Network meta-analysis

Body weight change in kilograms (diabetes)

Type 2 diabetes (adults); background therapy: basal insulin with or without non insulin drugs

weeks 20 to 36 (target week 26)Not stated by the trialsEach dose separatelyMean differenceSeparate part 2 of a disconnected network

Randomized trials

Treatments

4,102

Participants

Trial arms

In plain language

Across 8 trials with 4,102 participants, 0 of 5 treatments had a clearly better result than insulin degludec and liraglutide (IDegLira) subcutaneous once daily titrated on body weight change in kilograms (diabetes), 4 a clearly worse one, and for 1 the evidence could not tell it apart from insulin degludec and liraglutide (IDegLira) subcutaneous once daily titrated. The most favorable estimate was for Insulin degludec: mean difference 1.74 kg (95% credible interval 0.32 to 3.09).

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 degludec and liraglutide (IDegLira) subcutaneous once daily titrated

Mean difference in kg. Lower values favor the treatment.

Versus Insulin degludec and liraglutide (IDegLira) subcutaneous once daily titrated. 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 degludec and liraglutide (IDegLira) subcutaneous once daily titrated
Treatment	Bayesian MD (95% CrI)	95% prediction interval	Frequentist MD (95% CI)	Verdict
Insulin degludec INS_DEGLUDEC	1.74 (0.32 to 3.09)	-0.95 to 4.39	1.76 (0.99 to 2.54)	Worse
IGlarLixi 2:1 pen subcutaneous once daily titrated IGLARLIXI2_SC_TIT_QD	2.08 (-0.60 to 5.16)	-1.21 to 5.99	2.01 (0.45 to 3.57)	Unclear
Insulin glargine INS_GLARGINE	3.23 (0.93 to 5.76)	0.06 to 6.65	3.20 (1.91 to 4.49)	Worse
Basal bolus insulin OTHER_ACTIVE_basal_bolus_insulin	3.56 (1.14 to 5.87)	0.15 to 6.83	3.57 (2.28 to 4.86)	Worse
Premixed insulin INS_PREMIX	5.32 (1.46 to 9.90)	0.85 to 10.44	5.21 (2.17 to 8.25)	Worse

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	IDEGLIRA_SC_TIT_QD	INS_DEGLUDEC	IGLARLIXI2_SC_TIT_QD	INS_GLARGINE	OTHER_ACTIVE_basal_bolus_insulin	INS_PREMIX
IDEGLIRA_SC_TIT_QD	IDEGLIRA_SC_TIT_QD	-1.74 -3.09 to -0.32	-2.08 -5.16 to 0.60	-3.23 -5.76 to -0.93	-3.56 -5.87 to -1.14	-5.32 -9.90 to -1.46
INS_DEGLUDEC	1.74 0.32 to 3.09	INS_DEGLUDEC	-0.34 -3.78 to 2.77	-1.49 -4.53 to 1.23	-1.81 -4.58 to 0.93	-3.61 -8.49 to 0.57
IGLARLIXI2_SC_TIT_QD	2.08 -0.60 to 5.16	0.34 -2.77 to 3.78	IGLARLIXI2_SC_TIT_QD	-1.15 -2.82 to 0.74	-1.49 -4.89 to 2.64	-3.24 -6.55 to -0.12
INS_GLARGINE	3.23 0.93 to 5.76	1.49 -1.23 to 4.53	1.15 -0.74 to 2.82	INS_GLARGINE	-0.32 -3.55 to 3.27	-2.09 -5.80 to 1.33
OTHER_ACTIVE_basal_bolus_insulin	3.56 1.14 to 5.87	1.81 -0.93 to 4.58	1.49 -2.64 to 4.89	0.32 -3.27 to 3.55	OTHER_ACTIVE_basal_bolus_insulin	-1.76 -7.08 to 2.87
INS_PREMIX	5.32 1.46 to 9.90	3.61 -0.57 to 8.49	3.24 0.12 to 6.55	2.09 -1.33 to 5.80	1.76 -2.87 to 7.08	INS_PREMIX

Heterogeneity, fit and convergence

Bayesian random effects (primary)

Heterogeneity (tau): 0.778 (95% CrI 0.177 to 2.611)
Residual deviance: 16.4 for 16 data points
DIC: 32.3 (pD 15.9)
Largest R-hat: 1.002
Smallest ESS: bulk 1,402, tail 1,867
Divergent transitions: 0
Convergence: All criteria met
Priors: PR01 N(0, 25^2); PR03 N(0, 12.5^2); PR07 half normal(0, 2.5^2) on tau

Frequentist check (netmeta)

Method: inverse variance, REML, MD
Tau: 0.583
I squared: 76%
Q (total): 12.30 on 3 df, P = 0.006
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	Baseline BMI or body weight (kg/m2) effect modifier, prognostic factor; 6 of 8	Sex (percent female) effect modifier, prognostic factor; 8 of 8	Background glucose lowering therapy (stratum S0 to S4) effect modifier, prognostic factor; 8 of 8	Asian ancestry or region (percent Asian) effect modifier, prognostic factor; 4 of 8	Kidney function (eGFR) (mL/min/1.73 m2) prognostic factor, effect modifier; 1 of 8	Treatment duration (weeks) effect modifier; 8 of 8	Lifestyle co-intervention intensity (none standard intensive) effect modifier, prognostic factor; 8 of 8
DUAL™ V S001328	body weight 87.8 kg	49.73	S2	not reported	not reported	26	not_reported
LixiLan-L S001409	31.14	53.26	S2	2.72	not reported	30	not_reported
DUAL™ II China S001556	27.33	39.5	S2	100	not reported	26	not_reported
NCT02420262 S001760	body weight 87.7 kg	55.14	S2	not reported	not reported	26	not_reported
DUAL™ II Japan S002038	27.7	36.67	S2	100	not reported	26	not_reported
Lixilan-L-CN S002110	25.25	41.81 100 minus male share	S2	100 region: all sites in Asia	91.3	30	not_reported
DUAL™ II S002285	33.7	43.58	S2	not reported	not reported	26	not_reported
S002992 S002992	29.85	50.15	S2	not reported	not reported	26	not_reported

