Tirzepatide tops semaglutide for cardiometabolic protection in MASLD
The study authors recommend prospective head-to-head trials to validate the findings.
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11/21/2025
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by Doug Brunk
In a propensity-matched real-world cohort of adults with metabolic-associated steatotic liver disease (MASLD), use of tirzepatide was associated with a 70% reduction in major adverse cardiovascular events (MACE), fewer hospitalizations, and greater weight loss over three years compared with use of semaglutide.
“Cardiovascular disease (CVD) is the primary driver of mortality in patients with MASLD, yet pharmacotherapy addressing cardiometabolic risk factors are scarce,” presenting author Himsikhar Khataniar, a third-year internal medicine resident at Allegheny General Hospital, Pittsburgh, Pa., and colleagues wrote in a poster abstract presented during the annual meeting of the American Association for the Study of Liver Diseases. “Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) address weight and hyperglycemia, but dual incretin agonists that also stimulate glucose-dependent insulinotropic polypeptide (GIP) receptors may confer additional benefits. Tirzepatide, the first GLP-1/GIP co-agonist has outperformed semaglutide for weight and glycemic control in clinical trials. However, direct CVD data in MASLD are limited.”
Drawing from the U.S. TriNetX network, the researchers identified adults with an ICD-10 diagnosis of fatty liver disease and at least one metabolic risk factor (diabetes, obesity, hypertension, or dyslipidemia) who first filled a prescription for tirzepatide or semaglutide between January 2015 and December 2021. They excluded individuals with other liver diseases, prior GLP-1 RA use, bariatric surgery, critical-care admission, liver transplantation, previous MACE, or major liver outcomes, and used one-to-one propensity-score matching to balance age, sex, race, body-mass index (BMI), diabetes, hypertension, and dyslipidemia between treatment groups. The primary endpoint was a three-year composite MACE. Secondary endpoints included individual cardiovascular events, acute heart failure, all-cause mortality, all-cause hospitalization, and change in BMI.
Among 15,538 eligible MASLD patients, 1,500 initiated tirzepatide and 14,038 initiated semaglutide; propensity matching produced 1,497 patients in each cohort with well-balanced baseline characteristics. Over three years, tirzepatide was associated with a lower incidence of MACE compared with semaglutide (1.3% vs 4.1%). Myocardial infarction occurred less frequently with tirzepatide (0.7% vs 2%), while rates of stroke and acute heart failure were numerically lower but not statistically different compared with semaglutide. Tirzepatide also reduced all-cause hospitalization (21.3% vs 30.7%), while mortality remained low in both groups (≤0.67%). BMI reduction was greater with tirzepatide (–4.1 vs –2.2 kg/m²).
“These findings suggest that dual GLP-1/GIP receptor agonism provides superior cardiometabolic protection compared to GLP-1 monotherapy,” the authors concluded. “Prospective head-to-head clinical trials are warranted to validate these cardiovascular and liver-related benefits and to guide optimal therapeutic strategies for this high-risk population.”
They did not report having conflicts of interest.
Summary content
7 Key Takeaways
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The guidelines emphasize four-hour gastric emptying studies over two-hour testing. How do you see this affecting diagnostic workflows in practice?
Dr. Staller: Moving to a four-hour solid-meal scintigraphy will actually simplify decision-making. The two-hour reads miss a meaningful proportion of delayed emptying; standardizing on four hours reduces false negatives and the “maybe gastroparesis” purgatory that leads to repeat testing. Practically, it means closer coordination with nuclear medicine (longer slots, consistent standardized meal), updating order sets to default to a four-hour protocol, and educating front-line teams so patients arrive appropriately prepped. The payoff is fewer equivocal studies and more confident treatment plans.
Metoclopramide and erythromycin are the only agents conditionally recommended for initial therapy. How does this align with what is being currently prescribed?
Dr. Staller: This largely mirrors real-world practice. Metoclopramide remains the only FDA-approved prokinetic for gastroparesis, and short “pulsed” erythromycin courses are familiar to many of us—recognizing tachyphylaxis limits durability. Our recommendation is “conditional” because the underlying evidence is modest and patient responses are heterogeneous, but it formalizes what many clinicians already do: start with metoclopramide (lowest effective dose, limited duration, counsel on neurologic adverse effects) and reserve erythromycin for targeted use (exacerbations, bridging).
Several agents, including domperidone and prucalopride, received recommendations against first-line use. How will that influence discussions with patients who ask about these therapies?
Dr. Staller: Two points I share with patients: evidence and access/safety. For domperidone, the data quality is mixed, and US access is through an FDA IND mechanism; you’re committing patients to EKG monitoring and a non-trivial administrative lift. For prucalopride, the gastroparesis-specific evidence isn’t strong enough yet to justify first-line use. So, our stance is not “never,” it’s just “not first.” If someone fails or cannot tolerate initial therapy, we can revisit these options through shared decision-making, setting expectations about benefit, monitoring, and off-label use. The guideline language helps clinicians have a transparent, evidence-based conversation at the first visit.
The guidelines suggest reserving procedures like G-POEM and gastric electrical stimulation for refractory cases. In your practice, how do you decide when a patient is “refractory” to medical therapy?
Dr. Staller: I define “refractory” with three anchors.
1. Adequate trials of foundational care: dietary optimization and glycemic control; an antiemetic; and at least one prokinetic at appropriate dose/duration (with intolerance documented if stopped early).
2. Persistent, function-limiting symptoms: ongoing nausea/vomiting, weight loss, dehydration, ER visits/hospitalizations, or malnutrition despite the above—ideally tracked with a validated instrument (e.g., GCSI) plus nutritional metrics.
3. Objective correlation: delayed emptying on a standardized 4-hour solid-meal study that aligns with the clinical picture (and medications that slow emptying addressed).
At that point, referral to a center with procedural expertise for G-POEM or consideration of gastric electrical stimulation becomes appropriate, with multidisciplinary evaluation (GI, nutrition, psychology, and, when needed, surgery).
What role do you see dietary modification and glycemic control playing alongside pharmacologic therapy in light of these recommendations?
Dr. Staller: They’re the bedrock. A small-particle, lower-fat, calorie-dense diet—often leaning on nutrient-rich liquids—can meaningfully reduce symptom burden. Partnering with dietitians early pays dividends. For diabetes, tighter glycemic control can improve gastric emptying and symptoms; I explicitly review medications that can slow emptying (e.g., opioids; consider timing/necessity of GLP-1 receptor agonists) and encourage continuous glucose monitor-informed adjustments. Pharmacotherapy sits on top of those pillars; without them, medications will likely underperform.
The guideline notes “considerable unmet need” in gastroparesis treatment. Where do you think future therapies or research are most urgently needed?
Dr. Staller: I see three major areas.
1. Truly durable prokinetics: agents that improve emptying and symptoms over months, with better safety than legacy options (e.g., next-gen motilin/ghrelin agonists, better-studied 5-HT4 strategies).
2. Endotyping and biomarkers: we need to stop treating all gastroparesis as one disease. Clinical, physiologic, and microbiome/omic signatures that predict who benefits from which therapy (drug vs G-POEM vs GES) would transform care.
3. Patient-centered trials: larger, longer RCTs that prioritize validated symptom and quality-of-life outcomes, include nutritional endpoints, and reflect real-world medication confounders.
Our guideline intentionally highlights these gaps to hopefully catalyze better trials and smarter referral pathways.
Dr. Staller is with the Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston.