What this is
- This study compares the effectiveness of tirzepatide () and thiazolidinediones () in treating metabolic dysfunction-associated steatotic liver disease ().
- Using a large real-world dataset, the researchers matched patients initiating either treatment to assess clinical outcomes.
- The primary outcome was a composite measure including mortality and major adverse events related to liver, cardiovascular, and kidney health.
Essence
- Tirzepatide () is associated with lower risks of all-cause mortality and major adverse events compared to thiazolidinediones () in adults with .
Key takeaways
- use resulted in a 34% lower risk of the primary composite outcome compared to (HR, 0.66; 95% CI, 0.54–0.82). This indicates that patients on experienced fewer serious health events related to liver, cardiovascular, and kidney functions.
- was linked to a 52% reduction in all-cause mortality (HR, 0.48; 95% CI, 0.32–0.71) and a 50% reduction in major adverse kidney events (HR, 0.50; 95% CI, 0.36–0.69). These findings suggest may offer significant survival benefits.
- The study's results were consistent across various patient subgroups, reinforcing the potential of as a preferred treatment option for .
Caveats
- The observational design limits causal inference, meaning the findings cannot definitively establish that is superior to .
- Potential residual confounding exists, particularly related to prior GLP-1 receptor agonist use, which may influence outcomes.
- The study's follow-up duration was relatively short, which may not capture long-term outcomes associated with either treatment.
Definitions
- MASLD: A liver disease characterized by fat accumulation in the liver, associated with metabolic syndrome components.
- TZP: Tirzepatide, a dual agonist of GIP and GLP-1 receptors used for managing metabolic disorders.
- TZD: Thiazolidinediones, a class of medications used to improve insulin sensitivity and manage diabetes.
Simplified
Introduction
Metabolic dysfunction-associated steatotic liver disease (MASLD), previously referred to as non-alcoholic fatty liver disease (NAFLD), represents a significant and growing global health challenge, affecting an estimated 25%–30% of the adult population worldwide (Younossi et al., 2025; European Association for the Study of the Liver, 2024). Projections suggest that by 2040, the global prevalence of MASLD among adults will exceed 55% (Younossi et al., 2025). MASLD comprises a continuum of liver conditions ranging from simple steatosis to metabolic dysfunction-associated steatohepatitis (MASH), with potential progression to cirrhosis and hepatocellular carcinoma (HCC) (Owrangi et al., 2025). The condition is strongly associated with metabolic syndrome components, including obesity, T2D, dyslipidemia, and hypertension. In addition to liver-related morbidity, patients with MASLD face heightened risks of cardiovascular mortality, chronic kidney disease, and extrahepatic malignancies, all of which contribute to significant healthcare costs (Zhou et al., 2024; Ciardullo et al., 2024; Chan et al., 2024).
Considering its rising global burden and serious clinical consequences, there is an urgent need for effective pharmacologic treatments for MASLD. Thiazolidinediones (TZDs) have demonstrated benefits in several randomized controlled trials (RCTs) (Lee et al., 2025; Ratziu et al., 2008; Promrat et al., 2004) and meta-analyses (Mahady et al., 2011; Musso et al., 2017) showing improvements in liver histology, including reductions in steatosis, inflammation, and fibrosis. These findings have supported the use of TZDs to slow disease progression in patients with MASLD or MASH. Current guidelines recommend TZDs, along with sodium-glucose cotransporter 2 inhibitors (SGLT2is) and glucagon-like peptide-1 receptor agonists (GLP-1RAs), for patients with MASLD and T2D (Diaz et al., 2025; American Diabetes Association Professional Practice Committee, 2025). However, the clinical use of TZDs may be constrained by adverse effects such as weight gain, fluid retention, and an elevated risk of heart failure (Tang et al., 2003; Karalliedde and Buckingham, 2007).
To address these limitations, attention has turned to newer agents with more favorable safety and metabolic profiles. Tirzepatide (TZP), a dual glucose-dependent insulinotropic polypeptide (GIP) and GLP-1 receptor agonist, has shown considerable promise. In addition to its glucose-lowering effects, TZP induces substantial weight loss and may offer cardiovascular and heart failure benefits (Karalliedde and Buckingham, 2007; Jastreboff et al., 2022; Lin et al., 2025). SYNERGY-NASH trial demonstrated that TZP significantly improved MASH resolution without worsening fibrosis when compared to placebo (Loomba et al., 2024). Moreover, nearly half of the patients treated with TZP achieved at least a one-stage improvement in fibrosis without worsening MASH, compared to 30% in the placebo group (Loomba et al., 2024).
Despite the established benefits of TZDs in MASLD and the emerging promise of tirzepatide demonstrated in the SYNERGY-NASH trial (Loomba et al., 2024), Prior network meta-analyses suggest that GLP-1RA outperform TZDs in reducing liver fat content, BMI, and waist circumference in overweight or obese patients with MASLD outcomes (Park et al., 2023). However, whether TZP’s dual GIP/GLP-1 receptor agonism translates into superior real-world effectiveness over TZDs across the broader spectrum of MASLD outcomes, including liver-related, cardiovascular, and renal endpoints, remains unknown. To fill this important knowledge gap, we conducted a retrospective cohort study using a large real-world database to evaluate the comparative effectiveness of TZP versus TZD in adults diagnosed with MASLD.
