Network meta-analysis
Systolic blood pressure change
Type 2 diabetes (adults)
weeks 36 to 64 (target week 52)Treatment policyDoses of a drug pooledMean difference
9
Randomized trials
10
Treatments
913
Participants
18
Trial arms
In plain language
Across 9 trials with 913 participants, 0 of 9 treatments had a clearly better result than placebo on systolic blood pressure change, and for 9 the evidence could not tell them apart from placebo. The most favorable estimate was for Semaglutide tablet: mean difference -4.72 mmHg (95% credible interval -17.81 to 9.39).
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 mmHg. Lower values favor the treatment.
| Treatment | Bayesian MD (95% CrI) | 95% prediction interval | Frequentist MD (95% CI) | Verdict |
|---|---|---|---|---|
| Semaglutide tablet SEMA_PO | -4.72 (-17.81 to 9.39) | -21.13 to 13.35 | Unclear | |
| Tirzepatide injection TIRZ_SC | -4.42 (-14.65 to 5.58) | -19.84 to 10.42 | Unclear | |
| Liraglutide injection LIRA_SC | -3.85 (-13.42 to 6.91) | -18.09 to 11.14 | Unclear | |
| Dulaglutide injection DULA_SC | -3.74 (-20.06 to 14.11) | -22.71 to 17.28 | Unclear | |
| Semaglutide injection SEMA_SC | -2.48 (-12.19 to 7.67) | -16.71 to 12.79 | Unclear | |
| Standard care or no added treatment STANDARD_CARE | -1.95 (-15.30 to 11.91) | -18.89 to 16.25 | Unclear | |
| Insulin icodec with semaglutide injection ICOSEMA_SC | 0.16 (-14.14 to 14.46) | -17.93 to 18.14 | Unclear | |
| Insulin degludec INS_DEGLUDEC | 0.50 (-13.88 to 15.40) | -18.69 to 18.68 | Unclear | |
| Insulin glargine INS_GLARGINE | 1.10 (-13.04 to 15.20) | -16.74 to 19.04 | 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.
| Row versus column | PLACEBO | SEMA_PO | TIRZ_SC | LIRA_SC | DULA_SC | SEMA_SC | STANDARD_CARE | ICOSEMA_SC | INS_DEGLUDEC | INS_GLARGINE |
|---|---|---|---|---|---|---|---|---|---|---|
| PLACEBO | PLACEBO | 4.72 -9.39 to 17.81 | 4.42 -5.58 to 14.65 | 3.85 -6.91 to 13.42 | 3.74 -14.11 to 20.06 | 2.48 -7.67 to 12.19 | 1.95 -11.91 to 15.30 | -0.16 -14.46 to 14.14 | -0.50 -15.40 to 13.88 | -1.10 -15.20 to 13.04 |
| SEMA_PO | -4.72 -17.81 to 9.39 | SEMA_PO | -0.28 -16.17 to 17.52 | -0.90 -11.46 to 9.72 | -1.00 -11.83 to 9.45 | -2.23 -18.24 to 14.79 | -2.78 -21.47 to 16.91 | -4.89 -24.63 to 15.44 | -5.22 -24.31 to 15.27 | -5.85 -24.69 to 15.01 |
| TIRZ_SC | -4.42 -14.65 to 5.58 | 0.28 -17.52 to 16.17 | TIRZ_SC | -0.56 -15.21 to 13.18 | -0.73 -21.13 to 17.82 | -1.92 -16.18 to 11.47 | -2.51 -19.88 to 13.98 | -4.57 -22.42 to 13.05 | -4.89 -15.82 to 5.52 | -5.55 -15.89 to 4.71 |
| LIRA_SC | -3.85 -13.42 to 6.91 | 0.90 -9.72 to 11.46 | 0.56 -13.18 to 15.21 | LIRA_SC | -0.12 -15.55 to 14.96 | -1.38 -15.37 to 13.27 | -1.94 -18.70 to 15.26 | -4.05 -21.71 to 13.43 | -4.33 -21.85 to 14.10 | -4.92 -22.09 to 13.41 |
| DULA_SC | -3.74 -20.06 to 14.11 | 1.00 -9.45 to 11.83 | 0.73 -17.82 to 21.13 | 0.12 -14.96 to 15.55 | DULA_SC | -1.23 -20.10 to 18.75 | -1.79 -23.24 to 20.25 | -3.92 -25.46 to 18.81 | -4.19 -26.34 to 18.94 | -4.83 -25.69 to 18.40 |
