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Sgl8.5
Semaglutide Research
Mostly mechanism / observationalLimited safety
11 peer-reviewed studies
What the evidence says
Mostly mechanism / observational
Most Semaglutide studies are mechanism or observational rather than RCTs that measure a clinical effect — keep findings provisional.
Most evidence is from high-quality meta-analyses and randomised trials published 2016–2023 with a typical study size of 1,210 participants.
Based on 11 studies · 2 meta-analyses · 9 RCTs · 30,300 total participants
Confidence
High
By outcome
Weight management
Mostly mechanism / observational8 studies
Safety & adverse effects
Mostly mechanism / observational8 studies
Blood sugar & glycemic control
Mostly mechanism / observational6 studies
Cardiovascular outcomes
Mostly mechanism / observational5 studies
Active research area
7 studies in the last 5 years · Latest meta-analysis: 2022
20162023
1RCTn=17,604 · very large study2023
A primary cardiovascular end-point event occurred in 569 of the 8803 patients (6.5%) in the semaglutide group and in 701 of the 8801 patients (8.0%) in the placebo group (hazard ratio, 0.80; 95% confidence interval, 0.72 to 0.90; P<0.001).
Lincoff AM, Brown-Frandsen K, Colhoun HM, Deanfield J, Emerson SS, Esbjerg S, Hardt-Lindberg S, Hovingh GK, Kahn SE, Kushner RF, Lingvay I, Oral TK, Michelsen MM, Plutzky J, Tornøe CW, Ryan DH; SELECT Trial Investigators. · N Engl J Med (2023)
Large cardiovascular-outcomes RCT: 17,604 patients with preexisting cardiovascular disease and overweight/obesity but WITHOUT diabetes
Subcutaneous semaglutide 2.4 mg/week reduced cardiovascular death, nonfatal MI, or nonfatal stroke by 20% (HR 0.80; 95% CI 0.72-0.90; P<0.001) over ~40 months
6.5% vs 8.0% event rate; established a cardiovascular benefit in a non-diabetic obese population
The mean change in body weight from baseline to week 68 was -14.9% in the semaglutide group as compared with -2.4% with placebo, for an estimated treatment difference of -12.4 percentage points.
Wilding JPH, Batterham RL, Calanna S, Davies M, Van Gaal LF, Lingvay I, McGowan BM, Rosenstock J, Tran MTD, Wadden TA, Wharton S, Yokote K, Zeuthen N, Kushner RF; STEP 1 Study Group. · N Engl J Med (2021)
Double-blind RCT in 1,961 adults with obesity/overweight WITHOUT diabetes, randomized 2:1 to subcutaneous semaglutide 2.4 mg/week or placebo plus lifestyle for 68 weeks
Mean body-weight change -14.9% (semaglutide) vs -2.4% (placebo); treatment difference -12.4 percentage points (95% CI -13.4 to -11.5; P<0.001)
Weight reduction ≥5% in 86.4% vs 31.5%; ≥10% in 69.1% vs 12.0%; ≥15% in 50.5% vs 4.9%
The primary outcome occurred in 108 of 1648 patients (6.6%) in the semaglutide group and in 146 of 1649 patients (8.9%) in the placebo group (hazard ratio, 0.74; 95% confidence interval [CI], 0.58 to 0.95; P<0.001 for noninferiority).
Marso SP, Bain SC, Consoli A, Eliaschewitz FG, Jódar E, Leiter LA, Lingvay I, Rosenstock J, Seufert J, Warren ML, Woo V, Hansen O, Holst AG, Pettersson J, Vilsbøll T; SUSTAIN-6 Investigators. · N Engl J Med (2016)
Pre-approval cardiovascular-safety RCT in 3,297 patients with type 2 diabetes at high cardiovascular risk, semaglutide (0.5/1.0 mg/week) vs placebo for 104 weeks
Mean percentage HbA1c was reduced by 1.8 percentage points with semaglutide 1.0 mg versus 1.4 percentage points with dulaglutide 1.5 mg (ETD -0.41 percentage points); bodyweight was reduced by 6.5 kg vs 3.0 kg.
Pratley RE, Aroda VR, Lingvay I, Lüdemann J, Andreassen C, Navarria A, Viljoen A; SUSTAIN 7 investigators. · Lancet Diabetes Endocrinol (2018)
Head-to-head open-label phase-3b RCT, 1,201 patients with type 2 diabetes on metformin, semaglutide vs dulaglutide at matched dose levels for 40 weeks
Semaglutide superior on HbA1c at both dose levels (e.g. -1.8 vs -1.4 percentage points at high dose; P<0.0001)
Greater weight loss: 6.5 kg vs 3.0 kg at the high doses (P<0.0001)
Estimated change in mean bodyweight from baseline to week 68 was -9.6% with semaglutide 2.4 mg vs -3.4% with placebo; treatment difference -6.2 percentage points.
