From:  PPARs in molecular pathogenesis and drug treatment of type 2 diabetes-related MASLD

 Therapeutic trials on PPAR agonists in MASLD.

Author, year [Ref]*Study design, patients enrolled, duration of treatmentBiochemical responseLiver histology/imaging response, side effects
Laurin et al., 1996 [85]16 in the Clofibrate arm, 24 in the UDCA arm, for 1 year.Decreased ALP in the Clofibrate arm.No change in the Clofibrate arm.
Belfort et al., 2006 [86]RCT with 6 months of a low-calorie diet with Pioglitazone (n = 26) or diet and placebo (n = 21).Transaminases decreased in the Pioglitazone arm.Improved steatosis, inflammation, and ballooning, with no change in fibrosis, weight gain, despite a low-caloric diet in the Pioglitazone arm.
Fernández-Miranda et al., 2008 [87]Fenofibrate (n = 16) for 48 weeks, with no control arm.Significant decreases were observed in TG, glucose, liver enzymes, and MetS.Decreased ballooning, no change in grade of steatosis and inflammation/fibrosis.
Ratziu et al., 2008 [88]RCT with Rosiglitazone (n = 32), placebo (n = 31).Normalized transaminase levels (38% vs. 7%, p = 0.005).Improved steatosis (47% vs. 16%; p = 0.014), although only half of the patients responded, with no change in other histologic parameters, and weight gain in the Rosiglitazone arm.
Sanyal et al., 2010 [89]RCT with Pioglitazone (n = 80), vitamin E (n = 83), and placebo (n = 84) for 96 weeks.Transaminases improved in the vitamin E and Pioglitazone arms.Improvement in NASH compared to placebo (vitamin E, p = 0.001), with Pioglitazone (p = 0.04), both vitamin E and Pioglitazone were associated with significant reductions in steatosis and lobular inflammation. Improvement in fibrosis, with weight gain in Pioglitazone.
Torres et al., 2011 [90]RCT with n = 137, comparing Rosiglitazone and metformin to Rosiglitazone and losartan vs. Rosiglitazone alone for 48 weeks.Transaminases decreased in all groups.108 completed the study, with an overall improvement in all histologic parameters, and no added benefit of metformin (did not prevent weight gain) or losartan.
Cusi et al., 2016 [91]RCT for 18 months followed by an 18-month open-label phase with Pioglitazone (n = 50) or placebo (n = 51).More normalization in the Pioglitazone arm.Pioglitazone is associated with a better NAS reduction and resolution of NASH, steatosis, inflammation, and ballooning, with no improvement in fibrosis or weight gain.
Ratziu et al., 2016 [92]Elafibranor 120 mg, Elafibranor 80 mg, and placebo.Liver enzymes, lipids, glucose profiles, and markers of systemic inflammation were significantly reduced in the Elafibranor 120 mg group.Elafibranor 120 mg is superior to placebo, with NASH resolution without worsening of fibrosis in 19% vs. 12% in the placebo group (p = 0.045), based on a post hoc analysis for the modified definition.
Francque et al., 2021 [93]RCT for 24 weeks with Lanifibranor 1,200 mg (n = 83), Lanifibranor 800 mg (n = 83), and placebo (n = 81).Levels of liver enzymes decreased, and most biomarkers of lipid metabolism, inflammatory activation, and liver fibrosis improved with Lanifibranor.Both the 1,200 mg and 800 mg doses of Lanifibranor were superior to placebo for NASH resolution without worsening of fibrosis (49% and 39%, respectively, vs. 22%), improvement in fibrosis stage of at least 1 without worsening of NASH (48% and 34%, respectively, vs. 29%), and NASH resolution NASH + improvement in fibrosis stage of at least 1 (35% and 25%, respectively, vs. 9%). The dropout rate for adverse events was less than 5% and similar across the trial groups. Diarrhea, nausea, peripheral edema, anemia, and weight gain occurred more frequently with Lanifibranor than with placebo.