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 BMI or body weight: not reported by 2 of 8 trials
FlagBaseline, Sex: design means range from 39.9 (IDEGLIRA_SC_TIT_QD vs INS_DEGLUDEC) to 55.1 (IDEGLIRA_SC_TIT_QD vs OTHER_ACTIVE_basal_bolus_insulin) percent female; threshold 15
FlagBaseline, Asian ancestry or region: not reported by 4 of 8 trials
FlagBaseline, Asian ancestry or region: design means range from 51.4 (IGLARLIXI2_SC_TIT_QD vs INS_GLARGINE) to 100.0 (IDEGLIRA_SC_TIT_QD vs INS_DEGLUDEC) percent Asian; threshold 30
FlagBaseline, Kidney function (eGFR): not reported by 7 of 8 trials
NoteOutcome assessment, time point: selected time points span 26 to 30 weeks
NoteOutcome assessment, analysis set: mixed: full_analysis 5, modified_itt 2, randomized 1
NoteRisk of bias, blinding: mixed: double_blind 3, open_label 5
NoteData handling, input conversions: n_randomized 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
DUAL™ V	26	full_analysis	not stated	not stated	not stated	not stated	not stated	not stated	open_label	industry	2013	T2D uncontrolled on insulin glargine 20 to 50 U plus metformin
LixiLan-L	30	modified_itt	not stated	not stated	not stated	not stated	not stated	not stated	open_label	industry	2014	adults with T2D on basal insulin 15 to 40 U/d; HbA1c 7 to 10% and glargine 20 to 50 U after run in
DUAL™ II China	26	full_analysis	not stated	not stated	not stated	not stated	not stated	not stated	double_blind	industry	2017	age 18 or older; BMI 24 or higher; HbA1c 7.5 or higher; basal insulin 20 to 50 U plus metformin
NCT02420262	26	full_analysis	not stated	not stated	not stated	not stated	not stated	not stated	open_label	industry	2015	age 18 or older; HbA1c 7.0 to 10.0; BMI up to 40; glargine 20 to 50 U plus metformin
DUAL™ II Japan	26	full_analysis	not stated	not stated	not stated	not stated	not stated	not stated	double_blind	industry	2016	Japanese adults; BMI 23 kg/m2 or more; HbA1c 7.5 to 11.0 percent; basal or premix insulin 20 to 50 U with metformin
Lixilan-L-CN	30	modified_itt	not stated	not stated	not stated	not stated	not stated	not stated	open_label	industry	2019	Chinese adults; HbA1c 7.0 to 10.5 percent; basal insulin 10 to 25 U/day with up to 2 oral drugs; FPG at most 8.9 mmol/L
DUAL™ II	26	full_analysis	not stated	not stated	not stated	not stated	not stated	not stated	double_blind	industry	2011	HbA1c 7.5 to 10 percent; BMI 27 or higher; basal insulin 20 to 40 U plus metformin with or without SU or glinides
S002992	26	randomized	not stated	not stated	not stated	not stated	not stated	not stated	open_label	industry		adults 18 or older; HbA1c 7.5 to 10 percent; BMI 20 to less than 40; basal insulin 20 to 50 U plus metformin with or without SGLT2i

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
DUAL™ V	A1	IDEGLIRA_SC_TIT_QD	26	arm, change	-1.400	0.210	278		registry:outcomes
DUAL™ V	A2	INS_GLARGINE	26	arm, change	1.800	0.216	279		registry:outcomes
LixiLan-L	A1	IGLARLIXI2_SC_TIT_QD	30	arm, change	-0.670	0.181	365		registry:outcomes
LixiLan-L	A2	INS_GLARGINE	30	arm, change	0.700	0.178	365		registry:outcomes
DUAL™ II China	A1	IDEGLIRA_SC_TIT_QD	26	arm, change	-0.700	0.177	288		registry:outcomes
DUAL™ II China	A2	INS_DEGLUDEC	26	arm, change	0.500	0.229	139		registry:outcomes
NCT02420262	A1	IDEGLIRA_SC_TIT_QD	26	arm, change	-0.930	0.220	244		registry:outcomes
NCT02420262	A2	OTHER_ACTIVE_basal_bolus_insulin	26	arm, change	2.640	0.220	246		registry:outcomes
DUAL™ II Japan	A1	IDEGLIRA_SC_TIT_QD	26	arm, change	-0.700	0.342	105		registry:outcomes
DUAL™ II Japan	A2	INS_DEGLUDEC	26	arm, change	0.700	0.263	105		registry:outcomes
Lixilan-L-CN	A1	IGLARLIXI2_SC_TIT_QD	30	arm, change	-0.300	0.200	202		R0014540:Table 2
Lixilan-L-CN	A2	INS_GLARGINE	30	arm, change	0.700	0.200	201		R0014540:Table 2
DUAL™ II	A1	IDEGLIRA_SC_TIT_QD	26	arm, change	-2.700	0.262	199		registry:outcomes
DUAL™ II	A2	INS_DEGLUDEC	26	arm, change	0.000	0.241	199		registry:outcomes
S002992	A1	IGLARLIXI2_SC_TIT_QD	26	arm, final	80.200	0.789	443	n_randomized	R0010673:Results
S002992	A2	INS_PREMIX	26	arm, final	83.400	0.902	444	n_randomized	R0010673:Results

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