The Intricate Relationship between Type 2 Diabetes Mellitus (T2DM), Insulin Resistance (IR), and Nonalcoholic Fatty Liver Disease (NAFLD)

Table 1

Clinical trials which encompass the antidiabetic drug effects on NAFLD. BMI: body mass index; AST: aspartataminotransferaza, ALT: alanine aminotransferase, HbA1c: glycated haemoglobin, DNL: de novo lipogenesis.

Agents	Study type	Dose	Time	Outcomes	Ref.
Rosiglitazone	Randomized placebo-controlled (FLIRT) Trial	4 mg/day 1 month and after 8 mg/day	1 year and 4 months	Improvement of steatosis correlated with reduction of transaminase level improvement in insulin sensitivity.	[163]
	Randomized placebo-controlled (FLIRT 2) extension trial	4 mg/day 1 month and after 8 mg/day	3 years	Improvement in ALT and liver steatosis but no results on ballooning and fibrosis.	[164]
Pioglitazone	Randomized, double-blind, placebo-controlled trial	30 mg/day	2 years	Improvement in individual histologic scores, adipose tissue, hepatic, and muscle insulin sensitivity.	[166]
Pioglitazone vs. ipragliflozin	Open-label, randomized, active-controlled trial	15-30 mg/day vs. 50 mg/day	6 months	AST and ALT, HbA1c, and fasting plasma glucose were similarly reduced in the two-treatment group.	[169]
Liraglutide	Randomised, placebo-controlled phase 2 study (LEAN) study	1.8 mg/day	1 year	Improvements in histological steatosis and hepatocyte ballooning.	[172]
	Double-blind, randomised, placebo-controlled trial	1.8 mg/day	3 months	Reduced BMI, DNL, IR, and hepatic steatosis.	[173]
	Open-label, active-controlled parallel-group, multicentre trial	3 mg/day	6 months	Reduced BMI, hepatic steatosis, and hepatocellular apoptosis.	[176]
	Prospective, single-center study (LEAN-J).	1.2 mg/day	2 years	31% reduction of hepatic steatosis	[179]
Canagliflozin	A prospective study	100 mg/day	6 months	Improvement in histopathologic features and markers of liver dysfunction	[183]
	A prospective study	100 mg/day	6 months	Histological improvement, improvement of IR.	[184]
	Prospective study	100 mg/day	6 months	Improvement in ALT and liver steatosis	[186]
Empagliflozin	Randomised controlled trials (E-LIFT Trial)	10 mg/day	5 months	Improvement in liver steatosis and serum ALT level.	[187]
	Single-arm, open-label, pilot study	25 mg/day	6 months	Reduction in BMI, cholesterol, GGT, ballooning, and fibrosis.	[188]
Dapagliflozin	Randomised controlled trial	10 mg/day	4 months	Reduction in BMI, AST, ALT, and liver steatosis.	[189]
	An open-label, randomized trial	5 mg/day	6 months	Improvements in hepatic steatosis, along with attenuation of fibrosis in a subset of patients with significant fibrosis.	[190]
Luseogliflozin	A prospective, single-arm trial (LEAD trial)	2.5 mg/day	6 months	Improvement of steatosis correlated with reduction of transaminase level	[195]