Non-alcoholic fatty liver disease in type 2 diabetes: Emerging evidence of benefit of peroxisome proliferator-activated receptors agonists and incretin-based therapies

Table 2 Summary of studies of peroxisome proliferator-activated receptors dual and pan agonists in nonalcoholic fatty liver disease

Drug class and mechanism	Agent	Trial design	Biochemical response	Histological response	Comments
PPAR α/δ agonist[33]	Elafibranor	276 patients, Elafibranor 80 mg vs 120 mg vs placebo, 52 wk, GOLDEN trial	Liver enzymes, lipids, glucose profiles, and markers of systemic inflammation were significantly reduced in the elafibranor 120-mg group	Elafibranor 120 mg was superior to the placebo, with NASH resolution without worsening of fibrosis in 19% versus 12% in the placebo group (P = 0.045), based on a post hoc analysis for the modified definition	No change in primary outcome in intention to treat analysis
		1070 patients, Elafibranor 120 mg vs placebo, 72 wk, RESOLVE IT trial	Improvement in TG, ALT, and GGT	138 (19.2%) patients in the Ela group and 52 (14.7%) patients in the placebo group achieved resolution of NASH without worsening of fibrosis (P = 0.066)	Despite the absence of safety signals, the RESOLVE-IT trial was discontinued due to the limited effect of Ela on surrogate efficacy endpoints
PPAR α/γ agonist[34-38]	Tesaglitazar, Muraglitazar, Aleglitazar		Favorable lipid profile with muraglitazar	No change	Trials terminated early due to nephrotoxicity, cardiotoxicity and gastrointestinal hemorrhage respectively
	Saroglitazar	106 patients, 16 wk vs placebo	Improvement in ALT and lipid profile	No data	DCGI approved for NAFLD in India
		85 patients, 12 wk vs placebo	Improvement in ALT and TG	Significant reduction in liver fibrosis (fibroscan)
Pan PPAR agonists[39,40]	Bezafibrate		Improve HbA1c and atherogenic dyslipidemia in mice	No data	Mostly animal data. Human studies are ongoing
	Lanifibranor		Improve insulin sensitivity in mice	Improve steatosis and fibrosis in liver tissue in mice

ALT: Alanine aminotransferase; DCGI: Drug Controller General of India; GGT: Gamma glutamyl transferase; PPAR: Peroxisome proliferator-activated receptor; TG: Triglyceride.