Network meta-analysis
HbA1c change
Type 2 diabetes (adults); background therapy: no glucose lowering drug (lifestyle only)
weeks 36 to 64 (target week 52)Not stated by the trialsEach dose separatelyMean difference
5
Randomized trials
12
Treatments
1,790
Participants
16
Trial arms
In plain language
Across 5 trials with 1,790 participants, 2 of 11 treatments had a clearly better result than placebo on HbA1c change, and for 9 the evidence could not tell them apart from placebo. The most favorable estimate was for Semaglutide 14 mg oral once daily (original tablet): mean difference -1.46 percentage points (95% credible interval -2.19 to -0.25).
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 14 mg oral once daily (original tablet) SEMA_PO_14MG_QD | -1.46 (-2.19 to -0.25) | -2.62 to 0.18 | -1.60 (-1.94 to -1.26) | Better |
| Dulaglutide 0.75 mg subcutaneous once weekly DULA_SC_0p75MG_QW | -1.38 (-2.35 to 0.28) | -2.63 to 0.73 | -1.60 (-2.03 to -1.17) | Unclear |
| Semaglutide 7 mg oral once daily (original tablet) SEMA_PO_7MG_QD | -1.36 (-2.11 to -0.15) | -2.49 to 0.40 | -1.50 (-1.86 to -1.14) | Better |
| Albiglutide 50 mg subcutaneous once weekly ALBI_SC_50MG_QW | -1.35 (-2.30 to 0.39) | -2.64 to 0.76 | -1.57 (-2.01 to -1.13) | Unclear |
| Liraglutide 0.9 mg injection once daily LIRA_SC_0p9MG_QD | -1.19 (-1.84 to 0.07) | -2.22 to 0.63 | -1.40 (-1.79 to -1.01) | Unclear |
| Albiglutide 30 mg subcutaneous once weekly ALBI_SC_30MG_QW | -1.07 (-2.00 to 0.61) | -2.28 to 0.97 | -1.30 (-1.74 to -0.86) | Unclear |
| Semaglutide 3 mg oral once daily (original tablet) SEMA_PO_3MG_QD | -0.98 (-1.76 to 0.26) | -2.16 to 0.74 | -1.10 (-1.47 to -0.73) | Unclear |
| Efpeglenatide 4 mg subcutaneous once weekly EFPE_SC_4MG_QW | -0.83 (-1.87 to 0.36) | -2.19 to 0.74 | -0.90 (-1.61 to -0.19) | Unclear |
| Efpeglenatide 6 mg subcutaneous once weekly EFPE_SC_6MG_QW | -0.82 (-1.89 to 0.36) | -2.24 to 0.79 | -0.90 (-1.61 to -0.19) | Unclear |
| Efpeglenatide 2 mg subcutaneous once weekly EFPE_SC_2MG_QW | -0.73 (-1.81 to 0.47) | -2.20 to 0.85 | -0.80 (-1.51 to -0.09) | Unclear |
| Glibenclamide GLIBENCLAMIDE | -0.67 (-1.59 to 1.10) | -1.87 to 1.52 | -0.90 (-1.38 to -0.42) | 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_PO_14MG_QD | DULA_SC_0p75MG_QW | SEMA_PO_7MG_QD | ALBI_SC_50MG_QW | LIRA_SC_0p9MG_QD | ALBI_SC_30MG_QW | SEMA_PO_3MG_QD | EFPE_SC_4MG_QW | EFPE_SC_6MG_QW | EFPE_SC_2MG_QW | GLIBENCLAMIDE |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| PLACEBO | PLACEBO | 1.46 0.25 to 2.19 | 1.38 -0.28 to 2.35 | 1.36 0.15 to 2.11 | 1.35 -0.39 to 2.30 | 1.19 -0.07 to 1.84 | 1.07 -0.61 to 2.00 | 0.98 -0.26 to 1.76 | 0.83 -0.36 to 1.87 | 0.82 -0.36 to 1.89 | 0.73 -0.47 to 1.81 | 0.67 -1.10 to 1.59 |