Methods
Data source
This retrospective cohort study utilized data from the TriNetX research network, a global federated platform comprising electronic health records from approximately 170 million individuals from 146 healthcare organizations (HCOs) across North America, Europe, the Middle East, and the Asia-Pacific region. The dataset includes comprehensive clinical information such as diagnoses, prescriptions, laboratory findings, procedures, and genomic profiles. The Chi Mei Hospital institutional review board approved this TriNetX database study (approval number: 11402-E02) and waived the requirement for informed consent since the research used only aggregated statistical data from de-identified sources. All study procedures were conducted in accordance with the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines.
Study design
We identified adult individuals (≥18 years) with a diagnosis of MASLD who initiated either TZP or TZD therapy between 1 January 2022, and 31 May 2025. MASLD was defined based on the presence of hepatic steatosis, determined by diagnostic codes for NAFLD or nonalcoholic steatohepatitis (NASH), in combination with at least one cardiometabolic risk factor. These included insulin resistance (evidenced by a diagnosis of T2D, hemoglobin A1c ≥ 5.7%, use of antidiabetic agents, or fasting plasma glucose ≥100 mg/dL), central obesity (body mass index [BMI] ≥ 25 kg/m2 or waist circumference ≥94 cm), elevated blood pressure (systolic blood pressure [SBP] ≥ 130 mmHg, diastolic blood pressure ≥85 mmHg, or use of antihypertensives), reduced high-density lipoprotein cholesterol (HDL <40 mg/dL or the use of lipid-modifying therapy), and hypertriglyceridemia (triglyceride concentration ≥150 mg/dL) (Kuo et al., 2025a; Kuo et al., 2025b).
Participants were categorized into two groups based on treatment exposure. The TZP group included individuals who initiated TZP following a diagnosis of MASLD, whereas the TZD group consisted of those who commenced TZD therapy after their MASLD diagnosis. The index date was defined as the date of the first prescription of the assigned study drug. To preserve the integrity of the new-user design and avoid misclassification bias, individuals were excluded if they: (1) had prior exposure to the assigned treatment before the index date; (2) experienced any study outcomes, including major adverse cardiovascular events (MACEs), major adverse kidney events (MAKEs), or major adverse liver outcomes (MALOs) before the index date; (3) received the comparator drug at any time prior to the index date; or (4) had insufficient follow-up information. A detailed description of all definitions and coding algorithms used to identify baseline characteristics, clinical conditions, medications, procedures, and laboratory values is provided in. Supplementary Table 1
Covariates and propensity score matching
After defining the study groups, index dates, outcomes, and relevant covariates, we constructed a baseline covariate matrix using data collected during the 12-month period preceding each patient’s index date. Propensity scores were estimated using logistic regression models, which calculated the likelihood of assignment to the TZD group based on observed baseline characteristics. We implemented 1:1 matching between groups using a greedy nearest-neighbor algorithm with a caliper of 0.1 pooled standard deviations, ensuring optimal alignment between individuals in the smaller and larger cohorts. Covariate balance between matched groups was assessed using standardized mean differences (SMD), with values below 0.1 indicating acceptable balance (Haukoos and Lewis, 2015).
The propensity score matching (PSM) procedure accounted for a comprehensive range of baseline covariates. Demographic variables included age (years), sex (female or male), and race (White, Black or African American, Asian, Other, or Unknown). Clinical comorbidities considered in the matching included T2D, dyslipidemia, overweight and obesity, chronic kidney disease, nicotine dependence, alcohol-related disorders, chronic lower respiratory diseases, ischemic heart diseases, cerebrovascular diseases, heart failure, atrial fibrillation and flutter, obstructive sleep apnea, neoplasms, fatty liver, hepatic fibrosis, MASH, and cirrhosis. T2D-related complications were classified into kidney, ophthalmic, neurological, and circulatory categories. Medication use was included in the covariates and covered both antihypertensive agents, including angiotensin-converting enzyme inhibitors (ACEis), angiotensin II receptor blockers (ARBs), beta-blockers, calcium channel blockers, and diuretics, and lipid-lowering agents, such as HMG-CoA reductase inhibitors, fibrates, and ezetimibe. Anti-diabetic drug use comprised metformin, sulfonylureas, thiazolidinediones, alpha-glucosidase inhibitors, dipeptidyl peptidase-4 inhibitors (DPP4is), SGLT2is, GLP-1RAs, and insulin. In addition, the analysis incorporated key laboratory and clinical parameters, including aspartate aminotransferase, alanine aminotransferase, platelet counts, hemoglobin A1c level, estimated glomerular filtration rate, BMI, HDL-C, low-density lipoprotein cholesterol, total cholesterol, and triglycerides. All variables were evaluated before and after matching to ensure balance between the TZP and TZD groups. Complete definitions and operational codes for all covariates are provided in. Supplementary Table 2
Outcomes and follow-up
The primary outcome was a composite endpoint encompassing all-cause mortality, MACEs, MAKEs, and MALOs. Each of these individual components also served as predefined secondary outcomes, as defined in previous studies (Wu et al., 2025a; Wu et al., 2025b; Wu et al., 2025c). Briefly, MACEs were defined as the incidence of cerebral infarction, acute myocardial infarction, cardiac arrest, or death. MAKEs included the onset of end-stage renal disease, resumption of dialysis, initiation of new dialysis treatment, or death. MALOs were defined by the presence of complications such as bleeding esophageal varices, hepatic encephalopathy, ascites-related events, hepatocellular carcinoma, liver transplantation, or death. In addition to effectiveness outcomes, selected safety outcomes were also evaluated, including nausea, vomiting, diarrhea, edema, heart failure exacerbation, fracture, and hypoglycemia. Outcome assessment began 1 day after the index date and continued until the first occurrence of an outcome event, patient death, the last recorded clinical visit, or 12 months post-index date, whichever came first.
