Network meta-analysis

HbA1c change

Type 2 diabetes (adults); background therapy: no glucose lowering drug (lifestyle only)

weeks 36 to 64 (target week 52)Hypothetical (as if everyone stayed on treatment)Doses of a drug pooledMean difference

Randomized trials

Treatments

2,665

Participants

Trial arms

In plain language

Across 5 trials with 2,665 participants, 2 of 5 treatments had a clearly better result than placebo on HbA1c change, and for 3 the evidence could not tell them apart from placebo. The most favorable estimate was for tirzepatide injection: mean difference -1.93 percentage points (95% credible interval -2.74 to -0.89).

Tirzepatide injection: better than placebo but not among the most effective (certainty pending).
Orforglipron tablet: better than placebo but not among the most effective (certainty pending).
Albiglutide injection: not convincingly different from placebo (certainty pending).
Dulaglutide injection: not convincingly different from placebo (certainty pending).
Metformin: 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

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	Confidence
Tirzepatide injection TIRZ_SC	-1.93 (-2.74 to -0.89)	-3.12 to -0.45	-1.98 (-2.21 to -1.75)	Better	pending
Orforglipron tablet ORFO_PO	-1.25 (-2.09 to -0.22)	-2.49 to 0.20	-1.28 (-1.53 to -1.03)	Better	pending
Albiglutide injection ALBI_SC	-0.93 (-1.85 to 0.05)	-2.24 to 0.51	-0.94 (-1.18 to -0.71)	Unclear	pending
Dulaglutide injection DULA_SC	-0.62 (-1.70 to 0.72)	-2.00 to 1.08	-0.69 (-1.01 to -0.36)	Unclear	pending
Metformin METFORMIN	-0.50 (-1.81 to 1.11)	-2.03 to 1.33	-0.57 (-0.94 to -0.21)	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
Albiglutide injection versus Placebo	pending	some	pending	some	some	some	pending
Dulaglutide injection versus Placebo	pending	some	pending	major	none	some	pending
Metformin versus Placebo	pending	some	pending	major	none	some	pending
Orforglipron tablet versus Placebo	pending	some	pending	some	none	some	pending
Tirzepatide injection versus Placebo	pending	some	pending	none	none	some	pending

Every other comparison (10)

Confidence in the other comparisons
Comparison	Within study bias	Reporting bias	Indirectness	Imprecision	Heterogeneity	Incoherence	Confidence
Albiglutide injection versus Dulaglutide injection	pending	some	pending	major	none	some	pending
Albiglutide injection versus Metformin	pending	some	pending	major	none	some	pending
Dulaglutide injection versus Metformin	pending	some	pending	major	none	some	pending
Albiglutide injection versus Orforglipron tablet	pending	some	pending	major	none	some	pending
Dulaglutide injection versus Orforglipron tablet	pending	some	pending	major	none	some	pending
Metformin versus Orforglipron tablet	pending	some	pending	major	none	some	pending
Albiglutide injection versus Tirzepatide injection	pending	some	pending	major	none	some	pending
Dulaglutide injection versus Tirzepatide injection	pending	some	pending	none	some	some	pending
Metformin versus Tirzepatide injection	pending	some	pending	some	none	some	pending
Orforglipron tablet versus Tirzepatide 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	Rank 6	Mean rank
TIRZ_SC	86%	10%	3%	1%			1.2
ORFO_PO	9%	62%	17%	7%	4%	1%	2.4
ALBI_SC	4%	16%	53%	12%	13%	2%	3.2
DULA_SC		6%	16%	50%	23%	5%	4.0
METFORMIN	1%	6%	10%	22%	47%	15%	4.5
PLACEBO			1%	9%	13%	77%	5.7

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	ORFO_PO	ALBI_SC	DULA_SC	METFORMIN
PLACEBO	PLACEBO	1.93 0.89 to 2.74	1.25 0.22 to 2.09	0.93 -0.05 to 1.85	0.62 -0.72 to 1.70	0.50 -1.11 to 1.81
TIRZ_SC	-1.93 -2.74 to -0.89	TIRZ_SC	-0.68 -1.97 to 0.68	-1.00 -2.25 to 0.41	-1.32 -2.22 to -0.38	-1.44 -2.73 to -0.17
ORFO_PO	-1.25 -2.09 to -0.22	0.68 -0.68 to 1.97	ORFO_PO	-0.32 -1.59 to 0.98	-0.63 -2.26 to 0.84	-0.75 -2.57 to 0.89
ALBI_SC	-0.93 -1.85 to 0.05	1.00 -0.41 to 2.25	0.32 -0.98 to 1.59	ALBI_SC	-0.31 -1.93 to 1.12	-0.43 -2.32 to 1.16
DULA_SC	-0.62 -1.70 to 0.72	1.32 0.38 to 2.22	0.63 -0.84 to 2.26	0.31 -1.12 to 1.93	DULA_SC	-0.12 -1.09 to 0.84
METFORMIN	-0.50 -1.81 to 1.11	1.44 0.17 to 2.73	0.75 -0.89 to 2.57	0.43 -1.16 to 2.32	0.12 -0.84 to 1.09	METFORMIN

Heterogeneity, fit and convergence

Bayesian random effects (primary)

Heterogeneity (tau): 0.299 (95% CrI 0.015 to 1.037)
Residual deviance: 9.9 for 10 data points
DIC: 19.9 (pD 9.9)
Largest R-hat: 1.003
Smallest ESS: bulk 1,828, tail 2,390
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.

