# Cardiovascular, Renal, and Hepatic Outcome Trials

> Heart, Kidney, and Liver Data at Semaglutide New Mexico — A detailed semaglutide New Mexico review of SUSTAIN-6, SELECT, STEP-HFpEF, FLOW chronic kidney disease data, and ESSENCE steatohepatitis biopsy outcomes.

**Part Three · Cardiovascular, Renal & Hepatic Outcomes**

How human trials tested semaglutide across 3,297 patients with diabetes in SUSTAIN-6, 17,604 patients without diabetes in SELECT, 3,533 kidney disease patients in FLOW, and 1,197 liver biopsy patients in ESSENCE.

## Multi-Organ Outcome Highlights

- SUSTAIN-6 (2016, n = 3,297) and SELECT (2023, n = 17,604) demonstrated cardiovascular event reductions in patients with and without type 2 diabetes.
- STEP-HFpEF (2023) showed improvements in KCCQ symptom/physical-limitation score in patients with obesity-related heart failure with preserved ejection fraction.
- FLOW (2024, n = 3,533) cut the primary kidney-disease composite (kidney failure, at least 50% eGFR decline, or kidney/cardiovascular death) by 24% (HR 0.76; 95% CI 0.66-0.88) using a 1.0 mg once-weekly subcutaneous dose.
- ESSENCE (2025, n = 800 interim of 1,197) resolved steatohepatitis without worsening fibrosis in 62.9% vs 34.3% placebo and improved fibrosis without worsening steatohepatitis in 36.8% vs 22.4%.

## From SUSTAIN-6 in Type 2 Diabetes to SELECT and STEP-HFpEF in Obesity

Cardiovascular outcome trials tested subcutaneous semaglutide first in patients with type 2 diabetes and later in adults with overweight or obesity without diabetes, starting with the 2016 [SUSTAIN-6 cardiovascular outcomes trial](https://pubmed.ncbi.nlm.nih.gov/27633186/). Marso and colleagues enrolled 3,297 patients with type 2 diabetes at high cardiovascular risk and assigned them to once-weekly 0.5 mg or 1.0 mg subcutaneous dosing. The active arms lowered the composite of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke (HR 0.74; 95% CI 0.58-0.95; P<0.001 for noninferiority), while also flagging a diabetic retinopathy complication signal (HR 1.76; 95% CI 1.11-2.78; P=0.02).

Seven years later, the 2023 [SELECT cardiovascular trial in obesity](https://pubmed.ncbi.nlm.nih.gov/37952131/) asked whether similar cardiovascular protection occurred in patients without diabetes. Lincoff and colleagues enrolled 17,604 adults with preexisting cardiovascular disease and a body mass index of 27 or greater receiving once-weekly 2.4 mg subcutaneous semaglutide or placebo. SELECT found a 20% relative risk reduction in major adverse cardiovascular events versus placebo (HR 0.80; 95% CI 0.72-0.90; P<0.001).

Also in 2023, Kosiborod and colleagues reported the [STEP-HFpEF preserved ejection fraction trial](https://pubmed.ncbi.nlm.nih.gov/37622681/). In patients with obesity-related heart failure with preserved ejection fraction, once-weekly 2.4 mg subcutaneous dosing improved heart-failure-related symptoms and physical limitations on the KCCQ symptom/physical-limitation score and produced greater weight loss than placebo.

![Chronological timeline of published semaglutide studies from SUSTAIN-6 in 2016 through ESSENCE and SURMOUNT-5 in 2025](images/organ-trial-timeline.svg)

*Chronology of published semaglutide studies from 2016 to 2025: [SUSTAIN-6](https://pubmed.ncbi.nlm.nih.gov/27633186/) (2016), the [JCI Insight rodent neural study](https://pubmed.ncbi.nlm.nih.gov/32213703/) (2020), [STEP 1](https://pubmed.ncbi.nlm.nih.gov/33567185/) and the [safety review](https://pubmed.ncbi.nlm.nih.gov/34305810/) (2021), [STEP 5](https://pubmed.ncbi.nlm.nih.gov/36216945/) and [STEP TEENS](https://pubmed.ncbi.nlm.nih.gov/36322838/) (2022), [SELECT](https://pubmed.ncbi.nlm.nih.gov/37952131/) and [STEP-HFpEF](https://pubmed.ncbi.nlm.nih.gov/37622681/) (2023), [FLOW](https://pubmed.ncbi.nlm.nih.gov/38785209/) (primary kidney-disease composite of kidney failure, at least 50% eGFR decline, or kidney/cardiovascular death) and the [StatPearls monograph](https://www.ncbi.nlm.nih.gov/books/NBK603723/) (2024), and [ESSENCE](https://pubmed.ncbi.nlm.nih.gov/40305708/) (steatohepatitis resolution without worsening fibrosis), [SURMOUNT-5](https://pubmed.ncbi.nlm.nih.gov/40353578/), and the [alcohol use disorder trial](https://pubmed.ncbi.nlm.nih.gov/39937469/) (2025).*

- **0.74** — Hazard ratio for MACE in SUSTAIN-6 (95% CI 0.58-0.95)
- **0.80** — Hazard ratio for MACE in SELECT across 17,604 adults (20% lower risk)
- **0.76** — Hazard ratio for primary kidney-disease composite (kidney failure, at least 50% eGFR decline, or kidney/CV death) in FLOW
- **62.9%** — Steatohepatitis resolution without worsening fibrosis in ESSENCE vs 34.3% on placebo

## Renal Protection in FLOW (2024) and Biopsy Resolution in ESSENCE (2025)

The 2024 [FLOW chronic kidney disease study](https://pubmed.ncbi.nlm.nih.gov/38785209/) by Perkovic and colleagues enrolled 3,533 patients with type 2 diabetes and chronic kidney disease. Participants received once-weekly 1.0 mg subcutaneous semaglutide or placebo. Treatment reduced the primary composite of major kidney-disease events—defined as kidney failure, a 50% or greater decline in estimated glomerular filtration rate (eGFR), or death from kidney or cardiovascular causes—by 24% compared with placebo (HR 0.76; 95% CI 0.66-0.88). When I review FLOW alongside SUSTAIN-6, I note this dosing distinction: FLOW studied 1.0 mg once weekly; SUSTAIN-6 studied 0.5 mg or 1.0 mg once weekly, with the reported cardiovascular result covering those studied doses.

In hepatology, Sanyal and the ESSENCE Study Group published 2025 Phase 3 data from their [trial in metabolic dysfunction-associated steatohepatitis](https://pubmed.ncbi.nlm.nih.gov/40305708/) (MASH). The trial enrolled 1,197 patients with biopsy-confirmed MASH and stage 2-3 liver fibrosis, with an interim analysis of 800 patients. Once-weekly 2.4 mg subcutaneous dosing achieved resolution of steatohepatitis without worsening of liver fibrosis in 62.9% of treated patients versus 34.3% on placebo (a difference of 28.7 percentage points; P<0.001). Improvement in liver fibrosis without worsening of steatohepatitis occurred in 36.8% of the semaglutide group versus 22.4% of the placebo group (a difference of 14.4 percentage points; P<0.001).

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On Semaglutide New Mexico, I share my own notes on published research for educational reading only, offering no medical advice, clinical care, or treatment instructions.