Efficacy and safety of semaglutide in non-alcoholic fatty liver disease

Table 1 Baseline characteristics of included studies

Ref.	Location sponsor	Study design	Sample size (n)	Demographics (%)	Intervention/comparator(s)	Outcomes assessed
Newsome et al[20], 2021	16 countrie, 143 sites; Novo Nordisk	MC, DB, four-arm parallel-group RCT; duration: 72 wk; randomization: 3:3:3:1:1:1	320	Age (SD): 55.0 (10.6); male/female: 125(39)/195(61); T2DM: 199 (62)	Semaglutide: 0.1 mg SQ OD (n = 80); 0.2 mg SQ OD (n = 78); 0.4 mg SQ OD (n = 82); and placebo (n = 80)	Primary: Resolution of NASH; secondary: Liver fibrosis stage, total and component of NAS, ALT, AST, liver stiffness, liver steatosis, cardiometabolic parameters, adverse events
Flint et al[21], 2021	Germany, 2 sites; Novo Nordisk	Two-centre, DB, two-arm parallel-group RCT; duration: 72 wk; randomization: 1:1	67	Age (SD): 60.0 (9.3); male/female: 47(70)/20(30); T2DM: 49 (73)	Semaglutide: 0.4 mg SQ OD (n = 34); placebo (n = 33)	Primary: Liver stiffness MRE at week 48; secondary: Liver stiffness at week 24 and 72, liver steatosis, ALT, AST, cardiometabolic parameters, adverse events
Loomba et al[17], 2023	5 countries, 38 sites; Novo Nordisk	MC, DB, two-arm-parallel group RCT; duration: 48 wk; randomization: 2:1	71	Age (SD): 59.5 (8.0); male/female: 22(31)/49(61); T2DM: 53 (75)	Semaglutide: 2.4 mg SQ qw (n = 47); Placebo (n = 24)	Primary: Liver fibrosis stage; secondary: Liver stiffness, liver steatosis, NASH resolution, total and component of NAS, ALT, AST, cardiometabolic parameters, adverse events

MC: Multi-centre; DB: Double-blind; RCT: Randomized controlled trial; SD: Standard deviation; T2DM: Type 2 diabetes mellitus; SQ: Subcutaneous; OD: Once daily; qw: Weekly; NASH: Non-alcoholic steatohepatitis; NAS: NAFLD activity score; ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; MRE: Magnetic resonance elastography.

Table 2 Grading of recommendations assessment, development, and evaluation summary of findings table

Outcomes	Anticipated absolute effects1 (95%CI)		Relative effect (95%CI)	Number of participants (studies)	Certainty of the evidence (GRADE)
	Risk with placebo	Risk with semaglutide
Resolution of NASH with no worsening of liver fibrosis assessed with: Liver biopsy	183 per 1000	416 per 1000 (276 to 571)	OR 3.18 (1.70 to 5.95)	301 (2 RCTs)	+++O: Moderate2
Improvement in liver fibrosis stage without worsening of NASH assessed with: Liver biopsy	317 per 1000	248 per 1000 (65 to 613)	OR 0.71 (0.15 to 3.41)	301 (2 RCTs)	++OO: Low2,3,4
Liver stiffness assessed with: MRI-PDFF or Fibroscan	-	SMD 0.48 lower (0.86 lower to 0.11 lower)	-	350 (3 RCTs)	++++: High
Liver steatosis assessed with: MRE	The mean liver steatosis ranged from -0.57% to -2.57%	MD 4.96 % lower (9.92 lower to 0.01 higher)	-	138 (2 RCTs)	+++O: Moderate3
ALT	The mean ALT ranged from 1.90 U/L to -11.22 U/L	MD 14.06 U/L lower (22.06 lower to 6.07 lower)	-	458 (3 RCTs)	++++: High
AST	The mean AST ranged from 1.50 U/K to -5.76 U/K	MD 11.44 U/K lower (17.23 lower to 5.65 lower)	-	458 (3 RCTs)	++++: High
Serious adverse events	109 per 1000	147 per 1000 (84 to 244)	OR 1.40 (0.75 to 2.62)	456 (3 RCTs)	+++O: Moderate2,4

¹The risk in the intervention group [and its 95% confidence interval (95%CI)] is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95%CI).

²Few events.

³Possibly substantial heterogeneity.

⁴Wide confidence interval including no effect and does not exclude appreciable benefit or harm.

GRADE Working Group grades of evidence. High certainty: We are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect. Very low certainty: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect. CI: Confidence interval; MD: Mean difference; OR: Odds ratio; SMD: Standardised mean difference; MRI-PDFF: MRI proton density fat fraction; MRE: Magnetic resonance elastography.