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    GLP-1 outcome trials explained: heart, kidney, liver and beyond

    Outcome trials test whether a drug prevents real events such as heart attacks or kidney failure, not just whether it lowers weight. Semaglutide cut major cardiovascular events by about 20% in SELECT and major kidney events by 24% in FLOW, and both results led to new FDA indications.[1][2][3][4]

    Editor reviewedStrict sourcingUpdated GLP-1 and metabolic medicineHealth and medicine

    Weight loss is a surrogate. What patients, doctors and payers care about is whether a drug prevents heart attacks, kidney failure, liver scarring or death. Outcome trials answer that, and since 2023 they have changed what GLP-1 drugs are approved for.[3][4][5]

    How to read an outcome trial

    In an outcome trial, thousands of people get either the drug or a dummy (placebo) for years. Researchers then count how many in each group have a serious event. Results are often reported as a “hazard ratio”: 0.80 means the event happened at about 80% of the placebo rate, a 20% relative reduction.[1] The absolute difference is usually smaller. In SELECT it was 6.5% versus 8.0% of patients over more than three years.[1]

    Most cardiovascular outcome trials use a time-to-first-event composite such as MACE (cardiovascular death, non-fatal myocardial infarction, non-fatal stroke). Some test superiority against placebo, as SELECT did. Others test non-inferiority against an active comparator, as SURPASS-CVOT did with a margin of 1.05.[1][6] Readers should watch for early stopping, active versus placebo comparators, and how discontinuations are handled.[2][7]

    Heart: SELECT and SURPASS-CVOT

    SELECT enrolled 17,604 adults aged 45 or older with cardiovascular disease, a BMI of 27 or more and no diabetes. Semaglutide 2.4 mg reduced the composite of cardiovascular death, heart attack or stroke (hazard ratio 0.80).[1] On 8 March 2024 the FDA approved Wegovy to reduce these risks, the first weight-loss medicine with such an indication.[3]

    SURPASS-CVOT compared tirzepatide with dulaglutide, an older GLP-1 drug with proven heart benefit, in 13,165 people with type 2 diabetes and heart disease. Tirzepatide met non-inferiority, but the superiority test was not significant (hazard ratio 0.92; P=0.09).[6]

    Kidney: FLOW

    FLOW randomised 3,533 people with type 2 diabetes and chronic kidney disease to semaglutide or placebo. It was stopped early at a prespecified interim analysis, after a median 3.4 years of follow-up. The risk of major kidney events, or kidney- or cardiovascular-related death, was 24% lower with semaglutide.[2] The FDA expanded Ozempic’s label to this population on 28 January 2025.[4]

    Liver: ESSENCE

    MASH (metabolic dysfunction-associated steatohepatitis) is an inflammatory form of fatty liver disease. In an interim analysis of ESSENCE, steatohepatitis resolved without worsening fibrosis in 62.9% of semaglutide patients versus 34.3% on placebo at 72 weeks.[8] In August 2025 the FDA granted Wegovy accelerated approval for noncirrhotic MASH with F2–F3 fibrosis. The decision rested on interim liver-biopsy results while the 240-week trial continues.[5][8]

    Sleep apnea and a negative result in Alzheimer’s

    In SURMOUNT-OSA, tirzepatide reduced breathing interruptions during sleep by 25.3 events per hour versus 5.3 on placebo.[9] On 20 December 2024 the FDA approved Zepbound as the first drug treatment for moderate-to-severe obstructive sleep apnea in adults with obesity.[10]

    Not every hoped-for benefit has held up. In the evoke and evoke+ trials, 3,808 adults with early Alzheimer’s disease took semaglutide or placebo. Novo Nordisk reported that the drug did not slow disease progression, although Alzheimer’s biomarkers improved.[11] The result is a reminder that biomarker changes do not always translate into clinical benefit.[11]

    Questions readers ask

    Did semaglutide reduce heart attacks in people without diabetes?

    In SELECT, among 17,604 adults with cardiovascular disease and overweight or obesity but no diabetes, the combined rate of cardiovascular death, heart attack or stroke was 6.5% on semaglutide versus 8.0% on placebo.[1]

    Are GLP-1 drugs approved for liver disease?

