Network meta-analysis

Discontinuation due to gastrointestinal adverse events

Metabolic dysfunction associated steatotic liver disease or steatohepatitis

longest follow-upRecorded harmsEach dose separatelyHazard ratio (from event counts)

Randomized trials

Treatments

799

Participants

Events

In plain language

Across 4 trials with 799 participants, 0 of 8 treatments had a clearly better result than placebo on discontinuation due to gastrointestinal adverse events, 2 a clearly worse one, and for 6 the evidence could not tell them apart from placebo. The most favorable estimate was for Tirzepatide 10 mg subcutaneous once weekly: hazard ratio (from event counts) 0.16 (95% credible interval 0.00 to 3.31).

Lower 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

Hazard ratio (from event counts). Lower 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 HR (95% CrI)	95% prediction interval	Verdict
Tirzepatide 10 mg subcutaneous once weekly TIRZ_SC_10MG_QW	0.16 (0.00 to 3.31)	0.00 to 3.68	Unclear
Semaglutide 0.1 mg injection once daily SEMA_SC_0p1MG_QD	1.20 (0.08 to 14.38)	0.07 to 16.34	Unclear
Tirzepatide 15 mg subcutaneous once weekly TIRZ_SC_15MG_QW	1.90 (0.20 to 17.91)	0.17 to 21.29	Unclear
Tirzepatide 5 mg subcutaneous once weekly TIRZ_SC_5MG_QW	1.94 (0.22 to 20.20)	0.19 to 22.41	Unclear
Semaglutide 0.4 mg injection once daily SEMA_SC_0p4MG_QD	2.54 (0.25 to 27.15)	0.21 to 29.60	Unclear
Semaglutide 2.4 mg subcutaneous once weekly SEMA_SC_2p4MG_QW	3.41 (0.23 to 94.54)	0.19 to 105	Unclear
Survodutide 6.0 mg subcutaneous once weekly SURV_SC_6p0MG_QW	4.81 (1.39 to 21.37)	1.04 to 25.35	Worse
Semaglutide 0.2 mg injection once daily SEMA_SC_0p2MG_QD	9.55 (1.47 to 85.08)	1.30 to 98.58	Worse

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: hazard ratio (from event counts) 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	TIRZ_SC_10MG_QW	SEMA_SC_0p1MG_QD	TIRZ_SC_15MG_QW	TIRZ_SC_5MG_QW	SEMA_SC_0p4MG_QD	SEMA_SC_2p4MG_QW	SURV_SC_6p0MG_QW	SEMA_SC_0p2MG_QD
PLACEBO	PLACEBO	6.06 0.30 to 321	0.83 0.07 to 13.23	0.53 0.06 to 5.04	0.52 0.05 to 4.60	0.39 0.04 to 3.94	0.29 0.01 to 4.34	0.21 0.05 to 0.72	0.10 0.01 to 0.68
TIRZ_SC_10MG_QW	0.16 0.00 to 3.31	TIRZ_SC_10MG_QW	0.13 0.00 to 8.30	0.09 0.00 to 2.14	0.09 0.00 to 2.05	0.06 0.00 to 2.90	0.04 0.00 to 2.89	0.03 0.00 to 0.88	0.02 0.00 to 0.66
SEMA_SC_0p1MG_QD	1.20 0.08 to 14.38	7.42 0.12 to 796	SEMA_SC_0p1MG_QD	0.63 0.02 to 17.64	0.61 0.02 to 16.59	0.48 0.03 to 6.11	0.34 0.00 to 14.54	0.24 0.01 to 4.01	0.13 0.01 to 0.94
TIRZ_SC_15MG_QW	1.90 0.20 to 17.91	11.55 0.47 to 859	1.58 0.06 to 51.02	TIRZ_SC_15MG_QW	0.98 0.10 to 9.61	0.74 0.03 to 20.00	0.53 0.01 to 17.99	0.38 0.03 to 5.08	0.20 0.01 to 3.98
TIRZ_SC_5MG_QW	1.94 0.22 to 20.20	11.66 0.49 to 903	1.64 0.06 to 57.27	1.02 0.10 to 9.64	TIRZ_SC_5MG_QW	0.74 0.03 to 19.62	0.55 0.01 to 18.49	0.39 0.03 to 5.72	0.20 0.01 to 3.99
SEMA_SC_0p4MG_QD	2.54 0.25 to 27.15	16.18 0.34 to 1555	2.10 0.16 to 38.48	1.34 0.05 to 33.94	1.36 0.05 to 31.38	SEMA_SC_0p4MG_QD	0.73 0.01 to 27.24	0.52 0.04 to 7.72	0.27 0.03 to 1.52
SEMA_SC_2p4MG_QW	3.41 0.23 to 94.54	23.47 0.35 to 4008	2.97 0.07 to 219	1.89 0.06 to 85.70	1.82 0.05 to 101	1.38 0.04 to 75.32	SEMA_SC_2p4MG_QW	0.72 0.03 to 25.96	0.35 0.01 to 17.04
SURV_SC_6p0MG_QW	4.81 1.39 to 21.37	31.16 1.14 to 2142	4.13 0.25 to 91.88	2.63 0.20 to 35.75	2.58 0.17 to 34.79	1.93 0.13 to 27.62	1.40 0.04 to 33.12	SURV_SC_6p0MG_QW	0.51 0.04 to 5.28
SEMA_SC_0p2MG_QD	9.55 1.47 to 85.08	62.23 1.52 to 5403	7.77 1.06 to 122	5.11 0.25 to 118	5.05 0.25 to 114	3.67 0.66 to 29.99	2.83 0.06 to 100	1.95 0.19 to 24.27	SEMA_SC_0p2MG_QD

