Network meta-analysis

HbA1c change

Type 2 diabetes (adults); background therapy: basal insulin with or without non insulin drugs

weeks 36 to 64 (target week 52)Hypothetical (as if everyone stayed on treatment)Each dose separatelyMean difference

Randomized trials

Treatments

2,409

Participants

Trial arms

In plain language

Across 3 trials with 2,409 participants, 6 of 7 treatments had a clearly better result than placebo on HbA1c change, and for 1 the evidence could not tell it apart from placebo. The most favorable estimate was for Tirzepatide 15 mg subcutaneous once weekly: mean difference -1.68 percentage points (95% credible interval -2.08 to -1.17).

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

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

Versus Placebo. 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 MD (95% CrI)	95% prediction interval	Frequentist MD (95% CI)	Verdict
Tirzepatide 15 mg subcutaneous once weekly TIRZ_SC_15MG_QW	-1.68 (-2.08 to -1.17)	-2.25 to -0.97	-1.70 (-1.90 to -1.50)	Better
Tirzepatide 10 mg subcutaneous once weekly TIRZ_SC_10MG_QW	-1.59 (-1.96 to -1.10)	-2.16 to -0.88	-1.60 (-1.81 to -1.40)	Better
Tirzepatide 5 mg subcutaneous once weekly TIRZ_SC_5MG_QW	-1.30 (-1.70 to -0.81)	-1.88 to -0.58	-1.32 (-1.52 to -1.11)	Better
Orforglipron 12 mg oral once daily ORFO_PO_12MG_QD	-1.27 (-1.75 to -0.74)	-1.92 to -0.56	-1.28 (-1.53 to -1.03)	Better
Orforglipron 36 mg oral once daily ORFO_PO_36MG_QD	-1.12 (-1.59 to -0.60)	-1.78 to -0.39	-1.13 (-1.40 to -0.86)	Better
Orforglipron 3 mg oral once daily ORFO_PO_3MG_QD	-0.76 (-1.26 to -0.25)	-1.43 to -0.05	-0.77 (-1.01 to -0.53)	Better
Insulin lispro (prandial) INS_LISPRO	-0.42 (-0.91 to 0.20)	-1.08 to 0.40	-0.44 (-0.66 to -0.22)	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	PLACEBO	TIRZ_SC_15MG_QW	TIRZ_SC_10MG_QW	TIRZ_SC_5MG_QW	ORFO_PO_12MG_QD	ORFO_PO_36MG_QD	ORFO_PO_3MG_QD	INS_LISPRO
PLACEBO	PLACEBO	1.68 1.17 to 2.08	1.59 1.10 to 1.96	1.30 0.81 to 1.70	1.27 0.74 to 1.75	1.12 0.60 to 1.59	0.76 0.25 to 1.26	0.42 -0.20 to 0.91
TIRZ_SC_15MG_QW	-1.68 -2.08 to -1.17	TIRZ_SC_15MG_QW	-0.10 -0.44 to 0.26	-0.39 -0.73 to -0.03	-0.41 -1.05 to 0.29	-0.56 -1.22 to 0.14	-0.92 -1.55 to -0.20	-1.27 -1.72 to -0.83
TIRZ_SC_10MG_QW	-1.59 -1.96 to -1.10	0.10 -0.26 to 0.44	TIRZ_SC_10MG_QW	-0.29 -0.64 to 0.06	-0.31 -0.97 to 0.36	-0.47 -1.09 to 0.21	-0.82 -1.44 to -0.13	-1.17 -1.62 to -0.73
TIRZ_SC_5MG_QW	-1.30 -1.70 to -0.81	0.39 0.03 to 0.73	0.29 -0.06 to 0.64	TIRZ_SC_5MG_QW	-0.02 -0.66 to 0.68	-0.18 -0.82 to 0.52	-0.53 -1.17 to 0.19	-0.88 -1.35 to -0.45
ORFO_PO_12MG_QD	-1.27 -1.75 to -0.74	0.41 -0.29 to 1.05	0.31 -0.36 to 0.97	0.02 -0.68 to 0.66	ORFO_PO_12MG_QD	-0.15 -0.68 to 0.37	-0.51 -1.00 to -0.00	-0.85 -1.61 to -0.12
ORFO_PO_36MG_QD	-1.12 -1.59 to -0.60	0.56 -0.14 to 1.22	0.47 -0.21 to 1.09	0.18 -0.52 to 0.82	0.15 -0.37 to 0.68	ORFO_PO_36MG_QD	-0.36 -0.87 to 0.18	-0.70 -1.50 to 0.00
ORFO_PO_3MG_QD	-0.76 -1.26 to -0.25	0.92 0.20 to 1.55	0.82 0.13 to 1.44	0.53 -0.19 to 1.17	0.51 0.00 to 1.00	0.36 -0.18 to 0.87	ORFO_PO_3MG_QD	-0.34 -1.12 to 0.34
INS_LISPRO	-0.42 -0.91 to 0.20	1.27 0.83 to 1.72	1.17 0.73 to 1.62	0.88 0.45 to 1.35	0.85 0.12 to 1.61	0.70 -0.00 to 1.50	0.34 -0.34 to 1.12	INS_LISPRO

