Network meta-analysis
HbA1c change
Type 2 diabetes (adults); background therapy: one or more non insulin glucose lowering drugs
weeks 36 to 64 (target week 52)Treatment policyEach dose separatelyMean differenceSeparate part 2 of a disconnected network
9
Randomized trials
13
Treatments
5,430
Participants
23
Trial arms
In plain language
Across 9 trials with 5,430 participants, 6 of 12 treatments had a clearly better result than placebo on HbA1c change, and for 6 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 -1.08 percentage points (95% credible interval -1.46 to -0.59).
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 | -1.08 (-1.46 to -0.59) | -1.62 to -0.41 | -1.10 (-1.29 to -0.91) | Better |
| Insulin icodec and semaglutide (IcoSema) subcutaneous once weekly titrated ICOSEMA_SC_TIT_QW | -0.93 (-1.67 to -0.14) | -1.78 to -0.00 | -0.95 (-1.43 to -0.47) | Better |
| Semaglutide 7 mg oral once daily (original tablet) SEMA_PO_7MG_QD | -0.85 (-1.30 to -0.23) | -1.48 to -0.08 | -0.88 (-1.11 to -0.65) | Better |
| Semaglutide oral once daily (original tablet), flexible dose: 3, 7 or 14 mg adjusted by HbA1c and tolerability SEMA_PO_FLEX_QD | -0.84 (-1.52 to 0.02) | -1.65 to 0.13 | -0.88 (-1.26 to -0.50) | Unclear |
| Dulaglutide 0.75 mg subcutaneous once weekly DULA_SC_0p75MG_QW | -0.84 (-1.37 to -0.17) | -1.51 to -0.02 | -0.88 (-1.19 to -0.57) | Better |
| Liraglutide 1.8 mg subcutaneous once daily LIRA_SC_1p8MG_QD | -0.79 (-1.21 to -0.31) | -1.38 to -0.16 | -0.80 (-0.99 to -0.61) | Better |
| Semaglutide 2.0 mg subcutaneous once weekly SEMA_SC_2p0MG_QW | -0.79 (-1.34 to -0.22) | -1.47 to -0.07 | -0.80 (-1.25 to -0.35) | Better |
| Sitagliptin SITAGLIPTIN | -0.55 (-1.05 to 0.11) | -1.19 to 0.28 | -0.58 (-0.82 to -0.34) | Unclear |
| Semaglutide 1.0 mg subcutaneous once weekly SEMA_SC_1p0MG_QW | -0.49 (-1.13 to 0.20) | -1.24 to 0.35 | -0.50 (-0.97 to -0.03) | Unclear |
| Semaglutide 3 mg oral once daily (original tablet) SEMA_PO_3MG_QD | -0.42 (-0.86 to 0.19) | -0.98 to 0.35 | -0.46 (-0.69 to -0.23) | Unclear |
| Canagliflozin CANAGLIFLOZIN | 0.01 (-0.77 to 0.83) | -0.85 to 0.97 | 0.00 (-0.50 to 0.50) | Unclear |
| Exenatide extended release 2 mg subcutaneous once weekly EXENER_SC_2MG_QW | 0.02 (-0.74 to 0.83) | -0.84 to 0.95 | 0.01 (-0.49 to 0.51) | 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 | ICOSEMA_SC_TIT_QW | SEMA_PO_7MG_QD | SEMA_PO_FLEX_QD | DULA_SC_0p75MG_QW | LIRA_SC_1p8MG_QD | SEMA_SC_2p0MG_QW | SITAGLIPTIN | SEMA_SC_1p0MG_QW | SEMA_PO_3MG_QD | CANAGLIFLOZIN | EXENER_SC_2MG_QW |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| PLACEBO | PLACEBO | 1.08 0.59 to 1.46 | 0.93 0.14 to 1.67 | 0.85 0.23 to 1.30 | 0.84 -0.02 to 1.52 | 0.84 0.17 to 1.37 | 0.79 0.31 to 1.21 | 0.79 0.22 to 1.34 | 0.55 -0.11 to 1.05 | 0.49 -0.20 to 1.13 | 0.42 -0.19 to 0.86 | -0.01 -0.83 to 0.77 | -0.02 -0.83 to 0.74 |
