Network meta-analysis

HbA1c below 7 percent

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 separatelyOdds ratioSeparate part 2 of a disconnected network

Randomized trials

Treatments

1,009

Participants

684

Events

In plain language

Across 2 trials with 1,009 participants, 4 of 6 treatments had a clearly better result than placebo on HbA1c below 7 percent, and for 2 the evidence could not tell them apart from placebo. The most favorable estimate was for Tirzepatide 10 mg subcutaneous once weekly: odds ratio 42.44 (95% credible interval 2.33 to 211).

Higher 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

Odds ratio. Higher 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 OR (95% CrI)	95% prediction interval	Frequentist OR (95% CI)	Verdict
Tirzepatide 10 mg subcutaneous once weekly TIRZ_SC_10MG_QW	42.44 (2.33 to 211)	1.14 to 332	71.50 (21.35 to 239)	Better
Tirzepatide 15 mg subcutaneous once weekly TIRZ_SC_15MG_QW	20.38 (1.23 to 74.89)	0.61 to 129	30.64 (13.05 to 71.97)	Better
Tirzepatide 5 mg subcutaneous once weekly TIRZ_SC_5MG_QW	17.29 (1.30 to 64.83)	0.55 to 117	26.08 (11.56 to 58.82)	Better
Orforglipron 12 mg oral once daily ORFO_PO_12MG_QD	11.30 (1.07 to 38.49)	0.53 to 78.43	14.01 (7.81 to 25.13)	Better
Orforglipron 36 mg oral once daily ORFO_PO_36MG_QD	5.93 (0.61 to 20.01)	0.28 to 41.70	7.32 (4.30 to 12.48)	Unclear
Orforglipron 3 mg oral once daily ORFO_PO_3MG_QD	4.16 (0.47 to 14.50)	0.20 to 31.65	5.03 (2.99 to 8.45)	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: odds 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	TIRZ_SC_10MG_QW	TIRZ_SC_15MG_QW	TIRZ_SC_5MG_QW	ORFO_PO_12MG_QD	ORFO_PO_36MG_QD	ORFO_PO_3MG_QD
PLACEBO	PLACEBO	0.02 0.00 to 0.43	0.05 0.01 to 0.82	0.06 0.02 to 0.77	0.09 0.03 to 0.93	0.17 0.05 to 1.64	0.24 0.07 to 2.11
TIRZ_SC_10MG_QW	42.44 2.33 to 211	TIRZ_SC_10MG_QW	2.12 0.27 to 16.67	2.50 0.29 to 18.61	3.92 0.25 to 34.40	7.48 0.42 to 64.85	10.56 0.54 to 86.32
TIRZ_SC_15MG_QW	20.38 1.23 to 74.89	0.47 0.06 to 3.72	TIRZ_SC_15MG_QW	1.15 0.17 to 7.20	1.85 0.13 to 14.85	3.49 0.22 to 26.31	5.00 0.32 to 36.34
TIRZ_SC_5MG_QW	17.29 1.30 to 64.83	0.40 0.05 to 3.39	0.87 0.14 to 5.72	TIRZ_SC_5MG_QW	1.59 0.13 to 11.50	2.99 0.22 to 23.25	4.37 0.26 to 31.01
ORFO_PO_12MG_QD	11.30 1.07 to 38.49	0.26 0.03 to 4.08	0.54 0.07 to 7.78	0.63 0.09 to 7.93	ORFO_PO_12MG_QD	1.90 0.30 to 11.26	2.74 0.40 to 14.69
ORFO_PO_36MG_QD	5.93 0.61 to 20.01	0.13 0.02 to 2.38	0.29 0.04 to 4.51	0.33 0.04 to 4.47	0.53 0.09 to 3.28	ORFO_PO_36MG_QD	1.43 0.22 to 7.93
ORFO_PO_3MG_QD	4.16 0.47 to 14.50	0.09 0.01 to 1.85	0.20 0.03 to 3.09	0.23 0.03 to 3.82	0.37 0.07 to 2.47	0.70 0.13 to 4.47	ORFO_PO_3MG_QD

Heterogeneity, fit and convergence

Bayesian random effects (primary)

Heterogeneity (tau): 0.516 (95% CrI 0.099 to 2.136), log scale
Residual deviance: 8.1 for 8 data points
DIC: 15.9 (pD 7.8)
Largest R-hat: 1.001
Smallest ESS: bulk 1,759, tail 2,016
Divergent transitions: 0
Convergence: All criteria met
Priors: PR02 N(0, 5^2); PR05 N(0, 2.5^2); PR09 log normal(-1.77, 1.52^2) on tau^2 (Biological markers (dichotomised), pharm vs placebo control)

Frequentist check (netmeta)

Method: inverse variance, REML, OR
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
ACHIEVE-5 S001044	8.5	S2	15
SURPASS-5 S001608	8.32	S2	13.3

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: modified_itt 1, randomized 1
NoteData handling, input conversions: count_from_percent 8

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
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 odds 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	Events / N	Flags	Source
ACHIEVE-5	A1	PLACEBO	40	arm, responders	33 / 141	count_from_percent	registry:outcomes
ACHIEVE-5	A2	ORFO_PO_3MG_QD	40	arm, responders	83 / 137	count_from_percent	registry:outcomes
ACHIEVE-5	A3	ORFO_PO_12MG_QD	40	arm, responders	107 / 132	count_from_percent	registry:outcomes
ACHIEVE-5	A4	ORFO_PO_36MG_QD	40	arm, responders	94 / 136	count_from_percent	registry:outcomes
SURPASS-5	A1	TIRZ_SC_5MG_QW	40	arm, responders	107 / 115	count_from_percent	registry:outcomes
SURPASS-5	A2	TIRZ_SC_10MG_QW	40	arm, responders	110 / 113	count_from_percent	registry:outcomes
SURPASS-5	A3	TIRZ_SC_15MG_QW	40	arm, responders	110 / 117	count_from_percent	registry:outcomes
SURPASS-5	A4	PLACEBO	40	arm, responders	40 / 118	count_from_percent	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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