GLP-1 Medications, Heart and Liver: What Trials Show

By the Healthy Weight Loss 4 U Clinical Content Team · Published October 20, 2026 · Updated October 20, 2026 · 9 min read

Key takeaways

• SELECT randomized 17,604 adults aged 45 or older with established heart disease, a BMI of 27 or higher and no diabetes; the primary composite occurred in 6.5% on Wegovy versus 8.0% on placebo (hazard ratio 0.80) ^[2].
• The FDA added a cardiovascular risk-reduction indication to Wegovy on March 8, 2024, limited to adults with established cardiovascular disease and obesity or overweight ^[3].
• In ESSENCE, 62.9% of 534 semaglutide participants had steatohepatitis resolution without worse fibrosis at week 72, versus 34.3% of 266 on placebo ^[6].
• The Wegovy MASH indication (August 15, 2025) rests on liver biopsy findings at week 72, so it is an accelerated approval that depends on a confirmatory trial ^[1][5].
• Zepbound's label lists no cardiovascular risk-reduction indication, and the large tirzepatide trial in adults with obesity without diabetes (SURMOUNT-MMO, 15,374 enrolled) was listed as ongoing, with estimated primary completion in October 2027 ^[8][10].

What do heart and liver outcome trials test, and why do they matter?

Outcome trials test whether a medicine changes events that matter to patients, such as heart attacks, strokes and liver complications, rather than only weight or lab values. Weight loss trials tell us how much weight changes. Outcome trials follow people for years and count events, which is a harder test and takes far more participants.

The stakes are high. Heart disease is the leading cause of death in the United States, and 919,032 people died from cardiovascular disease in 2023, about 1 in every 3 deaths ^[11]. On the liver side, about 24% of US adults have NAFLD (also called MASLD), and about 1.5% to 6.5% have the inflamed form called NASH or MASH, which can lead to scarring (fibrosis), cirrhosis and a higher chance of liver-related death ^[12]. NAFLD is present in up to 75% of people with overweight and in more than 90% of people with severe obesity ^[12].

This article covers the two best-documented semaglutide trials, SELECT for the heart and ESSENCE for the liver, and then looks at where tirzepatide stands. For each, it states who was enrolled, what was measured and what has not been shown.

What did the SELECT trial find?

SELECT found that semaglutide, the active ingredient in Wegovy, lowered the risk of a first major cardiovascular event compared with placebo in adults with heart disease and overweight or obesity. The FDA label describes the trial as 17,604 people randomized, 8,803 to Wegovy and 8,801 to placebo, with a median follow-up of 41.8 months ^[2].

The primary outcome was a composite of cardiovascular death, nonfatal heart attack or nonfatal stroke. It occurred in 6.5% (569 people) on Wegovy and 8.0% (701 people) on placebo, a hazard ratio of 0.80 (95% confidence interval 0.72 to 0.90) ^[2]. That is a 1.5 percentage point absolute difference over the trial period. The trial was randomized, double-blind and placebo-controlled, and the sponsor was Novo Nordisk ^[4].

Read the components carefully. The label reports the lower risk of the combined outcome as statistically significant, and the heart attack and all-cause death results have confidence intervals that stay below 1.0. For cardiovascular death and stroke taken on their own, the confidence intervals include 1.0, so those individual results cannot be called conclusive by themselves ^[2].

Adverse events led to treatment discontinuation in 16.6% of the semaglutide group and 8.2% of the placebo group, mainly because of gastrointestinal intolerance ^[4].

Who was enrolled in SELECT, and who was not?

SELECT enrolled adults aged 45 or older with a BMI of 27 or higher and established cardiovascular disease, defined as a prior heart attack, prior stroke or peripheral artery disease, and it excluded people with type 1 or type 2 diabetes ^[2]. The mean age was 62, the mean body weight was 97 kg and the mean BMI was 33 ^[2]. About 28% of participants were women, so roughly 72% were men ^[4].

