Combination therapy with pioglitazone/exenatide/metformin reduces the prevalence of hepatic fibrosis and steatosis: The efficacy and durability of initial combination therapy for type 2 diabetes ( EDICT )
Abstract
Aim To compare the efficacy of triple therapy (metformin/exenatide/pioglitazone) versus stepwise conventional therapy (metformin → glipizide → glargine insulin) on liver fat content and hepatic fibrosis in newly diagnosed, drug-naïve patients with type 2 diabetes. Methods Sixty-eight patients completed the 6-year follow-up and had an end-of-study (EOS) FibroScan to provide measures of steatosis (controlled attenuation parameter [CAP] in dB/m) and fibrosis (liver stiffness measurement [LSM] in kPa); 59 had magnetic resonance imaging-proton density fat fraction (MRI-PDFF) to measure liver fat. Results At EOS, HbA1c was 6.8% and 6.0% in triple and conventional therapy groups, respectively (P = .0006). Twenty-seven of 39 subjects (69%) receiving conventional therapy had grade 2/3 steatosis (CAP, FibroScan) versus nine of 29 (31%) in triple therapy (P = .0003). Ten of 39 (26%) subjects receiving conventional therapy had stage 3/4 fibrosis (LSM) versus two of 29 (7%) in triple therapy (P = .04). Conventional therapy subjects had more liver fat (MRI-PDFF) than triple therapy (12.9% vs. 8.8%, P = .03). The severity of steatosis (CAP) (r = 0.42, P Conclusions At EOS, subjects with type 2 diabetes treated with triple therapy had less hepatic steatosis and fibrosis versus conventional therapy; the severity of hepatic steatosis and fibrosis were both strongly and inversely correlated with insulin resistance; and changes in liver fibrosis scores (APRI, NFS, Fibrosis-4, and AST/ALT ratio)…
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Combination therapy with pioglitazone plus GLP-1 RA is safe and effective and has been shown to reduce hepatic steatosis in adults with type 2 diabetes with biopsy-proven MASH or those at higher risk of clinically significant liver fibrosis identified with noninvasive tests.
“Combination therapy with pioglitazone plus GLP-1 RA should also be considered for treatment of hyperglycemia in adults with type 2 diabetes with biopsyproven MASH or those at higher risk of clinically significant liver fibrosis identified with noninvasive tests, as such therapy is safe and effective and has been shown to reduce hepatic steatosis (154-156).”
From 9. Pharmacologic Approaches to Glycemic Treatment: Standards of Care in Diabetes—2025 (2025) · cites this paper as [156]
Cites
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A placebo-controlled trial of pioglitazone in subjects with nonalcoholic steatohepatitis
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“OGTT-derived indices of insulin sensitivity and insulin secretion were calculated from plasma glucose, insulin, and C-peptide concentrations during OGTT, as previously described.(20,21) The Matsuda Index and Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) were used to quantitate insulin sensitivity.”
MethodSelf-citationJayakumar, S., Middleton, M. S., Lawitz, E. J., Mantry, P. S., Caldwell, S. H., Arnold, H., Mae Diehl, A., Ghalib, R., Elkhashab, M., Abdelmalek, M. F., et al. (2019) · Journal of Hepatology · doi:10.1016/j.jhep.2018.09.024 · Cited by 208 · see citing works
Bril, F., Barb, D., Lomonaco, R., Lai, J., & Cusi, K. (2020) · Journal of Hepatology · doi:10.1016/j.jhep.2019.09.018 · Cited by 55 · see citing works
Abdul-Ghani, M., Puckett, C., Adams, J., Khattab, A., Baskoy, G., Cersosimo, E., Triplitt, C., & DeFronzo, R. A. (2021) · Diabetes Care · doi:10.2337/dc20-0978 · Cited by 55 · see citing works
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9. Pharmacologic Approaches to Glycemic Treatment: Standards of Care in Diabetes—2025
American Diabetes Association Professional Practice Committee, ElSayed, N. A., McCoy, R. G., Aleppo, G., Bajaj, M., Balapattabi, K., Beverly, E. A., Briggs Early, K., Bruemmer, D., Echouffo-Tcheugui, J. B., et al. (2025) · Diabetes Care · doi:10.2337/dc25-s009 · Cited by 728 · see citing works
- Authors
- Lavynenko, O., Abdul‐Ghani, M., Alatrach, M., Puckett, C., Adams, J., Abdelgani, S., Alkhouri, N., Triplitt, C., Clarke, G. D., Vasquez, J. A., Li, J., Cersosimo, E., Gastaldelli, A., & DeFronzo, R. A.
- Affiliations
- The University of Texas at San Antonio Health Science Center (US)
- University of Texas Health Science Center and Texas Diabetes Institute San Antonio Texas
- Corresponding author
- DeFronzo, Ralph A.
- ORCID
- Venue
- Diabetes, Obesity and Metabolism
- Publisher
- Wiley
- Published
- 2022-02-09
- Volume
- 24
- Issue
- 5
- Pages
- 899-907
- ISSN
- 1462-8902 (ISSN-L)
- 1463-1326
- OpenAlex
- W4205246355
- Cited by
- 44
- References
- 10
- Citations by year
- 2026: 4 · 2025: 14 · 2024: 15 · 2023: 7 · 2022: 4
- FWCI
- 7.22
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Diabetes Obesity and Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of Diabetes and Digestive and Kidney Diseases (1R01DK103841‐01A1, R01DK107680)
- American Diabetes Association (R01DK24092‐34)
- Topics
- Health Sciences › Medicine › Epidemiology › Liver Disease Diagnosis and Treatment
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes, Cardiovascular Risks, and Lipoproteins
- Keywords
- type 2 diabetes, hepatic steatosis, liver fibrosis, pioglitazone, exenatide, metformin, triple therapy, non-alcoholic fatty liver disease, liver fat, insulin sensitivity, Matsuda index, FibroScan, controlled attenuation parameter, liver stiffness measurement, proton density fat fraction, APRI, glipizide, insulin glargine, drug-naive patients, glycemic control, transaminases, treatment durability
- MeSH terms
- Pioglitazone, Exenatide, Diabetes Mellitus, Type 2, Humans, Liver, Liver Cirrhosis, Metformin, Prevalence, Non-alcoholic Fatty Liver Disease
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