Statistical analysis
Continuous variables were reported as means with standard deviations, while categorical variables were presented as frequencies and percentages. To enhance comparability across treatment groups, PSM was applied prior to conducting primary, subgroup, and sensitivity analyses to balance baseline covariates. Time-to-event outcomes were evaluated using Cox proportional hazards regression to estimate hazard ratios (HRs) and corresponding 95% confidence intervals (CIs). Kaplan-Meier plots and log-rank tests were employed to compare survival distributions between groups. Prespecified subgroup analyses were conducted stratified by age, sex, BMI, TZD types, and comorbid conditions including type 2 diabetes, heart failure, obstructive sleep apnea, MASH, and cirrhosis. To examine the validity and robustness of our results, we selected negative control outcomes, including hernia, hearing loss, and traumatic brain injury, based on their presumed lack of pharmacological association with TZP or TZD. Hernias are mechanical structural conditions unlikely to be influenced by TZP or TZD; hearing loss represents a sensory disorder with no established metabolic drug pathway; and traumatic brain injury is an externally caused event biologically independent of the study medications. Additionally, we calculated E-values to evaluate the potential influence of residual confounding (VanderWeele and Ding, 2017). A landmark analysis was also implemented to explore the impact of time-dependent effects (Morgan, 2019). All statistical procedures were executed within the TriNetX analytics platform.
Additional analysis
To further evaluate potential confounding related to prior GLP-1RA exposure, we performed a sensitivity analysis restricted to patients without prior GLP-1RA use before the index date. We also conducted a sensitivity analysis extending the follow-up period to 2 years to assess whether the observed associations persisted over a longer observation period. Additionally, we performed a sensitivity analysis examining the individual components of the composite outcome separately, to better distinguish mortality from non-fatal clinical events.
Results
Patients’ selection
A total of 169,845,419 adults were identified from 146 HCOs within the Global Collaborative Network of the TriNetX platform on 15 June 2025. Of these, 81,020,894 had records of HCO visits between 1 January 2022, and 31 May 2025. After applying exclusion criteria, 47,284 patients with MASLD who were newly treated with TZP or TZD remained. Of these, 36,137 were newly prescribed TZP, while 11,147 received TZD. After 1:1 PSM to reduce the risk of bias attributed to confounding, 9,262 well-matched patients were included in both the TZP and TZD groups (Figure 1). The median follow-up duration was 289 days (168–365 days) in the TZP group and 365 days (365–365 days) in the TZD group.
Study design and selection flow. HCO, healthcare organization; MASLD, metabolic dysfunction-associated steatotic liver disease; TZD, thiazolidinedione; TZP, tirzepatide.
Demographic features of included patients
Before PSM, individuals in the TZP group were younger than those in the TZD group (55.5 ± 12.0 years vs. 59.4 ± 12.6 years), with significant differences in the distributions of sex and race. The TZP group had a higher prevalence of overweight/obesity (65.6% vs. 60.5%), chronic kidney disease (55.8% vs. 28.4%), ischemic heart diseases (21.6% vs. 14.7%), obstructive sleep apnea (30.4% vs. 13.0%), atrial fibrillation and flutter (7.6% vs. 3.7%), and neoplasms (5.7% vs. 3.9%) compared to the TZD group. Prior use of GLP-1RAs was more common in the TZP group (49.7% vs. 17.4%), while sulfonylureas (9.8% vs. 28.5%) and DPP4is (4.4% vs. 16.9%) were more common in the TZD group. The TZP group had higher BMI (38.6 ± 8.0 vs. 33.6 ± 7.5 kg/m2), lower proportion with HbA1c ≥ 7% (42.9% vs. 54.6%), lower proportion with HDL cholesterol <50 mg/dL (49.2% vs. 42.2%), and higher proportion with triglycerides ≥150 mg/dL (38.4% vs. 35.0%). After PSM, baseline characteristics were well balanced between the TZP and TZD groups, with SMDs <0.1 for all variables except BMI level (Table 1).
