off-treatment extension of a randomized trial (STEP 1)
- Who / how many
- 327 participants from the STEP 1 trial
- What they found
- After stopping semaglutide and lifestyle support, people regained 11.6 percentage points of their lost weight within a year, about two-thirds of the loss, and cardiometabolic improvements reverted towards baseline.
- Limitations
- Exploratory analysis in a subset of the original trial. Suggests that treatment may need to continue to keep the benefit.
Weghuber D, Barrett T, Barrientos-Pérez M · N Engl J Med · 2022 · PMID 36322838
humanRandomized, double-blind, placebo-controlled trial (STEP TEENS)
- Who / how many
- 201 adolescents aged 12 to <18 with obesity or overweight with a comorbidity
- What they found
- BMI changed by -16.1% with semaglutide 2.4 mg vs +0.6% with placebo over 68 weeks. 73% of the semaglutide group lost at least 5% of weight. Gallstones were more common with semaglutide, and serious adverse events occurred in 11% vs 9%.
- Limitations
- Funded by Novo Nordisk. Adolescents only; 68 weeks, so long-term effects on growth and development are unknown.
Pratley RE, Aroda VR, Lingvay I · Lancet Diabetes Endocrinol · 2018 · PMID 29397376
humanOpen-label phase 3b head-to-head (SUSTAIN 7)
- Who / how many
- Adults with type 2 diabetes on metformin
- What they found
- Semaglutide was superior to dulaglutide at both doses for lowering HbA1c and body weight at week 40, with a similar safety profile.
- Limitations
- Open-label, 40 weeks, and funded by Novo Nordisk.
Bliddal H, Bays H, Czernichow S · N Engl J Med · 2024 · PMID 39476339
humanRandomized, double-blind, placebo-controlled phase 3 (STEP 9)
- Who / how many
- 407 adults with obesity and moderate knee osteoarthritis
- What they found
- Semaglutide 2.4 mg produced greater weight loss and greater reductions in knee osteoarthritis pain than placebo over 68 weeks. More participants stopped treatment because of adverse events with semaglutide (6.7% vs 3.0%), mainly gastrointestinal.
- Limitations
- Manufacturer-funded; pain is self-reported, and weight loss itself may explain much of the pain reduction.
Moiz A, Levett JY, Filion KB · Am J Cardiol · 2024 · PMID 38679221
reviewSystematic review and meta-analysis
- Who / how many
- 4 randomized trials, 3,087 adults with overweight/obesity and no diabetes
- What they found
- Semaglutide 2.4 mg weekly lowered body weight by an average of about 12 percentage points more than placebo over at least 68 weeks. Gastrointestinal events were more common (relative risk 1.47) but mostly mild to moderate and transient.
- Limitations
- Only four trials, all of similar design and mostly manufacturer funded.
More published research (summaries coming)
- Oral Semaglutide and Cardiovascular Outcomes in High-Risk Type 2 Diabetes. (N Engl J Med, 2025)
- Efficacy and Safety of Semaglutide for Weight Loss in Obesity Without Diabetes: A Systematic Review and Meta-Analysis. (J ASEAN Fed Endocr Soc, 2022)
- The effect of semaglutide 2.4 mg once weekly on energy intake, appetite, control of eating, and gastric emptying in adults with obesity. (Diabetes Obes Metab, 2021)
- Semaglutide and cardiovascular outcomes by baseline and changes in adiposity measurements: a prespecified analysis of the SELECT trial. (Lancet, 2025)
- Effect of Continued Weekly Subcutaneous Semaglutide vs Placebo on Weight Loss Maintenance in Adults With Overweight or Obesity: The STEP 4 Randomized Clinical Trial. (JAMA, 2021)
- Subcutaneously administered tirzepatide vs semaglutide for adults with type 2 diabetes: a systematic review and network meta-analysis of randomised controlled trials. (Diabetologia, 2024)
- Once-weekly semaglutide 7·2 mg in adults with obesity (STEP UP): a randomised, controlled, phase 3b trial. (Lancet Diabetes Endocrinol, 2025)
- Safety, tolerability, pharmacokinetics, and pharmacodynamics of concomitant administration of multiple doses of cagrilintide with semaglutide 2·4 mg for weight management: a randomised, controlled, phase 1b trial. (Lancet, 2021)
Gastrointestinal effects (nausea, vomiting, diarrhea, constipation) are the most common and mostly occur during dose escalation. Weight is typically regained after stopping. Other known risks listed on labelling include gallbladder problems and pancreatitis; consult prescribing information for the full list.
