EVIDENCE BASE / PHASE 3
The trials that built the semaglutide evidence base
Nine pivotal programs, more than 25,000 patients, and a sequence of indications that has moved well beyond glycemic control. Here is what each trial actually measured — and what it found.
Most recent: ESSENCE — semaglutide in MASH (2025)
The ESSENCE Phase 3 trial, published in the New England Journal of Medicine on June 5, 2025, was the first successful Phase 3 trial of a GLP-1 receptor agonist in metabolic dysfunction-associated steatohepatitis (MASH) — the inflammatory liver disease formerly called NASH[11].
ESSENCE Part 1
Resolution of steatohepatitis without worsening of fibrosis: 62.9% semaglutide vs 34.3% placebo. Fibrosis improvement without worsening of steatohepatitis: 36.8% vs 22.4%[11].
The regulatory submission was accepted with Priority Review. MASH is a leading driver of progressive liver disease in adults with obesity and type 2 diabetes, and prior to ESSENCE no GLP-1 RA had produced confirmatory Phase 3 histology data.
FLOW — kidney and cardiovascular outcomes in T2DM-CKD (2024)
The FLOW trial established semaglutide as the first GLP-1 receptor agonist with confirmed kidney-protective outcomes in patients with type 2 diabetes and chronic kidney disease[4].
FLOW
Composite of kidney failure, sustained >=50% eGFR decline, kidney death, or CV death — HR 0.76 (95% CI 0.66–0.88, P=0.0003). CV events HR 0.82, CV death HR 0.71, all-cause mortality HR 0.80[4].
A prespecified subgroup analysis published in the European Heart Journal found that the cardiovascular benefit was consistent across all KDIGO risk strata — overall CV-event HR 0.82 (95% CI 0.68–0.98), with stratum-specific HRs of 0.67–0.84 and no significant interaction[16]. In other words, the benefit did not drop off in patients with more advanced CKD. FDA approval for the kidney/CV-death indication followed in 2025.
SELECT — cardiovascular outcomes in obesity without diabetes (2023)
SELECT (Semaglutide Effects on Cardiovascular Outcomes in People with Overweight or Obesity) was the trial that broadened the cardiovascular case for GLP-1 therapy beyond the diabetes population[3].
SELECT
Composite of CV death, nonfatal MI, or nonfatal stroke: 6.5% semaglutide vs 8.0% placebo — HR 0.80 (95% CI 0.72–0.90, P<0.001). All-cause mortality HR 0.81; heart failure composite HR 0.82; mean weight loss 9.4%[3].
A subsequent 208-week analysis published in Nature Medicine in 2024 documented a sustained mean weight reduction of −10.2%, with 67.8% of participants achieving >=5% weight loss and 44.2% achieving >=10% — the longest randomized weight-loss follow-up for a GLP-1 RA to date[15]. The SELECT data drove the March 2024 FDA approval for cardiovascular risk reduction in obesity without diabetes.
STEP — weight management
The STEP (Semaglutide Treatment Effect in People with Obesity) program established the chronic-weight-management indication.
STEP 1
Mean body weight change −14.9% vs −2.4% placebo; treatment difference −12.4 percentage points (P<0.001). 86% achieved >=5% loss; 50% achieved >=15%[2].
STEP 5 · two-year durability
Mean weight change at week 104: −15.2% semaglutide vs −2.6% placebo (P<0.0001). 77% achieved >=5% loss vs 34% placebo[8].
STEP 8 · semaglutide vs liraglutide
Mean body weight change −15.8% semaglutide vs −6.4% liraglutide vs −1.9% placebo; treatment difference semaglutide vs liraglutide −9.4 percentage points (95% CI −12.0 to −6.8, P<0.001)[7].
STEP TEENS
Mean BMI change −16.1% semaglutide vs +0.6% placebo (P<0.001). 73% of semaglutide arm achieved >=5% weight loss; ~45% dropped below the BMI cutoff for clinical obesity[9].
