Semaglutide has the most robust randomized-trial portfolio of any obesity drug. The STEP program (Semaglutide Treatment Effect in People with obesity) ran ten coordinated phase 3 trials between 2021 and 2024 covering obesity (STEP-1), obesity with type 2 diabetes (STEP-2), intensive lifestyle adjuncts (STEP-3), weight-loss maintenance (STEP-4 and STEP-1 withdrawal), two-year durability (STEP-5), comparison to liraglutide (STEP-8), adolescents (STEP-TEENS), and heart failure with preserved ejection fraction (STEP-HFpEF). Outside the STEP program, SELECT showed semaglutide reduces major adverse cardiovascular events 20% in obesity without diabetes, and OASIS-1 tested a 50 mg high-dose oral formulation.
Ranked papers
#1STEP-1
Wilding JPH, Batterham RL, Calanna S, et al. · N Engl J Med · 2021
Primary endpoint: Body weight change at 68 weeks
The pivotal STEP-1 trial randomized 1,961 adults with obesity (BMI ≥30, no diabetes) to semaglutide 2.4 mg weekly or placebo for 68 weeks. Primary outcome: −14.9% body weight vs −2.4% on placebo. Roughly half of participants on semaglutide lost ≥15% body weight. This trial established the FDA-approved Wegovy 2.4 mg dose and the modern benchmark for GLP-1 obesity efficacy.
PMID 33567185 ↗NCT03548935 ↗
#2STEP-2
Davies M, Færch L, Jeppesen OK, et al. · Lancet · 2021
Primary endpoint: Body weight change at 68 weeks
STEP-2 enrolled 1,210 adults with overweight/obesity AND type 2 diabetes — a population that typically loses less weight on GLP-1s. Semaglutide 2.4 mg produced −9.6% body weight vs −3.4% on placebo. A1C dropped 1.6 percentage points, confirming dual cardiometabolic benefit. Established the case for using Wegovy (rather than Ozempic) in T2D patients seeking weight management beyond glycemic control.
PMID 33667417 ↗NCT03552757 ↗
#3STEP-3
Wadden TA, Bailey TS, Billings LK, et al. · JAMA · 2021
Primary endpoint: Body weight change at 68 weeks
STEP-3 paired semaglutide 2.4 mg with intensive behavioral therapy (30 visits over 68 weeks, 1,000-1,500 kcal/day diet). Semaglutide group lost −16.0% vs placebo+IBT −5.7%. Demonstrated that GLP-1s and lifestyle therapy are additive, not redundant — important for insurance prior-auth criteria that require concurrent lifestyle programs.
PMID 33625476 ↗NCT03611582 ↗
#4STEP-4
Rubino D, Abrahamsson N, Davies M, et al. · JAMA · 2021
Primary endpoint: Weight change from week 20 to week 68
STEP-4 randomized participants who had already lost ~10.6% body weight on semaglutide 2.4 mg through a 20-week run-in. Continuing semaglutide produced an additional −7.9% weight loss; switching to placebo caused +6.9% regain. Crystallized the chronic-disease framing: stopping a GLP-1 reverses weight loss almost completely within a year, like stopping a blood-pressure med.
PMID 33755728 ↗NCT03548987 ↗
#5STEP-5
Garvey WT, Batterham RL, Bhatta M, et al. · Nat Med · 2022
Primary endpoint: Body weight change at 104 weeks
STEP-5 extended STEP-1's design to two years (104 weeks). Semaglutide 2.4 mg maintained −15.2% body weight at year 2 (vs −2.6% placebo) — answering the durability question that critics raised after STEP-1. Half of completers maintained ≥15% loss at two years. This is the longest randomized data set for semaglutide as of 2026.
PMID 36216945 ↗NCT03693430 ↗
#6STEP-8
Rubino DM, Greenway FL, Khalid U, et al. · JAMA · 2022
Primary endpoint: Body weight change at 68 weeks
STEP-8 was the first head-to-head between two FDA-approved GLP-1 obesity drugs. Semaglutide 2.4 mg weekly produced −15.8% body weight vs liraglutide 3.0 mg daily −6.4% at 68 weeks. Established semaglutide as the dominant GLP-1 monotherapy for obesity and effectively retired Saxenda as a first-line choice.
PMID 35015037 ↗NCT04074161 ↗
#7STEP-TEENS
Weghuber D, Barrett T, Barrientos-Pérez M, et al. · N Engl J Med · 2022
Primary endpoint: BMI change at 68 weeks
STEP-TEENS enrolled 201 adolescents aged 12-17 with obesity. Semaglutide 2.4 mg produced −16.1% BMI vs +0.6% placebo. Drove the December 2022 FDA approval of Wegovy for adolescents ≥12 — the first GLP-1 with a pediatric weight-management label, opening the pathway for state-Medicaid pediatric coverage.
PMID 36322838 ↗NCT04102189 ↗
#8STEP-HFpEF
Kosiborod MN, Abildstrøm SZ, Borlaug BA, et al. · N Engl J Med · 2023
Primary endpoint: Change in KCCQ-CSS (heart-failure quality-of-life score) and body weight
STEP-HFpEF tested semaglutide 2.4 mg in 529 patients with heart failure with preserved ejection fraction (HFpEF) and obesity — historically a population with no effective drug therapy. Semaglutide improved KCCQ-CSS by 7.8 points (vs 2.6 placebo) and reduced body weight 13.3% more than placebo. Established a new indication framework: GLP-1s as HFpEF disease-modifying therapy, not just weight-loss drugs.
PMID 37622681 ↗NCT04788511 ↗
#9SELECT
Lincoff AM, Brown-Frandsen K, Colhoun HM, et al. · N Engl J Med · 2023
Primary endpoint: First MACE (cardiovascular death, nonfatal MI, nonfatal stroke)
SELECT randomized 17,604 adults with established cardiovascular disease + obesity (no diabetes) to semaglutide 2.4 mg or placebo. Primary MACE outcome: 6.5% (sema) vs 8.0% (placebo) = 20% relative risk reduction (HR 0.80, p<0.001). This trial drove the March 2024 FDA cardiovascular-risk-reduction indication for Wegovy and is the single most consequential trial in modern obesity medicine.
PMID 37952131 ↗NCT03574597 ↗
#10OASIS-1
Knop FK, Aroda VR, do Vale RD, et al. · Lancet · 2023
Primary endpoint: Body weight change at 68 weeks
OASIS-1 tested high-dose oral semaglutide 50 mg daily in 667 adults with obesity (no diabetes). Produced −15.1% body weight vs −2.4% placebo at 68 weeks — comparable to injectable Wegovy 2.4 mg. Filed for FDA approval as oral Wegovy in 2024 (pending). If approved, would be the first oral GLP-1 weight-loss drug, directly competing with Foundayo (orforglipron).
PMID 37385278 ↗NCT05035095 ↗
About this list
We curate ranked, citation-anchored PubMed paper lists for the most-searched questions in obesity medicine. Every citation on this page was checked against PubMed on August 2026. Each paper card links directly to PubMed and to ClinicalTrials.gov where applicable.
Browse our full index of research lists or our long-form research articles.
See also: our semaglutide overview page.