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.

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.

Table 3 Summary of trials exploring the efficacy of incretin-based therapies in nonalcoholic steatohepatitis

Ref.	Agent	Comparator	Participants	Duration	Outcomes
Newsome et al[50], 2021	Semaglutide 0.1, 0.2 or 0.4 mg s/c once daily	Placebo	NASH with F1, F2, or F3 fibrosis stage	72 wk	NASH resolution without worsening of fibrosis: 40% (0.1 mg), 36% (0.2 mg), 59% (0.4 mg), 33% (placebo); Improvement in fibrosis (P < 0.001 for 0.4 mg vs placebo); 43% (0.4 mg), 33% (placebo) (P = 0.48); Weight loss: 13% (0.4 mg), 1% placebo
Loomba et al[51], 2023	Semaglutide 2.4 mg s/c	Placebo (1: 2)	NASH with compensated cirrhosis	48 wk	Improvement in liver fibrosis by ≥ 1 stage without worsening NASH: 11% Semaglutide, 29% placebo (P = 0.087); Resolution of NASH at 48 wk: 34% semaglutide, 21% placebo (P = 0.29); No new safety concerns
Romero-Gomez et al[52], 2023	Efinopegdutide 10 mg s/c once weekly	Semaglutide 1 mg s/c once weekly	NAFLD with liver fat content (LFC) ≥ 10%	24 wk	Relative reduction in LFC from baseline higher with efinopegdutide (72.7%) than semaglutide (42.3%); Similar reduction in body weight
Alkhouri et al[53], 2022	Semaglutide 2.4 mg s/c + cilofexor once daily (30 or 100 mg)+ fircosostat (20 mg)	Semaglutide alone Semaglutide+cilofexor/fircosostat	NASH (MRI-PDFF > 10%, elastography ≥ 7 kPa	24 wk	Combination well tolerated; Greater reduction in liver fat with combination groups vs semaglutide (10%-11% vs 8.6%); Similar weight loss in all the groups
Flint et al[54], 2021	Semaglutide 0.4 mg s/c once daily	Placebo	NAFLD, steatosis ≥ 10% (MRI-PDFF), MRE: 2.5-4.63 kPa	48 wk	≥ 30% reduction in liver steatosis at 24, 48 and 72 wk (64.7%, 76.5%, 73.5%) significantly higher than placebo; Change in liver stiffness in NAFLD not significantly different compared to placebo; Improvement in liver enzymes, body weight and HbA1c
Armstrong et al[55], 2016	Liraglutide 1.8 mg/d s/c	Placebo	Biopsy proven NASH	48 wk	39% had resolution of NASH (vs 9% placebo); Progression of fibrosis: 9% Liraglutide, 36% placebo
Khoo et al[56], 2017	Liraglutide 3.0 mg/d	Diet and moderate exercise	Obesity and NAFLD (Liver fat content > 5% on MRI)	26 wk	Similar reduction in weight, liver fat, liver enzymes in both the groups without any significant difference between the two
Yan et al[57], 2019	Liraglutide 1.8 mg/d	Insulin glargine or sitagliptin	T2D and NAFLD	26 wk	Liraglutide and sitagliptin along with metformin reduced body weight, liver fat content, visceral adipose tissue in addition to glycemic control in contrast to Insulin, subcutaneous fat also decreased in liraglutide arm
Bizino et al[58], 2020	Liraglutide 1.8 mg/d	Placebo	T2D and NAFLD	26 wk	Liraglutide reduced significantly more body weight and subcutaneous fat but not visceral fat
Guo et al[59], 2020	Liraglutide 1.8 mg/d	Insulin glargine or placebo	T2D and NAFLD	26 wk	Liraglutide plus 2 gm metformin for 26 wk significantly reduced liver, subcutaneous and visceral fat
Zhang et al[60], 2020	Liraglutide 1.8 mg/d	Pioglitazone	T2D and NAFLD	24 wk	Liraglutide reduced liver fat significantly compare to pioglitazone which could be attributed to weight loss
Liu et al[61], 2020	Exenatide 1.8 mg/d	Insulin glargine	T2D and NAFLD	24 wk	Both reduced liver fat but exenatide led to higher reduction in body weight, visceral fat, liver enzymes
Miyake et al[62], 2022 (Trial Registration: jRCTs061210009)	Semaglutide 0.5 mg/wk + Luseogliflozin 2.5 mg/d	Semaglutide 0.5 mg/wk	T2D and NASH	52 wk	Ongoing study
Gastaldelli et al[63], 2022	Dual GIP/GLP-1R agonist: tirzepatide10 mg or 15 mg/wk	Insulin degludec	T2D and NAFLD	52 wk	Significant decrease in liver fat content, visceral and subcutaneous adipose tissue compared to insulin degludec
Kuchay et al[64], 2020	Glucagon-like peptide-1 receptor (GLP-1r) agonist (GLP-1 RA)	Usual care	T2D and NAFLD	24 wk	Dulaglutide significantly reduces liver fat comma gamma glutamyl transpeptidase

GIP: Glucose-dependent insulinotropic polypeptide; MRE: Magnetic resonance elastography; NAFLD: Nonalcoholic fatty liver disease; NASH: Nonalcoholic steatohepatitis; PDFF: Proton density fat fraction.