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 2 of a disconnected network

Randomized trials

Treatments

453

Participants

201

Events

In plain language

Across 4 trials with 453 participants, 0 of 4 treatments had a clearly better result than dulaglutide flexible dose injection once weekly on level 2 or 3 hypoglycemia (participants), and for 4 the evidence could not tell them apart from dulaglutide flexible dose injection once weekly. The most favorable estimate was for Liraglutide 1.2 mg subcutaneous once daily: hazard ratio (from event counts) 1.23 (95% credible interval 0.15 to 10.60).

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 Dulaglutide flexible dose injection once weekly

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

Versus Dulaglutide flexible dose injection 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 Dulaglutide flexible dose injection once weekly
Treatment	Bayesian HR (95% CrI)	95% prediction interval	Verdict
Liraglutide 1.2 mg subcutaneous once daily LIRA_SC_1p2MG_QD	1.23 (0.15 to 10.60)	0.12 to 13.36	Unclear
Exenatide extended release plus pioglitazone 2 to 30 mg injection once weekly EXENER_SC_2-30MG_QW	1.55 (0.11 to 25.52)	0.09 to 29.44	Unclear
Basal bolus insulin OTHER_ACTIVE_basal_bolus_insulin	2.63 (0.21 to 42.30)	0.16 to 47.59	Unclear
Insulin dose increase OTHER_ACTIVE_insulin_dose_increase	3.42 (0.30 to 37.05)	0.24 to 46.29	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	DULA_SC_FLEX_0p75-1p5_QW	LIRA_SC_1p2MG_QD	EXENER_SC_2-30MG_QW	OTHER_ACTIVE_basal_bolus_insulin	OTHER_ACTIVE_insulin_dose_increase
DULA_SC_FLEX_0p75-1p5_QW	DULA_SC_FLEX_0p75-1p5_QW	0.81 0.09 to 6.72	0.65 0.04 to 8.85	0.38 0.02 to 4.86	0.29 0.03 to 3.32
LIRA_SC_1p2MG_QD	1.23 0.15 to 10.60	LIRA_SC_1p2MG_QD	0.78 0.02 to 23.58	0.46 0.01 to 13.41	0.36 0.09 to 1.52
EXENER_SC_2-30MG_QW	1.55 0.11 to 25.52	1.27 0.04 to 40.43	EXENER_SC_2-30MG_QW	0.60 0.19 to 1.72	0.45 0.01 to 18.48
OTHER_ACTIVE_basal_bolus_insulin	2.63 0.21 to 42.30	2.17 0.07 to 71.04	1.67 0.58 to 5.36	OTHER_ACTIVE_basal_bolus_insulin	0.77 0.02 to 31.10
OTHER_ACTIVE_insulin_dose_increase	3.42 0.30 to 37.05	2.75 0.66 to 11.65	2.22 0.05 to 68.99	1.29 0.03 to 40.84	OTHER_ACTIVE_insulin_dose_increase

Heterogeneity, fit and convergence

Bayesian random effects (primary)

Heterogeneity (tau): 0.335 (95% CrI 0.074 to 1.365), log scale
Residual deviance: 7.8 for 8 data points
DIC: 14.6 (pD 6.8)
Largest R-hat: 1.001
Smallest ESS: bulk 3,136, tail 3,748
Divergent transitions: 0
Convergence: All criteria met
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; 4 of 4	Background glucose lowering therapy (stratum S0 to S4) effect modifier, prognostic factor; 4 of 4
NCT02846233 S000236	9.99	S3
NCT02887625 S002035	10	S1
S003094 S003094	8.74	S4
S003442 S003442	7.9	S0

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 7.9 (DULA_SC_FLEX_0p75-1p5_QW vs LIRA_SC_1p2MG_QD) to 10.0 (EXENER_SC_2-30MG_QW vs OTHER_ACTIVE_basal_bolus_insulin) percent; threshold 0.5
FlagBaseline, Background glucose lowering therapy: each design has a different category: DULA_SC_FLEX_0p75-1p5_QW vs LIRA_SC_1p2MG_QD = S0; DULA_SC_FLEX_0p75-1p5_QW vs OTHER_ACTIVE_basal_bolus_insulin = S3; EXENER_SC_2-30MG_QW vs OTHER_ACTIVE_basal_bolus_insulin = S1; LIRA_SC_1p2MG_QD vs OTHER_ACTIVE_insulin_dose_increase = S4
FlagOutcome assessment, definition: confounded with design: any hypoglycemia, blood glucose below 70 mg/dL 1, glucose below 60 mg/dL or symptoms relieved by glucose 1, Hypoglycemia, not defined 1, Severe hypoglycemia requiring third party assistance 1
NoteOutcome assessment, time point: selected time points span 12 to 78.21 weeks
NoteOutcome assessment, analysis set: mixed: completers 1, other 2, randomized 1
NoteOutcome assessment, proportion method: mixed: not stated 3, observed 1
NoteRisk of bias, blinding: mixed: not_reported 1, open_label 3
NoteRisk of bias, funding: mixed: mixed 1, non_industry 3
NoteData handling, input conversions: count_from_percent 4, 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
NCT02846233	16	randomized	any hypoglycemia, blood glucose below 70 mg/dL	not stated	not stated	not stated	not stated	not stated	open_label	non_industry	2016	age over 21; BMI 30 or more; HbA1c above 8 percent; eGFR above 45; basal plus prandial or premixed insulin
NCT02887625	78.21	other	glucose below 60 mg/dL or symptoms relieved by glucose	not stated	not stated	observed	not stated	not stated	open_label	mixed	2015	age 18 to 75; HbA1c above 7.5 percent on near maximal metformin plus sulfonylurea
S003094	12	completers	Severe hypoglycemia requiring third party assistance	not stated	not stated	not stated	not stated	not stated	open_label	non_industry	2011	HbA1c 7.5 to 11%; BMI 25 or more; waist 90 cm men, 85 cm women; insulin 10 U/day or more for 3 months
S003442	24	other	Hypoglycemia, not defined	not stated	not stated	not stated	not stated	not stated	not_reported	non_industry	2019	Women with T2D by ADA criteria; no weight loss drugs within 24 weeks

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
NCT02846233	A1	DULA_SC_FLEX_0p75-1p5_QW	16	arm, events	0 / 12		R0028441:Table 5
NCT02846233	A2	OTHER_ACTIVE_basal_bolus_insulin	16	arm, events	1 / 10		R0028441:Table 5
NCT02887625	A1	EXENER_SC_2-30MG_QW	78.21	arm, events	81 / 129	count_from_percent	R0026120:Results
NCT02887625	A2	OTHER_ACTIVE_basal_bolus_insulin	78.21	arm, events	98 / 122	count_from_percent	R0026120:Results
S003094	A1	LIRA_SC_1p2MG_QD	12	arm, events	5 / 42	count_from_percent	R0026794:Results
S003094	A2	OTHER_ACTIVE_insulin_dose_increase	12	arm, events	13 / 42	count_from_percent	R0026794:Results
S003442	A1	DULA_SC_FLEX_0p75-1p5_QW	24	arm, events	1 / 48	printed_denominator	R0016372:Table 4
S003442	A2	LIRA_SC_1p2MG_QD	24	arm, events	2 / 48	printed_denominator	R0016372:Table 4

Rerun this analysis yourself

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