| SEMA_PO_14MG_QD | -1.08 -1.46 to -0.59 | SEMA_PO_14MG_QD | -0.14 -1.04 to 0.75 | -0.23 -0.58 to 0.08 | -0.24 -0.92 to 0.37 | -0.24 -0.71 to 0.19 | -0.29 -0.70 to 0.19 | -0.29 -0.98 to 0.42 | -0.53 -0.98 to -0.17 | -0.59 -1.36 to 0.22 | -0.66 -1.03 to -0.36 | -1.09 -1.97 to -0.17 | -1.10 -2.00 to -0.18 |
| ICOSEMA_SC_TIT_QW | -0.93 -1.67 to -0.14 | 0.14 -0.75 to 1.04 | ICOSEMA_SC_TIT_QW | -0.09 -1.05 to 0.81 | -0.09 -1.21 to 0.94 | -0.10 -1.12 to 0.86 | -0.15 -1.01 to 0.76 | -0.15 -0.70 to 0.46 | -0.39 -1.36 to 0.56 | -0.45 -0.85 to 0.01 | -0.52 -1.47 to 0.39 | -0.95 -1.53 to -0.32 | -0.96 -1.57 to -0.29 |
| SEMA_PO_7MG_QD | -0.85 -1.30 to -0.23 | 0.23 -0.08 to 0.58 | 0.09 -0.81 to 1.05 | SEMA_PO_7MG_QD | -0.00 -0.67 to 0.64 | -0.01 -0.45 to 0.44 | -0.06 -0.55 to 0.54 | -0.06 -0.79 to 0.76 | -0.30 -0.72 to 0.12 | -0.36 -1.17 to 0.55 | -0.43 -0.76 to -0.12 | -0.86 -1.77 to 0.17 | -0.87 -1.79 to 0.14 |
| SEMA_PO_FLEX_QD | -0.84 -1.52 to 0.02 | 0.24 -0.37 to 0.92 | 0.09 -0.94 to 1.21 | 0.00 -0.64 to 0.67 | SEMA_PO_FLEX_QD | -0.00 -0.70 to 0.73 | -0.06 -0.75 to 0.79 | -0.06 -0.94 to 0.95 | -0.30 -0.79 to 0.22 | -0.36 -1.31 to 0.70 | -0.43 -1.05 to 0.23 | -0.85 -1.90 to 0.30 | -0.86 -1.91 to 0.27 |
| DULA_SC_0p75MG_QW | -0.84 -1.37 to -0.17 | 0.24 -0.19 to 0.71 | 0.10 -0.86 to 1.12 | 0.01 -0.44 to 0.45 | 0.00 -0.73 to 0.70 | DULA_SC_0p75MG_QW | -0.06 -0.63 to 0.62 | -0.05 -0.83 to 0.82 | -0.29 -0.84 to 0.26 | -0.35 -1.23 to 0.60 | -0.42 -0.88 to 0.01 | -0.85 -1.81 to 0.20 | -0.86 -1.82 to 0.16 |
| LIRA_SC_1p8MG_QD | -0.79 -1.21 to -0.31 | 0.29 -0.19 to 0.70 | 0.15 -0.76 to 1.01 | 0.06 -0.54 to 0.55 | 0.06 -0.79 to 0.75 | 0.06 -0.62 to 0.63 | LIRA_SC_1p8MG_QD | -0.00 -0.71 to 0.71 | -0.24 -0.89 to 0.29 | -0.30 -1.10 to 0.49 | -0.37 -0.97 to 0.10 | -0.80 -1.71 to 0.13 | -0.81 -1.73 to 0.10 |
| SEMA_SC_2p0MG_QW | -0.79 -1.34 to -0.22 | 0.29 -0.42 to 0.98 | 0.15 -0.46 to 0.70 | 0.06 -0.76 to 0.79 | 0.06 -0.95 to 0.94 | 0.05 -0.82 to 0.83 | 0.00 -0.71 to 0.71 | SEMA_SC_2p0MG_QW | -0.24 -1.09 to 0.50 | -0.30 -0.73 to 0.11 | -0.37 -1.19 to 0.34 | -0.80 -1.46 to -0.20 | -0.81 -1.43 to -0.21 |
| SITAGLIPTIN | -0.55 -1.05 to 0.11 | 0.53 0.17 to 0.98 | 0.39 -0.56 to 1.36 | 0.30 -0.12 to 0.72 | 0.30 -0.22 to 0.79 | 0.29 -0.26 to 0.84 | 0.24 -0.29 to 0.89 | 0.24 -0.50 to 1.09 | SITAGLIPTIN | -0.05 -0.89 to 0.86 | -0.13 -0.53 to 0.29 | -0.56 -1.48 to 0.48 | -0.57 -1.50 to 0.44 |