| SEMA_PO_14MG_QD | -1.46 -2.19 to -0.25 | SEMA_PO_14MG_QD | -0.07 -1.53 to 1.14 | -0.10 -1.09 to 0.88 | -0.11 -1.64 to 1.09 | -0.27 -1.34 to 0.62 | -0.39 -1.86 to 0.79 | -0.49 -1.53 to 0.54 | -0.61 -1.93 to 0.98 | -0.62 -1.97 to 1.01 | -0.71 -2.05 to 0.88 | -0.79 -2.30 to 0.38 |
| DULA_SC_0p75MG_QW | -1.38 -2.35 to 0.28 | 0.07 -1.14 to 1.53 | DULA_SC_0p75MG_QW | -0.02 -1.27 to 1.49 | -0.04 -1.40 to 1.30 | -0.18 -1.12 to 0.79 | -0.31 -1.69 to 1.00 | -0.41 -1.69 to 1.08 | -0.53 -1.96 to 1.46 | -0.55 -1.99 to 1.46 | -0.64 -2.06 to 1.38 | -0.72 -2.16 to 0.61 |
| SEMA_PO_7MG_QD | -1.36 -2.11 to -0.15 | 0.10 -0.88 to 1.09 | 0.02 -1.49 to 1.27 | SEMA_PO_7MG_QD | -0.03 -1.53 to 1.18 | -0.17 -1.28 to 0.76 | -0.30 -1.78 to 0.91 | -0.39 -1.44 to 0.65 | -0.52 -1.88 to 1.09 | -0.53 -1.89 to 1.08 | -0.62 -1.97 to 1.04 | -0.69 -2.21 to 0.46 |
| ALBI_SC_50MG_QW | -1.35 -2.30 to 0.39 | 0.11 -1.09 to 1.64 | 0.04 -1.30 to 1.40 | 0.03 -1.18 to 1.53 | ALBI_SC_50MG_QW | -0.15 -1.09 to 0.91 | -0.27 -1.29 to 0.78 | -0.38 -1.55 to 1.20 | -0.49 -1.97 to 1.48 | -0.51 -1.91 to 1.56 | -0.58 -2.08 to 1.39 | -0.68 -2.07 to 0.68 |
| LIRA_SC_0p9MG_QD | -1.19 -1.84 to 0.07 | 0.27 -0.62 to 1.34 | 0.18 -0.79 to 1.12 | 0.17 -0.76 to 1.28 | 0.15 -0.91 to 1.09 | LIRA_SC_0p9MG_QD | -0.12 -1.16 to 0.78 | -0.23 -1.15 to 0.91 | -0.34 -1.62 to 1.28 | -0.36 -1.56 to 1.33 | -0.44 -1.70 to 1.19 | -0.53 -1.58 to 0.34 |
| ALBI_SC_30MG_QW | -1.07 -2.00 to 0.61 | 0.39 -0.79 to 1.86 | 0.31 -1.00 to 1.69 | 0.30 -0.91 to 1.78 | 0.27 -0.78 to 1.29 | 0.12 -0.78 to 1.16 | ALBI_SC_30MG_QW | -0.10 -1.24 to 1.41 | -0.22 -1.67 to 1.75 | -0.23 -1.63 to 1.79 | -0.32 -1.73 to 1.66 | -0.41 -1.82 to 0.94 |
| SEMA_PO_3MG_QD | -0.98 -1.76 to 0.26 | 0.49 -0.54 to 1.53 | 0.41 -1.08 to 1.69 | 0.39 -0.65 to 1.44 | 0.38 -1.20 to 1.55 | 0.23 -0.91 to 1.15 | 0.10 -1.41 to 1.24 | SEMA_PO_3MG_QD | -0.13 -1.48 to 1.56 | -0.14 -1.49 to 1.50 | -0.23 -1.59 to 1.41 | -0.30 -1.85 to 0.91 |
| EFPE_SC_4MG_QW | -0.83 -1.87 to 0.36 | 0.61 -0.98 to 1.93 | 0.53 -1.46 to 1.96 | 0.52 -1.09 to 1.88 | 0.49 -1.48 to 1.97 | 0.34 -1.28 to 1.62 | 0.22 -1.75 to 1.67 | 0.13 -1.56 to 1.48 | EFPE_SC_4MG_QW | -0.01 -1.11 to 1.10 | -0.09 -1.18 to 1.00 | -0.19 -2.22 to 1.26 |
| EFPE_SC_6MG_QW | -0.82 -1.89 to 0.36 | 0.62 -1.01 to 1.97 | 0.55 -1.46 to 1.99 | 0.53 -1.08 to 1.89 | 0.51 -1.56 to 1.91 | 0.36 -1.33 to 1.56 | 0.23 -1.79 to 1.63 | 0.14 -1.50 to 1.49 | 0.01 -1.10 to 1.11 | EFPE_SC_6MG_QW | -0.09 -1.16 to 1.01 | -0.18 -2.23 to 1.30 |
