Network meta-analysis

Serious adverse events

Type 1 diabetes

longest follow-upRecorded harmsDoses of a drug pooledHazard ratio (from event counts)

Randomized trials

Treatments

2,465

Participants

208

Events

In plain language

Across 6 trials with 2,465 participants, 0 of 6 treatments had a clearly better result than placebo on serious adverse events, and for 6 the evidence could not tell them apart from placebo. The most favorable estimate was for Tirzepatide injection: hazard ratio (from event counts) 0.56 (95% credible interval 0.01 to 45.66).

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

Hazard ratio (from event counts). Lower values favor the treatment.

Versus Placebo, 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 Placebo
Treatment	Bayesian HR (95% CrI)	95% prediction interval	Verdict
Tirzepatide injection TIRZ_SC	0.56 (0.01 to 45.66)	0.01 to 53.49	Unclear
Exenatide extended release and dapagliflozin injection DAPAEXEN_SC	0.62 (0.01 to 52.19)	0.00 to 58.36	Unclear
Exenatide extended release injection EXENER_SC	0.68 (0.01 to 54.01)	0.00 to 56.76	Unclear
Dapagliflozin DAPAGLIFLOZIN	0.68 (0.01 to 46.45)	0.01 to 54.34	Unclear
Liraglutide injection LIRA_SC	1.01 (0.48 to 2.11)	0.29 to 3.54	Unclear
Semaglutide injection SEMA_SC	2.96 (0.12 to 96.74)	0.10 to 114	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: hazard ratio (from event counts) 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	DAPAEXEN_SC	EXENER_SC	DAPAGLIFLOZIN	LIRA_SC	SEMA_SC
PLACEBO	PLACEBO	1.78 0.02 to 163	1.60 0.02 to 185	1.48 0.02 to 188	1.47 0.02 to 162	0.99 0.48 to 2.07	0.34 0.01 to 8.16
TIRZ_SC	0.56 0.01 to 45.66	TIRZ_SC	0.86 0.00 to 582	0.86 0.00 to 569	0.85 0.00 to 500	0.55 0.01 to 47.29	0.18 0.00 to 40.00
DAPAEXEN_SC	0.62 0.01 to 52.19	1.16 0.00 to 567	DAPAEXEN_SC	0.94 0.00 to 542	0.95 0.00 to 543	0.61 0.01 to 55.87	0.20 0.00 to 48.32
EXENER_SC	0.68 0.01 to 54.01	1.16 0.00 to 643	1.07 0.00 to 521	EXENER_SC	1.01 0.00 to 497	0.65 0.00 to 58.45	0.20 0.00 to 54.34
DAPAGLIFLOZIN	0.68 0.01 to 46.45	1.18 0.00 to 551	1.05 0.00 to 555	0.99 0.00 to 604	DAPAGLIFLOZIN	0.68 0.01 to 48.79	0.22 0.00 to 51.64
LIRA_SC	1.01 0.48 to 2.11	1.82 0.02 to 165	1.65 0.02 to 199	1.54 0.02 to 206	1.48 0.02 to 178	LIRA_SC	0.34 0.01 to 9.00
SEMA_SC	2.96 0.12 to 96.74	5.61 0.03 to 1439	5.00 0.02 to 1697	4.88 0.02 to 1521	4.64 0.02 to 1545	2.93 0.11 to 107	SEMA_SC

Heterogeneity, fit and convergence

Bayesian random effects (primary)

Heterogeneity (tau): 0.318 (95% CrI 0.082 to 1.142), log scale
Residual deviance: 7.4 for 14 data points
DIC: 12.2 (pD 4.8)
Largest R-hat: 1.001
Smallest ESS: bulk 3,893, tail 3,842
Divergent transitions: 0
Convergence: All criteria met
Priors: PR02 N(0, 5^2); PR05 N(0, 2.5^2); PR09 log normal(-1.87, 1.52^2) on tau^2 (Adverse events, pharm vs placebo control)

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.

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 52 weeks
NoteOutcome assessment, definition: mixed: not stated 4, severe hypoglycemia, serious adverse event row 1, severe hypoglycemia, undefined 1
NoteRisk of bias, funding: mixed: industry 2, mixed 1, non_industry 1, not_reported 2
NoteData handling, input conversions: arms_combined 2, printed_denominator 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
NCT01753362	26	safety	not stated	not stated	not stated	not stated	not stated	not stated	double_blind	not_reported	2012	type 1 diabetes 1 year or more on insulin; undetectable C-peptide; overweight or obese
ADJUNCT TWO™	27	safety	not stated	not stated	not stated	not stated	not stated	not stated	double_blind	industry	2014	type 1 diabetes at least 12 months; BMI 20 or more; HbA1c 7.0 to 10 percent; basal bolus insulin
NCT02962492	12	safety	severe hypoglycemia, serious adverse event row	not stated	not stated	not stated	not stated	not stated	double_blind	not_reported	2016	established type 1 diabetes on insulin
ADJUST-T1D	26	safety	not stated	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
ADJUNCT ONE™	52	safety	not stated	not stated	not stated	not stated	not stated	not stated	double_blind	industry	2013	T1D at least 12 months; BMI 20 or higher; HbA1c 7.0 to 10 percent; CSII or basal bolus insulin
S003007	12	safety	severe hypoglycemia, undefined	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 hazard ratio (from event counts) 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	Events / N	Flags	Source
NCT01753362	A1	PLACEBO	26	arm, events	0 / 26	printed_denominator	registry:adverse_events
NCT01753362	A2	LIRA_SC	26	arm, events	0 / 40	printed_denominator	registry:adverse_events
ADJUNCT TWO™	A1+A2+A3	LIRA_SC	27	arm, events	55 / 628	arms_combined	registry:adverse_events
ADJUNCT TWO™	A4	PLACEBO	27	arm, events	14 / 207		registry:adverse_events
NCT02962492	A1	PLACEBO	12	arm, events	0 / 13		registry:adverse_events
NCT02962492	A2	DAPAGLIFLOZIN	12	arm, events	0 / 17		registry:adverse_events
NCT02962492	A3	EXENER_SC	12	arm, events	0 / 17		registry:adverse_events
NCT02962492	A4	DAPAEXEN_SC	12	arm, events	0 / 23		registry:adverse_events
ADJUST-T1D	A1	SEMA_SC	26	arm, events	1 / 36		registry:adverse_events
ADJUST-T1D	A2	PLACEBO	26	arm, events	0 / 36		registry:adverse_events
ADJUNCT ONE™	A1+A2+A3	LIRA_SC	52	arm, events	100 / 1,050	arms_combined	registry:adverse_events
ADJUNCT ONE™	A4	PLACEBO	52	arm, events	38 / 348		registry:adverse_events
S003007	A1	TIRZ_SC	12	arm, events	0 / 12		R0014500:Results
S003007	A2	PLACEBO	12	arm, events	0 / 12		R0014500:Results

Rerun this analysis yourself

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