Network meta-analysis
Percent body weight change
Type 2 diabetes (adults); background therapy: one or more non insulin glucose lowering drugs
weeks 20 to 40 (target week 26)Hypothetical (as if everyone stayed on treatment)Each dose separatelyMean difference
6
Randomized trials
12
Treatments
1,499
Participants
17
Trial arms
In plain language
Across 6 trials with 1,499 participants, 0 of 11 treatments had a clearly better result than placebo on percent body weight change, and for 11 the evidence could not tell them apart from placebo. The most favorable estimate was for Lotiglipron 260 mg tablet once daily: mean difference -5.32 percentage points (95% credible interval -10.61 to 1.08).
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 |
|---|---|---|---|---|
| Lotiglipron 260 mg tablet once daily LOTI_PO_260MG_QD | -5.32 (-10.61 to 1.08) | -13.12 to 3.29 | -5.42 (-7.20 to -3.64) | Unclear |
| Loti po 200mg qd LOTI_PO_200MG_QD | -5.21 (-10.56 to 0.72) | -12.87 to 3.24 | -5.36 (-6.85 to -3.88) | Unclear |
| Semaglutide 1.0 mg subcutaneous once weekly SEMA_SC_1p0MG_QW | -4.31 (-9.24 to 1.02) | -11.91 to 3.59 | -4.38 (-5.37 to -3.40) | Unclear |
| Lotiglipron 140 mg tablet once daily LOTI_PO_140MG_QD | -4.24 (-9.55 to 1.94) | -11.99 to 4.39 | -4.37 (-6.13 to -2.61) | Unclear |
| Semaglutide 14 mg oral once daily (original tablet) SEMA_PO_14MG_QD | -2.97 (-10.66 to 5.13) | -12.17 to 7.13 | -3.10 (-4.51 to -1.69) | Unclear |
| Lotiglipron 80 mg tablet once daily LOTI_PO_80MG_QD | -2.33 (-7.63 to 3.90) | -9.77 to 6.17 | -2.44 (-4.16 to -0.72) | Unclear |
| Semaglutide 7 mg oral once daily (original tablet) SEMA_PO_7MG_QD | -1.99 (-9.86 to 6.14) | -11.69 to 8.19 | -2.10 (-3.46 to -0.74) | Unclear |
| Liraglutide 1.8 mg subcutaneous once daily LIRA_SC_1p8MG_QD | -1.20 (-10.36 to 8.82) | -12.14 to 10.34 | -1.30 (-2.87 to 0.27) | Unclear |
| Semaglutide 3 mg oral once daily (original tablet) SEMA_PO_3MG_QD | 0.00 (-7.83 to 7.75) | -9.53 to 9.64 | -0.10 (-1.46 to 1.26) | Unclear |
| Dulaglutide 0.75 mg subcutaneous once weekly DULA_SC_0p75MG_QW | 0.53 (-9.11 to 9.91) | -10.64 to 11.61 | 0.40 (-1.38 to 2.18) | Unclear |