Both groups also received standard care, such as blood pressure and cholesterol management, and lifestyle counseling ^[3]. The semaglutide effect was therefore measured on top of usual heart care, not in place of it.

That enrollment tells you what the trial did not test:

• People without established cardiovascular disease. The trial did not enroll them, and the FDA indication is limited to adults who have it ^[2][3].
• People with diabetes. They were excluded, so SELECT cannot speak to them ^[2].
• People under 45. The minimum age was 45 ^[2].
• A population with equal numbers of women and men. Women were about 28% of participants ^[4].

The label also notes that among patients aged 75 and older, more hip and pelvis fractures and more serious adverse reactions occurred on Wegovy than on placebo compared with younger patients ^[2]. SELECT does not tell us whether results are the same for every subgroup, and several subgroup analyses were exploratory ^[4].

What does the Wegovy label say about heart risk reduction?

The Wegovy label includes an indication to reduce the risk of major adverse cardiovascular events (cardiovascular death, nonfatal heart attack or nonfatal stroke) in adults with established cardiovascular disease and either obesity or overweight, used with a reduced-calorie diet and increased physical activity ^[1]. The FDA announced this new indication on March 8, 2024 and described Wegovy as the first weight loss medication approved for this purpose ^[3].

The current label (revised June 2026 on DailyMed) separates this from the weight management indication, which covers chronic weight management in adults and in children 12 and older with obesity, and in adults with overweight plus a weight-related condition ^[1]. Wegovy tablets carry the same cardiovascular risk-reduction indication for adults, while the injection alone carries the MASH indication ^[1][2].

The FDA's 2024 announcement also lists the safety information that comes with the heart indication. There is a boxed warning for thyroid C-cell tumors, and Wegovy should not be used by people with a personal or family history of medullary thyroid carcinoma or Multiple Endocrine Neoplasia syndrome type 2 ^[3]. Warnings also cover pancreatitis, gallbladder problems, kidney injury and other issues, and the most common side effects include nausea, diarrhea, vomiting and constipation ^[3].

One distinction matters for anyone comparing options. The trial results and the label apply to the FDA-approved product that was studied. Compounded drugs are not FDA-approved, and the FDA does not review them for safety, effectiveness or quality before they are marketed ^[13]. No outcome trial like SELECT supports a benefit claim for a compounded product.

Is there heart outcome evidence for tirzepatide?

Not yet in the population SELECT studied. The Zepbound (tirzepatide) label, revised August 2026, lists two indications, chronic weight management and moderate to severe obstructive sleep apnea in adults with obesity, and it lists no cardiovascular risk-reduction indication ^[10].

The trial built to answer the question, SURMOUNT-MMO, is placebo-controlled and has an actual enrollment of 15,374 adults aged 40 or older with a BMI of 27 or higher who either have established cardiovascular disease or have risk factors, and who do not have diabetes. Its primary outcome is a composite of all-cause death, nonfatal heart attack, nonfatal stroke, coronary revascularization or heart failure events. The registry lists it as active, not recruiting, with an estimated primary completion date of October 2027 (record last updated January 12, 2026) ^[8].

A different tirzepatide trial has reported. SURPASS-CVOT compared tirzepatide with dulaglutide, another GLP-1 medication, in 13,165 adults with type 2 diabetes and established atherosclerotic cardiovascular disease. Major events occurred in 12% on tirzepatide and 13% on dulaglutide (hazard ratio 0.92); the trial met its noninferiority goal, but superiority was not demonstrated. It had no placebo group and was published in the New England Journal of Medicine on December 17, 2025 ^[9].

Because SURPASS-CVOT enrolled people with diabetes and used an active comparator, it should not be read as a tirzepatide version of SELECT. This article makes no claim that tirzepatide lowers heart events in adults with obesity and no diabetes, because that result has not been published in the sources reviewed.

What did the ESSENCE trial show for the liver?

