Network meta-analysis

Systolic blood pressure change

Type 2 diabetes (adults)

weeks 64 to 130 (target week 104)Treatment policyEach dose separatelyMean differenceSeparate part 2 of a disconnected network

Randomized trials

Treatments

4,125

Participants

Trial arms

In plain language

Across 2 trials with 4,125 participants, 0 of 2 treatments had a clearly better result than placebo on systolic blood pressure change, and for 2 the evidence could not tell them apart from placebo. The most favorable estimate was for semaglutide 2.4 mg subcutaneous once weekly: mean difference -3.81 mmHg (95% credible interval -10.31 to 4.03).

Semaglutide 2.4 mg subcutaneous once weekly: not convincingly different from placebo (certainty pending).
Semaglutide 1.0 mg subcutaneous once weekly: 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 mmHg. 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
Semaglutide 2.4 mg subcutaneous once weekly SEMA_SC_2p4MG_QW	-3.81 (-10.31 to 4.03)	-13.53 to 7.40	-3.82 (-5.66 to -1.97)	Unclear	pending
Semaglutide 1.0 mg subcutaneous once weekly SEMA_SC_1p0MG_QW	-2.63 (-8.17 to 2.62)	-11.85 to 6.82	-2.63 (-3.74 to -1.53)	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
Semaglutide 1.0 mg subcutaneous once weekly versus Placebo	pending	some	pending	major	none	some	pending
Semaglutide 2.4 mg subcutaneous once weekly versus Placebo	pending	some	pending	major	none	some	pending

Every other comparison (1)

Confidence in the other comparisons
Comparison	Within study bias	Reporting bias	Indirectness	Imprecision	Heterogeneity	Incoherence	Confidence
Semaglutide 1.0 mg subcutaneous once weekly versus Semaglutide 2.4 mg subcutaneous once weekly	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	Mean rank
SEMA_SC_2p4MG_QW	72%	21%	7%	1.4
SEMA_SC_1p0MG_QW	25%	68%	6%	1.8
PLACEBO	3%	11%	87%	2.8

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	SEMA_SC_2p4MG_QW	SEMA_SC_1p0MG_QW
PLACEBO	PLACEBO	3.81 -4.03 to 10.31	2.63 -2.62 to 8.17
SEMA_SC_2p4MG_QW	-3.81 -10.31 to 4.03	SEMA_SC_2p4MG_QW	-1.16 -7.87 to 6.71
SEMA_SC_1p0MG_QW	-2.63 -8.17 to 2.62	1.16 -6.71 to 7.87	SEMA_SC_1p0MG_QW

Heterogeneity, fit and convergence

Bayesian random effects (primary)

Heterogeneity (tau): 1.675 (95% CrI 0.069 to 9.522)
Residual deviance: 4.7 for 5 data points
DIC: 9.3 (pD 4.6)
Largest R-hat: 1.001
Smallest ESS: bulk 1,672, tail 2,188
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): 0.15 on 1 df, P = 0.695
Q (between designs): 0.15, P = 0.695

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
Semaglutide 2.4 mg subcutaneous once weekly versus Placebo SEMA_SC_2p4MG_QW:PLACEBO	1	-4.00 -6.06 to -1.94	-3.08 -7.20 to 1.05	-3.82 -5.66 to -1.97	0.695
Semaglutide 1.0 mg subcutaneous once weekly versus Semaglutide 2.4 mg subcutaneous once weekly SEMA_SC_1p0MG_QW:SEMA_SC_2p4MG_QW	1	1.00 -1.06 to 3.06	1.93 -2.22 to 6.07	1.18 -0.66 to 3.02	0.695

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	PLACEBO:SEMA_SC_1p0MG_QW	PLACEBO:SEMA_SC_1p0MG_QW:SEMA_SC_2p4MG_QW
PLACEBO:SEMA_SC_1p0MG_QW	73	27
PLACEBO:SEMA_SC_2p4MG_QW	18	82

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; 1 of 2
FLOW S000953	not reported
STEP 2 S001740	35.7

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 BMI or body weight: not reported by 1 of 2 trials
NoteOutcome assessment, time point: selected time points span 68 to 104 weeks

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
FLOW	104	full_analysis	not stated	not stated	not stated	not stated	not stated	not stated	double_blind	industry	2019	age 18 or more; T2D with HbA1c 10% or less; eGFR 50 to 75 with UACR over 300 or eGFR 25 to under 50 with UACR over 100 mg/g
STEP 2	68	full_analysis	not stated	not stated	not stated	not stated	not stated	not stated	double_blind	industry	2018	age 18 or older; BMI 27 or more; HbA1c 7 to 10 percent; T2D on diet or up to 3 oral agents

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
FLOW	A1	SEMA_SC_1p0MG_QW	104	arm, change	-3.900	0.453	1,511	registry:outcomes
FLOW	A2	PLACEBO	104	arm, change	-1.400	0.477	1,472	registry:outcomes
STEP 2	A1	SEMA_SC_1p0MG_QW	68	arm, change	-3.000	0.770	379	registry:outcomes
STEP 2	A2	SEMA_SC_2p4MG_QW	68	arm, change	-4.000	0.712	387	registry:outcomes
STEP 2	A3	PLACEBO	68	arm, change	0.000	0.774	376	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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