| SEMA_SC | -2.48 -12.19 to 7.67 | 2.23 -14.79 to 18.24 | 1.92 -11.47 to 16.18 | 1.38 -13.27 to 15.37 | 1.23 -18.75 to 20.10 | SEMA_SC | -0.53 -10.85 to 9.39 | -2.62 -14.03 to 8.54 | -2.95 -20.19 to 15.04 | -3.56 -20.78 to 13.83 |
| STANDARD_CARE | -1.95 -15.30 to 11.91 | 2.78 -16.91 to 21.47 | 2.51 -13.98 to 19.88 | 1.94 -15.26 to 18.70 | 1.79 -20.25 to 23.24 | 0.53 -9.39 to 10.85 | STANDARD_CARE | -2.18 -17.18 to 13.86 | -2.37 -22.24 to 17.71 | -3.03 -21.67 to 16.63 |
| ICOSEMA_SC | 0.16 -14.14 to 14.46 | 4.89 -15.44 to 24.63 | 4.57 -13.05 to 22.42 | 4.05 -13.43 to 21.71 | 3.92 -18.81 to 25.46 | 2.62 -8.54 to 14.03 | 2.18 -13.86 to 17.18 | ICOSEMA_SC | -0.39 -21.18 to 20.61 | -1.01 -21.19 to 19.84 |
| INS_DEGLUDEC | 0.50 -13.88 to 15.40 | 5.22 -15.27 to 24.31 | 4.89 -5.52 to 15.82 | 4.33 -14.10 to 21.85 | 4.19 -18.94 to 26.34 | 2.95 -15.04 to 20.19 | 2.37 -17.71 to 22.24 | 0.39 -20.61 to 21.18 | INS_DEGLUDEC | -0.69 -15.45 to 14.95 |
| INS_GLARGINE | 1.10 -13.04 to 15.20 | 5.85 -15.01 to 24.69 | 5.55 -4.71 to 15.89 | 4.92 -13.41 to 22.09 | 4.83 -18.40 to 25.69 | 3.56 -13.83 to 20.78 | 3.03 -16.63 to 21.67 | 1.01 -19.84 to 21.19 | 0.69 -14.95 to 15.45 | INS_GLARGINE |
Heterogeneity, fit and convergence
Bayesian random effects (primary)
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.
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 BMI or body weight (kg/m2) effect modifier, prognostic factor; 8 of 9 |
|---|---|
| PIONEER 4 S000133 | 32.94 |
| COMBINE 2 S000155 | 31.11 |
| SCALE™ Insulin S000159 | 35.6 |
| STEP HFpEF DM S000161 | 36.9 median |
| PIONEER 10 S000234 | 26.26 |
| NCT03596450 S000545 | not reported |
| SURPASS-4 S001287 | 32.6 |
| SURPASS-3 S001591 | 33.5 |
| SURPASS-5 S001608 | 33.4 |
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 BMI or body weight: design means range from 26.3 (DULA_SC vs SEMA_PO) to 36.9 (PLACEBO vs SEMA_SC) kg/m2; threshold 3
- FlagHeterogeneity, tau above threshold: tau 3.31 exceeds the outcome threshold 2; the flags of this network are candidate explanations
- NoteOutcome assessment, time point: selected time points span 40 to 56 weeks
- NoteOutcome assessment, analysis set: mixed: completers 1, full_analysis 3, safety 5
- NoteOutcome assessment, intercurrent events (discontinuation): mixed: hypothetical 1, not stated 2, treatment_policy 6
- NoteOutcome assessment, intercurrent events (rescue): mixed: hypothetical 1, not stated 6, treatment_policy 2
- NoteRisk of bias, blinding: mixed: double_blind 4, open_label 4, 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 | safety | 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 | not stated | not stated | open_label | industry | 2022 | adults T2D on GLP-1 RA with or without oral drugs; HbA1c 7.0 to 10.0 percent |
| SCALE™ Insulin | 56 | full_analysis | not stated | not stated | not stated | not stated | treatment_policy | not stated | double_blind | industry | 2017 | age 18 or older; BMI 27 or higher; HbA1c 6.0 to 10 percent; basal insulin plus up to 2 oral drugs |
