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)Treatment policyDoses of a drug pooledMean difference
8
Randomized trials
8
Treatments
6,629
Participants
17
Trial arms
In plain language
Across 8 trials with 6,629 participants, 5 of 7 treatments had a clearly better result than placebo on HbA1c change, and for 2 the evidence could not tell them apart from placebo. The most favorable estimate was for Semaglutide injection: mean difference -1.26 percentage points (95% credible interval -2.09 to -0.28).
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.
Effects compared with Placebo
Mean difference in percentage points. Lower values favor the treatment.
| Treatment | Bayesian MD (95% CrI) | 95% prediction interval | Frequentist MD (95% CI) | Verdict |
|---|---|---|---|---|
| Semaglutide injection SEMA_SC | -1.26 (-2.09 to -0.28) | -2.31 to -0.06 | -1.29 (-1.81 to -0.77) | Better |
| Efsubaglutide alfa injection EFSUBA_SC | -1.04 (-1.72 to -0.34) | -2.00 to -0.05 | -1.06 (-1.50 to -0.62) | Better |
| Semaglutide tablet SEMA_PO | -0.92 (-1.42 to -0.34) | -1.73 to -0.03 | -0.93 (-1.26 to -0.61) | Better |
| Liraglutide injection LIRA_SC | -0.85 (-1.48 to -0.19) | -1.75 to 0.09 | -0.87 (-1.26 to -0.47) | Better |
| Dulaglutide injection DULA_SC | -0.77 (-1.28 to -0.20) | -1.59 to 0.12 | -0.78 (-1.07 to -0.48) | Better |
| Sitagliptin SITAGLIPTIN | -0.57 (-1.21 to 0.17) | -1.47 to 0.45 | -0.59 (-0.99 to -0.19) | Unclear |
| Visepegenatide injection VISEPE_SC | -0.57 (-1.18 to 0.12) | -1.45 to 0.38 | -0.57 (-0.91 to -0.23) | 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.
| Row versus column | PLACEBO | SEMA_SC | EFSUBA_SC | SEMA_PO | LIRA_SC | DULA_SC | SITAGLIPTIN | VISEPE_SC |
|---|---|---|---|---|---|---|---|---|
| PLACEBO | PLACEBO | 1.26 0.28 to 2.09 | 1.04 0.34 to 1.72 | 0.92 0.34 to 1.42 | 0.85 0.19 to 1.48 | 0.77 0.20 to 1.28 | 0.57 -0.17 to 1.21 | 0.57 -0.12 to 1.18 |
| SEMA_SC | -1.26 -2.09 to -0.28 | SEMA_SC | -0.21 -1.29 to 0.97 | -0.35 -1.06 to 0.44 | -0.41 -1.37 to 0.61 | -0.49 -1.35 to 0.49 | -0.69 -1.30 to -0.04 | -0.70 -1.76 to 0.44 |
| EFSUBA_SC | -1.04 -1.72 to -0.34 | 0.21 -0.97 to 1.29 | EFSUBA_SC | -0.13 -1.03 to 0.74 | -0.19 -1.17 to 0.76 | -0.28 -1.15 to 0.60 | -0.48 -1.46 to 0.44 | -0.48 -1.43 to 0.42 |
| SEMA_PO | -0.92 -1.42 to -0.34 | 0.35 -0.44 to 1.06 | 0.13 -0.74 to 1.03 | SEMA_PO | -0.07 -0.74 to 0.60 | -0.15 -0.70 to 0.42 | -0.35 -0.81 to 0.08 | -0.35 -1.20 to 0.50 |
| LIRA_SC | -0.85 -1.48 to -0.19 | 0.41 -0.61 to 1.37 | 0.19 -0.76 to 1.17 | 0.07 -0.60 to 0.74 | LIRA_SC | -0.08 -0.84 to 0.68 | -0.28 -1.10 to 0.49 | -0.29 -1.20 to 0.62 |
| DULA_SC | -0.77 -1.28 to -0.20 | 0.49 -0.49 to 1.35 | 0.28 -0.60 to 1.15 | 0.15 -0.42 to 0.70 | 0.08 -0.68 to 0.84 | DULA_SC | -0.20 -0.91 to 0.46 | -0.20 -1.05 to 0.62 |
| SITAGLIPTIN | -0.57 -1.21 to 0.17 | 0.69 0.04 to 1.30 | 0.48 -0.44 to 1.46 | 0.35 -0.08 to 0.81 | 0.28 -0.49 to 1.10 | 0.20 -0.46 to 0.91 | SITAGLIPTIN | -0.00 -0.92 to 0.94 |
| VISEPE_SC | -0.57 -1.18 to 0.12 | 0.70 -0.44 to 1.76 | 0.48 -0.42 to 1.43 | 0.35 -0.50 to 1.20 | 0.29 -0.62 to 1.20 | 0.20 -0.62 to 1.05 | 0.00 -0.94 to 0.92 | VISEPE_SC |
Heterogeneity, fit and convergence
Bayesian random effects (primary)
Frequentist check (netmeta)
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.
