Network meta-analysis

Systolic blood pressure change

Type 2 diabetes (adults)

weeks 64 to 130 (target week 104)Not stated by the trialsEach dose separatelyMean differenceSeparate part 4 of a disconnected network

Randomized trials

Treatments

2,320

Participants

Trial arms

In plain language

Across 3 trials with 2,320 participants, 0 of 4 treatments had a clearly better result than dulaglutide 0.75 mg subcutaneous once weekly on systolic blood pressure change, and for 4 the evidence could not tell them apart from dulaglutide 0.75 mg subcutaneous once weekly. The most favorable estimate was for sitagliptin: mean difference -0.93 mmHg (95% credible interval -8.96 to 6.56).

Sitagliptin: not convincingly different from dulaglutide 0.75 mg subcutaneous once weekly (certainty pending).
Dulaglutide 1.5 mg subcutaneous once weekly: not convincingly different from dulaglutide 0.75 mg subcutaneous once weekly (certainty pending).
Insulin degludec and liraglutide (IDegLira) subcutaneous once daily titrated: not convincingly different from dulaglutide 0.75 mg subcutaneous once weekly (certainty pending).
Insulin glargine: not convincingly different from dulaglutide 0.75 mg subcutaneous once weekly (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 Dulaglutide 0.75 mg subcutaneous once weekly

Mean difference in mmHg. Lower values favor the treatment.

Versus Dulaglutide 0.75 mg subcutaneous once weekly. 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 Dulaglutide 0.75 mg subcutaneous once weekly
Treatment	Bayesian MD (95% CrI)	95% prediction interval	Frequentist MD (95% CI)	Verdict	Confidence
Sitagliptin SITAGLIPTIN	-0.93 (-8.96 to 6.56)	-12.38 to 10.40	-0.98 (-3.09 to 1.14)	Unclear	pending
Dulaglutide 1.5 mg subcutaneous once weekly DULA_SC_1p5MG_QW	-0.75 (-6.40 to 4.86)	-10.43 to 9.08	-0.79 (-2.41 to 0.82)	Unclear	pending
Insulin degludec and liraglutide (IDegLira) subcutaneous once daily titrated IDEGLIRA_SC_TIT_QD	0.37 (-10.24 to 10.79)	-12.94 to 13.91	0.36 (-2.45 to 3.17)	Unclear	pending
Insulin glargine INS_GLARGINE	0.81 (-6.73 to 8.19)	-10.22 to 11.89	0.76 (-1.47 to 2.98)	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 Dulaglutide 0.75 mg subcutaneous once weekly
Comparison	Within study bias	Reporting bias	Indirectness	Imprecision	Heterogeneity	Incoherence	Confidence
Dulaglutide 1.5 mg subcutaneous once weekly versus Dulaglutide 0.75 mg subcutaneous once weekly	pending	some	pending	major	none	some	pending
Insulin degludec and liraglutide (IDegLira) subcutaneous once daily titrated versus Dulaglutide 0.75 mg subcutaneous once weekly	pending	some	pending	major	none	some	pending
Insulin glargine versus Dulaglutide 0.75 mg subcutaneous once weekly	pending	some	pending	major	none	some	pending
Sitagliptin versus Dulaglutide 0.75 mg subcutaneous once weekly	pending	some	pending	major	none	some	pending

Every other comparison (6)

Confidence in the other comparisons
Comparison	Within study bias	Reporting bias	Indirectness	Imprecision	Heterogeneity	Incoherence	Confidence
Dulaglutide 1.5 mg subcutaneous once weekly versus Insulin degludec and liraglutide (IDegLira) subcutaneous once daily titrated	pending	some	pending	major	none	some	pending
Dulaglutide 1.5 mg subcutaneous once weekly versus Insulin glargine	pending	some	pending	major	none	some	pending
Insulin degludec and liraglutide (IDegLira) subcutaneous once daily titrated versus Insulin glargine	pending	some	pending	major	none	some	pending
Dulaglutide 1.5 mg subcutaneous once weekly versus Sitagliptin	pending	some	pending	major	none	some	pending
Insulin degludec and liraglutide (IDegLira) subcutaneous once daily titrated versus Sitagliptin	pending	some	pending	major	none	some	pending
Insulin glargine versus Sitagliptin	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	Mean rank
SITAGLIPTIN	38%	21%	15%	12%	14%	2.4
DULA_SC_1p5MG_QW	25%	32%	23%	13%	7%	2.4
DULA_SC_0p75MG_QW	10%	20%	32%	20%	18%	3.2
IDEGLIRA_SC_TIT_QD	21%	14%	13%	22%	30%	3.3
INS_GLARGINE	5%	13%	17%	33%	32%	3.7

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	DULA_SC_0p75MG_QW	SITAGLIPTIN	DULA_SC_1p5MG_QW	IDEGLIRA_SC_TIT_QD	INS_GLARGINE
DULA_SC_0p75MG_QW	DULA_SC_0p75MG_QW	0.93 -6.56 to 8.96	0.75 -4.86 to 6.40	-0.37 -10.79 to 10.24	-0.81 -8.19 to 6.73
SITAGLIPTIN	-0.93 -8.96 to 6.56	SITAGLIPTIN	-0.16 -7.94 to 7.39	-1.30 -13.34 to 11.30	-1.74 -11.88 to 8.23
DULA_SC_1p5MG_QW	-0.75 -6.40 to 4.86	0.16 -7.39 to 7.94	DULA_SC_1p5MG_QW	-1.15 -11.64 to 9.54	-1.56 -8.66 to 5.74
IDEGLIRA_SC_TIT_QD	0.37 -10.24 to 10.79	1.30 -11.30 to 13.34	1.15 -9.54 to 11.64	IDEGLIRA_SC_TIT_QD	-0.43 -8.09 to 7.08
INS_GLARGINE	0.81 -6.73 to 8.19	1.74 -8.23 to 11.88	1.56 -5.74 to 8.66	0.43 -7.08 to 8.09	INS_GLARGINE