| EFPE_SC_2MG_QW | -0.73 -1.81 to 0.47 | 0.71 -0.88 to 2.05 | 0.64 -1.38 to 2.06 | 0.62 -1.04 to 1.97 | 0.58 -1.39 to 2.08 | 0.44 -1.19 to 1.70 | 0.32 -1.66 to 1.73 | 0.23 -1.41 to 1.59 | 0.09 -1.00 to 1.18 | 0.09 -1.01 to 1.16 | EFPE_SC_2MG_QW | -0.09 -2.17 to 1.41 |
| GLIBENCLAMIDE | -0.67 -1.59 to 1.10 | 0.79 -0.38 to 2.30 | 0.72 -0.61 to 2.16 | 0.69 -0.46 to 2.21 | 0.68 -0.68 to 2.07 | 0.53 -0.34 to 1.58 | 0.41 -0.94 to 1.82 | 0.30 -0.91 to 1.85 | 0.19 -1.26 to 2.22 | 0.18 -1.30 to 2.23 | 0.09 -1.41 to 2.17 | GLIBENCLAMIDE |
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; 5 of 5 | Background glucose lowering therapy (stratum S0 to S4) effect modifier, prognostic factor; 5 of 5 | Diabetes duration (years) effect modifier, prognostic factor; 5 of 5 | Asian ancestry or region (percent Asian) effect modifier, prognostic factor; 3 of 5 | Age (years) prognostic factor; 5 of 5 | Treatment duration (weeks) effect modifier; 5 of 5 |
|---|---|---|---|---|---|---|
| NCT00393718 S000330 | 9.27 | S0 | 8.24 | 100 region: all sites in Asia | 58.3 | 52 |
| NCT01558271 S000837 | 8.14 | S0 | 6.59 | 98.98 | 57.47 | 52 |
| NCT01733758 S001075 | 8.11 | S0 | 6.65 | not reported | 58.25 | 52 |
| PIONEER 9 S001943 | 8.2 | S0 | 7.6 | 100 | 59.4 | 52 |
| AMPLITUDE-M S002081 | 8.07 | S0 | 5.1 | not reported | 58.51 | 56 |
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 8.1 (EFPE_SC_2MG_QW vs EFPE_SC_4MG_QW vs EFPE_SC_6MG_QW vs PLACEBO) to 9.3 (GLIBENCLAMIDE vs LIRA_SC_0p9MG_QD) percent; threshold 0.5
- FlagBaseline, Diabetes duration: design means range from 5.1 (EFPE_SC_2MG_QW vs EFPE_SC_4MG_QW vs EFPE_SC_6MG_QW vs PLACEBO) to 8.2 (GLIBENCLAMIDE vs LIRA_SC_0p9MG_QD) years; threshold 3
- FlagBaseline, Asian ancestry or region: not reported by 2 of 5 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 52 to 56 weeks
- NoteOutcome assessment, analysis set: mixed: completers 1, full_analysis 3, randomized 1
| Trial | time weeks | analysis set | definition | instrument | adjudicated | proportion method | intercurrent events (discontinuation) | intercurrent events (rescue) | blinding | funding | start year | Eligibility |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| NCT00393718 | 52 | full_analysis | not stated | not stated | not stated | not stated | not stated | not stated | double_blind | industry | 2006 | age 20 or older; HbA1c 7.4 to 10.4 percent NGSP; with or without prior oral agents |
| NCT01558271 | 52 | full_analysis | not stated | not stated | not stated | not stated | not stated | not stated | double_blind | industry | 2012 | Japanese; age 20 or more; BMI 18.5 to 35; HbA1c 7.0 to 10.0 percent; OAM naive or OAM stopped |
