Network meta-analysis
HbA1c change
Type 1 diabetes
weeks 12 to 40 (target week 26)Not stated by the trialsDoses of a drug pooledMean difference
7
Randomized trials
9
Treatments
1,075
Participants
17
Trial arms
In plain language
Across 7 trials with 1,075 participants, 0 of 8 treatments had a clearly better result than placebo on HbA1c change, and for 8 the evidence could not tell them apart from placebo. The most favorable estimate was for Exenatide extended release and dapagliflozin injection: mean difference -0.78 percentage points (95% credible interval -1.60 to 0.13).
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 |
|---|---|---|---|---|
| Exenatide extended release and dapagliflozin injection DAPAEXEN_SC | -0.78 (-1.60 to 0.13) | -1.91 to 0.46 | -0.80 (-1.42 to -0.18) | Unclear |
| Semaglutide injection SEMA_SC | -0.30 (-1.11 to 0.52) | -1.48 to 0.91 | -0.30 (-0.92 to 0.32) | Unclear |
| Tirzepatide injection TIRZ_SC | -0.29 (-1.20 to 0.59) | -1.58 to 0.92 | -0.30 (-0.99 to 0.39) | Unclear |
| Exenatide extended release injection EXENER_SC | -0.27 (-1.18 to 0.65) | -1.50 to 0.98 | -0.30 (-1.00 to 0.40) | Unclear |
| Empagliflozin EMPAGLIFLOZIN | -0.25 (-1.38 to 0.92) | -1.67 to 1.20 | -0.25 (-1.13 to 0.63) | Unclear |
| Dapagliflozin DAPAGLIFLOZIN | -0.18 (-1.04 to 0.67) | -1.35 to 1.06 | -0.20 (-0.82 to 0.42) | Unclear |
| Liraglutide injection LIRA_SC | -0.05 (-0.50 to 0.53) | -0.97 to 1.03 | -0.03 (-0.40 to 0.35) | Unclear |
| Standard care or no added treatment STANDARD_CARE | 0.11 (-1.03 to 1.25) | -1.37 to 1.53 | 0.11 (-0.76 to 0.98) | 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 | DAPAEXEN_SC | SEMA_SC | TIRZ_SC | EXENER_SC | EMPAGLIFLOZIN | DAPAGLIFLOZIN | LIRA_SC | STANDARD_CARE |
|---|---|---|---|---|---|---|---|---|---|
| PLACEBO | PLACEBO | 0.78 -0.13 to 1.60 | 0.30 -0.52 to 1.11 | 0.29 -0.59 to 1.20 | 0.27 -0.65 to 1.18 | 0.25 -0.92 to 1.38 | 0.18 -0.67 to 1.04 | 0.05 -0.53 to 0.50 | -0.11 -1.25 to 1.03 |
| DAPAEXEN_SC | -0.78 -1.60 to 0.13 | DAPAEXEN_SC | -0.48 -1.68 to 0.75 | -0.49 -1.68 to 0.77 | -0.50 -1.41 to 0.42 | -0.53 -1.97 to 0.93 | -0.59 -1.42 to 0.24 | -0.72 -1.77 to 0.23 | -0.89 -2.31 to 0.61 |
| SEMA_SC | -0.30 -1.11 to 0.52 | 0.48 -0.75 to 1.68 | SEMA_SC | -0.01 -1.21 to 1.27 | -0.03 -1.25 to 1.17 | -0.05 -0.91 to 0.80 | -0.12 -1.32 to 1.06 | -0.24 -1.27 to 0.64 | -0.41 -1.24 to 0.45 |
| TIRZ_SC | -0.29 -1.20 to 0.59 | 0.49 -0.77 to 1.68 | 0.01 -1.27 to 1.21 | TIRZ_SC | -0.01 -1.34 to 1.24 | -0.04 -1.55 to 1.37 | -0.11 -1.37 to 1.09 | -0.24 -1.36 to 0.75 | -0.39 -1.88 to 1.04 |
| EXENER_SC | -0.27 -1.18 to 0.65 | 0.50 -0.42 to 1.41 | 0.03 -1.17 to 1.25 | 0.01 -1.24 to 1.34 | EXENER_SC | -0.03 -1.49 to 1.45 | -0.09 -1.01 to 0.83 | -0.23 -1.33 to 0.81 | -0.38 -1.80 to 1.04 |
| EMPAGLIFLOZIN | -0.25 -1.38 to 0.92 | 0.53 -0.93 to 1.97 | 0.05 -0.80 to 0.91 | 0.04 -1.37 to 1.55 | 0.03 -1.45 to 1.49 | EMPAGLIFLOZIN | -0.06 -1.50 to 1.34 | -0.19 -1.49 to 1.01 | -0.35 -1.23 to 0.54 |
| DAPAGLIFLOZIN | -0.18 -1.04 to 0.67 | 0.59 -0.24 to 1.42 | 0.12 -1.06 to 1.32 | 0.11 -1.09 to 1.37 | 0.09 -0.83 to 1.01 | 0.06 -1.34 to 1.50 | DAPAGLIFLOZIN | -0.12 -1.17 to 0.83 | -0.29 -1.71 to 1.14 |