| Sitagliptin SITAGLIPTIN | 0.98 (-5.14 to 7.79) | -7.67 to 9.84 | 0.90 (-0.35 to 2.15) | 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 | LOTI_PO_260MG_QD | LOTI_PO_200MG_QD | SEMA_SC_1p0MG_QW | LOTI_PO_140MG_QD | SEMA_PO_14MG_QD | LOTI_PO_80MG_QD | SEMA_PO_7MG_QD | LIRA_SC_1p8MG_QD | SEMA_PO_3MG_QD | DULA_SC_0p75MG_QW | SITAGLIPTIN |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| PLACEBO | PLACEBO | 5.32 -1.08 to 10.61 | 5.21 -0.72 to 10.56 | 4.31 -1.02 to 9.24 | 4.24 -1.94 to 9.55 | 2.97 -5.13 to 10.66 | 2.33 -3.90 to 7.63 | 1.99 -6.14 to 9.86 | 1.20 -8.82 to 10.36 | -0.00 -7.75 to 7.83 | -0.53 -9.91 to 9.11 | -0.98 -7.79 to 5.14 |
| LOTI_PO_260MG_QD | -5.32 -10.61 to 1.08 | LOTI_PO_260MG_QD | -0.08 -5.80 to 5.95 | -1.02 -8.29 to 6.91 | -1.06 -6.92 to 5.09 | -2.30 -11.85 to 7.59 | -2.99 -9.10 to 2.83 | -3.34 -12.84 to 7.03 | -4.11 -14.76 to 7.47 | -5.31 -14.40 to 4.95 | -5.83 -16.35 to 5.83 | -6.30 -14.98 to 2.75 |
| LOTI_PO_200MG_QD | -5.21 -10.56 to 0.72 | 0.08 -5.95 to 5.80 | LOTI_PO_200MG_QD | -0.93 -8.34 to 7.03 | -0.99 -6.95 to 4.95 | -2.22 -11.55 to 7.63 | -2.92 -8.95 to 3.01 | -3.29 -12.75 to 7.02 | -4.00 -15.09 to 6.99 | -5.22 -14.30 to 4.83 | -5.75 -16.26 to 5.92 | -6.22 -14.71 to 2.55 |
| SEMA_SC_1p0MG_QW | -4.31 -9.24 to 1.02 | 1.02 -6.91 to 8.29 | 0.93 -7.03 to 8.34 | SEMA_SC_1p0MG_QW | -0.07 -8.05 to 7.40 | -1.33 -8.75 to 5.98 | -1.99 -9.92 to 5.56 | -2.32 -9.72 to 4.92 | -3.09 -12.17 to 5.78 | -4.29 -11.56 to 2.83 | -4.80 -13.98 to 4.16 | -5.29 -10.68 to -0.05 |
| LOTI_PO_140MG_QD | -4.24 -9.55 to 1.94 | 1.06 -5.09 to 6.92 | 0.99 -4.95 to 6.95 | 0.07 -7.40 to 8.05 | LOTI_PO_140MG_QD | -1.27 -10.70 to 8.77 | -1.91 -8.00 to 4.00 | -2.28 -11.97 to 8.29 | -3.08 -13.68 to 8.51 | -4.27 -13.72 to 6.19 | -4.74 -15.35 to 6.74 | -5.25 -14.05 to 4.05 |
| SEMA_PO_14MG_QD | -2.97 -10.66 to 5.13 | 2.30 -7.59 to 11.85 | 2.22 -7.63 to 11.55 | 1.33 -5.98 to 8.75 | 1.27 -8.77 to 10.70 | SEMA_PO_14MG_QD | -0.66 -10.66 to 8.87 | -1.00 -6.59 to 4.98 | -1.79 -7.58 to 4.15 | -2.98 -8.56 to 2.77 | -3.49 -11.33 to 4.85 | -3.98 -9.40 to 1.66 |
| LOTI_PO_80MG_QD | -2.33 -7.63 to 3.90 | 2.99 -2.83 to 9.10 | 2.92 -3.01 to 8.95 | 1.99 -5.56 to 9.92 | 1.91 -4.00 to 8.00 | 0.66 -8.87 to 10.66 | LOTI_PO_80MG_QD | -0.38 -9.94 to 9.88 | -1.12 -11.95 to 10.29 | -2.35 -11.30 to 7.63 | -2.85 -13.24 to 8.48 | -3.31 -11.88 to 5.55 |
| SEMA_PO_7MG_QD | -1.99 -9.86 to 6.14 | 3.34 -7.03 to 12.84 | 3.29 -7.02 to 12.75 | 2.32 -4.92 to 9.72 | 2.28 -8.29 to 11.97 | 1.00 -4.98 to 6.59 | 0.38 -9.88 to 9.94 | SEMA_PO_7MG_QD | -0.80 -8.86 to 6.98 | -1.99 -7.67 to 3.90 | -2.50 -10.39 to 5.55 | -3.00 -8.61 to 2.69 |