Heterogeneity, fit and convergence

Bayesian random effects (primary)

Heterogeneity (tau): 0.114 (95% CrI 0.005 to 0.580)
Residual deviance: 11.5 for 12 data points
DIC: 22.6 (pD 11.1)
Largest R-hat: 1.006
Smallest ESS: bulk 1,409, tail 1,702
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
I squared: 0%
Q (total): 1.48 on 2 df, P = 0.476
Q (between designs): 1.48, P = 0.476

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; 3 of 3	Background glucose lowering therapy (stratum S0 to S4) effect modifier, prognostic factor; 3 of 3	Diabetes duration (years) effect modifier, prognostic factor; 3 of 3	Asian ancestry or region (percent Asian) effect modifier, prognostic factor; 3 of 3	Age (years) prognostic factor; 3 of 3	Treatment duration (weeks) effect modifier; 3 of 3
SURPASS-6 S000108	8.8	S2	13.78	0.57	58.8	52
ACHIEVE-5 S001044	8.5	S2	15	25.64	60.2	40
SURPASS-5 S001608	8.32	S2	13.3	17.89	60.59	40

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 40 to 52 weeks
NoteOutcome assessment, analysis set: mixed: modified_itt 2, randomized 1
NoteRisk of bias, blinding: mixed: double_blind 2, open_label 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
SURPASS-6	52	modified_itt	not stated	not stated	not stated	not stated	hypothetical	hypothetical	open_label	industry	2020	adults 18 or older; HbA1c 7.5 to 11 percent; BMI 23 to 45; basal insulin at least 30 U/day with or without up to 2 oral drugs
ACHIEVE-5	40	randomized	not stated	not stated	not stated	not stated	hypothetical	hypothetical	double_blind	industry	2023	adults with T2D on insulin glargine with or without metformin or SGLT2 inhibitor
SURPASS-5	40	modified_itt	not stated	not stated	not stated	not stated	hypothetical	hypothetical	double_blind	industry	2019	HbA1c 7.0 to 10.5 percent; BMI 23 or higher; insulin glargine above 0.25 U/kg or 20 U daily with or without metformin

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	Source
SURPASS-6	A1	TIRZ_SC_5MG_QW	52	arm, change	-2.050	0.080	241	R0009666:Supplement eTable 9
SURPASS-6	A2	TIRZ_SC_10MG_QW	52	arm, change	-2.270	0.080	234	R0009666:Supplement eTable 9
SURPASS-6	A3	TIRZ_SC_15MG_QW	52	arm, change	-2.460	0.080	233	R0009666:Supplement eTable 9
SURPASS-6	A4	INS_LISPRO	52	arm, change	-1.160	0.050	692	R0009666:Supplement eTable 9
ACHIEVE-5	A1	PLACEBO	40	arm, change	-0.770	0.078	141	registry:outcomes
ACHIEVE-5	A2	ORFO_PO_3MG_QD	40	arm, change	-1.540	0.097	137	registry:outcomes
ACHIEVE-5	A3	ORFO_PO_12MG_QD	40	arm, change	-2.050	0.098	132	registry:outcomes
ACHIEVE-5	A4	ORFO_PO_36MG_QD	40	arm, change	-1.900	0.111	136	registry:outcomes
SURPASS-5	A1	TIRZ_SC_5MG_QW	40	arm, change	-2.230	0.081	115	registry:outcomes
SURPASS-5	A2	TIRZ_SC_10MG_QW	40	arm, change	-2.590	0.081	113	registry:outcomes
SURPASS-5	A3	TIRZ_SC_15MG_QW	40	arm, change	-2.590	0.083	117	registry:outcomes
SURPASS-5	A4	PLACEBO	40	arm, change	-0.930	0.079	118	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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