Effects of Novel Dual GIP and GLP-1 Receptor Agonist Tirzepatide on Biomarkers of Nonalcoholic Steatohepatitis in Patients With Type 2 Diabetes
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OBJECTIVE: To determine the effect of tirzepatide, a dual agonist of glucose-dependent insulinotropic polypeptide and glucagon-like peptide 1 receptors, on biomarkers of nonalcoholic steatohepatitis (NASH) and fibrosis in patients with type 2 diabetes mellitus (T2DM). RESEARCH DESIGN AND METHODS: Patients with T2DM received either once weekly tirzepatide (1, 5, 10, or 15 mg), dulaglutide (1.5 mg), or placebo for 26 weeks. Changes from baseline in alanine aminotransferase (ALT), aspartate aminotransferase (AST), keratin-18 (K-18), procollagen III (Pro-C3), and adiponectin were analyzed in a modified intention-to-treat population. RESULTS: Significant (P < 0.05) reductions from baseline in ALT (all groups), AST (all groups except tirzepatide 10 mg), K-18 (tirzepatide 5, 10, 15 mg), and Pro-C3 (tirzepatide 15 mg) were observed at 26 weeks. Decreases with tirzepatide were significant compared with placebo for K-18 (10 mg) and Pro-C3 (15 mg) and with dulaglutide for ALT (10, 15 mg). Adiponectin significantly increased from baseline with tirzepatide compared with placebo (10, 15 mg). CONCLUSIONS: In post hoc analyses, higher tirzepatide doses significantly decreased NASH-related biomarkers and increased adiponectin in patients with T2DM.
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Pioglitazone therapy, GLP-1 RA therapy, and metabolic surgery have all been shown to reduce NASH activity; pioglitazone therapy and metabolic surgery may also improve hepatic fibrosis.
“Pioglitazone therapy, GLP-1 RA therapy, and metabolic surgery have all been shown to reduce NASH activity; pioglitazone therapy and metabolic surgery may also improve hepatic fi brosis (188,292 -298).”
From Management of Hyperglycemia in Type 2 Diabetes, 2022. A Consensus Report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) (2022) · cites this paper as [298]
The Introduction (page unavailable) says GLP-1 receptor agonists may have efficacy in NASH, and the Conclusions mention fibrosis improvement in a study of pioglitazone and vitamin E. But the paper does not establish that these therapies reduce NASH activity, does not isolate pioglitazone's effect on fibrosis, and does not address metabolic surgery. Its own tirzepatide findings concern biomarkers in patients with type 2 diabetes, not demonstrated efficacy in patients with NASH. (LLM, conf=0.84)
Experimental — accuracy not yet measuredHartman et al. found that once-weekly administration of tirzepatide for 26 weeks significantly reduced biomarkers of NASH and fibrosis (ALT, AST, keratin-18, and procollagen-C3) and increased adiponectin compared with placebo at a higher tirzepatide dose (15 mg) in patients with T2D.
“More recently, Hartman et al. found that once-weekly administration of tirzepatide for 26 weeks significantly reduced biomarkers of NASH and fibrosis (ALT, AST, keratin-18, and procollagen-C3) and increased adiponectin compared with placebo at a higher tirzepatide dose (15 mg) in patients with T2D [85].”
From Gut-pancreas-liver Axis as a target for treatment of NAFLD/NASH (2020) · cites this paper as [85]
Development of dual GLP-1/glucagon receptor or GLP-1/GIP agonists or triagonists with first promising results in NASH may show another promising approach in drug development.
“Apart from combining existing drugs, the development of dual GLP-1/glucagon receptor or GLP-1/GIP agonists or even triagonists237 with first promising results in NASH237–239 may show up another promising approach in drug development.”
From Novel therapeutic targets for cholestatic and fatty liver disease (2022) · cites this paper as [238]
The favorable effects of tirzepatide on HF may be related to an amelioration of blood volume expansion that characterizes obesity-related HF, and the decrease in adipocyte mass would be expected to minimize the antinatriuretic effects of secreted adipocytokines (particularly leptin and aldosterone).
“The favorable effects of tirzepatide on HF may be related to an amelioration of the blood volume expansion that characterizes obesity-related HF,41 and the decrease in adipocyte mass would be expected to minimize the antinatriuretic effects of secreted adipocytokines (particularly leptin and aldosterone).42–44”
From Effects of Tirzepatide on the Clinical Trajectory of Patients With Heart Failure, Preserved Ejection Fraction, and Obesity (2025) · cites this paper as [43]
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- Authors
- Hartman, M. L., Sanyal, A. J., Loomba, R., Wilson, J. M., Nikooienejad, A., Bray, R., Karanikas, C. A., Duffin, K. L., Robins, D. A., & Haupt, A.
- Affiliations
- Eli Lilly (United States) (US)
- Virginia Commonwealth University (US)
- University of California San Diego (US)
- Corresponding author
- Hartman, Mark L.
- ORCID
- Venue
- Diabetes Care
- Publisher
- American Diabetes Association
- Published
- 2020-04-14
- Volume
- 43
- Issue
- 6
- Pages
- 1352-1355
- ISSN
- 0149-5992 (ISSN-L)
- 1935-5548
- PMC
- PMC7245348
- OpenAlex
- W3015345942
- Cited by
- 351
- References
- 19
- Citations by year
- 2026: 36 · 2025: 60 · 2024: 64 · 2023: 78 · 2022: 57 · 2021: 39 · 2020: 16
- FWCI
- 34.02
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Diabetes Care (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- Eli Lilly and Company
- Topics
- Health Sciences › Medicine › Epidemiology › Liver Disease Diagnosis and Treatment
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
- Health Sciences › Medicine › Nephrology › Chronic Kidney Disease and Diabetes
- Keywords
- tirzepatide, nonalcoholic steatohepatitis, liver fibrosis, type 2 diabetes, dulaglutide, alanine aminotransferase, aspartate aminotransferase, cytokeratin 18, type III procollagen, adiponectin, liver biomarkers
- MeSH terms
- Glucagon-Like Peptide-1 Receptor Agonists, Tirzepatide, Adult, Alanine Transaminase, Aspartate Aminotransferases, Diabetes Mellitus, Type 2, Glucagon-Like Peptides, Female, Gastric Inhibitory Polypeptide, Humans, Immunoglobulin Fc Fragments, Liver Cirrhosis, Male, Middle Aged, Receptors, Gastrointestinal Hormone, Recombinant Fusion Proteins, Biomarkers, Treatment Outcome, Non-alcoholic Fatty Liver Disease
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