| SEMA_SC_1p0MG_QW | -0.49 -1.13 to 0.20 | 0.59 -0.22 to 1.36 | 0.45 -0.01 to 0.85 | 0.36 -0.55 to 1.17 | 0.36 -0.70 to 1.31 | 0.35 -0.60 to 1.23 | 0.30 -0.49 to 1.10 | 0.30 -0.11 to 0.73 | 0.05 -0.86 to 0.89 | SEMA_SC_1p0MG_QW | -0.07 -0.96 to 0.74 | -0.50 -0.95 to -0.04 | -0.51 -0.97 to -0.02 |
| SEMA_PO_3MG_QD | -0.42 -0.86 to 0.19 | 0.66 0.36 to 1.03 | 0.52 -0.39 to 1.47 | 0.43 0.12 to 0.76 | 0.43 -0.23 to 1.05 | 0.42 -0.01 to 0.88 | 0.37 -0.10 to 0.97 | 0.37 -0.34 to 1.19 | 0.13 -0.29 to 0.53 | 0.07 -0.74 to 0.96 | SEMA_PO_3MG_QD | -0.43 -1.34 to 0.59 | -0.44 -1.37 to 0.58 |
| CANAGLIFLOZIN | 0.01 -0.77 to 0.83 | 1.09 0.17 to 1.97 | 0.95 0.32 to 1.53 | 0.86 -0.17 to 1.77 | 0.85 -0.30 to 1.90 | 0.85 -0.20 to 1.81 | 0.80 -0.13 to 1.71 | 0.80 0.20 to 1.46 | 0.56 -0.48 to 1.48 | 0.50 0.04 to 0.95 | 0.43 -0.59 to 1.34 | CANAGLIFLOZIN | -0.01 -0.65 to 0.63 |
| EXENER_SC_2MG_QW | 0.02 -0.74 to 0.83 | 1.10 0.18 to 2.00 | 0.96 0.29 to 1.57 | 0.87 -0.14 to 1.79 | 0.86 -0.27 to 1.91 | 0.86 -0.16 to 1.82 | 0.81 -0.10 to 1.73 | 0.81 0.21 to 1.43 | 0.57 -0.44 to 1.50 | 0.51 0.02 to 0.97 | 0.44 -0.58 to 1.37 | 0.01 -0.63 to 0.65 | EXENER_SC_2MG_QW |
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; 9 of 9 | Background glucose lowering therapy (stratum S0 to S4) effect modifier, prognostic factor; 9 of 9 | Diabetes duration (years) effect modifier, prognostic factor; 7 of 9 | Asian ancestry or region (percent Asian) effect modifier, prognostic factor; 8 of 9 | Age (years) prognostic factor; 9 of 9 | Treatment duration (weeks) effect modifier; 9 of 9 |
|---|---|---|---|---|---|---|
| PIONEER 4 S000133 | 7.98 | S1 | 7.6 | 13.4 | 56.2 | 52 |
| COMBINE 2 S000155 | 8 | S1 | 12.64 | 27.65 | 59.1 | 52 |
| PIONEER 10 S000234 | 8.31 | S1 | 9.36 | 100 | 58.43 | 52 |
| SUSTAIN™ 3 S000329 | 8.34 | S1 | 9.2 | not reported | 56.55 | 56 |
| PIONEER 7 S001153 | 7.93 | S1 | 8.71 | 15.08 | 57.64 | 104 |
| SUSTAIN FORTE S001353 | 8.9 | S1 | 9.5 | 7.18 | 58.05 | 40 |
| NCT05486065 S001555 | 8.35 | S1 | 6.96 | 1.49 | 52.76 | 40 |
| SUSTAIN 8 S001847 | 8.25 | S1 | not reported | 15.86 | 56.6 | 52 |
| PIONEER 3 S002267 | 8.33 | S1 | not reported | 13.14 | 57.75 | 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 7.9 (SEMA_PO_FLEX_QD vs SITAGLIPTIN) to 8.9 (SEMA_SC_1p0MG_QW vs SEMA_SC_2p0MG_QW) percent; threshold 0.5
- FlagBaseline, Diabetes duration: not reported by 2 of 9 trials
- FlagBaseline, Diabetes duration: design means range from 7.0 (PLACEBO vs SEMA_SC_2p0MG_QW) to 12.6 (ICOSEMA_SC_TIT_QW vs SEMA_SC_1p0MG_QW) years; threshold 3