| LIRA_SC | -0.05 -0.50 to 0.53 | 0.72 -0.23 to 1.77 | 0.24 -0.64 to 1.27 | 0.24 -0.75 to 1.36 | 0.23 -0.81 to 1.33 | 0.19 -1.01 to 1.49 | 0.12 -0.83 to 1.17 | LIRA_SC | -0.16 -1.32 to 1.15 |
| STANDARD_CARE | 0.11 -1.03 to 1.25 | 0.89 -0.61 to 2.31 | 0.41 -0.45 to 1.24 | 0.39 -1.04 to 1.88 | 0.38 -1.04 to 1.80 | 0.35 -0.54 to 1.23 | 0.29 -1.14 to 1.71 | 0.16 -1.15 to 1.32 | STANDARD_CARE |
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 | Baseline HbA1c (percent) effect modifier, prognostic factor; 7 of 7 | Diabetes duration (years) effect modifier, prognostic factor; 4 of 7 | Asian ancestry or region (percent Asian) effect modifier, prognostic factor; 1 of 7 | Age (years) prognostic factor; 7 of 7 | Treatment duration (weeks) effect modifier; 7 of 7 |
|---|---|---|---|---|---|
| ENDIS S000977 | 7.45 | 20.67 | not reported | 47.9 | 12 |
| TODINELI S001560 | 8.23 | 32 | not reported | 50.5 | 26 |
| NCT01753362 S001628 | 7.85 | not reported | not reported | 46.1 | 26 |
| ADJUNCT TWO™ S001732 | 8.08 | not reported | not reported | 43.15 | 26 |
| NCT02962492 S002146 | 7.69 | not reported | not reported | 46.63 | 12 |
| ADJUST-T1D S002321 | 7.75 | 22.65 | 1.39 | 40.15 | 26 |
| S003007 S003007 | 7.25 | 23.25 | not reported | 41.1 | 12 |
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 7.2 (PLACEBO vs TIRZ_SC) to 8.1 (LIRA_SC vs PLACEBO) percent; threshold 0.5
- FlagBaseline, Diabetes duration: not reported by 3 of 7 trials
- FlagBaseline, Diabetes duration: design means range from 20.7 (EMPAGLIFLOZIN vs SEMA_SC vs STANDARD_CARE) to 32.0 (LIRA_SC vs PLACEBO) years; threshold 3
- FlagBaseline, Asian ancestry or region: not reported by 6 of 7 trials
- FlagHeterogeneity, tau above threshold: tau 0.32 exceeds the outcome threshold 0.3; the flags of this network are candidate explanations
- NoteOutcome assessment, time point: selected time points span 12 to 26 weeks
- NoteOutcome assessment, analysis set: mixed: completers 3, full_analysis 1, modified_itt 1, other 1, randomized 1
- NoteOutcome assessment, definition: mixed: change in HbA1c from week 0 to week 12 1, HbA1c change from baseline, central laboratory 1, HbA1c value at week 26 1, not stated 4
- NoteRisk of bias, blinding: mixed: double_blind 6, open_label 1
- NoteRisk of bias, funding: mixed: industry 1, mixed 2, non_industry 2, not_reported 2
- NoteData handling, input conversions: arms_combined 1, median_converted 2
| Trial | time weeks | analysis set | definition | instrument | adjudicated | proportion method | intercurrent events (discontinuation) | intercurrent events (rescue) | blinding | funding | start year | Eligibility |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| ENDIS | 12 | completers | not stated | not stated | not stated | not stated | not stated | not stated | open_label | non_industry | 2021 | type 1 diabetes on MDI or CSII with CGM; HbA1c 9.0 or less; BMI 22 or more; CrCl 60 or more; no atherosclerotic disease |
