LivingGLP1
Network meta-analysis

HbA1c change

Type 2 diabetes (adults); background therapy: one or more non insulin glucose lowering drugs

weeks 20 to 36 (target week 26)Hypothetical (as if everyone stayed on treatment)Doses of a drug pooledMean difference
19
Randomized trials
13
Treatments
11,980
Participants
41
Trial arms

In plain language

Across 19 trials with 11,980 participants, 11 of 12 treatments had a clearly better result than placebo on HbA1c change, and for 1 the evidence could not tell it apart from placebo. The most favorable estimate was for Tirzepatide injection: mean difference -1.54 percentage points (95% credible interval -2.04 to -1.01).

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.
DULA_SCEXEN_SCIGLARLIXI_SCINS_DEGLUDECINS_GLARGINELIRA_SCLIXI_SCPLACEBOSEMA_POSEMA_SCSITAGLIPTINTIRZ_SCVISEPE_SC
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

Mean difference in percentage points. Lower values favor the treatment.
-2-1.5-1-0.50← favors treatmentfavors reference →Tirzepatide injectionSemaglutide injectionInsulin glargine with lixisenati…Semaglutide tabletLiraglutide injectionDulaglutide injectionInsulin degludecInsulin glargineExenatide injectionSitagliptinVisepegenatide injectionLixisenatide injection
Versus Placebo. 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
TreatmentBayesian MD (95% CrI)95% prediction intervalFrequentist MD (95% CI)Verdict
Tirzepatide injection
TIRZ_SC
-1.54 (-2.04 to -1.01)-2.25 to -0.82-1.56 (-2.01 to -1.12)Better
Semaglutide injection
SEMA_SC
-1.32 (-1.71 to -0.90)-1.98 to -0.66-1.34 (-1.69 to -0.98)Better
Insulin glargine with lixisenatide injection
IGLARLIXI_SC
-1.16 (-1.64 to -0.68)-1.85 to -0.47-1.18 (-1.60 to -0.75)Better
Semaglutide tablet
SEMA_PO
-1.10 (-1.43 to -0.74)-1.71 to -0.50-1.11 (-1.40 to -0.82)Better
Liraglutide injection
LIRA_SC
-1.07 (-1.48 to -0.65)-1.73 to -0.42-1.09 (-1.45 to -0.73)Better
Dulaglutide injection
DULA_SC
-1.07 (-1.32 to -0.82)-1.63 to -0.50-1.08 (-1.30 to -0.86)Better
Insulin degludec
