TABLE 2.
Placebo‐controlled or active‐controlled RCTs with different drugs that have PPAR gamma agonist activity for the treatment of NAFLD. Pioglitazone is a single agonist with PPAR gamma activity, saroglitazar is a dual agonist with PPAR alpha and gamma activity and lanifibranor is a pan PPAR agonist with PPAR alpha, delta and gamma activity)
| Study | RCT characteristics | Interventions (n), RCT duration | Key efficacy outcomes | Major adverse effects |
|---|---|---|---|---|
| Belfort et al. 71 USA | Adults with T2DM or prediabetes and biopsy‐confirmed NASH. Mean age: 51 years; men: 45%; BMI: 33.2 kg/m2; HbA1: 6.2% | A. Pioglitazone 30 mg/d for 2 months, then 45 mg/day (n = 29) B. Placebo (n = 25). Length: 24 weeks | Pioglitazone versus placebo, improvement in hepatic fat content (54% vs. 0%, p < 0.001), necro‐inflammation (85% vs. 38%, p = 0.001). Percent with liver fibrosis improvement was not significant: 46% vs. 33%, p = 0.08. Weight: 2.5 kg (p < 0.001) vs. −0.5 kg (p = 0.53), p = 0.003 | Withdrawal due to AEs: 1/29 (3.5%) in pioglitazone group vs. 1/25 (4%) in the placebo group |
| Aithal 72 UK | Non‐diabetic adults with biopsy‐confirmed NASH. Mean age: 53 years; men: 61%; BMI: 30.3 kg/m2; HbA1: NR; ALT and AST: no reported | A. Pioglitazone 30 mg/day (n = 37). B. Placebo (n = 37). Length: 52 weeks | Pioglitazone versus placebo. Number (%) with improvement (p‐ value), between‐groups p‐value: Steatosis: 15/31 (48%) (p = 0.001) vs. 11/30 (37%) (p = 0.03), p = 0.19. Liver fibrosis: 9/31 (29%) (p = 0.006) vs. 6/30 (20%) (p = 0.81), p = 0.05. Weight: 2.6 kg (p = 0.005) vs. −3.5 kg (p = 0.69), p = 0.02 | Withdrawal due to AEs: 3/37 (8.1%) in pioglitazone group vs. 4/37 (10.8%) in the placebo group |
| Sanyal 73 USA, PIVENS | Non‐diabetic adults with biopsy‐confirmed NASH. Mean age: 46 years; men: 40%; BMI: 34 kg/m2; ALT: 83 IU/L; AST: 56 IU/L | A. Pioglitazone 30 mg/day (n = 80). B. Vitamin E 800 IU/d (n = 84). C. Placebo (n = 83). Length: 96 weeks | Pioglitazone versus placebo. NASH improvement, n (%): 27/80 (34%) (p = 0.04) vs. 36/84 (43%) (p = 0.001) vs. 16/83 (19%). NAFLD activity score: −1.9 (p < 0.001) vs. ‐1.9 (p < 0.001) vs. −0.5. Steatosis: −0.8 (p < 0.001) vs. −0.7 (p < 0.001) vs. ‐0.1. Fibrosis: −0.4 (p = 0.10) vs. −0.3 (p = 0.19) vs. −0.1. Weight: 4.7 kg (p < 0.001) vs. 0.4 (p = 0.65) vs. 0.7 kg | Withdrawal due to AEs: None |
| Sharma 74 India | Adults with biopsy‐confirmed NASH. Mean age: 39 years; men: 54%; BMI: 24.9 kg/m2. | A. Pentoxifylline 1200 mg/day (n = 29) B. Pioglitazone 30 mg/day (n = 30). Length: 24 weeks | Pioglitazone versus pentoxifylline. Brunt's score: −0.34 (p = 0.10) vs. −1.2 (p = 0.005), p = 0.04. Steatosis: −0.83 (p = 0.02) vs. −1.18 (p = 0.005), p = 0.60. Fibrosis: 0.08 (p = 0.70) vs. −0.46 (p = 0.19), p = 0.26 | Withdrawal due to AEs: None |