STEP-HFpEF
Change in KCCQ-CSS: +16.6 semaglutide vs +8.7 placebo (estimated treatment difference +7.8 points; 95% CI 4.8–10.9, P<0.001). Mean body weight change −13.3% vs −2.6%[10].
SUSTAIN and PIONEER — type 2 diabetes
The original SUSTAIN program (SUSTAIN 1–5) covered the spectrum of type 2 diabetes treatment scenarios — treatment-naive (SUSTAIN 1), background metformin or TZD (SUSTAIN 2), exenatide ER comparator (SUSTAIN 3), insulin glargine comparator (SUSTAIN 4), and basal insulin add-on (SUSTAIN 5). Across these trials, HbA1c reductions ranged from 0.7% to 2.5% on 0.5 mg and from 0.9% to 2.8% on 1.0 mg, with body weight reductions of 3.5–6.5 kg[13].
SUSTAIN-6
MACE composite 6.6% semaglutide vs 8.9% placebo, HR 0.74 (95% CI 0.58–0.95, P<0.001 for noninferiority). Diabetic retinopathy complications HR 1.76 (95% CI 1.11–2.78, P=0.02) — reflected in the FDA prescribing information[1].
The SUSTAIN-6 signal for diabetic retinopathy complications appears to be driven by rapid HbA1c reduction in patients with pre-existing retinopathy rather than direct semaglutide toxicity. Coordinated ophthalmologic monitoring is recommended in patients with established retinopathy who start GLP-1 therapy.
SUSTAIN 7 · semaglutide vs dulaglutide
Mean HbA1c reduction: 1.5% (sema 0.5 mg) vs 1.1% (dula 0.75 mg); 1.8% (sema 1.0 mg) vs 1.4% (dula 1.5 mg). Significantly greater weight loss at both doses[6].
PIONEER 6
MACE HR 0.79 (95% CI 0.57–1.11, P<0.001 noninferiority). All-cause mortality 1.4% vs 2.8% placebo (HR 0.51, P=0.008); CV death HR 0.49[5].
PIONEER PLUS
HbA1c reduction −1.5% (14 mg), −1.8% (25 mg), −2.0% (50 mg). Body weight reduction −4.4 kg, −6.7 kg, −8.0 kg respectively[20].
Emerging research: alcohol use disorder
Beyond the metabolic indications, an exploratory area worth flagging is substance use. A single-site Phase 2 randomized clinical trial published in JAMA Psychiatry in 2025 tested low-dose semaglutide in 48 non-treatment-seeking adults with alcohol use disorder. The titration schedule was 0.25 mg weekly for four weeks, then 0.5 mg weekly for four weeks, then 1.0 mg for one week — a 9-week protocol[12].
Semaglutide in AUD
Significant reductions in laboratory grams of alcohol consumed, peak breath alcohol concentration, weekly alcohol craving, and heavy drinking days, with medium-to-large effect sizes. Reductions in cigarettes per day in smokers[12].
This is a small Phase 2 study, not a regulatory submission, but it has spurred larger trials of GLP-1 RAs in addiction medicine — a research arc to watch.
FDA approval timeline
| YEAR | INDICATION | BASIS |
|---|---|---|
Dec 2017 | Glycemic control, T2DM (subcutaneous, 0.5 / 1.0 mg) | SUSTAIN program |
Sep 2019 | Glycemic control, T2DM (oral, 7 / 14 mg) | PIONEER program |
Jun 2021 | Chronic weight management (adults, BMI >=30 or >=27 + comorbidity) | STEP program |
Dec 2022 | Chronic weight management (adolescents 12+) | STEP TEENS |
Mar 2024 | CV risk reduction (obesity/overweight, no diabetes) | SELECT |
2025 | Kidney/CV-death risk reduction (T2DM with CKD) | FLOW |
2025 | MASH with moderate-to-advanced fibrosis (submission, Priority Review) | ESSENCE |