Heterogeneity, fit and convergence

Bayesian random effects (primary)

Heterogeneity (tau): 0.217 (95% CrI 0.039 to 1.021), log scale
Residual deviance: 12.0 for 12 data points
DIC: 20.9 (pD 8.9)
Largest R-hat: 1.001
Smallest ESS: bulk 5,063, tail 4,747
Divergent transitions: 0
Convergence: All criteria met
Priors: PR02 N(0, 5^2); PR05 N(0, 2.5^2); PR09 log normal(-2.99, 1.74^2) on tau^2 (Withdrawals/drop-outs, pharm vs placebo control)

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.

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	Sex (percent female) effect modifier, prognostic factor; 4 of 4	Asian ancestry or region (percent Asian) effect modifier, prognostic factor; 4 of 4
SYNERGY-NASH S000031	57.01	11.49
NCT02970942 S000922	60.62	15
NCT03987451 S001764	69.04	1.32
NCT06309992 S001918	60.59	0.93

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.

NoteOutcome assessment, time point: selected time points span 48 to 72 weeks
NoteOutcome assessment, analysis set: mixed: randomized 1, safety 3
NoteOutcome assessment, definition: mixed: Discontinued treatment due to gastrointestinal adverse events 1, not stated 3

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
SYNERGY-NASH	52	randomized	not stated	not stated	not stated	not stated	not stated	not stated	double_blind	industry	2019	age 18 to 80, BMI 27 to 50, biopsy MASH with NAS 4 or more and fibrosis F2 to F3, HbA1c up to 9.5 percent
NCT02970942	72	safety	Discontinued treatment due to gastrointestinal adverse events	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	safety	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
NCT06309992	52	safety	not stated	not stated	not stated	not stated	not stated	not stated	double_blind	industry	2024	age 18 or more; BMI 30 or more, or 27 with complication; MRI-PDFF 8 percent or more plus NIT or biopsy MASH

Trial data

What each trial contributes. Arm rows give the arm value with its standard error, or events over participants; contrast rows give the hazard ratio (from event counts) 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	Source
SYNERGY-NASH	A1	TIRZ_SC_5MG_QW	52	arm, events	2 / 47	R0018381:Table 3
SYNERGY-NASH	A2	TIRZ_SC_10MG_QW	52	arm, events	0 / 47	R0018381:Table 3
SYNERGY-NASH	A3	TIRZ_SC_15MG_QW	52	arm, events	2 / 48	R0018381:Table 3
SYNERGY-NASH	A4	PLACEBO	52	arm, events	1 / 48	R0018381:Table 3
NCT02970942	A1	SEMA_SC_0p1MG_QD	72	arm, events	1 / 80	registry:outcomes
NCT02970942	A2	SEMA_SC_0p2MG_QD	72	arm, events	6 / 78	registry:outcomes
NCT02970942	A3	SEMA_SC_0p4MG_QD	72	arm, events	2 / 82	registry:outcomes
NCT02970942	A4	PLACEBO	72	arm, events	0 / 80	registry:outcomes
NCT03987451	A1	SEMA_SC_2p4MG_QW	48	arm, events	2 / 47	R0017043:Results
NCT03987451	A2	PLACEBO	48	arm, events	0 / 24	R0017043:Results
NCT06309992	A1	SURV_SC_6p0MG_QW	52	arm, events	29 / 146	R0011245:Table 3
NCT06309992	A2	PLACEBO	52	arm, events	3 / 72	R0011245:Table 3

Rerun this analysis yourself

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