Network meta-analysis

HbA1c below 7 percent

Type 2 diabetes (adults); background therapy: one or more non insulin glucose lowering drugs

weeks 36 to 64 (target week 52)Not stated by the trialsEach dose separatelyOdds ratioSeparate part 3 of a disconnected network

Randomized trials

Treatments

3,585

Participants

2,422

Events

In plain language

Across 5 trials with 3,585 participants, 0 of 8 treatments had a clearly better result than semaglutide 1.0 mg subcutaneous once weekly on HbA1c below 7 percent, 1 a clearly worse one, and for 7 the evidence could not tell them apart from semaglutide 1.0 mg subcutaneous once weekly. The most favorable estimate was for Semaglutide 2.0 mg subcutaneous once weekly: odds ratio 1.52 (95% credible interval 0.54 to 4.37).

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 Semaglutide 1.0 mg subcutaneous once weekly

Odds ratio. Higher values favor the treatment.

Versus Semaglutide 1.0 mg subcutaneous once weekly, 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 Semaglutide 1.0 mg subcutaneous once weekly
Treatment	Bayesian OR (95% CrI)	95% prediction interval	Verdict
Semaglutide 2.0 mg subcutaneous once weekly SEMA_SC_2p0MG_QW	1.52 (0.54 to 4.37)	0.33 to 6.67	Unclear
Insulin degludec and liraglutide (IDegLira) subcutaneous once daily titrated IDEGLIRA_SC_TIT_QD	1.17 (0.32 to 5.56)	0.24 to 8.17	Unclear
Semaglutide 0.5 mg subcutaneous once weekly SEMA_SC_0p5MG_QW	0.61 (0.23 to 1.83)	0.16 to 2.83	Unclear
Dulaglutide 1.5 mg subcutaneous once weekly DULA_SC_1p5MG_QW	0.56 (0.20 to 1.78)	0.13 to 2.67	Unclear
Liraglutide 1.8 mg subcutaneous once daily LIRA_SC_1p8MG_QD	0.45 (0.18 to 1.43)	0.11 to 2.26	Unclear
Insulin degludec INS_DEGLUDEC	0.34 (0.09 to 1.49)	0.06 to 2.31	Unclear
Canagliflozin CANAGLIFLOZIN	0.33 (0.12 to 1.06)	0.08 to 1.63	Unclear
Dulaglutide 0.75 mg subcutaneous once weekly DULA_SC_0p75MG_QW	0.30 (0.12 to 0.95)	0.08 to 1.53	Worse

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	SEMA_SC_1p0MG_QW	SEMA_SC_2p0MG_QW	IDEGLIRA_SC_TIT_QD	SEMA_SC_0p5MG_QW	DULA_SC_1p5MG_QW	LIRA_SC_1p8MG_QD	INS_DEGLUDEC	CANAGLIFLOZIN	DULA_SC_0p75MG_QW
SEMA_SC_1p0MG_QW	SEMA_SC_1p0MG_QW	0.66 0.23 to 1.85	0.85 0.18 to 3.08	1.65 0.55 to 4.33	1.80 0.56 to 4.92	2.21 0.70 to 5.71	2.98 0.67 to 10.55	3.04 0.94 to 8.02	3.29 1.05 to 8.22
SEMA_SC_2p0MG_QW	1.52 0.54 to 4.37	SEMA_SC_2p0MG_QW	1.30 0.19 to 6.67	2.51 0.56 to 10.05	2.73 0.59 to 11.04	3.36 0.69 to 13.47	4.54 0.69 to 22.13	4.63 0.91 to 19.40	4.99 1.05 to 18.62
IDEGLIRA_SC_TIT_QD	1.17 0.32 to 5.56	0.77 0.15 to 5.18	IDEGLIRA_SC_TIT_QD	1.94 0.35 to 11.85	2.11 0.38 to 13.32	2.59 0.88 to 8.24	3.51 1.16 to 10.24	3.55 0.65 to 22.60	3.82 0.72 to 23.92
SEMA_SC_0p5MG_QW	0.61 0.23 to 1.83	0.40 0.10 to 1.80	0.52 0.08 to 2.88	SEMA_SC_0p5MG_QW	1.09 0.36 to 3.16	1.35 0.30 to 5.51	1.81 0.31 to 9.39	1.83 0.43 to 7.88	1.99 0.63 to 5.84
DULA_SC_1p5MG_QW	0.56 0.20 to 1.78	0.37 0.09 to 1.70	0.47 0.08 to 2.60	0.91 0.32 to 2.80	DULA_SC_1p5MG_QW	1.23 0.27 to 5.63	1.66 0.26 to 9.13	1.68 0.38 to 7.72	1.82 0.62 to 5.38
LIRA_SC_1p8MG_QD	0.45 0.18 to 1.43	0.30 0.07 to 1.44	0.39 0.12 to 1.13	0.74 0.18 to 3.31	0.81 0.18 to 3.66	LIRA_SC_1p8MG_QD	1.35 0.44 to 3.63	1.36 0.33 to 5.99	1.49 0.35 to 6.60
INS_DEGLUDEC	0.34 0.09 to 1.49	0.22 0.05 to 1.46	0.28 0.10 to 0.86	0.55 0.11 to 3.22	0.60 0.11 to 3.77	0.74 0.28 to 2.25	INS_DEGLUDEC	1.00 0.20 to 6.22	1.10 0.21 to 6.42
CANAGLIFLOZIN	0.33 0.12 to 1.06	0.22 0.05 to 1.09	0.28 0.04 to 1.54	0.55 0.13 to 2.33	0.60 0.13 to 2.66	0.73 0.17 to 3.00	1.00 0.16 to 4.92	CANAGLIFLOZIN	1.08 0.24 to 4.50
DULA_SC_0p75MG_QW	0.30 0.12 to 0.95	0.20 0.05 to 0.96	0.26 0.04 to 1.39	0.50 0.17 to 1.58	0.55 0.19 to 1.62	0.67 0.15 to 2.86	0.91 0.16 to 4.85	0.92 0.22 to 4.18	DULA_SC_0p75MG_QW