- FlagBaseline, Asian ancestry or region: design means range from 1.5 (PLACEBO vs SEMA_SC_2p0MG_QW) to 100.0 (DULA_SC_0p75MG_QW vs SEMA_PO_14MG_QD vs SEMA_PO_3MG_QD vs SEMA_PO_7MG_QD) percent Asian; threshold 30
- FlagBaseline, Treatment duration: design means range from 40.0 (PLACEBO vs SEMA_SC_2p0MG_QW) to 104.0 (SEMA_PO_FLEX_QD vs SITAGLIPTIN) weeks; threshold 26
- NoteOutcome assessment, time point: selected time points span 40 to 56 weeks
- NoteOutcome assessment, analysis set: mixed: full_analysis 7, other 1, randomized 1
- NoteOutcome assessment, intercurrent events (discontinuation): mixed: hypothetical 4, not stated 1, treatment_policy 4
- NoteOutcome assessment, intercurrent events (rescue): mixed: hypothetical 4, not stated 1, treatment_policy 4
- NoteRisk of bias, blinding: mixed: double_blind 5, open_label 3, single_blind 1
| Trial | time weeks | analysis set | definition | instrument | adjudicated | proportion method | intercurrent events (discontinuation) | intercurrent events (rescue) | blinding | funding | start year | Eligibility |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| PIONEER 4 | 52 | other | 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 |
| COMBINE 2 | 52 | full_analysis | not stated | not stated | not stated | not stated | treatment_policy | treatment_policy | open_label | industry | 2022 | adults T2D on GLP-1 RA with or without oral drugs; HbA1c 7.0 to 10.0 percent |
| PIONEER 10 | 52 | 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 |
| SUSTAIN™ 3 | 56 | full_analysis | not stated | not stated | not stated | not stated | hypothetical | hypothetical | open_label | industry | 2013 | age 18 or older; T2D on stable 1 to 2 oral drugs; HbA1c 7.0 to 10.5 percent; eGFR 60 or more |
| PIONEER 7 | 52 | randomized | not stated | not stated | not stated | not stated | hypothetical | hypothetical | open_label | industry | 2016 | age 18 or more; HbA1c 7.5 to 9.5 percent; one or two oral glucose lowering drugs |
| SUSTAIN FORTE | 40 | full_analysis | not stated | not stated | not stated | not stated | hypothetical | hypothetical | double_blind | industry | 2019 | T2D on metformin with or without SU; HbA1c 8.0 to 10.0 percent; duration at least 6 months |
| NCT05486065 | 40 | full_analysis | not stated | not stated | not stated | not stated | hypothetical | hypothetical | double_blind | industry | 2022 | age 18 to 64; HbA1c 7.0 to 10.5; BMI 27 or more; on metformin |
