LivingGLP1
Network meta-analysis

Diarrhea

Metabolic dysfunction associated steatotic liver disease or steatohepatitis

longest follow-upRecorded harmsEach dose separatelyHazard ratio (from event counts)
5
Randomized trials
9
Treatments
866
Participants
207
Events

In plain language

Across 5 trials with 866 participants, 0 of 8 treatments had a clearly better result than placebo on diarrhea, 1 a clearly worse one, and for 7 the evidence could not tell them apart from placebo. The most favorable estimate was for Tirzepatide 15 mg subcutaneous once weekly: hazard ratio (from event counts) 1.18 (95% credible interval 0.38 to 3.52).

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.
PLACEBOSEMA_SC_0p1MG_QDSEMA_SC_0p2MG_QDSEMA_SC_0p4MG_QDSEMA_SC_2p4MG_QWSURV_SC_6p0MG_QWTIRZ_SC_10MG_QWTIRZ_SC_15MG_QWTIRZ_SC_5MG_QW
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.
0.250.512451020← favors treatmentfavors reference →Tirzepatide 15 mg subcutaneous o…Semaglutide 0.4 mg injection onc…Tirzepatide 5 mg subcutaneous on…Tirzepatide 10 mg subcutaneous o…Semaglutide 0.2 mg injection onc…Semaglutide 0.1 mg injection onc…Semaglutide 2.4 mg subcutaneous …Survodutide 6.0 mg subcutaneous …
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
TreatmentBayesian HR (95% CrI)95% prediction intervalFrequentist HR (95% CI)Verdict
Tirzepatide 15 mg subcutaneous once weekly
TIRZ_SC_15MG_QW
1.18 (0.38 to 3.52)0.28 to 4.581.25 (0.49 to 3.16)Unclear
Semaglutide 0.4 mg injection once daily
SEMA_SC_0p4MG_QD
1.34 (0.56 to 3.06)0.41 to 4.451.43 (0.74 to 2.79)Unclear
Tirzepatide 5 mg subcutaneous once weekly
TIRZ_SC_5MG_QW
1.44 (0.46 to 4.24)0.36 to 5.981.58 (0.63 to 3.92)Unclear
Tirzepatide 10 mg subcutaneous once weekly
TIRZ_SC_10MG_QW
1.68 (0.55 to 4.92)0.43 to 6.611.91 (0.78 to 4.68)Unclear
Semaglutide 0.2 mg injection once daily
SEMA_SC_0p2MG_QD
2.07 (0.75 to 5.46)0.54 to 7.612.38 (1.13 to 5.04)Unclear
Semaglutide 0.1 mg injection once daily
SEMA_SC_0p1MG_QD
2.12 (0.79 to 5.84)0.57 to 7.552.45 (1.16 to 5.15)Unclear
Semaglutide 2.4 mg subcutaneous once weekly
SEMA_SC_2p4MG_QW
2.37 (0.49 to 14.13)0.41 to 16.952.61 (0.52 to 13.16)Unclear
Survodutide 6.0 mg subcutaneous once weekly
SURV_SC_6p0MG_QW
3.36 (1.05 to 10.42)0.78 to 14.253.88 (1.65 to 9.13)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 columnPLACEBOTIRZ_SC_15MG_QWSEMA_SC_0p4MG_QDTIRZ_SC_5MG_QWTIRZ_SC_10MG_QWSEMA_SC_0p2MG_QDSEMA_SC_0p1MG_QDSEMA_SC_2p4MG_QWSURV_SC_6p0MG_QW
PLACEBOPLACEBO0.85
0.28 to 2.61		0.75
0.33 to 1.78		0.70
0.24 to 2.18		0.60
0.20 to 1.82		0.48
0.18 to 1.33		0.47
0.17 to 1.27		0.42
0.07 to 2.03		0.30
0.10 to 0.95
TIRZ_SC_15MG_QW1.18
0.38 to 3.52		TIRZ_SC_15MG_QW0.87
0.22 to 3.57		0.82
0.26 to 2.55		0.70
0.23 to 2.11		0.57
0.13 to 2.53		0.54
0.13 to 2.47		0.49
0.06 to 3.43		0.35
0.07 to 1.72
SEMA_SC_0p4MG_QD1.34
0.56 to 3.06		1.15
0.28 to 4.56		SEMA_SC_0p4MG_QD0.93
0.24 to 3.91		0.79
0.20 to 3.06		0.64
0.24 to 1.86		0.62
0.23 to 1.73		0.56
0.08 to 3.37		0.40
0.10 to 1.72
TIRZ_SC_5MG_QW1.44
0.46 to 4.24		1.22
0.39 to 3.80		1.08
0.26 to 4.24		TIRZ_SC_5MG_QW0.84
0.29 to 2.54		0.69
0.16 to 3.20		0.67
0.15 to 3.05		0.60
0.07 to 4.18		0.43
0.08 to 2.08
TIRZ_SC_10MG_QW1.68
0.55 to 4.92		1.43
0.47 to 4.29		1.27
0.33 to 4.98		1.18
0.39 to 3.50		TIRZ_SC_10MG_QW0.82
0.19 to 3.49		0.80
0.19 to 3.42		0.69
0.09 to 4.85		0.50
0.11 to 2.45
SEMA_SC_0p2MG_QD2.07
0.75 to 5.46		1.76
0.40 to 7.93		1.55
0.54 to 4.10		1.45
0.31 to 6.26		1.21
0.29 to 5.35		SEMA_SC_0p2MG_QD0.97
0.34 to 2.76		0.86
0.11 to 5.49		0.62
0.13 to 2.76
SEMA_SC_0p1MG_QD2.12
0.79 to 5.84		1.84
0.40 to 7.98		1.61
0.58 to 4.30		1.50
0.33 to 6.87		1.26
0.29 to 5.25		1.03
0.36 to 2.95		SEMA_SC_0p1MG_QD0.89
0.12 to 5.67		0.64
0.14 to 2.95
SEMA_SC_2p4MG_QW2.37
0.49 to 14.13		2.05
0.29 to 17.50		1.79
0.30 to 13.26		1.67
0.24 to 13.77		1.44
0.21 to 11.41		1.16
0.18 to 8.88		1.12
0.18 to 8.11		SEMA_SC_2p4MG_QW0.71
0.10 to 5.58
SURV_SC_6p0MG_QW3.36
1.05 to 10.42		2.85
0.58 to 14.35		2.53
0.58 to 10.53		2.33
0.48 to 12.09		1.99
0.41 to 9.48		1.62
0.36 to 7.62		1.57
0.34 to 7.19		1.40
0.18 to 9.96		SURV_SC_6p0MG_QW

