# Semaglutide Research: The Trials, Organ by Organ > Semaglutide research, read in full: the ESSENCE liver trial, STEP weight data, SUSTAIN and SELECT cardiovascular outcomes, FLOW kidney results, and the comparison with tirzepatide. All cited. Liver first, then weight, heart, kidney, and the head-to-head — each finding a frame, each citation a caption. ## Start here Semaglutide research is unusually deep. Across more than a decade, the same molecule was tested in tens of thousands of people, and each large trial read it through a different organ — the pancreas and blood sugar, the brain and appetite, the heart, the kidney, and now the liver. This page walks that record finding by finding. A word on what these trials are. They are mostly randomized controlled trials — people are sorted by chance into the drug or a placebo (a dummy injection), so the two groups differ only in the treatment. That design is what lets a number like "14.9% weight loss" mean something. Where a result comes from a review or a pharmacovigilance database instead, this page says so. Every figure below is tied to a numbered study in the [Semaglutide references](/references), and none of it is dosing advice. ## The liver: ESSENCE and the MASH result The newest and, for this reading room, the leading finding is hepatic. In the ESSENCE phase-3 trial of 1,197 adults with biopsy-confirmed MASH and stage 2-3 fibrosis, once-weekly semaglutide 2.4 mg resolved steatohepatitis without worsening fibrosis in 62.9% of participants versus 34.3% on placebo — a 28.7 percentage-point difference (P<0.001) [8]. Fibrosis improved without worsening steatohepatitis in 36.8% versus 22.4%, a 14.4 percentage-point difference (P<0.001) [8]. What makes this remarkable is that MASH is largely silent. The benefit was read not from how people felt but from liver biopsies taken before and after — the histology changed. This is the evidence that anchored the 2025 MASH indication. ## Semaglutide weight loss: the STEP program The weight-loss evidence is the most familiar. In STEP 1, once-weekly subcutaneous semaglutide 2.4 mg produced a mean body-weight change of -14.9% from baseline to week 68, against -2.4% with placebo, in adults with overweight or obesity without diabetes [1] — and a companion report appeared in the Lancet [10]. The loss persisted with continued treatment: a two-year analysis (STEP 5) showed sustained, clinically meaningful reduction [1]. Durability cuts both ways. The STEP 4 withdrawal trial showed that continuing the drug kept weight falling while switching to placebo brought regain [20], and the STEP 1 extension recorded a mean regain of roughly 11.6 percentage points within a year of stopping [19]. The honest reading is that the effect is real and large while the drug is present, and that it depends on the drug being present. ## The heart: SUSTAIN-6 and SELECT Two cardiovascular-outcome trials carry the most weight. SUSTAIN-6 enrolled 3,297 people with type 2 diabetes at high cardiovascular risk; once-weekly semaglutide reduced the composite of cardiovascular death, nonfatal heart attack, or nonfatal stroke (HR 0.74; 95% CI 0.58-0.95) [2]. The same trial surfaced the retinopathy caution (HR 1.76) in people undergoing rapid glycemic correction [2]. SELECT extended the question to people without diabetes. Among 17,604 adults with established cardiovascular disease and a BMI of 27 or higher, semaglutide 2.4 mg reduced major adverse cardiovascular events by 20% versus placebo (HR 0.80; 95% CI 0.72-0.90; P<0.001) [3] — the result that established cardiovascular benefit beyond the diabetes setting. ## The kidney: FLOW The kidney evidence is recent and decisive. In the FLOW trial of 3,533 people with type 2 diabetes and chronic kidney disease, once-weekly semaglutide 1.0 mg reduced major kidney-disease events — kidney failure, a 50% or greater fall in filtration rate, or death from kidney or cardiovascular causes — by 24% versus placebo (HR 0.76; 95% CI 0.66-0.88) [6]. It is the trial that added an organ to the list. ## Glycemic control: SUSTAIN, PIONEER, and the comparisons Where semaglutide began was blood sugar. A meta-analysis of once-daily oral semaglutide reported reductions in HbA1c (a blood marker of average glucose over about three months) and body weight, with a cardiovascular profile consistent with the GLP-1 receptor agonist class [11]. In a head-to-head against another weekly GLP-1 agonist, dulaglutide, semaglutide produced greater HbA1c and weight reductions in SUSTAIN 7 [12]. And SUSTAIN FORTE showed that a 2.0 mg weekly dose lowered HbA1c more than the 1.0 mg dose, supporting a higher approved diabetes dose [13]. ## Semaglutide vs tirzepatide The most-asked comparison is with tirzepatide, a newer agent that activates two gut-hormone receptors (GIP and GLP-1) rather than one. In the SURMOUNT-5 head-to-head trial of 751 adults with obesity, tirzepatide produced greater mean weight loss than semaglutide at 72 weeks: -20.2% versus -13.7%, a difference of about 6.5 percentage points that was statistically significant (P<0.001) [7]. The two are different molecules with different targets; on the single axis of weight loss in this trial, tirzepatide went further, while semaglutide carries the deeper and broader outcomes record across heart, kidney, and liver [3][6][8]. ## Compounded semaglutide A note the literature insists on. During a federally declared shortage from roughly 2022 into early 2025, compounding pharmacies were permitted to prepare semaglutide outside the approved manufactured product. The compounding pathway was curtailed once the shortage was declared resolved in 2025 [23]. The approved-product evidence base summarized on this site — STEP, SUSTAIN, SELECT, FLOW, ESSENCE — was generated with the manufactured product; compounded or non-pharmaceutical sources fall outside that evidence base. This site documents the research record and does not source, supply, or evaluate any product. --- A dark reading room for an approved medicine's record — study summaries traced to their sources, never a prescription.