Gawrieh et al., 2021 [94]RCT for 16 weeks with Saroglitazar 1 mg (n = 26), 2 mg (n = 25), or 4 mg (n = 27) vs. placebo (n = 28).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, vs. 3.4% (5.6) in placebo (p < 0.001 for all). Saroglitazar 4 mg improved adiponectin [–0.3 μg/mL (0.3) vs. 1.3 μg/mL (0.3)], HOMA-IR [–1.3 (1.8) vs. –6.3 (1.7)], and TG [–5.3 mg/dL (10.7) vs. –68.7 mg/dL (10.3)] (p < 0.05 for all), lipoprotein particle composition and size, and reduced lipotoxic lipid species.Compared to placebo, Saroglitazar 4 mg improved LFC [4.1% (5.9) vs. –19.7% (5.6)], and Saroglitazar was well-tolerated. A mean weight gain of 1.5 kg was observed with Saroglitazar 4 mg vs. 0.3 kg with placebo (p = 0.27).
Grobbee et al., 2022 [95]Post-hoc analysis of an RCT enrolling 7,226 T2D individuals with recent CAD assigned to receive aleglitazar or placebo for two years.LFS, LAP, and FIB-4 decreased with treatment, while scores in the placebo group remained unaffected or increased (p < 0.001). NFS responded differently but remained consistently lower than placebo. In the treatment group, more participants shifted to a lower FIB-4 and NFS category or improved with respect to the LAP cut-off values compared to placebo (p < 0.001 for FIB-4 and LAP, p < 0.004 for NFS).NA
Cooreman et al., 2024 [96]Secondary and exploratory outcomes of the NATIVE trial (ClinicalTrials.gov NCT03008070) were analyzed.With Lanifibranor, TG, HDL-C, apolipoproteins, insulin, HOMA-IR, HbA1c, FG, hs-CRP, ferritin, and diastolic BP improved significantly, regardless of diabetes status. Most patients with pre-diabetes returned to normal FG levels. Significant increases in adiponectin levels correlated with improvement in hepatic and CMH markers.Steatosis improved significantly, independent of diabetes status. Patients had an average weight gain of 2.5 kg, with 49% gaining at least 2.5% weight. Therapeutic benefits were similar regardless of weight change.
Tan et al., 2025 [97]This prospective cohort study enrolled 235 T2D patients with MASLD who received either Chiglitazar or other glucose-lowering medications over a 24-week period. Forty Chiglitazar users, 195 non-Chiglitazar users, and 31 matched pairs were derived after 1:1 PSM.NAThe adjusted mean reduction in CAP from baseline to 24 weeks was significantly greater in the Chiglitazar group [–28.38 dB/m (95% CI: 36.11 to –20.65)] than in the non-Chiglitazar group [–16.74 dB/m (95% CI: –24.47 to –9.01)], with a between-group difference of –11.64 dB/m (95% CI: –22.38 to –0.90, p = 0.038). LSM changes were similar between groups [difference in LS mean: 0.11 (95% CI: –1.04 to 0.82), p = 0.813].

*: These original studies have been identified using the keywords “PPAR” AND “NAFLD” OR “MAFLD” OR “MASLD” OR “NASH” OR “MASH” AND “trial”. Studies regarding primary biliary cholangitis, cardiovascular outcomes unlinked from liver health were excluded. ALP: alkaline phosphatase; ALT: alanine aminotransferase; BP: blood pressure; CMH: cardiometabolic health; CAD: coronary artery disease; CAP: controlled attenuation parameter; FG: fasting glucose; FIB-4: Fibrosis-4; HbA1c: glycosylated hemoglobin; HDL-C: high-density lipoprotein cholesterol; hs-CRP: high-sensitivity C-reactive protein; HOMA-IR: homeostatic model assessment-insulin resistance; LFC: liver fat content; LAP: liver accumulation product; LFS: liver fat score; LSM: liver stiffness measurement; MASLD: metabolic dysfunction-associated steatotic liver disease; MetS: metabolic syndrome; NA: not addressed; NAFLD: nonalcoholic fatty liver disease; NAS: NAFLD activity score; NFS: NAFLD fibrosis score; PPAR: peroxisome proliferator-activated receptor; PSM: propensity score matching; RCT: randomized controlled trial; T2D: type 2 diabetes; TG: triglycerides.