| Variables | Before matching | After matching | ||||
|---|---|---|---|---|---|---|
| TZP group (n = 36,137) | TZD group (n = 11,147) | SMD | TZP group (n = 9,262) | TZD group (n = 9,262) | SMD | |
| Age at index, years | ||||||
| Mean (SD) | 55.5 (12.0) | 59.4 (12.6) | 0.314 | 58.3 (11.6) | 58.6 (12.6) | 0.019 |
| Sex, n (%) | ||||||
| Female | 22,390 (62.0) | 5,903 (53.1) | 0.179 | 5,054 (54.6) | 5,083 (54.9) | 0.006 |
| Male | 12,820 (35.5) | 5,027 (45.3) | 0.2 | 4,049 (43.7) | 4,017 (43.4) | 0.007 |
| Race, n (%) | ||||||
| White | 26,756 (74) | 7,447 (67.0) | 0.154 | 6,596 (71.2) | 6,567 (70.9) | 0.007 |
| Black or african american | 3,333 (9.2) | 710 (6.4) | 0.106 | 643 (6.9) | 649 (7.0) | 0.003 |
| Asian | 1,308 (3.6) | 1,092 (9.8) | 0.25 | 629 (6.8) | 633 (6.8) | 0.002 |
| Other race | 1,552 (4.3) | 506 (4.6) | 0.013 | 446 (4.8) | 436 (4.7) | 0.005 |
| Unknown race | 2,717 (7.5) | 1,225 (11.0) | 0.121 | 850 (9.2) | 874 (9.4) | 0.009 |
| Comorbidities, n (%) | ||||||
| T2D | 29,913 (82.7) | 9,252 (83.3) | 0.015 | 7,529 (82.0) | 7,508 (81.7) | 0.006 |
| Disorders of lipoprotein metabolism and other lipidemias | 23,742 (65.7) | 6,919 (62.3) | 0.071 | 5,738 (62.0) | 5,687 (61.4) | 0.011 |
| Overweight and obesity | 23,702 (65.6) | 6,723 (60.5) | 0.105 | 5,527 (59.7) | 5,576 (60.2) | 0.011 |
| Chronic kidney disease | 20,163 (55.8) | 3,151 (28.4) | 0.578 | 2,986 (32.2) | 2,989 (32.3) | 0.001 |
| Nicotine dependence | 3,822 (10.6) | 1,217 (11.0) | 0.012 | 968 (10.5) | 962 (10.4) | 0.002 |
| Chronic lower respiratory diseases | 584 (1.6) | 151 (1.4) | 0.021 | 119 (1.3) | 127 (1.4) | 0.008 |
| Ischemic heart diseases | 7,823 (21.6) | 1,630 (14.7) | 0.182 | 1,441 (15.6) | 1,440 (15.5) | <0.001 |
| Cerebrovascular diseases | 5,528 (15.3) | 1,494 (13.5) | 0.053 | 1,254 (13.5) | 1,270 (13.7) | 0.005 |
| Heart failure | 1,592 (4.4) | 620 (5.6) | 0.054 | 453 (4.9) | 493 (5.3) | 0.02 |
| Atrial fibrillation and flutter | 2,729 (7.6) | 413 (3.7) | 0.167 | 401 (4.3) | 394 (4.3) | 0.004 |
| Obstructive sleep apnea | 10,998 (30.4) | 1,455 (13.0) | 0.429 | 1,386 (15.4) | 1,376 (15.3) | 0.003 |
| Neoplasms | 2,065 (5.7) | 433 (3.9) | 0.085 | 384 (4.1) | 390 (4.2) | 0.003 |
| MASH | 2,653 (7.3) | 772 (7.0) | 0.015 | 630 (6.8) | 650 (7.0) | 0.009 |
| Other and unspecified cirrhosis of liver | 1,357 (3.8) | 425 (3.8) | 0.004 | 380 (4.1) | 372 (4.0) | 0.004 |
| T2D related complication, n (%) | ||||||
| Kidney complications | 4,275 (11.8) | 1,369 (12.3) | 0.015 | 1,140 (12.3) | 1,065 (11.5) | 0.025 |
| Ophthalmic complications | 1,665 (4.6) | 486 (4.4) | 0.011 | 413 (4.5) | 399 (4.3) | 0.007 |
| Neurological complications | 4,528 (12.5) | 1,364 (12.3) | 0.008 | 1,154 (12.5) | 1,113 (12.0) | 0.014 |
| Circulatory complications | 2,075 (5.7) | 477 (4.3) | 0.066 | 408 (4.4) | 415 (4.5) | 0.004 |
| Antihypertensives, n (%) | ||||||
| ACEis | 6,998 (19.4) | 2,613 (23.5) | 0.101 | 2,050 (22.1) | 2,029 (21.9) | 0.005 |
| ARBs | 9,056 (25.1) | 2,258 (20.3) | 0.113 | 1,856 (20) | 1,862 (20.1) | 0.002 |
| Beta blockers | 10,232 (28.3) | 2,730 (24.6) | 0.085 | 2,220 (24) | 2,294 (24.8) | 0.019 |
| Calcium channel blockers | 6,924 (19.2) | 2,083 (18.8) | 0.01 | 1,617 (17.5) | 1,675 (18.1) | 0.016 |
| Diuretics | 10,943 (30.3) | 2,614 (23.5) | 0.153 | 2,180 (23.5) | 2,239 (24.2) | 0.015 |
| Lipid-lowering medication, n (%) | ||||||