ESSENCE showed that, at week 72, more adults with biopsy-confirmed MASH and moderate to advanced fibrosis on semaglutide had improvement in liver biopsy findings than adults on placebo. It is an ongoing phase 3, double-blind, placebo-controlled trial that randomized participants 2 to 1 and is planned to run 240 weeks; the published results are a planned interim analysis (part 1) of the first 800 participants, 534 on semaglutide and 266 on placebo ^[6].

Participants had biopsy-confirmed MASH with fibrosis stage 2 or 3 and, according to the FDA, all received lifestyle changes ^[5][6]. The two co-primary biopsy endpoints at week 72 were resolution of steatohepatitis without worsening of fibrosis, and improvement in fibrosis without worsening of steatohepatitis ^[6].

The differences were 28.7 percentage points for steatohepatitis resolution and 14.4 points for fibrosis improvement, both statistically significant. A secondary endpoint, resolution plus fibrosis improvement together, was reached by 32.7% on semaglutide and 16.1% on placebo, and mean body weight fell 10.5% versus 2.0% ^[6]. Gastrointestinal adverse events were more common with semaglutide ^[6].

Note that the placebo group improved too. A third of placebo participants saw steatohepatitis resolve ^[6], so some improvement occurred without the study drug under trial conditions.

What does the Wegovy MASH indication cover, and what is still unproven?

The FDA approved Wegovy on August 15, 2025 for adults with noncirrhotic MASH who have moderate to advanced liver fibrosis (stages F2 to F3), as an accelerated approval ^[5][1]. Accelerated approval means the drug was approved on a surrogate endpoint, here the biopsy result at week 72, and the label states that continued approval for this indication may be contingent on verification of clinical benefit in a confirmatory trial ^[1].

What the trial has not yet shown is the clinical benefit that patients care about. The FDA states that the trial will continue for a total of 240 weeks to learn whether the week-72 improvements lead to fewer deaths, liver transplants and other liver-related events ^[5]. The sponsor has said it expects the part 2 results in 2029 ^[7]. Until then, the evidence is about liver tissue, not about those events.

The label adds another caution. Semaglutide decreases liver fat, stiffness and other noninvasive markers, but the label says that the clinical relevance of these changes is yet to be confirmed ^[2].

The boundaries of the indication are specific:

• It is for noncirrhotic disease. The FDA announcement does not state that Wegovy is approved to treat cirrhosis ^[5].
• It names moderate to advanced fibrosis (F2 to F3), the stage studied in ESSENCE. Results in other stages were not reported in the sources reviewed ^[1][6].
• It applies to the injection. The Wegovy tablets are not indicated for MASH ^[1].
• It applies to the FDA-approved product, not to compounded versions ^[13].

The FDA's MASH announcement lists the same exclusion as other Wegovy uses: no use in people with a personal or family history of medullary thyroid carcinoma or MEN 2 ^[5].

What this means in practice

• Heart and liver benefits shown in trials belong to specific groups: adults with established cardiovascular disease and no diabetes in SELECT ^[2], and adults with biopsy-confirmed MASH and F2 to F3 fibrosis in ESSENCE ^[6].
• A cardiovascular risk-reduction indication is not the same as a weight management indication. The Wegovy label lists them separately ^[1].
• The SELECT difference was 6.5% versus 8.0% for major events over a median of 41.8 months, and discontinuation because of side effects was 16.6% versus 8.2% ^[2][4]. Both numbers belong in the decision.
• The MASH indication is an accelerated approval based on liver biopsy findings; outcomes such as liver transplant and death are still being studied through 240 weeks ^[1][5].
• Tirzepatide does not have a heart or liver outcome indication on its label, and its large obesity outcome trial is not yet complete according to the registry ^[8][10].
• Compounded semaglutide or tirzepatide is not FDA-approved and has not been reviewed by the FDA for safety, effectiveness or quality, so trial results cannot be assumed to carry over ^[13].
• Medicine is only one piece of care. Both trials gave participants background care: standard heart care and lifestyle counseling in SELECT, and lifestyle changes in ESSENCE ^[3][5].