INS_DEGLUDEC
-0.80 (-1.50 to -0.08)-1.67 to 0.11-0.83 (-1.45 to -0.21)Better
Insulin glargine
INS_GLARGINE
-0.73 (-1.14 to -0.33)-1.40 to -0.09-0.75 (-1.09 to -0.40)Better
Exenatide injection
EXEN_SC
-0.60 (-1.07 to -0.11)-1.28 to 0.09-0.60 (-1.02 to -0.19)Better
Sitagliptin
SITAGLIPTIN
-0.59 (-0.93 to -0.23)-1.20 to 0.04-0.61 (-0.91 to -0.30)Better
Visepegenatide injection
VISEPE_SC
-0.56 (-1.08 to -0.04)-1.29 to 0.16-0.57 (-1.02 to -0.12)Better
Lixisenatide injection
LIXI_SC
-0.37 (-0.75 to 0.02)-1.02 to 0.27-0.38 (-0.71 to -0.04)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: 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 columnPLACEBOTIRZ_SCSEMA_SCIGLARLIXI_SCSEMA_POLIRA_SCDULA_SCINS_DEGLUDECINS_GLARGINEEXEN_SCSITAGLIPTINVISEPE_SCLIXI_SC
PLACEBOPLACEBO1.54
1.01 to 2.04
1.32
0.90 to 1.71
1.16
0.68 to 1.64
1.10
0.74 to 1.43
1.07
0.65 to 1.48
1.07
0.82 to 1.32
0.80
0.08 to 1.50
0.73
0.33 to 1.14
0.60
0.11 to 1.07
0.59
0.23 to 0.93
0.56
0.04 to 1.08
0.37
-0.02 to 0.75
TIRZ_SC-1.54
-2.04 to -1.01
TIRZ_SC-0.22
-0.86 to 0.43
-0.38
-1.04 to 0.31
-0.44
-1.02 to 0.15
-0.47
-1.10 to 0.16
-0.47
-0.96 to 0.05
-0.74
-1.27 to -0.23
-0.81
-1.39 to -0.19
-0.95
-1.62 to -0.25
-0.95
-1.54 to -0.35
-0.98
-1.68 to -0.25
-1.17
-1.78 to -0.52
SEMA_SC-1.32
-1.71 to -0.90
0.22
-0.43 to 0.86
SEMA_SC-0.16
-0.77 to 0.46
-0.22
-0.68 to 0.22
-0.25
-0.78 to 0.27
-0.25
-0.71 to 0.22
-0.53
-1.32 to 0.31
-0.59
-1.13 to -0.03
-0.73
-1.34 to -0.11
-0.73
-1.15 to -0.33
-0.76
-1.42 to -0.08
-0.96
-1.45 to -0.43
IGLARLIXI_SC-1.16
-1.64 to -0.68
0.38
-0.31 to 1.04
0.16
-0.46 to 0.77
IGLARLIXI_SC-0.06
-0.62 to 0.46
-0.08
-0.68 to 0.50
-0.09
-0.55 to 0.39
-0.36
-1.20 to 0.47
-0.42
-0.86 to 0.01
-0.56
-1.22 to 0.07
-0.57
-1.11 to -0.05
-0.60
-1.31 to 0.11
-0.79
-1.22 to -0.33
SEMA_PO-1.10
-1.43 to -0.74
0.44
-0.15 to 1.02
0.22
-0.22 to 0.68
0.06
-0.46 to 0.62
SEMA_PO-0.03
-0.44 to 0.36
-0.03
-0.37 to 0.35
-0.30
-1.07 to 0.47
-0.36
-0.82 to 0.12
-0.50
-1.09 to 0.06
-0.51
-0.81 to -0.21
-0.54
-1.13 to 0.09
