Table 2: Clinical trials of PPAR modulators for NAFLD/NASH.


gray!50 Reference PPAR subtype, intervention Population, duration NAFLD/NASH related outcomes comments

Laurin et al. (1996) [ 190 ] - PPARα: 2 g/d clofibrate - 13-15 mg/kg/d ursodeoxycholic acid 40 patients with biopsy-confirmed NASH 12 months - no changes in ALT, AST, GGT, bilirubin, triglycerides and cholesterol - no improvement in the histological grade of steatosis, inflammation or fibrosis - ALP↓ - no placebo control
Basarangoglu et al. (1999) [ 191 ] - PPARα: 600 mg/d gemfibrozil - placebo 46 patients with biopsy-confirmed NASH and persistent elevated ALT and AST levels 4 weeks - ALT↓, AST↓, GGT↓ - no change in mean triglyceride levels and mean body weight - no histology
Fernandez-Miranda et al. (2007) [ 192 ] - PPARα: 200 mg/d fenofibrate + diet and physical exercise 16 patients with biopsy-confirmed NASH 48 weeks - triglycerides↓ - glucose↓, tendency to improved insulin sensitivity - ALT↓, AST↓, GGT↓, ALP↓ - Apo-A1↑ - hepatocellular ballooning↓ - no change in grade of steatosis, lobular inflammation, fibrosis or NAFLD activity score - no placebo control
Riserus et al. (2008) [ 161 ] - PPARα: 20 µg/d GW590735 - PPARδ: 10 mg/d GW501516 - placebo 18 healthy but moderately over-weight participants (6 per group) 2 weeks GW590735: no effect except triglyceride lowering activity GW501516: - fasting plasma triglycerides↓ (-30%), Apo- B↓ (-26%), LDL↓ (-23%), insulin↓ (-11%), liver fat content↓ (-20%), urinary isoprostanes↓ (-30%), CPT-1b↓ - no histology
Bays et al. (2011) [ 196 ] - PPARδ: 50 mg/d or 100 mg/d MBX-8025 +/- 20 mg/d atorvastatin 181 over-weight participants with mixed dyslipidemia 8 weeks APO-B↓, non-HDL-cholesterol↓, LDL↓, HDL↑, triglycerides↓, GGT↓, ALP↓ combination with atorvastatin showed more efficacy - no NAFLD/NASH specific parameters - no histology
Caldwell et al. (2001) [ 203 ] - PPARγ: 400 mg/d troglitazone 10 female patients with biopsy-confirmed NASH 6 months - 7/10 responded (with normal ALT) outcome for responders: - ALT↓, AST↓ - persistent steatohepatitis in all cases - biopsy revealed one-point improvement in necroinflammatory grade in 4/7 - elongation of mitochondria - no placebo control - very short duration
Neuschwander-Tetri et al. (2003) [ 149 ] - PPARγ: 4 mg rosiglitazone twice daily 30 overweight or severely obese patients with increased ALT levels and biopsy-confirmed NASH (50% with impaired glucose tolerance or diabetes) 48 weeks - mean global necroinflammatory score improved - biopsies of 10 patients (45%) no longer met criteria for NASH after treatment - hepatocellular ballooning↓ - no statistically significant improvement in global fibrosis score - ALT↓, AST↓, GGT↓, ALP↓ - no significant changes in cholesterol and triglyceride levels - liver enzyme levels had increased to near pre-treatment levels 6 months after treatment - no placebo control
Promrat et al. (2004) [ 207 ] - PPARγ: 30 mg/d pioglitazone + healthy diet + pre-treatment weight-loss + no vitamin/mineral/ herbal supplement 18 nondiabetic patients with biopsy-confirmed NASH and elevated serum ALT or AST 48 weeks - steatosis, cellular injury, parenchymal inflammation, Mallory bodies, hepatocellular injury and fibrosis significantly improved in 67% - NASH activity score decreased by at least one point in all patients - ALT, AST, ALP normalized - improved insulin sensitivity - hepatic fat content↓ liver size↓ - no significant changes in total cholesterol, triglycerides, LDL and HDL cholesterol levels - no placebo control
Luyckx et al. (2006) (NCT00227110) [ 208 ] - PPARγ: pioglitazone - placebo + hypochaloric diet 55 patients with biopsy-confirmed NASH and impaired glucose tolerance or diabetes 6 months - improved glycaemic control and glucose tolerance - plasma free fatty acids↓ - insulin levels↓ - AST↓, ALT↓ - hepatic fat content↓ - improvement in steatosis, ballooning necrosis and inflammation - TNF-α level decreased by 11% - TGF-β level decreased by 18% - adiponectin↑ - no significant difference in fibrosis vs placebo - variations in fibrosis assessment by percutaneous biopsy [ 227 ]