| HMG CoA reductase inhibitors | 17,219 (47.6) | 5,328 (48.0) | 0.006 | 4,298 (46.4) | 4,263 (46) | 0.008 |
| Fibrates | 1,604 (4.4) | 762 (6.9) | 0.105 | 607 (6.6) | 563 (6.1) | 0.02 |
| Ezetimibe | 1,429 (4.0) | 359 (3.2) | 0.039 | 288 (3.1) | 305 (3.3) | 0.01 |
| Anti-diabetic drugs, n (%) | ||||||
| Metformin | 14,910 (41.3) | 5,404 (48.7) | 0.149 | 4,273 (46.1) | 4,190 (45.2) | 0.018 |
| Sulfonylureas | 3,527 (9.8) | 3,165 (28.5) | 0.49 | 1,957 (21.1) | 1,914 (20.7) | 0.011 |
| Alpha glucosidase inhibitors | 44 (0.1) | 74 (0.7) | 0.087 | 23 (0.2) | 19 (0.2) | 0.009 |
| DPP4i | 1,598 (4.4) | 1,881 (16.9) | 0.414 | 995 (11.0) | 972 (10.8) | 0.008 |
| SGLT2i | 6,864 (19.0) | 2,162 (19.5) | 0.012 | 1,785 (19.8) | 1,712 (19.0) | 0.021 |
| GLP1RA | 17,976 (49.7) | 1,934 (17.4) | 0.729 | 1,975 (21.3) | 1,908 (20.6) | 0.018 |
| Insulin | 9,363 (25.9) | 2,858 (25.7) | 0.004 | 2,508 (27.1) | 2,433 (26.3) | 0.018 |
| Type of TZDs, n (%) | ||||||
| Pioglitazone | - | 36,066 (99.9) | - | - | 9,204 (99.4) | - |
| Rosiglitazone | - | 71 (0.2) | - | - | 58 (0.6) | - |
| Aspartate aminotransferase, U/L | 29.5 ± 21.1 | 33.5 ± 38.3 | 0.13 | 30.7 ± 22.0 | 33.6 ± 40.5 | 0.088 |
| Alanine aminotransferase, U/L | 35.9 ± 29.0 | 40.1 ± 38.4 | 0.124 | 37.6 ± 30.2 | 40.2 ± 35.8 | 0.079 |
| Platelet counts, 10/uL3 | 258 ± 79.0 | 241 ± 82.6 | 0.206 | 245 ± 77.0 | 242 ± 83.4 | 0.04 |
| Hemoglobin A1c, % | ||||||
| ≥7 | 15,497 (42.9) | 6,067 (54.6) | 0.236 | 4,824 (52.1) | 4,744 (51.2) | 0.017 |
| eGFR, mL/min/1.73m2 | ||||||
| <45 | 2,862 (7.9) | 1,141 (10.3) | 0.082 | 894 (9.7) | 874 (9.4) | 0.007 |
| Systolic blood pressure, mmHg | ||||||
| ≥130 | 23,936 (66.2) | 6,062 (54.6) | 0.24 | 5,218 (56.3) | 5,208 (56.2) | 0.002 |
| Cholesterol in HDL, mg/dL | ||||||
| <50 | 17,791 (49.2) | 4,682 (42.2) | 0.142 | 3,927 (42.4) | 3,874 (41.8) | 0.012 |
| Cholesterol in LDL, mg/dL | ||||||
| ≥130 | 4,426 (12.2) | 985 (8.9) | 0.11 | 806 (8.7) | 841 (9.1) | 0.013 |
| Cholesterol, mg/dL | ||||||
| ≥200 | 6,449 (17.8) | 1,751 (15.8) | 0.056 | 1,409 (15.2) | 1,453 (15.7) | 0.013 |
| Triglyceride, mg/dL | ||||||
| ≥150 | 13,893 (38.4) | 3,890 (35.0) | 0.071 | 3,327 (35.9) | 3,226 (34.8) | 0.023 |
| Body mass index, kg/m2 | ||||||
| Mean (SD) | 38.6 (8.0) | 33.6 (7.5) | 0.641 | 36.6 (7.5) | 34.3 (7.5) | 0.306 |
| ≥25 | 24,602 (68.1) | 6,035 (54.3) | 0.285 | 5,287 (57.1) | 5,279 (57.0) | 0.002 |
| 25–29.9 | 4,553 (12.6) | 2,542 (22.8) | 0.271 | 1,964 (21.2) | 1,964 (21.2) | 0.001 |
| 30–34.9 | 10,082 (27.9) | 2,987 (26.8) | 0.024 | 2,603 (28.1) | 2,649 (28.6) | 0.012 |
| 35–39.9 | 10,087 (30.1) | 2,062 (18.5) | 0.274 | 1,954 (21.1) | 1,889 (20.4) | 0.017 |
| ≥40 | 12,648 (35.0) | 1,583 (14.2) | 0.496 | 1,547 (16.7) | 1,482 (16.0) | 0.018 |
Primary outcomes
During the one-year follow-up period, the incidence rate of the primary composite outcome was 1.8 per 100 person-years in the TZP group and 2.7 per 100 person-years in the TZD group. Accordingly, the TZP group was associated with a lower risk of the primary outcome compared to the TZD group (HR, 0.66; 95% CI, 0.54–0.82; E-value, 2.4; 95% LCL, 1.7) (Table 2). The Schoenfeld test indicated no violation of the proportional hazards assumption (p > 0.05). Survival analysis demonstrated a significantly higher cumulative probability of remaining free from the primary composite outcome in the TZP group compared to the TZD group (log-rank test, p < 0.001; Figure 2).