-0.73
-1.17 to -0.28
LIRA_SC-1.07
-1.48 to -0.65
0.47
-0.16 to 1.10
0.25
-0.27 to 0.78
0.08
-0.50 to 0.68
0.03
-0.36 to 0.44
LIRA_SC-0.00
-0.44 to 0.48
-0.27
-1.09 to 0.54
-0.34
-0.86 to 0.22
-0.48
-1.10 to 0.18
-0.48
-0.87 to -0.09
-0.51
-1.16 to 0.15
-0.71
-1.19 to -0.19
DULA_SC-1.07
-1.32 to -0.82
0.47
-0.05 to 0.96
0.25
-0.22 to 0.71
0.09
-0.39 to 0.55
0.03
-0.35 to 0.37
0.00
-0.48 to 0.44
DULA_SC-0.28
-1.00 to 0.43
-0.34
-0.68 to 0.01
-0.48
-0.96 to -0.01
-0.48
-0.88 to -0.10
-0.51
-1.09 to 0.05
-0.70
-1.12 to -0.28
INS_DEGLUDEC-0.80
-1.50 to -0.08
0.74
0.23 to 1.27
0.53
-0.31 to 1.32
0.36
-0.47 to 1.20
0.30
-0.47 to 1.07
0.27
-0.54 to 1.09
0.28
-0.43 to 1.00
INS_DEGLUDEC-0.06
-0.84 to 0.74
-0.20
-1.05 to 0.65
-0.21
-0.99 to 0.56
-0.24
-1.12 to 0.66
-0.43
-1.23 to 0.39
INS_GLARGINE-0.73
-1.14 to -0.33
0.81
0.19 to 1.39
0.59
0.03 to 1.13
0.42
-0.01 to 0.86
0.36
-0.12 to 0.82
0.34
-0.22 to 0.86
0.34
-0.01 to 0.68
0.06
-0.74 to 0.84
INS_GLARGINE-0.13
-0.74 to 0.45
-0.14
-0.64 to 0.34
-0.16
-0.83 to 0.47
-0.36
-0.85 to 0.11
EXEN_SC-0.60
-1.07 to -0.11
0.95
0.25 to 1.62
0.73
0.11 to 1.34
0.56
-0.07 to 1.22
0.50
-0.06 to 1.09
0.48
-0.18 to 1.10
0.48
0.01 to 0.96
0.20
-0.65 to 1.05
0.13
-0.45 to 0.74
EXEN_SC-0.00
-0.59 to 0.57
-0.03
-0.74 to 0.67
-0.23
-0.81 to 0.39
SITAGLIPTIN-0.59
-0.93 to -0.23
0.95
0.35 to 1.54
0.73
0.33 to 1.15
0.57
0.05 to 1.11
0.51
0.21 to 0.81
0.48
0.09 to 0.87
0.48
0.10 to 0.88
0.21
-0.56 to 0.99
0.14
-0.34 to 0.64
0.00
-0.57 to 0.59
SITAGLIPTIN-0.03
-0.66 to 0.61
-0.22
-0.62 to 0.20
VISEPE_SC-0.56
-1.08 to -0.04
0.98
0.25 to 1.68
0.76
0.08 to 1.42
0.60
-0.11 to 1.31
0.54
-0.09 to 1.13
0.51
-0.15 to 1.16
0.51
-0.05 to 1.09
0.24
-0.66 to 1.12
0.16
-0.47 to 0.83
0.03
-0.67 to 0.74
0.03
-0.61 to 0.66
VISEPE_SC-0.19
-0.85 to 0.45
LIXI_SC-0.37
-0.75 to 0.02
1.17
0.52 to 1.78
0.96
0.43 to 1.45
0.79
0.33 to 1.22
0.73
0.28 to 1.17
0.71
0.19 to 1.19
0.70
0.28 to 1.12
0.43
-0.39 to 1.23
0.36
-0.11 to 0.85
0.23
-0.39 to 0.81
0.22
-0.20 to 0.62
0.19
-0.45 to 0.85
LIXI_SC