Davies M, Færch L, Jeppesen OK, Pakseresht A, Pedersen SD, Perreault L, Rosenstock J, Shimomura I, Viljoen A, Wadden TA, Lingvay I; STEP 2 Study Group. · Lancet (2021)
Phase-3 RCT in 1,210 adults with overweight/obesity AND type 2 diabetes; semaglutide 2.4 mg vs 1.0 mg vs placebo for 68 weeks
Weight loss -9.6% (2.4 mg) vs -3.4% (placebo); difference -6.2 points (P<0.0001)
More patients achieved ≥5% weight loss (68.8% vs 28.5%; OR 4.88)
Major adverse cardiovascular events occurred in 61 of 1591 patients (3.8%) in the oral semaglutide group and 76 of 1592 (4.8%) in the placebo group (hazard ratio, 0.79; 95% CI, 0.57 to 1.11; P<0.001 for noninferiority).
Husain M, Birkenfeld AL, Donsmark M, Dungan K, Eliaschewitz FG, Franco DR, Jeppesen OK, Lingvay I, Mosenzon O, Pedersen SD, Tack CJ, et al. · N Engl J Med (2019)
Cardiovascular-safety RCT of oral semaglutide in 3,183 patients with type 2 diabetes at high CV risk, median 15.9 months
MACE non-inferior to placebo (HR 0.79; 95% CI 0.57-1.11)
Lower cardiovascular death (HR 0.49) and all-cause death (HR 0.51) as secondary outcomes
Subcutaneous semaglutide was the most efficacious in reducing body weight followed by oral semaglutide... The same agents also conferred the greatest reductions in systolic blood pressure.
Tsapas A, Karagiannis T, Avgerinos I, Liakos A, Bekiari E, et al. · Diabetes Obes Metab (2021)
Network meta-analysis of 424 trials (276,336 patients) across 21 antidiabetic medications and 9 drug classes
Subcutaneous semaglutide ranked the most efficacious for body-weight reduction, followed by oral semaglutide
Semaglutide also produced the greatest systolic blood-pressure reductions
The mean weight change from baseline was -15.8% with semaglutide vs -6.4% with liraglutide (difference, -9.4 percentage points [95% CI, -12.0 to -6.8]; P < .001).
Rubino DM, Greenway FL, Khalid U, O'Neil PM, Rosenstock J, Sørrig R, et al. · JAMA (2022)
Head-to-head RCT (338 adults, overweight/obesity without diabetes) of weekly semaglutide 2.4 mg vs daily liraglutide 3.0 mg for 68 weeks
Semaglutide produced markedly greater weight loss (-15.8% vs -6.4%; placebo -1.9%)
Higher odds of ≥10%, ≥15%, and ≥20% weight loss with semaglutide (e.g. ≥20%: 38.5% vs 6.0%)
With continued semaglutide, mean body weight change from week 20 to week 68 was -7.9% vs +6.9% with the switch to placebo (difference, -14.8 percentage points; P < .001).
Rubino D, Abrahamsson N, Davies M, Hesse D, Greenway FL, et al. · JAMA (2021)
Withdrawal-design RCT: after a 20-week semaglutide run-in (mean -10.6% weight), 803 participants continued semaglutide 2.4 mg or switched to placebo
Continued treatment kept losing weight (-7.9%) while placebo regained (+6.9%) — a 14.8-point difference
Demonstrates that benefit depends on ongoing use; weight regain follows discontinuation
Oral semaglutide reduced HbA1c (placebo-adjusted treatment differences at week 26: -0.6% [3 mg], -0.9% [7 mg], and -1.1% [14 mg]) and body weight.
Aroda VR, Rosenstock J, Terauchi Y, Altuntas Y, Lalic NM, Morales Villegas EC, Jeppesen OK, Christiansen E, Hertz CL, Haluzík M; PIONEER 1 Investigators. · Diabetes Care (2019)
Phase-3a RCT of the first oral GLP-1 agonist: 703 patients with type 2 diabetes on diet/exercise, oral semaglutide 3/7/14 mg daily vs placebo for 26 weeks
Dose-dependent HbA1c reduction (placebo-adjusted up to -1.1% to -1.4% by estimand)
Dose-dependent weight loss (up to -2.3 kg at 14 mg vs placebo)
GLP-1 receptor agonists had no significant effects on the occurrence of thyroid cancer (RR 1.30, 95% CI 0.86-1.97)... did not increase or decrease the risk of thyroid cancer, hyperthyroidism, hypothyroidism, thyroiditis, thyroid mass and goiter.
Hu W, Song R, Cheng R, Liu C, Guo R, Tang W, Zhang J, Zhao Q, Li X, Liu J. · Front Endocrinol (Lausanne) (2022)
Meta-analysis of RCTs evaluating GLP-1 receptor agonists (class, including semaglutide) and six categories of thyroid disorder
A modest association with 'overall thyroid disorders' (RR 1.28; 95% CI 1.03-1.60), driven by aggregate counts
No statistically significant increase in thyroid cancer specifically (RR 1.30; 95% CI 0.86-1.97) or in hyper/hypothyroidism, thyroiditis, mass, or goiter