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

Table 1 Summary of studies of peroxisome proliferator-activated receptors single agonists in nonalcoholic fatty liver disease

Drug class and mechanism	Agent	Trial design	Biochemical response	Histological response	Comments
PPARα (Fatty acid oxidation and Anti-inflammatory)[21,22]	Fenofibrate	16 patients, 48 wk vs placebo	Significant reduction in triglyceride and liver enzymes	Decreased ballooning, grade steatosis, inflammation/fibrosis no change	Limited efficacy
	Clofibrate	40 patients 1 yr vs UDCA	Reduced ALT	No change
PPAR β/δ (glucose homeostasis and insulin sensitivity)[23,24]	GW501516	6 patients, 2 wk vs placebo	Reduced TG and LDL	No data	Abandoned due to cancer risk in preclinical studies
	MBX-8025	181 overweight patients, 2 wk vs placebo	Favorable lipid profile and decreased liver enzymes	No data	Need more data
PPARγ (adipogenesis, insulin sensitization, fatty acid oxidation)[25-27]	Rosiglitazone	63 patients, 52 wk vs placebo	Normalized transaminase levels (38% vs 7%, P = 0.005)	Improved steatosis (47% vs 16%; P = 0.014), although only half of the patients responded, no change of other histologic parameters	Weight gain and painful swollen legs in rosiglitazone arm
	Pioglitazone	RCT, 61 patients, 12 months placebo or pioglitazone had paired biopsies	Improvement of ALT and GGT	Hepatocellular injury (P = 0.005), Mallory–Denk bodies (P = 0.004), and fibrosis (P = 0.05) were reduced in patients treated with pioglitazone	Weight gain with pioglitazone
		RCT, 259 patients pioglitazone vs vitamin E vs placebo 96 wk	Improvement of transaminases in the vitamin E and pioglitazone arm	Improvement in NASH as compared with placebo (pioglitazone P = 0.04), significant reductions in steatosis, lobular inflammation and fibrosis in pioglitazone arm	Weight gain in pioglitazone group

ALT: Alanine aminotransferase, GGT: Gamma glutamyl transferase, LDL: Low density lipoprotein, PPAR: Peroxisome proliferator-activated receptor, RCT: Randomized controlled trial, TG: Triglyceride, UDCA: Ursodeoxycolic acid.