| Cusi 75 USA | Patients with T2DM or prediabetes and biopsy‐confirmed NASH. Mean age: 51 years; men: 70%; BMI: 34.4 kg/m2; pre‐existing T2DM: 51% | A. Pioglitazone 45 mg/day (n = 50). B. Placebo (n = 51). All patients were prescribed a hypocaloric diet. Both groups followed with an open‐label phase with pioglitazone. Length: 72 weeks (144 weeks for the open‐label phase) | Pioglitazone versus placebo. Greater than 2‐point reduction of NAS without worsening fibrosis: 29% vs. 17%, p < 0.001. Fibrosis; greater than 1 point improvement: 39% vs 25%, p > 0.05 (NS). Fibrosis mean change in score improved with pioglitazone: 0 vs. −0.5, p < 0.05. Pioglitazone group gained 2.5 kg, p < 0.05. | NR |
| Gawrieh 76 USA, EVIDENCE IV | Patients with NASH or NAFLD and elevated serum ALT levels. Liver fat content was assessed by MRI‐PDFF. Mean age: 49 years; men: 53%; BMI: 34.3 kg/m2; pre‐existing T2DM: 52.8% | A. Saroglitazar 1 mg/day (n = 26) B. Saroglitazar 2 mg/day (n = 25) C. Saroglitazar 4 mg/day (n = 27) D. Placebo (n = 28). Length: 16 weeks |
Relative changes from baseline of liver fat content at week 16 (p‐value) for each group: A. LS (least squares) Mean = +3.8%, SE (standard error) = 5.7, p = 0.97. B. LS Mean = +0.5%, SE = 6.3, p = 0.68. C. LS Mean = −19.7%, SE = 5.6, p = 0.004. D. LS Mean = +4.1%, SE = 5.9. The LS mean difference between saroglitazar and placebo (95% CI) in liver fat content at week 16 was −0.3% (95% CI ‐16.8 to 16.2) (p = 0.97), − 3.6% (95% CI ‐20.8 to 13.5) (p = 0.67), and − 23.8% (95% CI ‐39.9 to −7.7) (p = 0.004) for saroglitazar 1‐mg, 2‐mg and 4‐mg groups, respectively |
AEs: 112 treatment‐ adverse events were reported in 59 patients. 13 patients in the saroglitazar 1 mg group, 13 patients in the saroglitazar 2 mg group, 14 patients in the saroglitazar 4 mg group, and 19 patients in the placebo group. No serious AEs occurred |
| Francque 77 Multinational, NATIVE | Patients with biopsy‐confirmed NASH and fibrosis. Mean age: 54 years; men: 42%; BMI: 32.9 kg/m2; pre‐existing T2DM: 41.7% | A. Lanifibranor 800 mg/day (n = 83). B. Lanifibranor 1200 mg/day (n = 83). C. Placebo (n = 81). Length: 24 weeks | Lanifibranor versus placebo. Resolution of NASH with no worsening of fibrosis: 33% (p = 0.04 vs. placebo) in lanifibranor 800 mg group, 45% (p < 0.001 vs. placebo) in lanifibranor 1200 mg group, and 19% in the placebo group. Improvement in fibrosis by at least 1 stage and no worsening of NASH: 28% (p = 0.53 vs. placebo) in lanifibranor 800 mg group, 42% (p = 0.011 vs. placebo) in lanifibranor 1200 mg group, and 24% in the placebo group. Resolution of NASH and improvement of fibrosis: 21% (p = 0.02 vs. placebo) in lanifibranor 800 mg group, 31% (p < 0.001 vs. placebo) in lanifibranor 1200 mg group, and 7% in the placebo group | Serious AEs: 3 patients in the lanifibranor 800 mg group, 7 patients in the lanifibranor 1200 mg group and 3 patients in the placebo group |
Abbreviations: BMI, body mass index; CI, confidence interval; MRI‐PDFF, magnetic resonance imaging‐proton density fat fraction; NAFLD, nonalcoholic fatty liver disease; NASH, nonalcoholic steatohepatitis; T2DM, type 2 diabetes mellitus.