| SUSTAIN 8 | 52 | full_analysis | not stated | not stated | not stated | not stated | not stated | not stated | double_blind | industry | 2017 | age 18 or older; HbA1c 7.0 to 10.5 percent; eGFR 60 or higher; metformin 1500 mg or maximum tolerated |
| PIONEER 3 | 52 | full_analysis | not stated | not stated | not stated | not stated | treatment_policy | treatment_policy | 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_14MG_QD | 52 | arm, change | -1.200 | 0.060 | 275 | registry:outcomes | |
| PIONEER 4 | A2 | LIRA_SC_1p8MG_QD | 52 | arm, change | -0.900 | 0.061 | 269 | registry:outcomes | |
| PIONEER 4 | A3 | PLACEBO | 52 | arm, change | -0.100 | 0.078 | 133 | registry:outcomes | |
| COMBINE 2 | A1 | ICOSEMA_SC_TIT_QW | 52 | arm, change | -1.350 | 0.040 | 342 | R0005851:Results | |
| COMBINE 2 | A2 | SEMA_SC_1p0MG_QW | 52 | arm, change | -0.900 | 0.040 | 341 | R0005851:Results | |
| PIONEER 10 | A1 | SEMA_PO_3MG_QD | 52 | arm, change | -0.900 | 0.100 | 131 | R0018421:Figure 2C | |
| PIONEER 10 | A2 | SEMA_PO_7MG_QD | 52 | arm, change | -1.400 | 0.100 | 132 | R0018421:Figure 2C | |
| PIONEER 10 | A3 | SEMA_PO_14MG_QD | 52 | arm, change | -1.700 | 0.100 | 130 | R0018421:Figure 2C | |
| PIONEER 10 | A4 | DULA_SC_0p75MG_QW | 52 | arm, change | -1.400 | 0.100 | 65 | R0018421:Figure 2C | |
| SUSTAIN™ 3 | A1 | SEMA_SC_1p0MG_QW | 56 | contrast, md | -0.510 | 0.087 | R0020680:Supplement Figure S3A | ||
| SUSTAIN™ 3 | A2 | EXENER_SC_2MG_QW | 56 | contrast, md | R0020680:Supplement Figure S3A | ||||
| PIONEER 7 | A3 | SEMA_PO_FLEX_QD | 52 | contrast, md | -0.300 | 0.153 | R0023369:Results | ||
| PIONEER 7 | A4 | SITAGLIPTIN | 52 | contrast, md | R0023369:Results | ||||
| SUSTAIN FORTE | A1 | SEMA_SC_1p0MG_QW | 40 | arm, change | -1.900 | 0.046 | 481 | registry:outcomes | |
| SUSTAIN FORTE | A2 | SEMA_SC_2p0MG_QW | 40 | arm, change | -2.200 | 0.050 | 480 | registry:outcomes | |
| NCT05486065 | A1 | SEMA_SC_2p0MG_QW | 40 | contrast, md | -0.800 | 0.230 | R0005510:Figure 1 | ||
| NCT05486065 | A4 | PLACEBO | 40 | contrast, md | R0005510:Figure 1 | ||||
| SUSTAIN 8 | A1 | SEMA_SC_1p0MG_QW | 52 | arm, change | -1.500 | 0.065 | 394 | registry:outcomes | |
| SUSTAIN 8 | A2 | CANAGLIFLOZIN | 52 | arm, change | -1.000 | 0.055 | 394 | registry:outcomes | |
| PIONEER 3 | A1 | SEMA_PO_3MG_QD | 52 | arm, change | -0.600 | 0.051 | 466 | registry:outcomes | |
| PIONEER 3 | A2 | SEMA_PO_7MG_QD | 52 | arm, change | -1.000 | 0.056 | 465 | registry:outcomes | |
| PIONEER 3 | A3 | SEMA_PO_14MG_QD | 52 | arm, change | -1.200 | 0.051 | 465 | registry:outcomes | |
| PIONEER 3 | A4 | SITAGLIPTIN | 52 | arm, change | -0.700 | 0.051 | 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.