| STEP HFpEF DM | 52 | full_analysis | not stated | not stated | not stated | not stated | treatment_policy | treatment_policy | double_blind | industry | 2021 | age 18 or older; heart failure with LVEF 45% or more; BMI 30 or more; type 2 diabetes with HbA1c 10% or less |
| PIONEER 10 | 52 | safety | not stated | not stated | not stated | not stated | hypothetical | hypothetical | single_blind | industry | 2017 | Japanese adults 20 or older; T2D; HbA1c 7.0 to 10.5 percent on one oral glucose lowering drug |
| NCT03596450 | 52.18 | completers | not stated | not stated | not stated | not stated | treatment_policy | not stated | open_label | industry | 2018 | adults with type 2 diabetes on metformin, later up to 2 oral drugs, needing intensification |
| SURPASS-4 | 42 | safety | not stated | not stated | not stated | not stated | treatment_policy | not stated | open_label | industry | 2018 | age 18 or older; HbA1c 7.5 to 10.5 percent; BMI 25 or more; increased cardiovascular risk; 1 to 3 oral agents |
| SURPASS-3 | 40 | safety | not stated | not stated | not stated | not stated | not stated | not stated | open_label | industry | 2019 | insulin naive; HbA1c 7.0 to 10.5 percent; BMI at least 25; metformin with or without SGLT2i; eGFR above 45 |
| SURPASS-5 | 40 | safety | not stated | not stated | not stated | not stated | treatment_policy | not stated | double_blind | industry | 2019 | HbA1c 7.0 to 10.5 percent; BMI 23 or higher; insulin glargine above 0.25 U/kg or 20 U daily with or without metformin |
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 | 52 | contrast, md | -1.000 | 1.276 | R0015836:Supplement Table S9 | ||
| PIONEER 4 | A2 | LIRA_SC | 52 | contrast, md | R0015836:Supplement Table S9 | ||||
| COMBINE 2 | A1 | ICOSEMA_SC | 52 | contrast, md | 2.640 | 0.977 | R0005851:Supplement Table 6 | ||
| COMBINE 2 | A2 | SEMA_SC | 52 | contrast, md | R0005851:Supplement Table 6 | ||||
| SCALE™ Insulin | A1 | LIRA_SC | 56 | contrast, md | -4.000 | 1.250 | R0024063:Table 2 | ||
| SCALE™ Insulin | A2 | PLACEBO | 56 | contrast, md | R0024063:Table 2 | ||||
| STEP HFpEF DM | A1 | SEMA_SC | 52 | contrast, md | -2.500 | 1.429 | R0020223:Table 2 | ||
| STEP HFpEF DM | A2 | PLACEBO | 52 | contrast, md | R0020223:Table 2 | ||||
| PIONEER 10 | A1 | SEMA_PO | 52 | contrast, md | -1.000 | 1.786 | R0018421:Supplement Table S4 | ||
| PIONEER 10 | A4 | DULA_SC | 52 | contrast, md | R0018421:Supplement Table S4 | ||||
| NCT03596450 | A1 | SEMA_SC | 52.18 | arm, change | -2.300 | 0.768 | 456 | registry:outcomes | |
| NCT03596450 | A2 | STANDARD_CARE | 52.18 | arm, change | -1.800 | 0.764 | 457 | registry:outcomes | |
| SURPASS-4 | A2 | TIRZ_SC | 42 | contrast, md | -5.600 | 0.893 | R0009496:Results | ||
| SURPASS-4 | A4 | INS_GLARGINE | 42 | contrast, md | R0009496:Results | ||||
| SURPASS-3 | A1 | TIRZ_SC | 40 | contrast, md | -4.900 | 0.969 | R0009496:Results | ||
| SURPASS-3 | A4 | INS_DEGLUDEC | 40 | contrast, md | R0009496:Results | ||||
| SURPASS-5 | A1 | TIRZ_SC | 40 | contrast, md | -4.400 | 1.735 | R0009496:Results | ||
| SURPASS-5 | A4 | PLACEBO | 40 | contrast, md | R0009496: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.