Stratified analyses of the primary composite outcome showed consistent results, with HRs below 1 across most patient subgroups (Figure 3). In the sex-stratified analysis, HRs were 0.71 (95% CI, 0.54–0.93) in females and 0.71 (95% CI, 0.53–0.97) in males. Age-stratified analysis showed HRs of 0.87 (95% CI, 0.63–1.18) for patients aged 18–64 years and 0.64 (95% CI, 0.49–0.85) for those aged ≥65 years. BMI-stratified analysis demonstrated significantly reduced risks across most categories: HRs were 0.59 (95% CI, 0.37–0.97) for BMI 25–29.9 kg/m2, 0.57 (95% CI, 0.38–0.86) for BMI 30–34.9 kg/m2, 0.76 (95% CI, 0.49–1.18) for BMI 35–39.9 kg/m2, and 0.61 (95% CI, 0.39–0.96) for BMI ≥40 kg/m2. The TZP group also had significantly lower HR among patients with comorbid T2D (HR, 0.67; 95% CI, 0.54–0.84), without heart failure (HR, 0.77; 95% CI, 0.63–0.95), without OSA (HR, 0.58; 95% CI, 0.48-0.73), without MASH (HR, 0.65; 95% CI, 0.52–0.81), and without cirrhosis (HR, 0.65; 95% CI, 0.52–0.8). The results were consistent when comparing tirzepatide with pioglitazone, while separate analysis for rosiglitazone was not feasible due to the limited number of patients and events.
Kaplan-Meier time-to-event free curves of the composite outcome comparing the TZP and TZD groups. TZD, thiazolidinedione; TZP, tirzepatide.
Stratified analysis of the composite outcome risk between the tirzepatide (TZP) and thiazolidinedione (TZD) groups. MASH, metabolic-dysfunction associated steatohepatitis.
| Outcome | TZP group (n = 9,262) | TZD group (n = 9,262) | HR (95% CI) | valueP | E-value (95% LCL) | ||
|---|---|---|---|---|---|---|---|
| Events (n) | Incidence rate per 100 PYs | Events (n) | Incidence rate per 100 PYs | ||||
| Primary outcome | |||||||
| Composite outcome | 133 | 1.8 | 254 | 2.7 | 0.66 (0.54,0.82) | <0.001 | 2.4 (1.7) |
| Secondary outcomes | |||||||
| All-cause mortality | 34 | 0.5 | 91 | 1 | 0.48 (0.32,0.71) | <0.001 | 3.6 (2.2) |
| MACE | 102 | 1.4 | 201 | 2.2 | 0.65 (0.51,0.82) | <0.001 | 2.5 (1.7) |
| MAKE | 53 | 0.7 | 134 | 1.4 | 0.50 (0.36,0.69) | <0.001 | 3.4 (2.3) |
| MALO | 69 | 0.9 | 136 | 1.5 | 0.64 (0.48,0.86) | 0.003 | 2.5 (1.6) |
Secondary outcomes
The use of TZP was associated with a significantly reduced risk of all-cause mortality (HR, 0.48; 95% CI, 0.32–0.71; E-value, 3.6; 95% LCL, 2.2), MACEs (HR, 0.65; 95% CI, 0.51–0.82; E-value, 2.5; 95% LCL, 1.7), MAKEs (HR, 0.50; 95% CI, 0.36–0.69; E-value, 3.4; 95% LCL, 2.3), and MALOs (HR, 0.64; 95% CI, 0.48–0.86; E-value, 2.5; 95% LCL, 1.6), as shown in Table 2.
