Network meta-analysis

Fibrosis improvement without worsening of steatohepatitis

Metabolic dysfunction associated steatotic liver disease or steatohepatitis

weeks 48 to 104 (target week 72)Treatment policyEach dose separatelyOdds ratio

Randomized trials

Treatments

301

Participants

102

Events

In plain language

Across 2 trials with 301 participants, 0 of 4 treatments had a clearly better result than placebo on fibrosis improvement without worsening of steatohepatitis, and for 4 the evidence could not tell them apart from placebo. The most favorable estimate was for Semaglutide 0.1 mg injection once daily: odds ratio 1.89 (95% credible interval 0.53 to 6.45).

Higher values favor the treatment. "Clearly" means the 95% credible interval excludes no difference. These are averages across trials; they do not say how any one person will respond. Not medical advice.

Network of trials

Each circle is a treatment; each line joins treatments that were randomized against each other in at least one trial.

Node area shows participants; line width shows trials comparing two treatments directly. Blue: GLP-1 receptor agonist containing treatments; grey: comparators. Hover over or tab to a node or line for details.

Effects compared with Placebo

Odds ratio. Higher values favor the treatment.

Versus Placebo, log scale. Blue: Bayesian random effects posterior median with 95% credible interval (thick) and 95% prediction interval (dashed). Amber diamond: frequentist estimate with 95% confidence interval. Hover over or tab to a row for its values.

Effects of each treatment versus Placebo
Treatment	Bayesian OR (95% CrI)	95% prediction interval	Frequentist OR (95% CI)	Verdict
Semaglutide 0.1 mg injection once daily SEMA_SC_0p1MG_QD	1.89 (0.53 to 6.45)	0.33 to 9.55	1.98 (0.93 to 4.22)	Unclear
Semaglutide 0.4 mg injection once daily SEMA_SC_0p4MG_QD	1.48 (0.42 to 4.84)	0.25 to 8.10	1.54 (0.72 to 3.30)	Unclear
Semaglutide 0.2 mg injection once daily SEMA_SC_0p2MG_QD	0.95 (0.25 to 3.40)	0.16 to 5.29	0.98 (0.45 to 2.11)	Unclear
Semaglutide 2.4 mg subcutaneous once weekly SEMA_SC_2p4MG_QW	0.31 (0.06 to 1.71)	0.04 to 2.43	0.29 (0.08 to 1.04)	Unclear

Ranking

How likely each treatment is to be among the best. Rankings ignore the size of differences and their certainty, so read them with the effects above.

League table

Every treatment against every other: odds ratio of the row treatment versus the column treatment, posterior median and 95% credible interval. Green: row clearly better; red: row clearly worse.

Every treatment in a row compared with every treatment in a column
Row versus column	PLACEBO	SEMA_SC_0p1MG_QD	SEMA_SC_0p4MG_QD	SEMA_SC_0p2MG_QD	SEMA_SC_2p4MG_QW
PLACEBO	PLACEBO	0.53 0.16 to 1.88	0.68 0.21 to 2.38	1.06 0.29 to 3.93	3.23 0.59 to 16.25
SEMA_SC_0p1MG_QD	1.89 0.53 to 6.45	SEMA_SC_0p1MG_QD	1.29 0.34 to 4.56	2.02 0.53 to 7.21	6.09 0.72 to 43.83
SEMA_SC_0p4MG_QD	1.48 0.42 to 4.84	0.78 0.22 to 2.92	SEMA_SC_0p4MG_QD	1.57 0.41 to 5.99	4.80 0.57 to 33.94
SEMA_SC_0p2MG_QD	0.95 0.25 to 3.40	0.50 0.14 to 1.88	0.64 0.17 to 2.44	SEMA_SC_0p2MG_QD	3.05 0.37 to 22.32
SEMA_SC_2p4MG_QW	0.31 0.06 to 1.71	0.16 0.02 to 1.40	0.21 0.03 to 1.76	0.33 0.04 to 2.73	SEMA_SC_2p4MG_QW

Heterogeneity, fit and convergence

Bayesian random effects (primary)

