Novel glucose-lowering drugs for non-alcoholic fatty liver disease

Table 1 Summary of included studies

Ref.	Study duration	Population	Assessment of NAFLD	Intervention	No. of participants
Alam et al[18], 2018	52 wk	NAFLD	Biopsy	Sitagliptin 100 mg QD + lifestyle modification	20
				Lifestyle modification	20
Cui et al[19], 2017	24 wk	NAFLD with prediabetes or early diabetes	MRI	Sitagliptin 100 mg QD	25
				PBO	25
Hussain et al[20], 2016	12 wk	NAFLD + dyslipidemia	Ultrasound	Vildagliptin 50 mg Bid	29
				PBO	29
Macauley et al[21], 2015	6 mo	T2DM with hepatic steatosis	Imaging (CT or ultrasound)	Vildagliptin 50 mg Bid	22
				PBO	22
Joy et al[22], 2017	24 wk	NASH	Biopsy	Sitagliptin 100 mg QD	6
				PBO	6
Li et al[23], 2019	24 wk	T2DM with NAFLD	Imaging or biopsy	Saxagliptin 5 mg QD	31
				Glimepiride 2 mg QD	33
				Glimepiride 2 mg QD + polyenephosphatidylcholine 456 mg TID	31
Yan et al[24], 2019	26 wk	T2DM with NAFLD	MRI	Liraglutide 1.8 mg + metformin	24
				Sitagliptin + metformin	27
				Glargine 0.2 IU/Kg/d + metformin	24
Armstrong et al[25], 2016	48 wk	T2DM with NASH	Biopsy	Liraglutide 1.8 mg QD	26
				PBO	26
Cusi et al[26], 2018	6 mo	T2DM with NAFLD/NASH	Laboratory liver tests	Duraglutide 1.5 mg QW	971
				PBO	528
Fan et al[27], 2013	12 wk	T2DM with NAFLD	Ultrasound	Exenatide	49
				Metformin	68
Feng et al[28], 2017	24 wk	T2DM with NAFLD	Ultrasound	Metformin 1000 mg Bid	29
				Gliclazide 120 mg/d	29
				Liraglutide 1.8 mg QD	29
Khoo et al[29], 2017	26 wk	NAFLD	MRI	Liraglutide 3.0 mg QD	12
				Diet and exercise	12
Shao et al[30], 2014	12 wk	T2DM with NAFLD	Ultrasound	Exenatide 10 μg bid + glargine	30
				Intensive insulin therapy	30
Tian et al[31], 2018	12 wk	T2DM with NAFLD	Ultrasound	Liraglutide 0.6-1.2 mg QD	52
				Metformin 1000-1500 mg/d	75
Eriksson et al[32], 2018	12 wk	T2DM with NAFLD	MRI	Dapagliflozin 10 mg QD	21
				PBO	21
				Dapagliflozin 10 mg QD + OM-3CA	22
				OM-3CA 4 g	20
Ito et al[33], 2017	24 wk	T2DM with NAFLD	Clinical laboratorytests or imaging	Ipragliflozin 50 mg QD	32
				Pioglitazone 15–30 mg QD	34
Kuchay et al[34], 2018	20 wk	T2DM with NAFLD	MRI	Empagliflozin 10 mg QD	22
				Control	20
Shibuya et al[35], 2018	6 mo	T2DM with NAFLD	Imaging (CT or ultrasound)	Luseogliflozin 2.5 mg QD	16
				Metformin 1500 mg QD	16
Shimizu et al[36], 2018	24 wk	T2DM with NAFLD	Transient elastography	Dapagliflozin 5 mg QD	33
				Control	24

NAFLD: Non-alcoholic fatty liver disease; MRI: Magnetic resonance imaging; T2DM: Type 2 diabetes mellitus; NASH: Nonalcoholic steatohepatitis; CT: Computed tomography.

Table 2 Comparison of body weight and body mass index changes from baseline in different treatment groups

	Studies	Participants	WMD	95%CI		P value
Body weight change
DPP-4 inhibitors	4	140/138	-1.20	-1.44	-0.95	< 0.0001
GLP-1 RAs	8	1222/821	-3.61	-5.74	-1.48	0.0009
SGLT2 inhibitors	5	146/135	-2.53	-3.35	-1.71	< 0.0001
BMI change
DPP-4 inhibitors	5	144/146	-0.59	-1.80	0.61	0.33
GLP-1 RAs	7	251/293	-1.46	-2.23	-0.69	0.0002
SGLT2 inhibitors	4	114/101	-1.72	-2.68	-0.75	0.0005

WMD: Weighted mean difference; CI: Confidence interval; DPP-4: Dipeptidyl peptidase-4; GLP-1 RA: Glucagon-like peptide-1 receptor agonist; SGLT2: Sodium-glucose cotransporter 2; BMI: Body mass index.

Table 3 Comparison of hemoglobin A1c change from baseline in different treatment groups

	Studies	Participants	WMD	95%CI		P value
HbA1c change
DPP-4 inhibitors	6	166/166	-0.42	-0.58	-0.25	< 0.0001
GLP-1 RAs	7	1210/809	-0.29	-0.85	0.26	0.30
SGLT2 inhibitors	5	146/135	-0.36	-0.80	0.08	0.11
HbA1c change (placebo-controlled studies only)
DPP-4 inhibitors	5	102/102	-0.38	-0.71	-0.05	0.02
GLP-1 RAs	3	1009/566	-0.88	-1.56	-0.19	0.01
SGLT2 inhibitors	1	21/21	-0.50	-0.84	-0.16	0.004

HbA1c: Hemoglobin A1c; WMD: Weighted mean difference; CI: Confidence interval; DPP-4: Dipeptidyl peptidase-4; GLP-1 RA: Glucagon-like peptide-1 receptor agonists; SGLT2: Sodium-glucose cotransporter 2.

Table 4 Comparison of magnetic resonance imaging proton density fat fraction and visceral fat area change from baseline in different treatment groups

	Studies	Participants	WMD	95%CI		P value
MRI-PDFF change
DPP-4 inhibitors	2	52/49	-2.31	-4.92	0.29	0.08
GLP-1 RAs	1	24/24	-3.20	-5.98	-0.42	0.02
SGLT2 inhibitors	2	65/61	-1.18	-2.38	0.03	0.06
VFA change
DPP-4 inhibitors	1	27/24	-23.10	-38.84	-7.36	0.004
GLP-1 RAs	1	24/24	-30.40	-46.86	-13.94	0.0003
SGLT2 inhibitors	2	48/50	-23.48	-25.85	-21.12	< 0.0001

MRI-PDFF: Magnetic resonance imaging proton density fat fraction; VAF: Visceral fat area; WMD: Weighted mean difference; CI: Confidence interval; DPP-4: Dipeptidyl peptidase-4; GLP-1 RA: Glucagon-like peptide-1 receptor agonist; SGLT2: Sodium-glucose cotransporter 2.

Table 5 Meta-regression analyses of association between weight change difference and difference of alanine aminotransferase, aspartate aminotransferase, magnetic resonance imaging proton density fat fraction, and visceral fat area between antidiabetes drugs and controls (ß coefficient value, P value, and 95%CI are shown)

	ß	P value	95%CI
ALT	0.064	0.267	-0.053-0.181
AST	0.020	0.735	-0.104-0.144
MRI-PDFF	0.308	0.701	-2.678-3.294
VFA	1.776	0.343	-11.723-15.275

ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; MRI-PDFF: Magnetic resonance imaging proton density fat fraction; VFA: Visceral fat area.