Network meta-analysis

HbA1c change

Type 2 diabetes (adults); background therapy: one or more non insulin glucose lowering drugs

weeks 20 to 36 (target week 26)Treatment policyDoses of a drug pooledMean differenceSeparate part 2 of a disconnected network

Randomized trials

Treatments

1,298

Participants

Trial arms

In plain language

Across 2 trials with 1,298 participants, 0 of 3 treatments had a clearly better result than insulin glargine on HbA1c change, and for 3 the evidence could not tell them apart from insulin glargine. The most favorable estimate was for Insulin glargine with lixisenatide injection: mean difference -0.50 percentage points (95% credible interval -1.47 to 0.49).

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 Insulin glargine

Mean difference in percentage points. Lower values favor the treatment.

Versus Insulin glargine. 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 Insulin glargine
Treatment	Bayesian MD (95% CrI)	95% prediction interval	Frequentist MD (95% CI)	Verdict
Insulin glargine with lixisenatide injection IGLARLIXI_SC	-0.50 (-1.47 to 0.49)	-1.92 to 0.93	-0.50 (-0.61 to -0.39)	Unclear
Insulin degludec with liraglutide injection IDEGLIRA_SC	-0.25 (-1.33 to 0.77)	-1.72 to 1.25	-0.26 (-0.45 to -0.07)	Unclear
Lixisenatide injection LIXI_SC	0.50 (-0.56 to 1.47)	-0.93 to 1.93	0.50 (0.36 to 0.64)	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: mean difference 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	INS_GLARGINE	IGLARLIXI_SC	IDEGLIRA_SC	LIXI_SC
INS_GLARGINE	INS_GLARGINE	0.50 -0.49 to 1.47	0.25 -0.77 to 1.33	-0.50 -1.47 to 0.56
IGLARLIXI_SC	-0.50 -1.47 to 0.49	IGLARLIXI_SC	-0.25 -1.70 to 1.22	-1.00 -1.99 to 0.03
IDEGLIRA_SC	-0.25 -1.33 to 0.77	0.25 -1.22 to 1.70	IDEGLIRA_SC	-0.76 -2.13 to 0.73
LIXI_SC	0.50 -0.56 to 1.47	1.00 -0.03 to 1.99	0.76 -0.73 to 2.13	LIXI_SC

Heterogeneity, fit and convergence

Bayesian random effects (primary)

Heterogeneity (tau): 0.325 (95% CrI 0.016 to 1.069)
Residual deviance: 5.0 for 5 data points
DIC: 10.1 (pD 5.0)
Largest R-hat: 1.001
Smallest ESS: bulk 2,508, tail 2,979
Divergent transitions: 0
Convergence: All criteria met
Priors: PR01 N(0, 5^2); PR03 N(0, 2.5^2); PR07 half normal(0, 0.5^2) on tau

Frequentist check (netmeta)

Method: inverse variance, REML, MD
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.

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	Baseline HbA1c (percent) effect modifier, prognostic factor; 2 of 2	Background glucose lowering therapy (stratum S0 to S4) effect modifier, prognostic factor; 2 of 2	Diabetes duration (years) effect modifier, prognostic factor; 2 of 2	Asian ancestry or region (percent Asian) effect modifier, prognostic factor; 2 of 2	Age (years) prognostic factor; 2 of 2	Treatment duration (weeks) effect modifier; 2 of 2
Lixilan-O-AP S000170	8.34	S1	8.55	100 region: all sites in Asia	56.02	24
DUALTM IX S001236	8.3	S1	9.55	15.75	56.65	26

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, Asian ancestry or region: design means range from 15.8 (IDEGLIRA_SC vs INS_GLARGINE) to 100.0 (IGLARLIXI_SC vs INS_GLARGINE vs LIXI_SC) percent Asian; threshold 30
FlagOutcome assessment, analysis set: confounded with design: full_analysis 1, modified_itt 1
FlagOutcome assessment, intercurrent events (rescue): confounded with design: not stated 1, treatment_policy 1
FlagHeterogeneity, tau above threshold: tau 0.33 exceeds the outcome threshold 0.3; the flags of this network are candidate explanations
NoteOutcome assessment, time point: selected time points span 24 to 26 weeks
NoteData handling, input conversions: n_randomized 3

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
Lixilan-O-AP	24	modified_itt	not stated	not stated	not stated	not stated	treatment_policy	treatment_policy	open_label	industry	2019	adults with T2D on metformin with or without a second OAD; HbA1c 7.5 to 11 percent, or 7 to 10 percent with a non SGLT2i second OAD
DUALTM IX	26	full_analysis	not stated	not stated	not stated	not stated	treatment_policy	not stated	open_label	industry	2016	adults; insulin naive type 2 diabetes on SGLT2 inhibitor with or without other oral drugs; HbA1c 7.0 to 11.0 percent; BMI 20 to 40

Trial data

What each trial contributes. Arm rows give the arm value with its standard error, or events over participants; contrast rows give the mean difference on the analysis scale 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	Events / N	Flags	Source
Lixilan-O-AP	A1	IGLARLIXI_SC	24	arm, change	-1.900	0.040	351	n_randomized	R0013321:Table 2
Lixilan-O-AP	A2	INS_GLARGINE	24	arm, change	-1.400	0.040	350	n_randomized	R0013321:Table 2
Lixilan-O-AP	A3	LIXI_SC	24	arm, change	-0.900	0.060	177	n_randomized	R0013321:Table 2
DUALTM IX	A1	IDEGLIRA_SC	26	arm, change	-1.940	0.066	210		registry:outcomes
DUALTM IX	A2	INS_GLARGINE	26	arm, change	-1.680	0.072	210		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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