    In August 2025 the FDA granted Wegovy accelerated approval for noncirrhotic MASH with moderate to advanced fibrosis, based on the ESSENCE trial.[5][8]

    Did semaglutide work for Alzheimer's disease?

    No. Novo Nordisk reported in November 2025 that the evoke and evoke+ trials did not show slower disease progression, even though biomarkers improved.[11]

    Is tirzepatide better than older GLP-1 drugs for the heart?

    In SURPASS-CVOT, tirzepatide was non-inferior to dulaglutide for major cardiovascular events (hazard ratio 0.92), but superiority was not shown.[6]

    Sources

    Each numbered claim is a statement we checked against the sources listed with it. Status shows how well established it is.

    1. [1]

      In the SELECT trial of 17,604 adults aged 45 or older with cardiovascular disease and overweight or obesity but no diabetes, semaglutide 2.4 mg reduced cardiovascular death, heart attack or stroke to 6.5% versus 8.0% on placebo (hazard ratio 0.80). confirmedas of 2023-11-11

    2. [2]

      In the FLOW trial of 3,533 people with type 2 diabetes and chronic kidney disease, semaglutide lowered the risk of major kidney events or kidney- or cardiovascular-related death by 24% (hazard ratio 0.76); the trial stopped early at a prespecified interim analysis after a median 3.4 years of follow-up. confirmedas of 2024-05-24

    3. [3]

      On 8 March 2024 the FDA approved Wegovy to reduce the risk of cardiovascular death, heart attack and stroke in adults with cardiovascular disease and obesity or overweight, the first weight-loss medicine with such an indication. confirmedas of 2024-03-08

    4. [4]

      On 28 January 2025 the FDA expanded Ozempic's label to reduce kidney and cardiovascular risks in adults with type 2 diabetes and chronic kidney disease. confirmedas of 2025-01-28

    5. [5]

      In August 2025 the FDA granted Wegovy accelerated approval for noncirrhotic MASH with moderate to advanced (F2 to F3) liver fibrosis. confirmedas of 2025-08-15

    6. [6]

      In SURPASS-CVOT, tirzepatide was non-inferior but not shown superior to dulaglutide, a GLP-1 drug previously shown to reduce cardiovascular events, for cardiovascular death, heart attack or stroke in 13,165 people with type 2 diabetes and heart disease (hazard ratio 0.92), using a non-inferiority margin of 1.05. confirmedas of 2025-12-01

    7. [7]

      In SELECT, adverse events led to permanent discontinuation in 16.6% of semaglutide patients versus 8.2% on placebo. confirmedas of 2023-11-11

    8. [8]

      In part 1 of the ESSENCE trial in people with MASH and moderate or advanced liver fibrosis, steatohepatitis resolved without worsening fibrosis in 62.9% on semaglutide versus 34.3% on placebo at 72 weeks, in a planned interim analysis of the ongoing 240-week trial based on liver histology. confirmedas of 2025-04-30

    9. [9]

      In SURMOUNT-OSA trial 1, tirzepatide reduced the apnea-hypopnea index by 25.3 events per hour at 52 weeks versus 5.3 with placebo in adults with moderate-to-severe sleep apnea and obesity. confirmedas of 2024-06-21

    10. [10]

      On 20 December 2024 the FDA approved Zepbound for moderate to severe obstructive sleep apnea in adults with obesity, the first drug treatment for the condition. confirmedas of 2024-12-20

    11. [11]

      On 24 November 2025 Novo Nordisk reported that the evoke and evoke+ trials in 3,808 adults with early Alzheimer's disease did not show that semaglutide slowed disease progression, although Alzheimer's biomarkers improved. confirmedas of 2025-11-24

    Revision history (1)
    1. Page created.

    Created Oct 10, 2026. Last reviewed by an editor on Oct 10, 2026. Next scheduled review: Jan 10, 2027.

    Cite this page

    "GLP-1 outcome trials explained: heart, kidney, liver and beyond." ContentLora, updated Oct 10, 2026. https://contentlora.com/explain/glp-1-outcome-trials-explained

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