Heterogeneity, fit and convergence

Bayesian random effects (primary)

Heterogeneity (tau)
0.233 (95% CrI 0.141 to 0.411)
Residual deviance
38.9 for 39 data points
DIC
76.5 (pD 37.6)
Largest R-hat
1.002
Smallest ESS
bulk 2,089, tail 3,555
Divergent transitions
0
Convergence
All criteria met
Priors
PR01 N(0, 5^2); PR03 N(0, 2.5^2); PR07 half normal(0, 0.5^2) on tau

Frequentist check (netmeta)

Method
inverse variance, REML, MD
Tau
0.216
I squared
86%
Q (total)
73.31 on 10 df, P = 0.000
Q (between designs)
51.06, P = 0.000

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
TrialBaseline HbA1c (percent)
effect modifier, prognostic factor; 19 of 19
Background glucose lowering therapy (stratum S0 to S4)
effect modifier, prognostic factor; 19 of 19
Diabetes duration (years)
effect modifier, prognostic factor; 18 of 19
Asian ancestry or region (percent Asian)
effect modifier, prognostic factor; 17 of 19
Age (years)
prognostic factor; 19 of 19
Treatment duration (weeks)
effect modifier; 19 of 19
AWARD-1
S002153
8.07S18.772.4555.6552
GETGOAL-M
S002188
8.05S16.28.254.6524
NCT03131687
S000010
8.13S18.511.6657.226
PIONEER 4
S000133
7.98S17.613.456.252
NCT01476475
S000191
8.05S16.70.6256.7524
PIONEER 10
S000234
8.31S19.3610058.4352
NCT01584232
S000246
8.05S18.8510056.826
AWARD-10
S000305
8.04S19.38not reported57.2724
NCT00976937
S000415
8.13S14.40.643.0524
SUSTAIN 9
S000483
8.05S19.723.5157.0530
PIONEER 12
S000522
8.12S15.6375.2253.2526
AWARD-8
S001068
8.4S17.61.757.824
LIRA-SWITCH™
S001119
8.25S17.75not reported56.426
AWARD-2
S001130
8.14S19.116.9156.6678
NCT04504396
S001230
8.47S15.14100
region: all sites in Asia
53.224
SUSTAIN
S001311
8.1S16.3785.0353.0330
SURPASS-3
S001591
8.17S18.45.457.452
LIXILAN JP-O1
S002018
8.39S18.67100
region: all sites in Asia
5852
PIONEER 3
S002267
8.33S1not reported13.1457.7578

