Network meta-analysis

Hospitalization for heart failure

Type 2 diabetes (adults)

longest follow-upCause specific hazardsDoses of a drug pooledHazard ratio

Randomized trials

Treatments

Participants

Trial arms

In plain language

Across 4 trials, 0 of 4 treatments had a clearly better result than placebo on hospitalization for heart failure, and for 4 the evidence could not tell them apart from placebo. The most favorable estimate was for efpeglenatide injection: hazard ratio 0.63 (95% credible interval 0.31 to 1.37).

Efpeglenatide injection: not convincingly different from placebo (certainty pending).
Semaglutide tablet: not convincingly different from placebo (certainty pending).
Exenatide extended release injection: not convincingly different from placebo (certainty pending).
Semaglutide injection: 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
Efpeglenatide injection EFPE_SC	0.63 (0.31 to 1.37)	0.25 to 1.67	0.61 (0.38 to 0.98)	Unclear	pending
Semaglutide tablet SEMA_PO	0.87 (0.39 to 1.97)	0.33 to 2.23	0.86 (0.48 to 1.55)	Unclear	pending
Exenatide extended release injection EXENER_SC	0.94 (0.51 to 1.74)	0.39 to 2.20	0.94 (0.78 to 1.13)	Unclear	pending
Semaglutide injection SEMA_SC	1.11 (0.57 to 2.12)	0.44 to 2.52	1.11 (0.77 to 1.61)	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): some concerns.

Confidence in each comparison with Placebo
Comparison	Within study bias	Reporting bias	Indirectness	Imprecision	Heterogeneity	Incoherence	Confidence
Efpeglenatide injection versus Placebo	pending	some	pending	major	none	some	pending
Exenatide extended release injection versus Placebo	pending	some	pending	major	none	some	pending
Semaglutide tablet versus Placebo	pending	some	pending	major	none	some	pending
Semaglutide injection versus Placebo	pending	some	pending	major	none	some	pending

Every other comparison (6)

Confidence in the other comparisons
Comparison	Within study bias	Reporting bias	Indirectness	Imprecision	Heterogeneity	Incoherence	Confidence
Efpeglenatide injection versus Exenatide extended release injection	pending	some	pending	major	none	some	pending
Efpeglenatide injection versus Semaglutide tablet	pending	some	pending	major	none	some	pending
Exenatide extended release injection versus Semaglutide tablet	pending	some	pending	major	none	some	pending
Efpeglenatide injection versus Semaglutide injection	pending	some	pending	major	none	some	pending
Exenatide extended release injection versus Semaglutide injection	pending	some	pending	major	none	some	pending
Semaglutide tablet versus Semaglutide injection	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	Rank 4	Rank 5	Mean rank
EFPE_SC	67%	19%	6%	4%	3%	1.6
SEMA_PO	20%	32%	14%	14%	20%	2.8
EXENER_SC	7%	26%	30%	21%	15%	3.1
PLACEBO	1%	11%	34%	42%	13%	3.6
SEMA_SC	5%	12%	15%	20%	49%	4.0

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	EFPE_SC	SEMA_PO	EXENER_SC	SEMA_SC
PLACEBO	PLACEBO	1.59 0.73 to 3.18	1.15 0.51 to 2.53	1.06 0.57 to 1.94	0.90 0.47 to 1.74
EFPE_SC	0.63 0.31 to 1.37	EFPE_SC	0.72 0.25 to 2.32	0.66 0.27 to 1.78	0.56 0.22 to 1.60
SEMA_PO	0.87 0.39 to 1.97	1.39 0.43 to 3.93	SEMA_PO	0.92 0.35 to 2.58	0.78 0.29 to 2.24
EXENER_SC	0.94 0.51 to 1.74	1.51 0.56 to 3.67	1.09 0.39 to 2.84	EXENER_SC	0.85 0.35 to 2.10
SEMA_SC	1.11 0.57 to 2.12	1.78 0.62 to 4.47	1.29 0.45 to 3.51	1.18 0.48 to 2.87	SEMA_SC

Heterogeneity, fit and convergence

Bayesian random effects (primary)

Heterogeneity (tau): 0.155 (95% CrI 0.029 to 0.776), log scale
Residual deviance: 3.9 for 4 data points
DIC: 7.9 (pD 3.9)
Largest R-hat: 1.001
Smallest ESS: bulk 2,298, tail 2,417
Divergent transitions: 0
Convergence: All criteria met
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	EFPE_SC:PLACEBO	EXENER_SC:PLACEBO	PLACEBO:SEMA_PO	PLACEBO:SEMA_SC
EFPE_SC:PLACEBO	100
EXENER_SC:PLACEBO		100
PLACEBO:SEMA_PO			100
PLACEBO:SEMA_SC				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; 4 of 4	Established cardiovascular disease (percent of participants) prognostic factor; 4 of 4
AMPLITUDE-O S000755	64.57	89.6
NCT01144338 S000905	61.85	73.09
PIONEER 6 S001381	66	84.67
SUSTAIN™ 6 S001933	64.65	76.83

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, definition: confounded with design: death from any cause 1, First nonfatal MI, nonfatal stroke, or death from CV or undetermined causes 1, first of cardiovascular death, nonfatal MI or nonfatal stroke 1, Hospitalization for heart failure 1
NoteOutcome assessment, time point: selected time points span 87 to 391.35 weeks
NoteOutcome assessment, analysis set: mixed: full_analysis 2, randomized 2
NoteOutcome assessment, adjudicated: mixed: not stated 2, yes 2

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
AMPLITUDE-O	136.87	randomized	First nonfatal MI, nonfatal stroke, or death from CV or undetermined causes	not stated	yes	not stated	not stated	not stated	double_blind	industry	2018	T2D, HbA1c above 7%; age 18 or older with CVD, or age 50 (men) or 55 (women) with eGFR 25 to 59.9 plus a risk factor
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
SUSTAIN™ 6	109	full_analysis	first of cardiovascular death, nonfatal MI or nonfatal stroke	not stated	yes	not stated	not stated	not stated	double_blind	industry	2013	T2D HbA1c 7.0 or more; age 50 or more with CVD, CHF or CKD stage 3 or more, or age 60 or more with CV risk factor

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
AMPLITUDE-O	A1	PLACEBO	136.87	contrast, hr			R0004602:Results
AMPLITUDE-O	A4	EFPE_SC	136.87	contrast, hr	-0.494	0.242	R0004602:Results
NCT01144338	A1	PLACEBO	391.35	contrast, hr			registry:outcomes
NCT01144338	A2	EXENER_SC	391.35	contrast, hr	-0.062	0.095	registry:outcomes
PIONEER 6	A1	SEMA_PO	87	contrast, hr	-0.151	0.299	registry:outcomes
PIONEER 6	A2	PLACEBO	87	contrast, hr			registry:outcomes
SUSTAIN™ 6	A5	SEMA_SC	109	contrast, hr	0.104	0.188	registry:outcomes
SUSTAIN™ 6	A6	PLACEBO	109	contrast, hr			registry:outcomes

Rerun this analysis yourself

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