| NCT01733758 | 52 | completers | not stated | not stated | not stated | not stated | not stated | not stated | double_blind | industry | 2013 | Japanese adults; diet and exercise with or without one oral drug; HbA1c 7 to 10 percent after washout |
| PIONEER 9 | 52 | full_analysis | not stated | not stated | not stated | not stated | not stated | not stated | double_blind | industry | 2017 | Japanese adults 20 y or older; HbA1c 6.5 to 9.5 on one oral drug washed out, or 7.0 to 10.0 on diet and exercise |
| AMPLITUDE-M | 56 | randomized | not stated | not stated | not stated | not stated | not stated | not stated | double_blind | industry | 2017 | type 2 diabetes on diet and exercise, HbA1c 7 to 10 percent, no glucose lowering drug in prior 3 months |
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 |
|---|---|---|---|---|---|---|---|---|---|
| NCT00393718 | A1 | LIRA_SC_0p9MG_QD | 52 | arm, final | 7.700 | 0.100 | 263 | R0022766:Table 2 | |
| NCT00393718 | A2 | GLIBENCLAMIDE | 52 | arm, final | 8.200 | 0.100 | 130 | R0022766:Table 2 | |
| NCT01558271 | A1 | DULA_SC_0p75MG_QW | 52 | arm, change | -1.390 | 0.060 | 280 | R0011754:Results | |
| NCT01558271 | A2 | LIRA_SC_0p9MG_QD | 52 | arm, change | -1.190 | 0.080 | 136 | R0011754:Results | |
| NCT01733758 | A2 | ALBI_SC_30MG_QW | 52 | arm, change | -1.070 | 0.065 | 148 | registry:outcomes | |
| NCT01733758 | A3 | ALBI_SC_50MG_QW | 52 | arm, change | -1.340 | 0.065 | 135 | registry:outcomes | |
| NCT01733758 | A4 | LIRA_SC_0p9MG_QD | 52 | arm, change | -1.170 | 0.080 | 95 | registry:outcomes | |
| PIONEER 9 | A1 | SEMA_PO_3MG_QD | 52 | arm, change | -1.000 | 0.146 | 38 | registry:outcomes | |
| PIONEER 9 | A2 | SEMA_PO_7MG_QD | 52 | arm, change | -1.400 | 0.137 | 43 | registry:outcomes | |
| PIONEER 9 | A3 | SEMA_PO_14MG_QD | 52 | arm, change | -1.500 | 0.125 | 41 | registry:outcomes | |
| PIONEER 9 | A4 | LIRA_SC_0p9MG_QD | 52 | arm, change | -1.300 | 0.156 | 41 | registry:outcomes | |
| PIONEER 9 | A5 | PLACEBO | 52 | arm, change | 0.100 | 0.120 | 34 | registry:outcomes | |
| AMPLITUDE-M | A1 | EFPE_SC_2MG_QW | 56 | arm, change | -1.200 | 0.200 | 100 | R0007136:Results | |
| AMPLITUDE-M | A2 | EFPE_SC_4MG_QW | 56 | arm, change | -1.300 | 0.200 | 101 | R0007136:Results | |
| AMPLITUDE-M | A3 | EFPE_SC_6MG_QW | 56 | arm, change | -1.300 | 0.200 | 103 | R0007136:Results | |
| AMPLITUDE-M | A4 | PLACEBO | 56 | arm, change | -0.400 | 0.300 | 102 | R0007136:Results |
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.