| Trial | Age (years) prognostic factor; 8 of 8 | Baseline HbA1c (percent) effect modifier, prognostic factor; 8 of 8 | Background glucose lowering therapy (stratum S0 to S4) effect modifier, prognostic factor; 8 of 8 | Diabetes duration (years) effect modifier, prognostic factor; 7 of 8 | Asian ancestry or region (percent Asian) effect modifier, prognostic factor; 7 of 8 | Treatment duration (weeks) effect modifier; 8 of 8 |
|---|---|---|---|---|---|---|
| AWARD-10 S000305 | 57.27 | 8.04 | S1 | 9.38 | not reported | 24 |
| PIONEER 4 S000133 | 56.2 | 7.98 | S1 | 7.6 | 13.4 | 52 |
| PIONEER 10 S000234 | 58.43 | 8.31 | S1 | 9.36 | 100 | 52 |
| PIONEER 12 S000522 | 53.25 | 8.12 | S1 | 5.63 | 75.22 | 26 |
| NCT04504396 S001230 | 53.2 | 8.47 | S1 | 5.14 | 100 region: all sites in Asia | 24 |
| SUSTAIN S001311 | 53.03 | 8.1 | S1 | 6.37 | 85.03 | 30 |
| NCT04998032 S002121 | 53.71 | 8.66 | S1 | 41.93 | 100 region: all sites in Asia | 24 |
| PIONEER 3 S002267 | 57.75 | 8.33 | S1 | not reported | 13.14 | 78 |
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 8.0 (LIRA_SC vs PLACEBO vs SEMA_PO) to 8.7 (EFSUBA_SC vs PLACEBO) percent; threshold 0.5
- FlagBaseline, Diabetes duration: design means range from 5.1 (PLACEBO vs VISEPE_SC) to 41.9 (EFSUBA_SC vs PLACEBO) years; threshold 3
- FlagBaseline, Asian ancestry or region: design means range from 13.4 (LIRA_SC vs PLACEBO vs SEMA_PO) to 100.0 (DULA_SC vs SEMA_PO) percent Asian; threshold 30
- FlagBaseline, Treatment duration: design means range from 24.0 (DULA_SC vs PLACEBO) to 52.0 (DULA_SC vs SEMA_PO) weeks; threshold 26
- NoteOutcome assessment, time point: selected time points span 24 to 30 weeks
- NoteOutcome assessment, analysis set: mixed: full_analysis 6, modified_itt 2
- NoteOutcome assessment, intercurrent events (discontinuation): mixed: hypothetical 4, not stated 2, treatment_policy 2
- NoteOutcome assessment, intercurrent events (rescue): mixed: hypothetical 5, not stated 1, treatment_policy 2
- NoteRisk of bias, blinding: mixed: double_blind 7, single_blind 1
- NoteData handling, input conversions: arms_combined 5
| Trial | time weeks | analysis set | definition | instrument | adjudicated | proportion method | intercurrent events (discontinuation) | intercurrent events (rescue) | blinding | funding | start year | Eligibility |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| AWARD-10 | 24 | modified_itt | not stated | not stated | not stated | not stated | not stated | hypothetical | double_blind | industry | 2015 | T2D; HbA1c 7.0 to 9.5 percent; BMI 45 or lower; SGLT2i with or without metformin |
| PIONEER 4 | 26 | full_analysis | not stated | not stated | not stated | not stated | treatment_policy | treatment_policy | double_blind | industry | 2016 | Age 18 or older; T2D on metformin with or without SGLT2i; HbA1c 7.0 to 9.5 percent; eGFR 60 or more |
| PIONEER 10 | 26 | full_analysis | not stated | not stated | not stated | not stated | treatment_policy | treatment_policy | single_blind | industry | 2017 | Japanese adults 20 or older; T2D; HbA1c 7.0 to 10.5 percent on one oral glucose lowering drug |