Heterogeneity, fit and convergence

Bayesian random effects (primary)

Heterogeneity (tau)
0.299 (95% CrI 0.077 to 0.998), log scale
Residual deviance
13.4 for 14 data points
DIC
26.7 (pD 13.3)
Largest R-hat
1.001
Smallest ESS
bulk 3,619, tail 2,964
Divergent transitions
0
Convergence
All criteria met
Priors
PR02 N(0, 5^2); PR05 N(0, 2.5^2); PR09 log normal(-1.87, 1.52^2) on tau^2 (Adverse events, pharm vs placebo control)

Frequentist check (netmeta)

Method
inverse variance, REML, OR
Tau
0.000
I squared
0%
Q (total)
0.05 on 1 df, P = 0.825
Q (between designs)
0.05, P = 0.825

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.

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 52 to 79 weeks
  • NoteOutcome assessment, analysis set: mixed: randomized 1, safety 4
  • NoteData handling, input conversions: nonserious_only 4
Comparability items per trial
Trialtime weeksanalysis setdefinitioninstrumentadjudicatedproportion methodintercurrent events (discontinuation)intercurrent events (rescue)blindingfundingstart yearEligibility
SYNERGY-NASH56randomizednot statednot statednot statednot statednot statednot stateddouble_blindindustry2019age 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
NCT0335738079safetynot statednot statednot statednot statednot statednot stateddouble_blindindustry2017age 18 to 75; BMI 25 to 40; MRE stiffness 2.50 to 4.63 kPa; MRI PDFF 10 percent or more; HbA1c 9.5 or less
NCT0297094279safetynot statednot statednot statednot statednot statednot stateddouble_blindindustry2016age 18 to 75; biopsy NASH F1 to F3; NAS 4 or more; BMI above 25; HbA1c 10 percent or less
NCT0398745155safetynot statednot statednot statednot statednot statednot stateddouble_blindindustry2019age 18 to 75; biopsy NASH with F4 compensated cirrhosis; NAS 3 or more; BMI 27 or more
NCT0630999252safetynot statednot statednot statednot statednot statednot stateddouble_blindindustry2024age 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
TrialArmTreatmentWeekDataValueSEEvents / NFlagsSource
SYNERGY-NASHA1TIRZ_SC_5MG_QW56arm, events15 / 47R0018381:Table 3
SYNERGY-NASHA2TIRZ_SC_10MG_QW56arm, events17 / 47R0018381:Table 3
SYNERGY-NASHA3TIRZ_SC_15MG_QW56arm, events13 / 48R0018381:Table 3
SYNERGY-NASHA4PLACEBO56arm, events11 / 48R0018381:Table 3
NCT03357380A1SEMA_SC_0p4MG_QD79arm, events10 / 34R0011165:Table 3
NCT03357380A2PLACEBO79arm, events8 / 33R0011165:Table 3
NCT02970942A1SEMA_SC_0p1MG_QD79arm, events23 / 80nonserious_onlyregistry:adverse_events
NCT02970942A2SEMA_SC_0p2MG_QD79arm, events22 / 78nonserious_onlyregistry:adverse_events
NCT02970942A3SEMA_SC_0p4MG_QD79arm, events16 / 82nonserious_onlyregistry:adverse_events
NCT02970942A4PLACEBO79arm, events11 / 80nonserious_onlyregistry:adverse_events
NCT03987451A1SEMA_SC_2p4MG_QW55arm, events9 / 47R0017043:Table 2
NCT03987451A2PLACEBO55arm, events2 / 24R0017043:Table 2
NCT06309992A1SURV_SC_6p0MG_QW52arm, events43 / 146R0011245:Table 3
NCT06309992A2PLACEBO52arm, events7 / 72R0011245:Table 3

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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