| TODINELI | 26 | completers | HbA1c value at week 26 | not stated | not stated | not stated | not stated | not stated | double_blind | mixed | 2014 | age over 18; type 1 diabetes 2 years or more; HbA1c 6.5 percent or more; BMI over 22; confirmed polyneuropathy; eGFR 60 or more |
| NCT01753362 | 26 | completers | not stated | not stated | not stated | not stated | not stated | not stated | double_blind | not_reported | 2012 | type 1 diabetes 1 year or more on insulin; undetectable C-peptide; overweight or obese |
| ADJUNCT TWO™ | 26 | full_analysis | not stated | not stated | not stated | not stated | not stated | not stated | double_blind | industry | 2014 | type 1 diabetes at least 12 months; BMI 20 or more; HbA1c 7.0 to 10 percent; basal bolus insulin |
| NCT02962492 | 12 | other | change in HbA1c from week 0 to week 12 | not stated | not stated | not stated | not stated | not stated | double_blind | not_reported | 2016 | established type 1 diabetes on insulin |
| ADJUST-T1D | 26 | randomized | HbA1c change from baseline, central laboratory | not stated | not stated | not stated | not stated | not stated | double_blind | mixed | 2023 | age 18 to 65; type 1 diabetes on AID; BMI 30 or more |
| S003007 | 12 | modified_itt | not stated | not stated | not stated | not stated | not stated | not stated | double_blind | non_industry | 2024 | age 18 to 60; type 1 diabetes 2 years or more; BMI 30 or more |
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 |
|---|---|---|---|---|---|---|---|---|---|
| ENDIS | A1 | EMPAGLIFLOZIN | 12 | arm, change | -0.240 | 0.108 | 30 | R0021681:Table 2 | |
| ENDIS | A2 | SEMA_SC | 12 | arm, change | -0.290 | 0.111 | 30 | R0021681:Table 2 | |
| ENDIS | A3 | STANDARD_CARE | 12 | arm, change | 0.120 | 0.082 | 29 | R0021681:Table 2 | |
| TODINELI | A1 | LIRA_SC | 26 | arm, final | 8.616 | 0.124 | 19 | median_converted | R0012788:Table 3 |
| TODINELI | A2 | PLACEBO | 26 | arm, final | 8.235 | 0.205 | 20 | median_converted | R0012788:Table 3 |
| NCT01753362 | A1 | PLACEBO | 26 | arm, final | 7.640 | 0.165 | 26 | registry:outcomes | |
| NCT01753362 | A2 | LIRA_SC | 26 | arm, final | 7.600 | 0.155 | 40 | registry:outcomes | |
| ADJUNCT TWO™ | A1+A2+A3 | LIRA_SC | 26 | arm, change | -0.259 | 0.032 | 535 | arms_combined | registry:outcomes |
| ADJUNCT TWO™ | A4 | PLACEBO | 26 | arm, change | 0.010 | 0.049 | 190 | registry:outcomes | |
| NCT02962492 | A1 | PLACEBO | 12 | arm, change | -0.100 | 0.100 | 11 | registry:outcomes | |
| NCT02962492 | A2 | DAPAGLIFLOZIN | 12 | arm, change | -0.300 | 0.100 | 15 | registry:outcomes | |
| NCT02962492 | A3 | EXENER_SC | 12 | arm, change | -0.400 | 0.200 | 15 | registry:outcomes | |
| NCT02962492 | A4 | DAPAEXEN_SC | 12 | arm, change | -0.900 | 0.100 | 21 | registry:outcomes | |
| ADJUST-T1D | A1 | SEMA_SC | 26 | arm, change | -0.700 | 0.100 | 36 | registry:outcomes | |
| ADJUST-T1D | A2 | PLACEBO | 26 | arm, change | -0.400 | 0.100 | 36 | registry:outcomes | |
| S003007 | A1 | TIRZ_SC | 12 | arm, change | -0.500 | 0.153 | 11 | R0014500:Table 2 | |
| S003007 | A2 | PLACEBO | 12 | arm, change | -0.200 | 0.153 | 11 | R0014500:Table 2 |
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.