Heterogeneity, fit and convergence

Bayesian random effects (primary)

Heterogeneity (tau): 0.325 (95% CrI 0.072 to 1.208), log scale
Residual deviance: 12.0 for 12 data points
DIC: 24.0 (pD 12.0)
Largest R-hat: 1.004
Smallest ESS: bulk 1,827, tail 2,426
Divergent transitions: 0
Convergence: All criteria met
Priors: PR02 N(0, 5^2); PR05 N(0, 2.5^2); PR09 log normal(-2, 1.58^2) on tau^2 (Biological markers (dichotomised), pharm vs pharm)

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.

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; 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; 3 of 5
SUSTAIN 7 S000372	8.23	S1	7.4
SUSTAIN FORTE S001353	8.9	S1	9.5
SUSTAIN 8 S001847	8.25	S1	not reported
DUAL™ I Japan S001965	8.43	S1	9.43
S003432 S003432	8.35	S1	not reported

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 8.2 (DULA_SC_0p75MG_QW vs DULA_SC_1p5MG_QW vs SEMA_SC_0p5MG_QW vs SEMA_SC_1p0MG_QW) to 8.9 (SEMA_SC_1p0MG_QW vs SEMA_SC_2p0MG_QW) percent; threshold 0.5
FlagBaseline, Diabetes duration: not reported by 2 of 5 trials
NoteOutcome assessment, time point: selected time points span 40 to 52 weeks
NoteOutcome assessment, analysis set: mixed: full_analysis 4, other 1
NoteOutcome assessment, proportion method: mixed: not stated 2, not_stated 3
NoteRisk of bias, blinding: mixed: double_blind 2, open_label 3
NoteRisk of bias, funding: mixed: industry 4, non_industry 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
SUSTAIN 7	40	full_analysis	not stated	not stated	not stated	not_stated	not stated	not stated	open_label	industry	2016	age 18 or older; HbA1c 7.0 to 10.5 percent; eGFR 60 or higher; metformin background
SUSTAIN FORTE	40	full_analysis	not stated	not stated	not stated	not_stated	not stated	not stated	double_blind	industry	2019	T2D on metformin with or without SU; HbA1c 8.0 to 10.0 percent; duration at least 6 months
SUSTAIN 8	52	full_analysis	not stated	not stated	not stated	not_stated	not stated	not stated	double_blind	industry	2017	age 18 or older; HbA1c 7.0 to 10.5 percent; eGFR 60 or higher; metformin 1500 mg or maximum tolerated
DUAL™ I Japan	52	full_analysis	not stated	not stated	not stated	not stated	not stated	not stated	open_label	industry	2015	Japanese adults 20 or older; HbA1c 7.0 to 11.0 percent; BMI at least 20; insulin naive on one oral drug
S003432	52	other	not stated	not stated	not stated	not stated	not stated	not stated	open_label	non_industry	2020	age 18 to 65; type 2 diabetes 1 year or more; HbA1c 7.0 to 10.5 percent; BMI 30 or higher; stable 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	Value	SE	Events / N	Flags	Source
SUSTAIN 7	A1	SEMA_SC_0p5MG_QW	40	arm, responders			206 / 301	count_from_percent	registry:outcomes
SUSTAIN 7	A2	SEMA_SC_1p0MG_QW	40	arm, responders			236 / 300	count_from_percent	registry:outcomes
SUSTAIN 7	A3	DULA_SC_0p75MG_QW	40	arm, responders			156 / 299	count_from_percent	registry:outcomes
SUSTAIN 7	A4	DULA_SC_1p5MG_QW	40	arm, responders			199 / 299	count_from_percent	registry:outcomes
SUSTAIN FORTE	A1	SEMA_SC_1p0MG_QW	40	arm, responders			277 / 481	count_from_percent	registry:outcomes
SUSTAIN FORTE	A2	SEMA_SC_2p0MG_QW	40	arm, responders			324 / 480	count_from_percent	registry:outcomes
SUSTAIN 8	A1	SEMA_SC_1p0MG_QW	52	arm, responders			223 / 293	count_from_percent	registry:outcomes
SUSTAIN 8	A2	CANAGLIFLOZIN	52	arm, responders			159 / 313	count_from_percent	registry:outcomes
DUAL™ I Japan	A1	IDEGLIRA_SC_TIT_QD	52	arm, responders			245 / 275		registry:outcomes
DUAL™ I Japan	A2	INS_DEGLUDEC	52	arm, responders			189 / 271		registry:outcomes
DUAL™ I Japan	A3	LIRA_SC_1p8MG_QD	52	arm, responders			208 / 273		registry:outcomes
S003432	A1	SEMA_SC_1p0MG_QW	52	contrast, or	0.863	0.273			R0053844:Table 1
S003432	A2	LIRA_SC_1p8MG_QD	52	contrast, or					R0053844:Table 1

Rerun this analysis yourself

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