Network meta-analysis

Three point MACE

Type 2 diabetes (adults)

longest follow-upCause specific hazardsDoses of a drug pooledHazard ratio

Randomized trials

Treatments

Participants

Trial arms

In plain language

Across 6 trials, 0 of 6 treatments had a clearly better result than placebo on three point MACE, and for 6 the evidence could not tell them apart from placebo. The most favorable estimate was for Semaglutide injection: hazard ratio 0.74 (95% credible interval 0.42 to 1.35).

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	Verdict
Semaglutide injection SEMA_SC	0.74 (0.42 to 1.35)	0.34 to 1.69	Unclear
Albiglutide injection ALBI_SC	0.78 (0.45 to 1.39)	0.35 to 1.76	Unclear
Semaglutide tablet SEMA_PO	0.79 (0.43 to 1.46)	0.34 to 1.84	Unclear
Dulaglutide injection DULA_SC	0.88 (0.50 to 1.50)	0.40 to 1.96	Unclear
Exenatide extended release injection EXENER_SC	0.91 (0.53 to 1.54)	0.41 to 2.03	Unclear
Liraglutide injection LIRA_SC	0.95 (0.19 to 4.67)	0.18 to 5.10	Unclear

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 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	ALBI_SC	SEMA_PO	DULA_SC	EXENER_SC	LIRA_SC
PLACEBO	PLACEBO	1.35 0.74 to 2.37	1.28 0.72 to 2.24	1.26 0.69 to 2.35	1.14 0.67 to 1.99	1.10 0.65 to 1.87	1.05 0.21 to 5.15
SEMA_SC	0.74 0.42 to 1.35	SEMA_SC	0.95 0.42 to 2.11	0.94 0.41 to 2.24	0.85 0.39 to 1.88	0.82 0.36 to 1.85	0.79 0.15 to 4.18
ALBI_SC	0.78 0.45 to 1.39	1.05 0.47 to 2.39	ALBI_SC	0.99 0.43 to 2.27	0.89 0.40 to 2.00	0.86 0.40 to 1.91	0.82 0.16 to 4.33
SEMA_PO	0.79 0.43 to 1.46	1.06 0.45 to 2.46	1.01 0.44 to 2.34	SEMA_PO	0.90 0.41 to 2.06	0.87 0.38 to 1.94	0.84 0.16 to 4.50
DULA_SC	0.88 0.50 to 1.50	1.18 0.53 to 2.59	1.12 0.50 to 2.48	1.11 0.49 to 2.44	DULA_SC	0.97 0.44 to 2.06	0.93 0.17 to 4.84
EXENER_SC	0.91 0.53 to 1.54	1.22 0.54 to 2.79	1.17 0.52 to 2.53	1.15 0.52 to 2.64	1.03 0.49 to 2.28	EXENER_SC	0.97 0.18 to 4.97
LIRA_SC	0.95 0.19 to 4.67	1.27 0.24 to 6.81	1.22 0.23 to 6.43	1.19 0.22 to 6.44	1.08 0.21 to 5.76	1.03 0.20 to 5.64	LIRA_SC

Heterogeneity, fit and convergence

Bayesian random effects (primary)

Heterogeneity (tau): 0.147 (95% CrI 0.027 to 0.736), log scale
Residual deviance: 5.8 for 6 data points
DIC: 11.6 (pD 5.8)
Largest R-hat: 1.002
Smallest ESS: bulk 1,728, tail 1,361
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)

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	Age (years) prognostic factor; 6 of 6	Established cardiovascular disease (percent of participants) prognostic factor; 2 of 6	Kidney function (eGFR) (mL/min/1.73 m2) prognostic factor, effect modifier; 4 of 6	Albuminuria (mg/g) prognostic factor; 2 of 6
REWIND S000147	66.2	31.45	76.9	1.84
NCT01144338 S000905	61.85	73.09	76.85	23.35
NCT02465515 S001074	64.15	not reported	not reported	not reported
PIONEER 6 S001381	66	not reported	74.2	not reported
NCT01272232 S001792	54.9	not reported	not reported	not reported
SUSTAIN™ 6 S001933	64.65	not reported	76.15	not reported

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.

FlagBaseline, Age: design means range from 54.9 (LIRA_SC vs PLACEBO) to 66.2 (DULA_SC vs PLACEBO) years; threshold 10
FlagBaseline, Established cardiovascular disease: not reported by 4 of 6 trials
FlagBaseline, Established cardiovascular disease: design means range from 31.4 (DULA_SC vs PLACEBO) to 73.1 (EXENER_SC vs PLACEBO) percent of participants; threshold 20
FlagBaseline, Kidney function (eGFR): not reported by 2 of 6 trials
FlagBaseline, Albuminuria: not reported by 4 of 6 trials
NoteOutcome assessment, time point: selected time points span 56 to 391.35 weeks
NoteOutcome assessment, analysis set: mixed: full_analysis 2, randomized 3, safety 1
NoteOutcome assessment, definition: mixed: adjudicated cardiovascular death, nonfatal MI or nonfatal stroke 1, death from any cause 1, Death from any cause 1, first of cardiovascular death, nonfatal MI or nonfatal stroke 1, not stated 2
NoteOutcome assessment, adjudicated: mixed: not stated 2, yes 4
NoteOutcome assessment, intercurrent events (discontinuation): mixed: not stated 5, treatment_policy 1

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
REWIND	365.26	randomized	not stated	not stated	yes	not stated	treatment_policy	not stated	double_blind	industry	2011	age 50 or older with T2D; HbA1c 9.5 percent or less; BMI 23 or more; CV disease or risk factors
NCT01144338	391.35	randomized	Death from any cause	not stated	yes	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
NCT02465515	140.89	randomized	not stated	not stated	not stated	not stated	not stated	not stated	double_blind	industry	2015	type 2 diabetes with established cardiovascular disease
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
NCT01272232	56	safety	adjudicated cardiovascular death, nonfatal MI or nonfatal stroke	not stated	yes	not stated	not stated	not stated	double_blind	industry	2011	adults with T2D, BMI 27 or more, HbA1c 7.0 to 10.0 percent, diet alone or up to 3 oral drugs
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
REWIND	A1	PLACEBO	365.26	contrast, hr			R0018537:Table 2
REWIND	A2	DULA_SC	365.26	contrast, hr	-0.128	0.058	R0018537:Table 2
NCT01144338	A1	PLACEBO	391.35	contrast, hr			R0025316:Methods
NCT01144338	A2	EXENER_SC	391.35	contrast, hr	-0.094	0.048	R0025316:Methods
NCT02465515	A1	PLACEBO	140.89	contrast, hr			registry:outcomes
NCT02465515	A2	ALBI_SC	140.89	contrast, hr	-0.248	0.072	registry:outcomes
PIONEER 6	A1	SEMA_PO	87	contrast, hr	-0.236	0.170	registry:outcomes
PIONEER 6	A2	PLACEBO	87	contrast, hr			registry:outcomes
NCT01272232	A2	LIRA_SC	56	contrast, hr	-0.062	0.817	R0013170:Table 1
NCT01272232	A3	PLACEBO	56	contrast, hr			R0013170:Table 1
SUSTAIN™ 6	A5	SEMA_SC	109	contrast, hr	-0.301	0.126	registry:outcomes
SUSTAIN™ 6	A6	PLACEBO	109	contrast, hr			registry:outcomes

Rerun this analysis yourself

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