When to talk to a clinician

Whether any of this applies to you depends on your own history: whether you have had a heart attack, stroke or peripheral artery disease, whether you have diabetes, how your liver has been assessed, and which other medicines you take. Trial results describe groups of people, and they cannot tell any one person what will happen. Only a licensed clinician who knows your history can weigh the evidence, the warnings and the alternatives.

At Healthy Weight Loss 4 U, every program begins with a clinician evaluation, and that evaluation is where to raise questions about your heart or liver health, including any past liver tests or heart diagnoses. Bring your records and your medication list. If you have chest pain, sudden weakness, trouble speaking, or yellowing of the skin or eyes, seek urgent medical care rather than waiting for an appointment.

Frequently asked questions

Sources

1. WEGOVY (semaglutide) injection and tablets, prescribing information (revised 6/2026). DailyMed, U.S. National Library of Medicine (Novo Nordisk label), 2026. dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=ee06186f-2aa3-4990-a760-757579d8f77b
2. WEGOVY prescribing information (revised 05/2026), sections 1, 8.5, 12.2 and 14.1. U.S. Food and Drug Administration, 2026. www.accessdata.fda.gov/drugsatfda_docs/label/2026/215256s031lbl218316s003lbl.pdf
3. FDA Approves First Treatment to Reduce Risk of Serious Heart Problems Specifically in Adults with Obesity or Overweight. U.S. Food and Drug Administration, 2024. www.fda.gov/news-events/press-announcements/fda-approves-first-treatment-reduce-risk-serious-heart-problems-specifically-adults-obesity-or
4. SELECT: Semaglutide and Cardiovascular Outcomes in Obesity Without Diabetes (Lincoff et al., N Engl J Med 2023;389:2221-32), trial summary. American College of Cardiology, 2023. www.acc.org/Latest-in-Cardiology/Clinical-Trials/2023/11/09/15/04/select
5. FDA Approves Treatment for Serious Liver Disease Known as MASH. U.S. Food and Drug Administration, 2025. www.fda.gov/drugs/news-events-human-drugs/fda-approves-treatment-serious-liver-disease-known-mash
6. Phase 3 Trial of Semaglutide in Metabolic Dysfunction-Associated Steatohepatitis (Sanyal et al.), N Engl J Med 392(21):2089-2099. New England Journal of Medicine, 2025. doi.org/10.1056/NEJMoa2413258
7. Wegovy approved in the US for the treatment of MASH (company announcement; sponsor source). Novo Nordisk, 2025. www.novonordisk.com/news-and-media/news-and-ir-materials/news-details.html?id=916416
8. A Study of Tirzepatide on the Reduction on Morbidity and Mortality in Adults With Obesity (SURMOUNT-MMO), NCT05556512. ClinicalTrials.gov, U.S. National Library of Medicine, 2026. clinicaltrials.gov/study/NCT05556512
9. SURPASS-CVOT: Is Tirzepatide Superior to Dulaglutide in Patients With T2D and ASCVD? (journal scan of N Engl J Med 2025 report). American College of Cardiology, 2026. www.acc.org/Latest-in-Cardiology/Journal-Scans/2026/01/07/14/20/SURPASS-CVOT
10. ZEPBOUND (tirzepatide) prescribing information (revised 08/2026). Eli Lilly and Company (FDA-approved labeling), 2026. pi.lilly.com/us/zepbound-uspi.pdf
11. Heart Disease Facts and Statistics. Centers for Disease Control and Prevention, 2024. www.cdc.gov/heart-disease/data-research/facts-stats/index.html
12. Definition and Facts of NAFLD and NASH. National Institute of Diabetes and Digestive and Kidney Diseases (NIH), 2026. www.niddk.nih.gov/health-information/liver-disease/nafld-nash/definition-facts
13. FDA's Concerns with Unapproved GLP-1 Drugs Used for Weight Loss. U.S. Food and Drug Administration, 2026. www.fda.gov/drugs/postmarket-drug-safety-information-patients-and-providers/fdas-concerns-unapproved-glp-1-drugs-used-weight-loss

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