Heterogeneity, fit and convergence

Bayesian random effects (primary)

Heterogeneity (tau): 2.049 (95% CrI 0.098 to 9.502)
Residual deviance: 7.8 for 8 data points
DIC: 15.6 (pD 7.7)
Largest R-hat: 1.003
Smallest ESS: bulk 1,431, tail 2,450
Divergent transitions: 0
Convergence: All criteria met
Priors: PR01 N(0, 60^2); PR03 N(0, 30^2); PR07 half normal(0, 6^2) on tau

Frequentist check (netmeta)

Method: inverse variance, REML, MD
Tau: 0.000
I squared: 0%
Q (total): 0.61 on 1 df, P = 0.435
Q (between designs): 0.61, P = 0.435

Inconsistency

Do trials comparing two treatments directly agree with the indirect evidence through other treatments?

Frequentist node splitting (Back-calculation). A small P value means direct and indirect evidence disagree.
Comparison	Trials	Direct	Indirect	Network	P
Insulin glargine versus Dulaglutide 0.75 mg subcutaneous once weekly INS_GLARGINE:DULA_SC_0p75MG_QW	1	1.10 -1.28 to 3.48	-1.54 -7.72 to 4.64	0.76 -1.47 to 2.98	0.435
Sitagliptin versus Dulaglutide 0.75 mg subcutaneous once weekly SITAGLIPTIN:DULA_SC_0p75MG_QW	1	-1.28 -3.53 to 0.97	1.37 -4.88 to 7.61	-0.98 -3.09 to 1.14	0.435
Dulaglutide 1.5 mg subcutaneous once weekly versus Insulin glargine DULA_SC_1p5MG_QW:INS_GLARGINE	1	-1.21 -3.59 to 1.17	-3.85 -10.03 to 2.33	-1.55 -3.78 to 0.67	0.435
Dulaglutide 1.5 mg subcutaneous once weekly versus Sitagliptin DULA_SC_1p5MG_QW:SITAGLIPTIN	1	-0.12 -2.37 to 2.13	2.53 -3.72 to 8.77	0.18 -1.93 to 2.30	0.435

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	DULA_SC_0p75MG_QW:DULA_SC_1p5MG_QW:INS_GLARGINE	DULA_SC_0p75MG_QW:DULA_SC_1p5MG_QW:SITAGLIPTIN	IDEGLIRA_SC_TIT_QD:INS_GLARGINE
DULA_SC_0p75MG_QW:DULA_SC_1p5MG_QW	47	53
DULA_SC_0p75MG_QW:IDEGLIRA_SC_TIT_QD	48	10	42
DULA_SC_0p75MG_QW:INS_GLARGINE	85	15
DULA_SC_0p75MG_QW:SITAGLIPTIN	13	87

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 BMI or body weight (kg/m2) effect modifier, prognostic factor; 3 of 3
AWARD-2 S001130	31.55
DUAL™ VIII S001131	31.75
NCT00734474 S001242	31.07

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: full_analysis 1, modified_itt 1, randomized 1
FlagHeterogeneity, tau above threshold: tau 2.05 exceeds the outcome threshold 2; the flags of this network are candidate explanations
NoteOutcome assessment, time point: selected time points span 78 to 104 weeks
NoteOutcome assessment, intercurrent events (rescue): mixed: hypothetical 1, not stated 2
NoteRisk of bias, blinding: mixed: double_blind 1, open_label 2

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
AWARD-2	78	modified_itt	not stated	not stated	not stated	not stated	not stated	hypothetical	open_label	industry	2010	type 2 diabetes on metformin and glimepiride
DUAL™ VIII	104	full_analysis	not stated	not stated	not stated	not stated	not stated	not stated	open_label	industry	2016	adults with type 2 diabetes uncontrolled on oral drugs, insulin naive
NCT00734474	104	randomized	not stated	not stated	not stated	not stated	not stated	not stated	double_blind	industry	2008	age 18 to 75; HbA1c 7 to 9.5 percent on OAM or 8 to 9.5 on diet; BMI 25 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	Source
AWARD-2	A1	DULA_SC_1p5MG_QW	78	arm, change	-0.700	0.850	246	registry:outcomes
AWARD-2	A2	DULA_SC_0p75MG_QW	78	arm, change	-0.590	0.850	244	registry:outcomes
AWARD-2	A3	INS_GLARGINE	78	arm, change	0.510	0.870	238	registry:outcomes
DUAL™ VIII	A1	IDEGLIRA_SC_TIT_QD	104	arm, change	0.500	0.636	506	registry:outcomes
DUAL™ VIII	A2	INS_GLARGINE	104	arm, change	0.900	0.605	506	registry:outcomes
NCT00734474	A1	DULA_SC_1p5MG_QW	104	arm, change	-0.100	0.800	197	R0025391:Table 1
NCT00734474	A2	DULA_SC_0p75MG_QW	104	arm, change	1.300	0.800	192	R0025391:Table 1
NCT00734474	A3	SITAGLIPTIN	104	arm, change	0.020	0.820	191	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.

Open in the NMA lab