Emerging therapeutic options for non-alcoholic fatty liver disease: A systematic review

Table 4 Studies of dual-pan peroxisome proliferator-activated receptor agonists in the treatment of non-alcoholic fatty liver disease

Ref.	Human or animal	Study design	Number of participants	Key inclusion criteria	Investigational product/dose	Study endpoints	Key findings
Boeckmans et al[34], 2019	Human	In vitro study Duration: N/A	N/A	Hepatic cells generated from human skin-derived precursors with induced NASH	Elafibranor	Effect on hepatic steatosis and inflammatory chemokines	Reduction in hepatic lipid load, as well as the expression and secretion of inflammatory chemokines, which are responsible for the recruitment of immune cells
Boeckmans et al[33], 2021	Human	In vitro study. Duration: N/A	N/A	Hepatic cells generated from human skin-derived precursors with induced NASH	Elafibranor	Effect on hepatic steatosis, inflammatory chemokines, and pro-fibrotic gene expression	Attenuated lipid accumulation, inflammatory chemokine secretion, and pro-fibrotic gene expression
Cariou et al[27], 2013	Human	Multicenter, randomized, single-blind, placebo-controlled, crossover study. Duration: 8 wk	n = 22	Abdominally obese insulin-resistant males	GFT505: Placebo vs 80 mg daily	Effect on peripheral and hepatic insulin sensitivity with improvement in GIR	Improved peripheral insulin sensitivity with a 21% increase of the GIR (P = 0.048) and enhanced hepatic insulin sensitivity with a 44% increase in insulin suppression of endogenous glucose production (P = 0.006)
Chaudhuri et al[32], 2023	Human	Single-center, prospective, observational, open-label, single-arm study. Duration: 52 wk	n = 76	Patients with NAFLD and elevated ALT levels along with liver stiffness value ≥ 6 kPa and/or liver steatosis CAP > 290 dB/m	Saroglitazar 4 mg daily	Effect on liver stiffness and steatosis measured by LSM and CAP on FibroScan at baseline, 24 and 54 wk	There was significant improvement of LSM from baseline (11.03 ± 7.19 kPa) to 24-wk (9.29 ± 6.39 kPa) and 52-wk (8.59 ± 6.35 kPa) values, respectively (P < 0.001). There was a significant improvement in median CAP at 24 wk 281 dB/m, (P < 0.001) and 52 wk 287 dB/m, (P < 0.001) as compared with the baseline 328 dB/m
Hassan et al[29], 2019	Animal	Duration: 5 wk	n = 12	Mice with induced NASH by a high-fat emulsion diet (n = 6 per group)	Saroglitazar: Control vs 4 mg/kg daily	Histopathological effects of Saroglitazar by using light microscopy	In the control vs treatment group, steatosis score was 3 vs 0.5, hepatic ballooning was 2 vs 0.5, lobar hepatitis was 3 vs 1, and portal hepatitis was 3 vs 0.25, respectively (P < 0.05)
Padole et al[31], 2022	Human	Single-center prospective study Duration: 3 mo	n = 91	Patients with BMI > 23 kg/m2 diagnosed with NAFLD (CAP > 248 dB/m)	Saroglitazar 4 mg daily	Change from baseline of liver biomarker, hepatic steatosis, and fibrosis in patients who lost > 5% of the weight	Patients with > 5% of weight loss had a median AST of 36 vs 40 at baseline (P = 0.038), ALT 44 vs 53 (P < 0.01), kPa 5.9 vs 6.8 (P = 0.336) and CAP 265 vs 311 (P = 0.128)
Rajesh et al[28], 2022	Human	A single-arm, open-label prospective study Duration: 12 wk	n = 85	Patients with NAFLD (US, CT, or MRI) and type 2 diabetes mellitus, and dyslipidemia	Saroglitazar 4 mg daily	Evaluate the effect of Saroglitazar on liver function test, liver fibrosis score by FibroScan, lipid profiles, and HbA1c	From baseline, there was a reduction in ALT from 49 u/L to 48 (P < 0.05), fibrosis score 10 kPa to 6 (P < 0.0001), TG 359.89 to 103.04 (P = 0.0001), HbA1c 10.29% to 9.85% (P = 0.002)
Jain et al[30], 2018	Animal	Duration: 12 wk	n = 18	CDHFD-induced model of NASH in mice (n = 9 per group)	Saroglitazar: Control vs 3 mg/kg daily	Reversal of CDHFD-induced NASH after 8 wk	In control vs. treatment, respectively, steatosis score was 2.6 vs 0, ballooning 1.4 vs 0, inflammation 3 vs 1.1 (P < 0.1)
Jain et al[30], 2018	Animal	Duration: 12 wk	n = 16	CCL4-induced fibrosis model in mice (n = 8 per group)	Saroglitazar: Control vs 4 mg/kg daily	Reversal of CCl4-induced liver fibrosis after 4 wk	Saroglitazar protected mice from CCl4-induced liver fibrosis measured via Hematoxylin and Eosin stains
Staels et al[26], 2013	Animal	Duration: 7 wk	n = 16	Choline-deficient high-fat diet-induced model of NASH in mice (n = 8 per group)	GFT505: Control vs 10 mg/kg daily	Evaluate the prevention of the development of NASH in CDHFD mice	The percentage of animals with macrosteatosis in control vs treatment was 100% to 0%, inflammation was 100% to 0%, and the percentage of fibrosis was 1.3% to 0.8% (P < 0.01)
Staels et al[26], 2013	Animal	Duration: 7 wk	n = 12	CCl4-induced liver fibrosis in mice (n = 6 per group)	GFT505: Control vs 30 mg/kg daily	Evaluate the prevention of the development of NASH in CCL4 mice	The fibrotic surface of control vs treatment was 8% vs 4% in CCL4 mice (P < 0.001)
Ye et al[23], 2003	Animal	Duration: 2 wk	n = 6	High fat-fed rats	Ragaglitazar: 3 mg/kg-1 daily	Evaluate the benefits of Ragaglitazar on insulin sensitivity and lipid metabolism.	Enhanced insulin suppressibility of hepatic glucose output by 79% (P < 0.001), decrease in liver TG from baseline of 23 μmol/g to 7 μmol/g (P < 0.01)

N/A: Not applicable; NASH: Non-alcoholic steatohepatitis; n: Number; TG: Triglycerides; CCL4: Carbon tetrachloride; NFS: NAFLD fibrosis score; CAP: Controlled attenuation parameter; HbA1c: Hemoglobin A1c; NAFLD: Non-alcoholic fatty liver disease; GIR: Glucose infusion rate; CDHFD: Choline-deficient high-fat diet; BMI: Body mass index; ALT: Alanine transaminase; AST: Aspartate aminotransferase; US: Ultrasound; MRI: Magnetic resonance imaging; CT: Computerized tomography.