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, Diabetes duration: design means range from 4.4 (LIXI_SC vs SITAGLIPTIN) to 9.7 (PLACEBO vs SEMA_SC) years; threshold 3
  • FlagBaseline, Asian ancestry or region: design means range from 0.6 (LIXI_SC vs SITAGLIPTIN) to 100.0 (DULA_SC vs SEMA_PO) percent Asian; threshold 30
  • FlagBaseline, Age: design means range from 43.1 (LIXI_SC vs SITAGLIPTIN) to 58.4 (DULA_SC vs SEMA_PO) years; threshold 10
  • FlagBaseline, Treatment duration: design means range from 24.0 (DULA_SC vs PLACEBO) to 52.0 (DULA_SC vs EXEN_SC vs PLACEBO) weeks; threshold 26
  • NoteOutcome assessment, time point: selected time points span 24 to 30 weeks
  • NoteOutcome assessment, analysis set: mixed: full_analysis 9, modified_itt 10
  • NoteOutcome assessment, definition: mixed: change in HbA1c from baseline to week 26, LOCF 1, not stated 18
  • NoteOutcome assessment, intercurrent events (discontinuation): mixed: hypothetical 12, not stated 6, treatment_policy 1
  • NoteOutcome assessment, intercurrent events (rescue): mixed: hypothetical 18, not stated 1
  • NoteRisk of bias, blinding: mixed: double_blind 13, open_label 5, single_blind 1
  • NoteData handling, input conversions: arms_combined 10, n_randomized 4
Comparability items per trial
Trialtime weeksanalysis setdefinitioninstrumentadjudicatedproportion methodintercurrent events (discontinuation)intercurrent events (rescue)blindingfundingstart yearEligibility
AWARD-126modified_ittnot statednot statednot statednot statednot statedhypotheticaldouble_blindindustry2010adults with type 2 diabetes on metformin and pioglitazone
GETGOAL-M24modified_ittnot statednot statednot statednot statedhypotheticalhypotheticaldouble_blindindustry2008type 2 diabetes on metformin 1.5 g/day or more for 3 months; HbA1c 7 to 10 percent; FPG 13.9 mmol/L or less
NCT0313168726modified_ittnot statednot statednot statednot statedtreatment_policyhypotheticaldouble_blindindustry2017age 18 to 75; T2D at least 6 months; HbA1c 7.0 to 10.5%; BMI 23 to 50; diet and exercise or metformin
PIONEER 426full_analysisnot statednot statednot statednot statedhypotheticalhypotheticaldouble_blindindustry2016Age 18 or older; T2D on metformin with or without SGLT2i; HbA1c 7.0 to 9.5 percent; eGFR 60 or more
NCT0147647524modified_ittnot statednot statednot statednot statedhypotheticalhypotheticalopen_labelindustry2011Adults with T2D; HbA1c 7 to 10 percent on metformin at least 1.5 g/day; insulin naive
PIONEER 1026full_analysisnot statednot statednot statednot statedhypotheticalhypotheticalsingle_blindindustry2017Japanese adults 20 or older; T2D; HbA1c 7.0 to 10.5 percent on one oral glucose lowering drug
NCT0158423226full_analysisnot statednot statednot statednot statednot statedhypotheticalopen_labelindustry2012Japanese adults 20 years or older; BMI 18.5 to less than 35 kg/m2; HbA1c 7.0 to 10.0 percent; on sulfonylurea and/or biguanide
AWARD-1024modified_ittnot statednot statednot statednot statednot statedhypotheticaldouble_blindindustry2015T2D; HbA1c 7.0 to 9.5 percent; BMI 45 or lower; SGLT2i with or without metformin
NCT0097693724modified_ittnot statednot statednot statednot statedhypotheticalhypotheticaldouble_blindindustry2009age 18 to under 50; BMI 30 or more; HbA1c 7.0 to 10 percent; metformin at least 1.5 g/day
SUSTAIN 930full_analysisnot statednot statednot statednot statednot statednot stateddouble_blindindustry2017adults 18 or older (20 in Japan); HbA1c 7.0 to 10.5 percent; stable SGLT2i with or without metformin or SU
PIONEER 1226full_analysisnot statednot statednot statednot statedhypotheticalhypotheticaldouble_blindindustry2019adults with type 2 diabetes on metformin, HbA1c 7.0 to 10.5 percent
AWARD-824modified_ittnot statednot statednot statednot statednot statedhypotheticaldouble_blindindustry2013age 18 or older; BMI up to 45; HbA1c 7.5 to 9.5 percent on sulfonylurea at least half maximal dose
LIRA-SWITCH™26full_analysisnot statednot statednot statednot statedhypotheticalhypotheticaldouble_blindindustry2013age 18 or more; HbA1c 7.5 to 9.5 percent; BMI 20 or more; on sitagliptin 100 mg and metformin for 90 days or more
AWARD-226modified_ittnot statednot statednot statednot statednot statedhypotheticalopen_labelindustry2010type 2 diabetes on metformin and glimepiride
NCT0450439624full_analysisnot statednot statednot statednot statedhypotheticalhypotheticaldouble_blindindustry2020age 18 to 75; HbA1c 7.0 to 10.5 percent; BMI 40 or lower; eGFR 60 or higher; metformin monotherapy at least 1000 mg
SUSTAIN30full_analysisnot statednot statednot statednot statedhypotheticalhypotheticaldouble_blindindustry2017Adults 18 or older, HbA1c 7.0 to 10.5 percent on metformin monotherapy, eGFR 60 or more
SURPASS-324modified_ittnot statednot statednot statednot statedhypotheticalhypotheticalopen_labelindustry2019insulin naive; HbA1c 7.0 to 10.5 percent; BMI at least 25; metformin with or without SGLT2i; eGFR above 45
LIXILAN JP-O126modified_ittchange in HbA1c from baseline to week 26, LOCFnot statednot statednot statedhypotheticalhypotheticalopen_labelindustry2016insulin naive Japanese adults; HbA1c 7.5 to 10%; FPG 13.8 mmol/L or less; one or two OADs
PIONEER 326full_analysisnot statednot statednot statednot statedhypotheticalhypotheticaldouble_blindindustry2016adults with T2D; HbA1c 7.0 to 10.5 percent; metformin with or without sulfonylurea