| PIONEER 12 | 26 | full_analysis | not stated | not stated | not stated | not stated | hypothetical | hypothetical | double_blind | industry | 2019 | adults with type 2 diabetes on metformin, HbA1c 7.0 to 10.5 percent |
| NCT04504396 | 24 | full_analysis | not stated | not stated | not stated | not stated | hypothetical | hypothetical | double_blind | industry | 2020 | age 18 to 75; HbA1c 7.0 to 10.5 percent; BMI 40 or lower; eGFR 60 or higher; metformin monotherapy at least 1000 mg |
| SUSTAIN | 30 | full_analysis | not stated | not stated | not stated | not stated | hypothetical | hypothetical | double_blind | industry | 2017 | Adults 18 or older, HbA1c 7.0 to 10.5 percent on metformin monotherapy, eGFR 60 or more |
| NCT04998032 | 24 | modified_itt | not stated | not stated | not stated | not stated | not stated | not stated | double_blind | industry | 2021 | age 18 to 75; metformin monotherapy; HbA1c 7.5 to 10.5 at randomization; BMI 18.5 to 40; eGFR 60 or higher |
| PIONEER 3 | 26 | full_analysis | not stated | not stated | not stated | not stated | hypothetical | hypothetical | double_blind | industry | 2016 | adults 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 | Arm | Treatment | Week | Data | Value | SE | Events / N | Flags | Source |
|---|---|---|---|---|---|---|---|---|---|
| PIONEER 4 | A1 | SEMA_PO | 26 | arm, change | -1.200 | 0.100 | 285 | R0015836:Results | |
| PIONEER 4 | A2 | LIRA_SC | 26 | arm, change | -1.100 | 0.100 | 284 | R0015836:Results | |
| PIONEER 4 | A3 | PLACEBO | 26 | arm, change | -0.200 | 0.100 | 142 | R0015836:Results | |
| PIONEER 10 | A1+A2+A3 | SEMA_PO | 26 | arm, change | -1.599 | 0.061 | 393 | arms_combined | R0018421:Figure 2C |
| PIONEER 10 | A4 | DULA_SC | 26 | arm, change | -1.500 | 0.100 | 65 | R0018421:Figure 2C | |
| AWARD-10 | A1+A2 | DULA_SC | 24 | arm, change | -1.275 | 0.045 | 266 | arms_combined | registry:outcomes |
| AWARD-10 | A3 | PLACEBO | 24 | arm, change | -0.540 | 0.064 | 133 | registry:outcomes | |
| PIONEER 12 | A1+A2+A3 | SEMA_PO | 26 | arm, change | -1.196 | 0.033 | 1,016 | arms_combined | registry:outcomes |
| PIONEER 12 | A4 | SITAGLIPTIN | 26 | arm, change | -0.700 | 0.053 | 350 | registry:outcomes | |
| NCT04504396 | A1 | VISEPE_SC | 24 | arm, change | -1.250 | 0.048 | 310 | R0009432:Table 2 | |
| NCT04504396 | A2 | PLACEBO | 24 | arm, change | -0.680 | 0.048 | 310 | R0009432:Table 2 | |
| SUSTAIN | A1+A2 | SEMA_SC | 30 | arm, change | -1.600 | 0.044 | 578 | arms_combined | registry:outcomes |
| SUSTAIN | A3 | SITAGLIPTIN | 30 | arm, change | -0.900 | 0.053 | 290 | registry:outcomes | |
| NCT04998032 | A1 | EFSUBA_SC | 24 | arm, change | -1.800 | 0.107 | 171 | R0006975:Table 2 | |
| NCT04998032 | A2 | PLACEBO | 24 | arm, change | -0.740 | 0.122 | 173 | R0006975:Table 2 | |
| PIONEER 3 | A1+A2+A3 | SEMA_PO | 26 | arm, change | -1.000 | 0.029 | 1,396 | arms_combined | registry:outcomes |
| PIONEER 3 | A4 | SITAGLIPTIN | 26 | arm, change | -0.800 | 0.042 | 467 | registry:outcomes |
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.