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	ALBI_SC:PLACEBO	DULA_SC:METFORMIN	DULA_SC:TIRZ_SC	ORFO_PO:PLACEBO	PLACEBO:TIRZ_SC
ALBI_SC:PLACEBO	100
DULA_SC:PLACEBO			50		50
METFORMIN:PLACEBO		33	33		33
ORFO_PO:PLACEBO				100
PLACEBO:TIRZ_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	Baseline HbA1c (percent) effect modifier, prognostic factor; 5 of 5	Background glucose lowering therapy (stratum S0 to S4) effect modifier, prognostic factor; 5 of 5	Diabetes duration (years) effect modifier, prognostic factor; 5 of 5	Asian ancestry or region (percent Asian) effect modifier, prognostic factor; 5 of 5	Age (years) prognostic factor; 5 of 5	Treatment duration (weeks) effect modifier; 5 of 5
SURPASS J-mono S000239	8.2	S0	5.95	100	56.62	52
SURPASS-1 S000407	7.97	S0	4.7	35.15	54.11	40
NCT00849017 S000852	8.07	S0	3.97	2.36	52.9	156
NCT01126580 S001786	7.6	S0	2.63	7.56	55.56	52
ACHIEVE-1 S001950	7.98	S0	4.4	43.83	53.37	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.

FlagBaseline, Baseline HbA1c: design means range from 7.6 (DULA_SC vs METFORMIN) to 8.2 (DULA_SC vs TIRZ_SC) percent; threshold 0.5
FlagBaseline, Diabetes duration: design means range from 2.6 (DULA_SC vs METFORMIN) to 5.9 (DULA_SC vs TIRZ_SC) years; threshold 3
FlagBaseline, Asian ancestry or region: design means range from 2.4 (ALBI_SC vs PLACEBO) to 100.0 (DULA_SC vs TIRZ_SC) percent Asian; threshold 30
FlagBaseline, Treatment duration: design means range from 40.0 (ORFO_PO vs PLACEBO) to 156.0 (ALBI_SC vs PLACEBO) weeks; threshold 26
NoteOutcome assessment, time point: selected time points span 40 to 52 weeks
NoteOutcome assessment, intercurrent events (discontinuation): mixed: hypothetical 4, not stated 1
NoteOutcome assessment, intercurrent events (rescue): mixed: hypothetical 4, not stated 1
NoteData handling, input conversions: arms_combined 5

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 J-mono	52	modified_itt	not stated	not stated	not stated	not stated	hypothetical	hypothetical	double_blind	industry	2019	Japanese adults 20 or older; BMI 23 or more; HbA1c 7.0 to 10.0 percent; drug naive or oral monotherapy washed out
SURPASS-1	40	modified_itt	not stated	not stated	not stated	not stated	hypothetical	hypothetical	double_blind	industry	2019	adults; HbA1c 7.0 to 9.5 percent; BMI 23 or higher; no glucose lowering drug in prior 90 days
NCT00849017	52	modified_itt	not stated	not stated	not stated	not stated	hypothetical	hypothetical	double_blind	industry	2009	age 18 or older; HbA1c 7.0 to 10.0 percent; BMI 20 to 45; diet and exercise only
NCT01126580	52	modified_itt	not stated	not stated	not stated	not stated	not stated	not stated	double_blind	industry	2010	type 2 diabetes on diet and exercise or one oral drug; registry gives no ranges
ACHIEVE-1	40	modified_itt	not stated	not stated	not stated	not stated	hypothetical	hypothetical	double_blind	industry	2023	adults with type 2 diabetes on diet and exercise alone; HbA1c 7.0 to 9.5 percent

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
SURPASS J-mono	A1+A2+A3	TIRZ_SC	52	arm, change	-2.596	0.058	411	arms_combined	R0012580:Table 2
SURPASS J-mono	A4	DULA_SC	52	arm, change	-1.300	0.100	138		R0012580:Table 2
SURPASS-1	A1+A2+A3	TIRZ_SC	40	arm, change	-1.942	0.055	355	arms_combined	registry:outcomes
SURPASS-1	A4	PLACEBO	40	arm, change	0.040	0.105	112		registry:outcomes
NCT00849017	A1	PLACEBO	52	arm, change	0.150	0.097	98		registry:outcomes
NCT00849017	A2+A3	ALBI_SC	52	arm, change	-0.794	0.068	197	arms_combined	registry:outcomes
NCT01126580	A1+A2	DULA_SC	52	arm, change	-0.625	0.050	530	arms_combined	registry:outcomes
NCT01126580	A3	METFORMIN	52	arm, change	-0.510	0.070	265		registry:outcomes
ACHIEVE-1	A1	PLACEBO	40	arm, change	-0.150	0.113	138		registry:outcomes
ACHIEVE-1	A2+A3+A4	ORFO_PO	40	arm, change	-1.431	0.060	421	arms_combined	registry:outcomes

Rerun this analysis yourself

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