The trials that built the semaglutide evidence base

The evidence, in plain terms

The semaglutide research record is unusually deep for a single molecule: nine or more pivotal Phase 3 programs, more than 25,000 trial participants, and a sequence of indications that has moved well beyond blood-sugar control.

The glucose story came first. In type 2 diabetes, semaglutide reliably lowers HbA1c — the three-month average blood-sugar marker — and reduces body weight. Then came the outcome trials: SUSTAIN-6 cut heart events in people with diabetes; SELECT cut them in people with obesity and established heart disease but without diabetes; FLOW slowed kidney decline in diabetes with chronic kidney disease; ESSENCE established a liver-disease benefit in MASH.

Every number on this page is attributed to its trial. Where a study found a downside — the retinopathy signal in SUSTAIN-6, the weight-regain pattern after stopping — that finding is in the same block, not footnoted away.

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 enrolled 800 adults with biopsy-confirmed MASH and fibrosis stage 2 or 3. Participants received subcutaneous semaglutide 2.4 mg once weekly or placebo for 72 weeks before an interim primary analysis. Two histologic endpoints were prespecified:

• Resolution of steatohepatitis without worsening of fibrosis — achieved in 62.9% of semaglutide-treated patients vs 34.3% of placebo.
• Improvement in liver fibrosis without worsening of steatohepatitis — achieved in 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 randomized 3,533 adults with type 2 diabetes and CKD (eGFR 25–75 mL/min/1.73 m^2, with albuminuria) to subcutaneous semaglutide 1.0 mg weekly or placebo. The primary composite outcome combined kidney failure, sustained >=50% eGFR decline, kidney death, and cardiovascular death.

Over a median 3.4 years of follow-up, the composite outcome favored semaglutide with a hazard ratio of 0.76 (95% CI 0.66–0.88, P=0.0003). Secondary outcomes were consistent: cardiovascular events HR 0.82, CV death HR 0.71, all-cause mortality HR 0.80. The trial was stopped early for efficacy ^[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 randomized 17,604 adults aged 45 and older with established cardiovascular disease and BMI >=27, without diabetes, to subcutaneous semaglutide 2.4 mg weekly or placebo. Over a mean follow-up of approximately 40 months, the composite of cardiovascular death, nonfatal MI, or nonfatal stroke occurred in 6.5% of the semaglutide arm and 8.0% of placebo — HR 0.80 (95% CI 0.72–0.90, P<0.001) ^[3].

Secondary outcomes also favored semaglutide: all-cause mortality HR 0.81 (95% CI 0.71–0.93), and a heart failure composite HR 0.82 (95% CI 0.71–0.96). Mean body weight loss was 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 randomized 1,961 adults with BMI >=30 (or >=27 with a weight-related comorbidity) and no diabetes to subcutaneous semaglutide 2.4 mg weekly or placebo for 68 weeks. Mean body weight change was -14.9% vs -2.4% placebo, a treatment difference of -12.4 percentage points (P<0.001). 86% of the semaglutide arm achieved >=5% weight loss; 50% achieved >=15% ^[2].

STEP 5 extended the duration: 304 adults treated for 104 weeks lost a mean -15.2% (vs -2.6% placebo), demonstrating durability of the effect through two years ^[8].

STEP 8 was a head-to-head comparison with daily liraglutide. Over 68 weeks, semaglutide 2.4 mg weekly produced mean weight loss of -15.8% vs -6.4% for liraglutide 3.0 mg daily — a treatment difference of -9.4 percentage points (95% CI -12.0 to -6.8, P<0.001) ^[7].

STEP TEENS extended the indication to adolescents 12 and older. In 201 adolescents with BMI at or above the 95th percentile, mean BMI change at 68 weeks was -16.1% for semaglutide vs +0.6% for placebo; 73% of the semaglutide arm achieved >=5% weight loss, and roughly 45% dropped below the clinical obesity BMI cutoff ^[9].

STEP-HFpEF tested semaglutide in 529 adults with obesity and heart failure with preserved ejection fraction (LVEF >=45%). Over 52 weeks, the Kansas City Cardiomyopathy Questionnaire Clinical Summary Score improved by +16.6 points on semaglutide vs +8.7 on placebo — a +7.8 point treatment difference (95% CI 4.8–10.9, P<0.001) — alongside -13.3% weight loss ^[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, the cardiovascular safety trial, randomized 3,297 adults with T2DM at high CV risk to semaglutide 0.5 mg or 1.0 mg weekly. Over 104 weeks, the MACE composite occurred in 6.6% of the semaglutide arm vs 8.9% of placebo — HR 0.74 (95% CI 0.58–0.95, P<0.001 for noninferiority). The trial also surfaced a signal of increased diabetic retinopathy complications in the semaglutide arm (HR 1.76, 95% CI 1.11–2.78, P=0.02), which is reflected in the FDA prescribing information ^[1].

SUSTAIN 7 was a head-to-head against dulaglutide. Over 40 weeks in 1,201 adults on background metformin, mean HbA1c reduction was 1.5% for semaglutide 0.5 mg (vs 1.1% for dulaglutide 0.75 mg) and 1.8% for semaglutide 1.0 mg (vs 1.4% for dulaglutide 1.5 mg), with significantly greater weight loss at both doses ^[6].

PIONEER 6 was the cardiovascular safety trial for oral semaglutide. In 3,183 adults with T2DM at high CV risk, oral semaglutide 14 mg daily met the noninferiority threshold for MACE (HR 0.79, 95% CI 0.57–1.11). Notably, all-cause mortality was 1.4% vs 2.8% placebo (HR 0.51, P=0.008) and CV death HR was 0.49 — though the trial was not powered for superiority ^[5].

PIONEER PLUS investigated high-dose oral semaglutide. In 1,606 adults inadequately controlled on 1–3 oral agents, HbA1c reductions at 52 weeks were -1.5% (14 mg), -1.8% (25 mg), and -2.0% (50 mg), with body-weight reductions of -4.4 kg, -6.7 kg, and -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].

The trial reported 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 were observed in smokers as a secondary signal ^[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.