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
TrialArmTreatmentWeekDataValueSEEvents / NFlagsSource
NCT03131687A1PLACEBO26arm, change-0.0600.14044R0016215:Supplement Table 1
NCT03131687A2+A3+A4+A5TIRZ_SC26arm, change-1.6590.051188arms_combinedR0016215:Supplement Table 1
NCT03131687A6DULA_SC26arm, change-1.2100.14049R0016215:Supplement Table 1
PIONEER 4A1SEMA_PO26arm, change-1.4000.053285registry:outcomes
PIONEER 4A2LIRA_SC26arm, change-1.2000.053284registry:outcomes
PIONEER 4A3PLACEBO26arm, change-0.1000.059142registry:outcomes
NCT01476475A1IGLARLIXI_SC24arm, change-1.8200.058160registry:outcomes
NCT01476475A2INS_GLARGINE24arm, change-1.6400.057161registry:outcomes
PIONEER 10A1+A2+A3SEMA_PO26arm, change-1.5930.061370arms_combinedR0018421:Figure 2D
PIONEER 10A4DULA_SC26arm, change-1.6000.10062R0018421:Figure 2D
NCT01584232A1DULA_SC26arm, change-1.4400.050178R0016159:Table 2
NCT01584232A2INS_GLARGINE26arm, change-0.9000.050179R0016159:Table 2
AWARD-10A1+A2DULA_SC24arm, change-1.2600.045261arms_combinedregistry:outcomes
AWARD-10A3PLACEBO24arm, change-0.5100.065123registry:outcomes
NCT00976937A1LIXI_SC24arm, change-0.7000.100150R0012687:Results
NCT00976937A2SITAGLIPTIN24arm, change-0.7000.100160R0012687:Results
SUSTAIN 9A1SEMA_SC30contrast, md-1.4200.094R0021710:Figure 1
SUSTAIN 9A2PLACEBO30contrast, mdR0021710:Figure 1
PIONEER 12A1+A2+A3SEMA_PO26arm, change-1.2330.0321,082n_randomized;arms_combinedregistry:outcomes
PIONEER 12A4SITAGLIPTIN26arm, change-0.7000.053359n_randomizedregistry:outcomes
AWARD-8A1DULA_SC24arm, change-1.3800.080215registry:outcomes
AWARD-8A2PLACEBO24arm, change-0.1100.14053registry:outcomes
LIRA-SWITCH™A1LIRA_SC26contrast, md-0.6100.107R0025720:Results
LIRA-SWITCH™A2SITAGLIPTIN26contrast, mdR0025720:Results
AWARD-2A1+A2DULA_SC26arm, change-1.0240.039529arms_combinedregistry:outcomes
AWARD-2A3INS_GLARGINE26arm, change-0.6500.060258registry:outcomes
NCT04504396A1VISEPE_SC24arm, change-1.2700.054310R0009432:Table 2
NCT04504396A2PLACEBO24arm, change-0.7000.051310R0009432:Table 2
SUSTAINA1+A2SEMA_SC30arm, change-1.6510.042578arms_combinedregistry:outcomes
SUSTAINA3SITAGLIPTIN30arm, change-1.0000.053290registry:outcomes
SURPASS-3A1+A2+A3TIRZ_SC24arm, change-2.0970.0261,079n_randomized;arms_combinedR0007660:Table 1
SURPASS-3A4INS_DEGLUDEC24arm, change-1.3600.045365n_randomizedR0007660:Table 1
LIXILAN JP-O1A1IGLARLIXI_SC26arm, change-1.5800.072161R0015751:Table 2
LIXILAN JP-O1A2LIXI_SC26arm, change-0.5100.073160R0015751:Table 2
AWARD-1A1+A2DULA_SC26arm, change-1.4050.043540arms_combinedregistry:outcomes
AWARD-1A3EXEN_SC26arm, change-0.9900.060266registry:outcomes
AWARD-1A4PLACEBO26arm, change-0.4600.080119registry:outcomes
GETGOAL-MA1+A2LIXI_SC24arm, change-0.8510.050483arms_combinedR0025872:Results
GETGOAL-MA3PLACEBO24arm, change-0.4000.080164R0025872:Results
PIONEER 3A1+A2+A3SEMA_PO26arm, change-1.0660.0291,396arms_combinedregistry:outcomes
PIONEER 3A4SITAGLIPTIN26arm, change-0.8000.042467registry:outcomes

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