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Saroglitazar, a PPAR-α/γ agonist, for treatment of NAFLD: a randomized controlled double-blind phase 2 trial
Open accessAbstract
BACKGROUND AND AIMS: NAFLD is characterized by insulin resistance and dysregulated lipid and glucose metabolism. Saroglitazar, a dual peroxisome proliferator activated receptor-α/γ agonist, improves insulin sensitivity, and lipid and glycemic parameters. Saroglitazar improved NASH histology in animal studies. In this randomized controlled clinical trial, we evaluated the efficacy and safety of saroglitazar in patients with NAFLD/NASH. APPROACH AND RESULTS: were randomized in a 1:1:1:1 ratio to receive placebo or saroglitazar 1 mg, 2 mg, or 4 mg for 16 weeks. The primary efficacy endpoint was percentage change from baseline in ALT levels at week 16. Liver fat content (LFC) was assessed by MRI proton density fat fraction. The least-squares mean percent change from baseline in ALT at week 16 was -25.5% (5.8), -27.7% (5.9), and -45.8% (5.7), with saroglitazar 1 mg, 2 mg, and 4 mg, respectively, versus 3.4% (5.6) in placebo (P < 0.001 for all). Compared with placebo, saroglitazar 4 mg improved LFC (4.1% [5.9] vs. -19.7% [5.6]), adiponectin (-0.3 μg/mL [0.3] vs. 1.3 μg/mL [0.3]), homeostatic model assessment-insulin resistance (-1.3 [1.8] vs. -6.3 [1.7]), and triglycerides (-5.3 mg/dL [10.7] vs. -68.7 mg/dL [10.3]) (P < 0.05 for all). Saroglitazar 4 mg also improved lipoprotein particle composition and size and reduced lipotoxic lipid species. Saroglitazar was well-tolerated. A mean weight gain of 1.5 kg was observed with saroglitazar 4 mg versus 0.3 kg with placebo (P = 0.27). CONCLUSIONS: Saroglitazar 4 mg significantly improved ALT, LFC, insulin resistance, and atherogenic dyslipidemia in participants with NAFLD/NASH. (ClinicalTrials.gov identifier: NCT03061721.).
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“Two Phase II trials have investigated the effects of saroglitazar, a PPARα/γ agonist, and found improvement of ALT and hepatic fat (measured via MRI‐PDFF) [57] but no improvement of NAS (primary endpoint: delta change of NAS from baseline to Week 24 biopsy) [58].”
From Current treatment of non‐alcoholic fatty liver disease (2022) · cites this paper as [57]
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“Saroglitazar, a dual PPAR a / c agonist has been shown to improve insulin resistance, liver steatosis and liver enzymes 426 and is approved in India for the treatment of T2D and MASH.”
From EASL-EASD-EASO Clinical Practice Guidelines on the management of metabolic dysfunction-associated steatotic liver disease (MASLD). (2024) · cites this paper as [426]
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“This lack of basic information may have confounded true treatment effects and results in serious difficulties concerning cross-trial comparisons [240].”
From Obesity and MASLD: Is weight loss the (only) key to treat metabolic liver disease? (2024) · cites this paper as [240]
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Metadata
- Authors
- Gawrieh, S., Noureddin, M., Loo, N., Mohseni, R., Awasty, V., Cusi, K., Kowdley, K. V., Lai, M., Schiff, E., Parmar, D., Patel, P., & Chalasani, N.
- Affiliations
- Indiana University School of Medicine (US)
- Cedars-Sinai Medical Center (US)
- Texas Liver Institute (US)
- Catalina Research Institute (US)
- Marion General Hospital (US)
- University of Florida Health (US)
- Liver Institute Northwest (US)
- Beth Israel Deaconess Medical Center (US)
- University of Miami (US)
- Zydus Discovery DMCC,Dubai,UAE
- Zydus Lifesciences Limited (India) (IN)
- Corresponding author
- Chalasani, Naga
- ORCID
- Venue
- Hepatology
- Published
- 2021-07-19
- Volume
- 74
- Issue
- 4
- Pages
- 1809-1824
- ISSN
- 0270-9139 (ISSN-L)
- 1527-3350
- OpenAlex
- W3149930516
- Cited by
- 379
- References
- 48
- Citations by year
- 2026: 46 · 2025: 82 · 2024: 82 · 2023: 87 · 2022: 57 · 2021: 25
- FWCI
- 45.21
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Hepatology (publishedVersion)
- PubMed (publishedVersion)
- Purdue University Indianapolis (Indiana University) (submittedVersion)
- IUScholarWorks (Indiana University) (submittedVersion)
- Funders
- Amgen
- Eli Lilly and Company
- Pfizer
- AstraZeneca
- Gilead Sciences
- Celgene
- Novo Nordisk
- Allergan
- Janssen Research and Development
- Topics
- Health Sciences › Medicine › Hepatology › Liver Disease Diagnosis and Treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Peroxisome Proliferator-Activated Receptors
- Health Sciences › Medicine › Hepatology › Liver Diseases and Immunity
- Keywords
- saroglitazar, non-alcoholic fatty liver disease, nonalcoholic steatohepatitis, PPAR alpha/gamma agonist, insulin resistance, atherogenic dyslipidemia, liver fat, ALT, adiponectin, triglycerides, drug safety and tolerability, weight gain, PPARγ antagonist, PPARα
- MeSH terms
- Adipose Tissue, Adult, Alanine Transaminase, Alkaline Phosphatase, Aspartate Aminotransferases, Cholesterol, Double-Blind Method, Female, gamma-Glutamyltransferase, Humans, Insulin Resistance, Cholesterol, HDL, Cholesterol, LDL, Liver, Magnetic Resonance Imaging, Male, Middle Aged, Phenylpropionates, Pyrroles, Triglycerides, Cholesterol, VLDL, PPAR alpha, PPAR gamma, Elasticity Imaging Techniques, Non-alcoholic Fatty Liver Disease
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