Additional analyses
To assess for potential residual confounding, three negative control outcomes were examined. There was no significant difference between groups in the incidence of hernia (HR, 0.89; 95% CI, 0.71–1.12; p = 0.317), hearing loss (HR, 1.08; 95% CI, 0.81–1.43; p = 0.603), or traumatic brain injury (HR, 1.25; 95% CI, 0.55–2.85; p = 0.593) (). Landmark analysis from 1-month to 1-year follow-up showed consistent results for the primary composite outcome (HR, 0.73; 95% CI, 0.58–0.91; p = 0.005,). Supplementary Table 4 Supplementary Table 5
In a sensitivity analysis restricted to patients without prior GLP-1RA exposure before the index date, the direction of associations remained consistent with the primary analysis (). Additional sensitivity analysis extending follow-up to 2 years, the results likewise remained consistent with the primary analysis (). Regarding safety, TZP was not associated with higher risks of gastrointestinal adverse events, including nausea, vomiting, or diarrhea. In contrast, TZP users had significantly lower risks of edema, heart failure exacerbation, and fracture compared with TZD users (). Lastly, we examined the individual components of the composite outcomes. TZP was associated with lower risks of stroke, dialysis, end-stage kidney disease, and ascites compared with thiazolidinedione therapy, while no significant differences were observed for the remaining components (). Supplementary Table 6 Supplementary Table 7 Supplementary Table 8 Supplementary Table 9
Discussion
This retrospective study, which included over 18,000 individuals, is the first to compare the clinical effectiveness of TZP versus TZD in adults with MASLD. Our findings suggest that TZP is associated with improved clinical outcomes in this population. Specifically, TZP was associated with reductions of 52% in all-cause mortality, 35% in MACE, 50% in MAKE, and 36% in MALO. These associations remained consistent across most subgroups, including sex, age, BMI categories, and various comorbidities. These findings support the potential role of TZP as a preferred treatment option over TZD in adults with MASLD. Further prospective studies are warranted to confirm these benefits and inform clinical guidelines.
The superior effect of TZP compared to TZD observed in our study aligns with previous evidence. In a network meta-analysis (Souza et al., 2025) of 29 RCTs including 9,277 patients, TZP, along with pegozafermin and survodutide, was ranked among the most effective interventions, outperforming both vitamin E plus pioglitazone combination therapy and pioglitazone monotherapy in achieving MASH resolution without worsening fibrosis. In contrast, our study provides the first head-to-head comparison confirming the superiority of TZP for MASLD. Although both TZP and TZD are recommended for patients with MASLD (European Association for the Study of the Liver, 2024; American Diabetes Association Professional Practice Committee, 2025), our findings suggest that TZP may be associated with better clinical outcomes and could be considered the preferred therapeutic option in this clinical context.
The superior clinical benefits of TZP over TZD in MASLD can be attributed to multiple mechanisms supported by emerging scientific evidence. As a dual agonist of GIP and GLP-1 receptors, TZP induces potent and sustained weight loss, with clinical trials demonstrating mean reductions exceeding 25% of baseline body weight after prolonged treatment - substantially greater than those observed with placebo or other comparators (Aronne et al., 2024; Wadden et al., 2023; Aronne et al., 2025). This marked weight loss improves insulin sensitivity and reduces hepatic fat accumulation, directly benefiting liver health and slowing MASLD progression. Cardiovascular benefits are likely mediated through improvements in glycemic control, blood pressure, lipid profiles, and reductions in systemic inflammation, collectively lowering the risk of MACE and heart failure (Lin et al., 2023). TZP has been shown to slow kidney function decline and reduce albuminuria, potentially through hemodynamic and anti-inflammatory effects that mitigate kidney injury and progression to failure (Tian et al., 2025; Abasheva et al., 2024; Yang et al., 2025; Bosch et al., 2023). In parallel, TZP has demonstrated substantial benefits in patients with MASLD, including improvements in liver histology such as resolution of MASH and fibrosis without worsening disease severity (Loomba et al., 2024; Hu et al., 2025). These multifactorial effects on weight, metabolism, cardiovascular health, kidney function, and liver pathology provide a strong mechanistic rationale for the observed reductions in all-cause mortality, MALO, MACE, and MAKE in MASLD patients treated with TZP, underscoring its promise as a preferred therapeutic agent in this population.
