Network meta-analysis

Level 2 or 3 hypoglycemia (participants)

Type 2 diabetes (adults)

longest follow-upRecorded harmsEach dose separatelyHazard ratio (from event counts)Separate part 3 of a disconnected networkConvergence criteria not all met

Randomized trials

Treatments

1,868

Participants

903

Events

In plain language

Across 2 trials with 1,868 participants, 0 of 2 treatments had a clearly better result than insulin aspart (prandial) on level 2 or 3 hypoglycemia (participants), and for 2 the evidence could not tell them apart from insulin aspart (prandial). The most favorable estimate was for Liraglutide subcutaneous once daily, flexible dose: 1.2 or 1.8 mg by tolerability: hazard ratio (from event counts) 0.49 (95% credible interval 0.16 to 1.67).

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 Insulin aspart (prandial)

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

Versus Insulin aspart (prandial), 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 Insulin aspart (prandial)
Treatment	Bayesian HR (95% CrI)	95% prediction interval	Frequentist HR (95% CI)	Verdict
Liraglutide subcutaneous once daily, flexible dose: 1.2 or 1.8 mg by tolerability LIRA_SC_FLEX_QD	0.49 (0.16 to 1.67)	0.10 to 2.65		Unclear
Semaglutide 1.0 mg subcutaneous once weekly SEMA_SC_1p0MG_QW	0.52 (0.19 to 1.59)	0.11 to 2.98		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	INS_ASPART	LIRA_SC_FLEX_QD	SEMA_SC_1p0MG_QW
INS_ASPART	INS_ASPART	2.03 0.60 to 6.18	1.92 0.63 to 5.24
LIRA_SC_FLEX_QD	0.49 0.16 to 1.67	LIRA_SC_FLEX_QD	0.96 0.20 to 4.31
SEMA_SC_1p0MG_QW	0.52 0.19 to 1.59	1.04 0.23 to 5.01	SEMA_SC_1p0MG_QW

Heterogeneity, fit and convergence

Bayesian random effects (primary)

Heterogeneity (tau): 0.331 (95% CrI 0.074 to 1.409), log scale
Residual deviance: 3.9 for 4 data points
DIC: 7.9 (pD 3.9)
Largest R-hat: 1.002
Smallest ESS: bulk 3,138, tail 2,894
Divergent transitions: 1
Convergence: Not all met; read with caution
Priors: PR02 N(0, 5^2); PR05 N(0, 2.5^2); PR09 log normal(-2.1, 1.58^2) on tau^2 (Adverse events, 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; 2 of 2	Background glucose lowering therapy (stratum S0 to S4) effect modifier, prognostic factor; 2 of 2
SUSTAIN 11 S000363	8.55	S2
SIMPLE S002252	12.05	S2

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 8.5 (INS_ASPART vs SEMA_SC_1p0MG_QW) to 12.0 (INS_ASPART vs LIRA_SC_FLEX_QD) percent; threshold 0.5
FlagOutcome assessment, analysis set: confounded with design: completers 1, full_analysis 1
FlagOutcome assessment, proportion method: confounded with design: not stated 1, observed 1
NoteOutcome assessment, time point: selected time points span 26 to 52 weeks
NoteData handling, input conversions: count_from_percent 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
SUSTAIN 11	52	full_analysis	not stated	not stated	not stated	not stated	not stated	not stated	open_label	industry	2018	adults; HbA1c above 7.5 to 10.0 percent on insulin glargine plus metformin
SIMPLE	26	completers	not stated	not stated	not stated	observed	not stated	not stated	open_label	industry	2014	age 18 or older; HbA1c 10 or higher; no prandial insulin, DPP-4 inhibitor or GLP-1 RA

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
SUSTAIN 11	A1	SEMA_SC_1p0MG_QW	52	arm, events	330 / 874		R0022346:Table 2
SUSTAIN 11	A2	INS_ASPART	52	arm, events	528 / 874		R0022346:Table 2
SIMPLE	A1	INS_ASPART	26	arm, events	29 / 61	count_from_percent	registry:outcomes
SIMPLE	A2	LIRA_SC_FLEX_QD	26	arm, events	16 / 59	count_from_percent	registry:outcomes

Rerun this analysis yourself

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