Network meta-analysis

Total daily insulin dose change

Type 1 diabetes

weeks 12 to 40 (target week 26)Not stated by the trialsEach dose separatelyMean difference

Randomized trials

Treatments

176

Participants

Trial arms

In plain language

Across 5 trials with 176 participants, 1 of 6 treatments had a clearly better result than placebo on total daily insulin dose change, and for 5 the evidence could not tell them apart from placebo. The most favorable estimate was for Semaglutide 1.0 mg subcutaneous once weekly: mean difference -1.14 units per kg per day (95% credible interval -2.08 to -0.20).

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 units per kg per day. 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
Semaglutide 1.0 mg subcutaneous once weekly SEMA_SC_1p0MG_QW	-1.14 (-2.08 to -0.20)	-2.09 to -0.17	-22.60 (-29.00 to -16.20)	Better
Empagliflozin EMPAGLIFLOZIN	-0.20 (-1.16 to 0.76)	-1.18 to 0.77	-19.20 (-27.25 to -11.15)	Unclear
Tirzepatide 5 mg subcutaneous once weekly TIRZ_SC_5MG_QW	-0.18 (-0.41 to 0.06)	-0.50 to 0.17	-0.19 (-0.29 to -0.09)	Unclear
Dapagliflozin DAPAGLIFLOZIN	-0.01 (-0.23 to 0.20)	-0.33 to 0.30	-0.01 (-0.07 to 0.05)	Unclear
Standard care or no added treatment STANDARD_CARE	0.12 (-0.79 to 1.06)	-0.82 to 1.09	-15.20 (-22.91 to -7.49)	Unclear
Liraglutide subcutaneous once daily, flexible dose: 1.2 or 1.8 mg by tolerability LIRA_SC_FLEX_QD	0.37 (-0.59 to 1.36)	-0.62 to 1.38	5.83 (-8.01 to 19.67)	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: 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_1p0MG_QW	EMPAGLIFLOZIN	TIRZ_SC_5MG_QW	DAPAGLIFLOZIN	STANDARD_CARE	LIRA_SC_FLEX_QD
PLACEBO	PLACEBO	1.14 0.20 to 2.08	0.20 -0.76 to 1.16	0.18 -0.06 to 0.41	0.01 -0.20 to 0.23	-0.12 -1.06 to 0.79	-0.37 -1.36 to 0.59
SEMA_SC_1p0MG_QW	-1.14 -2.08 to -0.20	SEMA_SC_1p0MG_QW	-0.94 -2.27 to 0.40	-0.95 -1.91 to -0.00	-1.12 -2.08 to -0.18	-1.26 -2.56 to 0.07	-1.51 -2.88 to -0.15
EMPAGLIFLOZIN	-0.20 -1.16 to 0.76	0.94 -0.40 to 2.27	EMPAGLIFLOZIN	-0.02 -1.02 to 0.97	-0.19 -1.17 to 0.77	-0.33 -1.65 to 1.03	-0.58 -1.91 to 0.79
TIRZ_SC_5MG_QW	-0.18 -0.41 to 0.06	0.95 0.00 to 1.91	0.02 -0.97 to 1.02	TIRZ_SC_5MG_QW	-0.18 -0.47 to 0.17	-0.30 -1.27 to 0.64	-0.55 -1.57 to 0.45
DAPAGLIFLOZIN	-0.01 -0.23 to 0.20	1.12 0.18 to 2.08	0.19 -0.77 to 1.17	0.18 -0.17 to 0.47	DAPAGLIFLOZIN	-0.13 -1.09 to 0.82	-0.38 -1.40 to 0.60
STANDARD_CARE	0.12 -0.79 to 1.06	1.26 -0.07 to 2.56	0.33 -1.03 to 1.65	0.30 -0.64 to 1.27	0.13 -0.82 to 1.09	STANDARD_CARE	-0.25 -1.60 to 1.09
LIRA_SC_FLEX_QD	0.37 -0.59 to 1.36	1.51 0.15 to 2.88	0.58 -0.79 to 1.91	0.55 -0.45 to 1.57	0.38 -0.60 to 1.40	0.25 -1.09 to 1.60	LIRA_SC_FLEX_QD