The interpretation of our findings warrants careful consideration of the potential confounding role of prior GLP-1RA use. A substantial body of evidence has demonstrated that GLP-1RAs exert direct and indirect hepatoprotective effects in MASLD. Semaglutide has been shown to significantly reduce liver steatosis and improve histological activity in patients with MASH in a randomized trial (Sanyal et al., 2025), while liraglutide improved histological features of NASH and was associated with higher rates of resolution compared with placebo (Armstrong et al., 2016). These benefits extend beyond GLP-1RA monotherapy, with further evidence from meta-analyses and real-world studies confirming improvements in liver enzymes, hepatic fat content, and fibrosis-related markers (Ghosal et al., 2021; Ren et al., 2025). In our cohort, prior GLP-1RA use was substantially more prevalent in the TZP group before matching (49.7% vs. 17.4%), and despite achieving balance after PSM (∼21% in both groups), a meaningful proportion of patients in both arms had prior GLP-1RA exposure. Patients with such prior exposure may have already derived hepatic and metabolic benefits, including reductions in steatosis, inflammation, and cardiovascular risk, that could amplify the apparent advantage of TZP observed in the primary analysis. Indeed, when we restricted the analysis to patients without prior GLP-1RA use, effect estimates were more conservative, though the direction of all associations remained consistent (Supplementary Table 6). This pattern is consistent with the biological plausibility that residual hepatoprotective carry-over effects from prior GLP-1RA therapy partially contributed to the magnitude of TZP’s benefit in the primary cohort. Taken together, these findings underscore the importance of accounting for prior GLP-1RA exposure when interpreting comparative effectiveness studies of newer incretin-based therapies in MASLD.
This study has several notable strengths. Utilizing the TriNetX global network database allowed for the inclusion of a large, heterogeneous patient population, thereby improving statistical power and enhancing the generalizability of the results. The analysis of real-world clinical data adds to the translational relevance of the findings. Importantly, the adoption of an active comparator new-user design minimized biases related to treatment selection and temporal confounding, while PSM further ensured balanced baseline characteristics between the tirzepatide and comparator groups. Additionally, multiple sensitivity analyses, including landmark analysis and the use of negative control outcomes, were conducted to test the robustness of the findings under different assumptions and to assess potential residual confounding. Together, these comprehensive and rigorous methodological approaches strengthen the validity and clinical applicability of the observed associations.
Despite these strengths, several limitations should be acknowledged. First, although PSM effectively reduced confounding from measured covariates, BMI levels remained different between groups (Table 1). However, stratified analysis by BMI categories showed findings consistent with the primary analysis (Figure 3), supporting our results. Additionally, residual confounding from unmeasured factors, such as diet, exercise, and alcohol consumption, remains a limitation. Nevertheless, the high E-values observed indicate that any unmeasured confounder would need to be strongly associated with both the exposure and outcome to fully explain the observed associations, suggesting that the impact of residual confounding is likely limited. Second, detailed clinical information on MASLD severity, such as FIB-4, liver histology or fibrosis stage, was not available in the database, which may have led to disease misclassification or unmeasured heterogeneity in disease progression. To address this, subgroup analyses among individuals with MASH, or cirrhosis were performed and yielded results consistent with the primary findings. Third, the partially overlapping indications of TZP (approved for both obesity and T2D) and TZD (approved for T2D) represent a meaningful source of bias. Patients prescribed TZP are more likely to have a higher baseline BMI and a more obesity-driven phenotype, which may independently influence both liver-related and cardiovascular outcomes. Although PSM substantially reduced overt covariate imbalances and the high E-values support the robustness of our estimates, indication bias of this nature cannot be fully eliminated through statistical adjustment alone. Fourth, a potential temporal bias warrants consideration. Our study period begins in January 2022, so real-world adoption of TZP was likely concentrated toward the latter portion of the observation window. In contrast, TZD use is distributed more evenly across the study period, given its availability since the early 2000s. This temporal clustering may introduce differences in background standard-of-care practices, co-prescription patterns, and outcome ascertainment between groups. Although follow-up duration was analyzed as a time-to-event outcome to partially mitigate length-of-follow-up differences, and calendar-time adjusted analyses were considered, these were limited by sample size. Fifth, the statistical power for certain subgroup analyses, particularly in patients with comorbid OSA, was limited by the smaller number of patients and events within these strata. Although the direction of the association between TZP and the primary composite outcome among patients with OSA remained consistent with the overall analysis, the estimate did not reach statistical significance, and should therefore be interpreted with caution. This finding does not exclude a clinically meaningful benefit of TZP in this population; rather, it reflects the inherent limitation of subgroup analyses in observational cohorts, where sample sizes may be insufficient to detect modest effect differences with adequate precision. Adequately powered prospective studies specifically enrolling patients with MASLD and comorbid OSA are needed to clarify the therapeutic role of TZP in this subgroup. Lastly, the relatively short follow-up duration, particularly for the tirzepatide group given its initial FDA approval on 13 May 2022, may be insufficient to capture the full spectrum of long-term outcomes. Further studies are warranted to address these limitations.
Conclusion
In this large real-world cohort study, TZP was associated with significantly better clinical outcomes compared to TZD in adults with MASLD, including substantial reductions in all-cause mortality, MALO, MACE, and MAKE. These benefits were consistent across diverse patient subgroups and supported by strong mechanistic rationale and robust sensitivity analyses. Given its multifaceted effects on metabolic, cardiovascular, renal, and hepatic pathways, TZP represents a promising therapeutic option for MASLD. Future prospective trials are needed to validate these findings and to inform evidence-based treatment guidelines.