Heterogeneity (tau): 0.379 (95% CrI 0.096 to 1.366), log scale
Residual deviance: 5.9 for 6 data points
DIC: 11.9 (pD 5.9)
Largest R-hat: 1.001
Smallest ESS: bulk 3,930, tail 3,142
Divergent transitions: 0
Convergence: All criteria met
Priors: PR02 N(0, 5^2); PR05 N(0, 2.5^2); PR09 log normal(-1.77, 1.52^2) on tau^2 (Biological markers (dichotomised), pharm vs placebo control)

Frequentist check (netmeta)

Method: inverse variance, REML, OR
Tau: 0.000
Q (total): 0.00 on 0 df
Q (between designs): 0.00

Inconsistency

Do trials comparing two treatments directly agree with the indirect evidence through other treatments?

No comparison here has both direct and indirect evidence, so inconsistency cannot be checked by node splitting; the between designs Q above is the global check.

Small study effects

A comparison adjusted funnel plot: each point is one trial comparison, centered on its own network estimate. Asymmetry can signal that small trials with unfavorable results are missing.

Fewer than ten trial comparisons, too few to judge funnel plot asymmetry.

Baseline characteristics of the trials

The baseline value of each effect modifier or prognostic factor that applies here, per trial: mean or percent over arms, weighted by the number randomized. A note under a value names a stand in (a median for a mean, 100 minus the male share, Asian subgroup rows, an all Asian site list); "not reported" means no source of the trial prints it.

Baseline effect modifiers and prognostic factors per trial
Trial	Fibrosis stage (NASH CRN stage) effect modifier, prognostic factor; 1 of 2
NCT02970942 S000922	F0 0.0%, F1 28.1%, F2 22.5%, F3 49.4%, F4 0.0%
NCT03987451 S001764	not reported

Comparability of the trials

Checked across designs (the set of treatments each trial compares) for eligibility, outcome definition and assessment, and the baseline factors above. Flags point to possible intransitivity; notes describe variation that is not tied to design.

FlagOutcome assessment, analysis set: confounded with design: full_analysis 1, other 1
FlagOutcome assessment, definition: confounded with design: NASH resolution with no worsening of fibrosis 1, not stated 1
FlagOutcome assessment, proportion method: confounded with design: not stated 1, not_stated 1
NoteOutcome assessment, time point: selected time points span 48 to 72 weeks
NoteData handling, input conversions: count_from_percent 4

Comparability items per trial
Trial	time weeks	analysis set	definition	instrument	adjudicated	proportion method	intercurrent events (discontinuation)	intercurrent events (rescue)	blinding	funding	start year	Eligibility
NCT02970942	72	other	NASH resolution with no worsening of fibrosis	not stated	not stated	not_stated	not stated	not stated	double_blind	industry	2016	age 18 to 75; biopsy NASH F1 to F3; NAS 4 or more; BMI above 25; HbA1c 10 percent or less
NCT03987451	48	full_analysis	not stated	not stated	not stated	not stated	not stated	not stated	double_blind	industry	2019	age 18 to 75; biopsy NASH with F4 compensated cirrhosis; NAS 3 or more; BMI 27 or more

Trial data

What each trial contributes. Arm rows give the arm value with its standard error, or events over participants; contrast rows give the odds ratio on the analysis scale (log) against the trial's first row. Flags mark converted, combined or approximated inputs.

Trial data entering this analysis
Trial	Arm	Treatment	Week	Data	Events / N	Flags	Source
NCT02970942	A1	SEMA_SC_0p1MG_QD	72	arm, responders	28 / 57	count_from_percent	registry:outcomes
NCT02970942	A2	SEMA_SC_0p2MG_QD	72	arm, responders	19 / 59	count_from_percent	registry:outcomes
NCT02970942	A3	SEMA_SC_0p4MG_QD	72	arm, responders	24 / 56	count_from_percent	registry:outcomes
NCT02970942	A4	PLACEBO	72	arm, responders	19 / 58	count_from_percent	registry:outcomes
NCT03987451	A1	SEMA_SC_2p4MG_QW	48	arm, responders	5 / 47		R0017043:Results
NCT03987451	A2	PLACEBO	48	arm, responders	7 / 24		R0017043:Results

Rerun this analysis yourself

Remove treatments or trials and refit the frequentist and Bayesian models in your browser, with the same methods as the published analysis.

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