Heterogeneity, fit and convergence

Bayesian random effects (primary)

Heterogeneity (tau): 0.070 (95% CrI 0.003 to 0.234)
Residual deviance: 257.0 for 11 data points
DIC: 262.1 (pD 5.1)
Largest R-hat: 1.001
Smallest ESS: bulk 3,405, tail 3,246
Divergent transitions: 0
Convergence: All criteria met
Priors: PR01 N(0, 1^2); PR03 N(0, 0.5^2); PR07 half normal(0, 0.1^2) 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.

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.

NoteOutcome assessment, time point: selected time points span 12 to 26 weeks
NoteOutcome assessment, analysis set: mixed: completers 2, modified_itt 1, other 2
NoteOutcome assessment, definition: mixed: change in HbA1c from week 0 to week 12 1, Change in total daily insulin dose from AID pump data 1, HbA1c value at week 26 1, not stated 2
NoteRisk of bias, blinding: mixed: double_blind 4, open_label 1
NoteRisk of bias, funding: mixed: mixed 2, non_industry 2, not_reported 1
NoteData handling, input conversions: median_converted 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
ENDIS	12	completers	not stated	not stated	not stated	not stated	not stated	not stated	open_label	non_industry	2021	type 1 diabetes on MDI or CSII with CGM; HbA1c 9.0 or less; BMI 22 or more; CrCl 60 or more; no atherosclerotic disease
TODINELI	26	completers	HbA1c value at week 26	not stated	not stated	not stated	not stated	not stated	double_blind	mixed	2014	age over 18; type 1 diabetes 2 years or more; HbA1c 6.5 percent or more; BMI over 22; confirmed polyneuropathy; eGFR 60 or more
NCT02962492	12	other	change in HbA1c from week 0 to week 12	not stated	not stated	not stated	not stated	not stated	double_blind	not_reported	2016	established type 1 diabetes on insulin
ADJUST-T1D	26	other	Change in total daily insulin dose from AID pump data	not stated	not stated	not stated	not stated	not stated	double_blind	mixed	2023	age 18 to 65; type 1 diabetes on AID; BMI 30 or more
S003007	12	modified_itt	not stated	not stated	not stated	not stated	not stated	not stated	double_blind	non_industry	2024	age 18 to 60; type 1 diabetes 2 years or more; BMI 30 or more

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
ENDIS	A1	EMPAGLIFLOZIN	12	arm, change	-5.100	1.826	30		R0021681:Table 2
ENDIS	A2	SEMA_SC_1p0MG_QW	12	arm, change	-8.500	1.698	30		R0021681:Table 2
ENDIS	A3	STANDARD_CARE	12	arm, change	-1.100	1.393	29		R0021681:Table 2
TODINELI	A1	LIRA_SC_FLEX_QD	26	arm, final	54.000	5.778	19	median_converted	R0012788:Table 3
TODINELI	A2	PLACEBO	26	arm, final	48.167	4.058	20	median_converted	R0012788:Table 3
NCT02962492	A1	PLACEBO	12	arm, change	-0.010	0.020	11		registry:outcomes
NCT02962492	A2	DAPAGLIFLOZIN	12	arm, change	-0.020	0.020	15		registry:outcomes
ADJUST-T1D	A1	SEMA_SC_1p0MG_QW	26	arm, change	-17.400	2.321			R0014665:Results
ADJUST-T1D	A2	PLACEBO	26	arm, change	5.200	2.296			R0014665:Results
S003007	A1	TIRZ_SC_5MG_QW	12	arm, change	-0.190	0.043	11		R0014500:Table 2
S003007	A2	PLACEBO	12	arm, change	0.000	0.023	11		R0014500:Table 2

Rerun this analysis yourself

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