Lutchman et al. (2006) [ 209 ] - PPARγ: 30 mg/d pioglitazone 18 patients with biopsy-confirmed NASH 48 weeks - adiponectin↑ - no change in cytokines levels (IL-1a, IL-6, and TNF-α) - histological improvements assessed by semi-quantitative scoring revealed reduced steatosis, parenchymal inflammation, cell injury and fibrosis - correlations between change in adiponectin level and improvement in steatosis (P = 0.03) as well as in a summary NASH activity index score (P = 0.01) - no placebo control
Aithal et al. (2008) [ 210 ] - PPARγ: 30 mg/d pioglitazone - placebo + diet and exercise 74 non-diabetic patients with biopsy-confirmed NASH (61 completed study) 12 months reduction in: - plasma glucose↓, HbA 1 c ↓, HOMA index↓ - only 50% of patients responded - predictors of response were: absence of diabetes, severe steatosis, lower GGT levels
Ratziu et al. (2010) (FLIRT2, extension of FLIRT1) [ 212 ] - PPARγ: 8 mg/d rosiglitazone 40 patients that had completed FLIRT1 2 years (extension) - no significant change in mean NASH activity score, ballooning score, fibrosis stage or area of fibrosis - steatosis significantly decreased only in patients that had received placebo in FLIRT1 –> no benefit of extended treatment
Sanyal et al. (2010) (PIVENS) [ 213 ] - PPARγ: 30 mg/d pioglitazone - vitamin E (800 IU daily) - placebo 247 patients with biopsy-confirmed NASH 96 weeks - pioglitazone had no benefit over placebo in resolving steatosis (34% and 19%) - total NAFLD activity score↓ (-1.9 vs. -0.5), steatosis score↓ (-0.8 vs. -0.1), lobular inflammation↓ (-0.7 vs. -0.2), hepatocellular ballooning↓ (-0.4 vs. -0.2), fibrosis stage↓ (-0.4 vs -0.1) - ALT↓, AST↓, GGT↓, ALP↓, bilirubin↓ - superior efficacy with vitamin E - very variable cohort (diabetes, cirrhosis, etc.)
Torres et al. (2011) [ 214 ] - PPARγ: 4 mg/d rosiglitazone +/- losartan (50 mg/d) or metformin (2x 500 mg/d) 137 patients with biopsy-confirmed NASH 48 weeks - no difference in efficacy between groups - significant improvement in fibrosis - improved steatosis score (-0.85, -0.82, -0.74) and hepatocellular inflammation (-0.58, -0.32, -0.34) in all groups - ALT↓, AST↓, ALP↓ (all groups) - no benefit of metformin concerning weight-gain - no placebo control
Sharma et al. (2012) [ 215 ] - PPARγ: 30 mg/d pioglitazone - pentoxifylline (1200 mg/d) + reduced caloric intake + exercise 60 patients with biopsy-confirmed NASH and elevated ALT 6 months pioglitazone: - AST↓, ALT↓, insulin resistance↓ (HOMA), adiponectin levels↑ - steatosis↓, lobular inflammation↓, portal inflammation↓, Brunts grade↓ - TNF-α was not significantly reduced neither with pioglitazone nor with pentoxifylline - no significant change of fibrosis - no placebo control
Cusi et al. (2016) [ 216 ] - PPARγ: 45 mg/d pioglitazone - placebo + hypocaloric diet 101 patients with biopsy-confirmed NASH 18 months - reduction of at least 2 points in NAFLD disease activity score in 2 histologic categories without worsening of fibrosis in 58% - resolution of NASH in 51% - steatosis↓, inflammation↓, ballooning↓, fibrosis↓, liver fat content↓ - ALT↓, AST↓, triglyceride levels↓, free fatty acids↓
Cariou et al. (2011) [ 225 ] - PPARα/δ: 80 mg/d elafibranor - placebo S1: 94 abdominally obese patients with dyslipidemia, 28 days S2: 47 abdominally obese patients with pre-diabetes, 35 days - significant reduction in fasting plasma triglycerides - HDL cholesterol↑ - LDL cholesterol↓ only in S2 - S2 study: significant decrease of HOMA-index, fasting plasma glucose and fructosamine
Ratziu et al. (2016) (GOLDEN-505) [ 72 ] - PPARα/δ: 80 or 120 mg/d elafibranor - placebo 276 patients with biopsy-confirmed non-cirrhotic NASH - no significant difference between elafibranor and placebo in resolution of NASH without fibrosis worsening - NASH resolved in more patients without fibrosis worsening in the 120-mg arm (protocol definition: 21% vs. 17%, modified definition: 19% vs 12%) - liver enzymes, lipids, glucose profiles, and markers of systemic inflammation were significantly reduced in the elafibranor 120-mg arm - no changes in NAS between end of treatment and baseline biopsy - no changes and improvements in individual histologic scores of steatosis, ballooning, inflammation, and fibrosis - 120 mg elafibranor reduced the NAS by 2 points (48%) and improved steatosis, ballooning, and lobular inflammation with increasing baseline severity, - both elafibranor doses improved liver function tests (ALT, GGT and ALP) and lipid parameters (triglycerides, LDL cholesterol, HDL cholesterol) - high placebo response in patients with mild steatohepatitis - many non-responders