Network meta-analysis

Nausea

Children and adolescents with type 2 diabetes

longest follow-upRecorded harmsEach dose separatelyHazard ratio (from event counts)

Randomized trials

Treatments

395

Participants

Events

In plain language

Across 4 trials with 395 participants, 0 of 5 treatments had a clearly better result than placebo on nausea, and for 5 the evidence could not tell them apart from placebo. The most favorable estimate was for Lixisenatide 20 ug subcutaneous once daily: hazard ratio (from event counts) 0.68 (95% credible interval 0.07 to 10.72).

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	Frequentist HR (95% CI)	Verdict
Lixisenatide 20 ug subcutaneous once daily LIXI_SC_20UG_QD	0.68 (0.07 to 10.72)	0.05 to 13.17		Unclear
Exenatide extended release 2 mg subcutaneous once weekly EXENER_SC_2MG_QW	1.64 (0.23 to 17.36)	0.17 to 21.14	1.67 (0.18 to 15.79)	Unclear
Dulaglutide 0.75 mg subcutaneous once weekly DULA_SC_0p75MG_QW	1.69 (0.38 to 7.63)	0.25 to 10.51	1.87 (0.51 to 6.83)	Unclear
Dulaglutide 1.5 mg subcutaneous once weekly DULA_SC_1p5MG_QW	1.91 (0.45 to 8.36)	0.30 to 11.30	2.14 (0.60 to 7.60)	Unclear
Liraglutide flexible dose injection once daily LIRA_SC_FLEX_0p6-1p2-1p8_QD	2.38 (0.65 to 8.02)	0.45 to 12.17	2.70 (1.12 to 6.50)	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	LIXI_SC_20UG_QD	EXENER_SC_2MG_QW	DULA_SC_0p75MG_QW	DULA_SC_1p5MG_QW	LIRA_SC_FLEX_0p6-1p2-1p8_QD
PLACEBO	PLACEBO	1.48 0.09 to 15.24	0.61 0.06 to 4.39	0.59 0.13 to 2.65	0.52 0.12 to 2.21	0.42 0.12 to 1.53
LIXI_SC_20UG_QD	0.68 0.07 to 10.72	LIXI_SC_20UG_QD	0.39 0.02 to 12.36	0.40 0.03 to 8.80	0.35 0.02 to 7.65	0.29 0.02 to 5.46
EXENER_SC_2MG_QW	1.64 0.23 to 17.36	2.55 0.08 to 62.60	EXENER_SC_2MG_QW	0.97 0.08 to 15.01	0.85 0.08 to 12.63	0.70 0.07 to 10.23
DULA_SC_0p75MG_QW	1.69 0.38 to 7.63	2.51 0.11 to 38.19	1.03 0.07 to 11.81	DULA_SC_0p75MG_QW	0.88 0.21 to 3.82	0.72 0.11 to 4.84
DULA_SC_1p5MG_QW	1.91 0.45 to 8.36	2.83 0.13 to 44.70	1.17 0.08 to 13.14	1.13 0.26 to 4.73	DULA_SC_1p5MG_QW	0.82 0.13 to 5.34
LIRA_SC_FLEX_0p6-1p2-1p8_QD	2.38 0.65 to 8.02	3.46 0.18 to 49.63	1.44 0.10 to 15.26	1.39 0.21 to 9.49	1.22 0.19 to 7.89	LIRA_SC_FLEX_0p6-1p2-1p8_QD

Heterogeneity, fit and convergence

Bayesian random effects (primary)

Heterogeneity (tau): 0.360 (95% CrI 0.086 to 1.291), log scale
Residual deviance: 8.6 for 9 data points
DIC: 17.2 (pD 8.5)
Largest R-hat: 1.001
Smallest ESS: bulk 4,778, tail 4,720
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)

Frequentist check (netmeta)

Method: inverse variance, REML, OR
Tau: 0.000
Q (total): 0.00 on -4.44089209850063e-16 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.

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	Sex (percent female) effect modifier, prognostic factor; 4 of 4
Ellipse™ S000357	61.48
NCT01554618 S000457	58.43
AWARD-PEDS S000604	71.43
NCT02803918 S000673	69.55

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 6.43 to 53 weeks
NoteData handling, input conversions: nonserious_only 5

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
Ellipse™	53	safety	not stated	not stated	not stated	not stated	not stated	not stated	double_blind	industry	2012	age 10 to under 17; BMI above 85th percentile; HbA1c 7.0 to 11.0 (6.5 to 11.0 if treated)
NCT01554618	24	safety	not stated	not stated	not stated	not stated	not stated	not stated	double_blind	industry	2011	age 10 to below 18; HbA1c 6.5 to 11.0 (12.0 if insulin or sulfonylurea)
AWARD-PEDS	26	safety	not stated	not stated	not stated	not stated	not stated	not stated	double_blind	industry	2016	children and adolescents with type 2 diabetes
NCT02803918	6.43	safety	not stated	not stated	not stated	not stated	not stated	not stated	double_blind	industry	2017	Age 10 to 17; T2D on metformin and/or basal insulin; HbA1c above 6.5 to 11 percent; BMI above 85th percentile

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
Ellipse™	A1	LIRA_SC_FLEX_0p6-1p2-1p8_QD	53	arm, events	19 / 66	nonserious_only	registry:adverse_events
Ellipse™	A2	PLACEBO	53	arm, events	9 / 69	nonserious_only	registry:adverse_events
NCT01554618	A1	EXENER_SC_2MG_QW	24	arm, events	4 / 59		R0017380:Table 2
NCT01554618	A2	PLACEBO	24	arm, events	1 / 24		R0017380:Table 2
AWARD-PEDS	A1	PLACEBO	26	arm, events	4 / 51	nonserious_only	registry:adverse_events
AWARD-PEDS	A2	DULA_SC_0p75MG_QW	26	arm, events	7 / 51	nonserious_only	registry:adverse_events
AWARD-PEDS	A3	DULA_SC_1p5MG_QW	26	arm, events	8 / 52	nonserious_only	registry:adverse_events
NCT02803918	A1	LIXI_SC_20UG_QD	6.43	arm, events	2 / 18		R0009184:Table 4
NCT02803918	A2	PLACEBO	6.43	arm, events	1 / 5		R0009184:Table 4

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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