Network meta-analysis

Hospitalization for heart failure

Type 2 diabetes (adults)

longest follow-upCause specific hazardsEach dose separatelyHazard ratioConvergence criteria not all met

Randomized trials

Treatments

Participants

Trial arms

In plain language

Across 2 trials, 0 of 2 treatments had a clearly better result than placebo on hospitalization for heart failure, and for 2 the evidence could not tell them apart from placebo. The most favorable estimate was for semaglutide 14 mg oral once daily (original tablet): hazard ratio 0.87 (95% credible interval 0.38 to 1.94).

Semaglutide 14 mg oral once daily (original tablet): not convincingly different from placebo (certainty pending).
Exenatide extended release 2 mg subcutaneous 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. 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 14 mg oral once daily (original tablet) SEMA_PO_14MG_QD	0.87 (0.38 to 1.94)	0.32 to 2.40	0.86 (0.48 to 1.55)	Unclear	pending
Exenatide extended release 2 mg subcutaneous once weekly EXENER_SC_2MG_QW	0.95 (0.49 to 1.83)	0.39 to 2.41	0.94 (0.78 to 1.13)	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): some concerns.

Confidence in each comparison with Placebo
Comparison	Within study bias	Reporting bias	Indirectness	Imprecision	Heterogeneity	Incoherence	Confidence
Exenatide extended release 2 mg subcutaneous once weekly versus Placebo	pending	some	pending	major	none	some	pending
Semaglutide 14 mg oral once daily (original tablet) versus Placebo	pending	some	pending	major	none	some	pending

Every other comparison (1)

Confidence in the other comparisons
Comparison	Within study bias	Reporting bias	Indirectness	Imprecision	Heterogeneity	Incoherence	Confidence
Exenatide extended release 2 mg subcutaneous once weekly versus Semaglutide 14 mg oral once daily (original tablet)	pending	some	pending	major	none	some	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
SEMA_PO_14MG_QD	54%	18%	29%	1.8
EXENER_SC_2MG_QW	33%	38%	30%	2.0
PLACEBO	14%	45%	41%	2.3

League table

Every treatment against every other: hazard 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_PO_14MG_QD	EXENER_SC_2MG_QW
PLACEBO	PLACEBO	1.15 0.52 to 2.66	1.06 0.55 to 2.04
SEMA_PO_14MG_QD	0.87 0.38 to 1.94	SEMA_PO_14MG_QD	0.91 0.31 to 2.52
EXENER_SC_2MG_QW	0.95 0.49 to 1.83	1.09 0.40 to 3.24	EXENER_SC_2MG_QW

Heterogeneity, fit and convergence

Bayesian random effects (primary)

Heterogeneity (tau): 0.156 (95% CrI 0.030 to 0.888), log scale
Residual deviance: 2.0 for 2 data points
DIC: 4.0 (pD 2.0)
Largest R-hat: 1.002
Smallest ESS: bulk 1,994, tail 1,514
Divergent transitions: 1
Convergence: Not all met; read with caution
Priors: PR02 N(0, 5^2); PR05 N(0, 2.5^2); PR09 log normal(-3.71, 1.74^2) on tau^2 (Cause-specific mortality/major morbidity event/composite, pharm vs placebo control)

Frequentist check (netmeta)

Method: inverse variance, REML, HR
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.

Contribution of direct evidence

Percent contribution of each direct comparison (columns) to each network estimate (rows), from netcontrib.

Contribution of direct comparisons to network estimates
Network estimate	EXENER_SC_2MG_QW:PLACEBO	PLACEBO:SEMA_PO_14MG_QD
EXENER_SC_2MG_QW:PLACEBO	100
PLACEBO:SEMA_PO_14MG_QD		100

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	Age (years) prognostic factor; 2 of 2	Established cardiovascular disease (percent of participants) prognostic factor; 2 of 2
NCT01144338 S000905	61.85	73.09
PIONEER 6 S001381	66	84.67

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, randomized 1
FlagOutcome assessment, definition: confounded with design: death from any cause 1, Hospitalization for heart failure 1
NoteOutcome assessment, time point: selected time points span 87 to 391.35 weeks

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
NCT01144338	391.35	randomized	Hospitalization for heart failure	not stated	not stated	not stated	not stated	not stated	double_blind	industry	2010	age 18 or older; HbA1c 6.5 to 10.0 percent; eGFR 30 or more
PIONEER 6	87	full_analysis	death from any cause	not stated	not stated	not stated	not stated	not stated	double_blind	industry	2017	T2D; age 50 or more with CVD or CKD, or 60 or more with CV risk factors

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 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	Value	SE	Source
NCT01144338	A1	PLACEBO	391.35	contrast, hr			registry:outcomes
NCT01144338	A2	EXENER_SC_2MG_QW	391.35	contrast, hr	-0.062	0.095	registry:outcomes
PIONEER 6	A1	SEMA_PO_14MG_QD	87	contrast, hr	-0.151	0.299	registry:outcomes
PIONEER 6	A2	PLACEBO	87	contrast, hr			registry:outcomes

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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