# Semaglutide research summary — landmark trials and outcome data

> A trial-by-trial summary of the semaglutide evidence base: SUSTAIN, STEP, SELECT, FLOW, PIONEER, ESSENCE. Real hazard ratios, populations, and durations, with primary citations.

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.

## 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.

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An independent summary of published clinical-trial evidence — not medical advice, not a clinic, not a prescription.