Network meta-analysis

Constipation

Heart failure with left ventricular ejection fraction above 40 percent

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

Randomized trials

Treatments

1,260

Participants

100

Events

In plain language

Across 2 trials with 1,260 participants, 0 of 2 treatments had a clearly better result than placebo on constipation, and for 2 the evidence could not tell them apart from placebo. The most favorable estimate was for semaglutide 2.4 mg subcutaneous once weekly: hazard ratio (from event counts) 2.38 (95% credible interval 0.57 to 9.20).

Semaglutide 2.4 mg subcutaneous once weekly: not convincingly different from placebo (certainty pending).
Tirzepatide maximum tolerated dose injection once weekly: not convincingly different from placebo (certainty pending).

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	Frequentist HR (95% CI)	Verdict	Confidence
Semaglutide 2.4 mg subcutaneous once weekly SEMA_SC_2p4MG_QW	2.38 (0.57 to 9.20)	0.35 to 14.22		Unclear	pending
Tirzepatide maximum tolerated dose injection once weekly TIRZ_SC_MTD_5-10-15_QW	2.50 (0.64 to 8.28)	0.38 to 14.61		Unclear	pending

Confidence in the results

How much each comparison can be trusted, rated with CINeMA in six domains and summarized with GRADE.

Ratings follow the protocol's numeric rules from risk of bias and indirectness judgments made by language model reviewers (amendment A028); no human has verified them yet. Reporting bias (ROB-MEN): no concerns. Reference risk 21 per 1000.

Confidence in each comparison with Placebo
Comparison	Within study bias	Reporting bias	Indirectness	Imprecision	Heterogeneity	Incoherence	Confidence
Semaglutide 2.4 mg subcutaneous once weekly versus Placebo	pending	none	pending	major	none	none	pending
Tirzepatide maximum tolerated dose injection once weekly versus Placebo	pending	none	pending	major	none	none	pending

Every other comparison (1)

Confidence in the other comparisons
Comparison	Within study bias	Reporting bias	Indirectness	Imprecision	Heterogeneity	Incoherence	Confidence
Semaglutide 2.4 mg subcutaneous once weekly versus Tirzepatide maximum tolerated dose injection once weekly	pending	none	pending	major	none	none	pending

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.

Rank probabilities

Probability of each rank for each treatment
Treatment	Rank 1	Rank 2	Rank 3	Mean rank
PLACEBO	86%	12%	1%	1.1
SEMA_SC_2p4MG_QW	8%	44%	48%	2.4
TIRZ_SC_MTD_5-10-15_QW	5%	44%	51%	2.5

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	SEMA_SC_2p4MG_QW	TIRZ_SC_MTD_5-10-15_QW
PLACEBO	PLACEBO	0.42 0.11 to 1.74	0.40 0.12 to 1.56
SEMA_SC_2p4MG_QW	2.38 0.57 to 9.20	SEMA_SC_2p4MG_QW	0.96 0.14 to 6.21
TIRZ_SC_MTD_5-10-15_QW	2.50 0.64 to 8.28	1.04 0.16 to 6.96	TIRZ_SC_MTD_5-10-15_QW

Heterogeneity, fit and convergence

Bayesian random effects (primary)

Heterogeneity (tau): 0.376 (95% CrI 0.091 to 1.459), log scale
Residual deviance: 4.1 for 4 data points
DIC: 8.1 (pD 4.0)
Largest R-hat: 1.001
Smallest ESS: bulk 3,209, tail 3,175
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)

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.

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 57 to 162 weeks
NoteData handling, input conversions: nonserious_only 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
NCT04847557	162	safety	not stated	not stated	not stated	not stated	not stated	not stated	double_blind	industry	2021	age 40 or older; LVEF 50 percent or more; BMI 30 or more; NYHA II to IV; KCCQ-CSS 80 or less
STEP-HFpEF	57	safety	not stated	not stated	not stated	not stated	not stated	not stated	double_blind	industry	2021	LVEF 45 percent or more; NYHA II to IV; BMI 30 or more; KCCQ-CSS below 90; no diabetes, HbA1c below 6.5 percent

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	Flags	Source
NCT04847557	A1	TIRZ_SC_MTD_5-10-15_QW	162	arm, events	54 / 364	nonserious_only	registry:adverse_events
NCT04847557	A2	PLACEBO	162	arm, events	22 / 367	nonserious_only	registry:adverse_events
STEP-HFpEF	A1	SEMA_SC_2p4MG_QW	57	arm, events	17 / 263	nonserious_only	registry:adverse_events
STEP-HFpEF	A2	PLACEBO	57	arm, events	7 / 266	nonserious_only	registry:adverse_events

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.

Open in the NMA lab