| LIRA_SC_1p8MG_QD | -1.20 -10.36 to 8.82 | 4.11 -7.47 to 14.76 | 4.00 -6.99 to 15.09 | 3.09 -5.78 to 12.17 | 3.08 -8.51 to 13.68 | 1.79 -4.15 to 7.58 | 1.12 -10.29 to 11.95 | 0.80 -6.98 to 8.86 | LIRA_SC_1p8MG_QD | -1.18 -8.85 to 7.24 | -1.70 -11.11 to 8.59 | -2.18 -10.07 to 6.00 |
| SEMA_PO_3MG_QD | 0.00 -7.83 to 7.75 | 5.31 -4.95 to 14.40 | 5.22 -4.83 to 14.30 | 4.29 -2.83 to 11.56 | 4.27 -6.19 to 13.72 | 2.98 -2.77 to 8.56 | 2.35 -7.63 to 11.30 | 1.99 -3.90 to 7.67 | 1.18 -7.24 to 8.85 | SEMA_PO_3MG_QD | -0.49 -6.26 to 5.33 | -1.00 -6.50 to 4.39 |
| DULA_SC_0p75MG_QW | 0.53 -9.11 to 9.91 | 5.83 -5.83 to 16.35 | 5.75 -5.92 to 16.26 | 4.80 -4.16 to 13.98 | 4.74 -6.74 to 15.35 | 3.49 -4.85 to 11.33 | 2.85 -8.48 to 13.24 | 2.50 -5.55 to 10.39 | 1.70 -8.59 to 11.11 | 0.49 -5.33 to 6.26 | DULA_SC_0p75MG_QW | -0.51 -8.39 to 7.27 |
| SITAGLIPTIN | 0.98 -5.14 to 7.79 | 6.30 -2.75 to 14.98 | 6.22 -2.55 to 14.71 | 5.29 0.05 to 10.68 | 5.25 -4.05 to 14.05 | 3.98 -1.66 to 9.40 | 3.31 -5.55 to 11.88 | 3.00 -2.69 to 8.61 | 2.18 -6.00 to 10.07 | 1.00 -4.39 to 6.50 | 0.51 -7.27 to 8.39 | SITAGLIPTIN |
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 BMI or body weight (kg/m2) effect modifier, prognostic factor; 6 of 6 | Sex (percent female) effect modifier, prognostic factor; 6 of 6 | Asian ancestry or region (percent Asian) effect modifier, prognostic factor; 6 of 6 | Kidney function (eGFR) (mL/min/1.73 m2) prognostic factor, effect modifier; 5 of 6 | Treatment duration (weeks) effect modifier; 6 of 6 | Lifestyle co-intervention intensity (none standard intensive) effect modifier, prognostic factor; 6 of 6 |
|---|---|---|---|---|---|---|
| PIONEER 4 S000133 | 32.94 | 48 | 13.4 | 95.8 | 52 | not_reported |
| PIONEER 10 S000234 | 26.26 | 25.74 | 100 | 96.57 | 52 | not_reported |
| NCT05579977 S000448 | 35.44 | 52.05 | 13.22 | not reported | 32 | not_reported |
| SUSTAIN 9 S000483 | 31.9 | 41.72 | 23.51 | 95.2 | 30 | not_reported |
| PIONEER 12 S000522 | 28.58 | 41.7 | 75.22 | 103.5 | 26 | not_reported |
| SUSTAIN S001311 | 27.8 | 42.5 | 85.03 | 109.33 median | 30 | not_reported |
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_0p75MG_QW vs SEMA_PO_3MG_QD) to 35.4 (LOTI_PO_140MG_QD vs LOTI_PO_200MG_QD vs LOTI_PO_260MG_QD vs LOTI_PO_80MG_QD vs PLACEBO) kg/m2; threshold 3
- FlagBaseline, Sex: design means range from 25.7 (DULA_SC_0p75MG_QW vs SEMA_PO_3MG_QD) to 52.1 (LOTI_PO_140MG_QD vs LOTI_PO_200MG_QD vs LOTI_PO_260MG_QD vs LOTI_PO_80MG_QD vs PLACEBO) percent female; threshold 15
- FlagBaseline, Asian ancestry or region: design means range from 13.2 (LOTI_PO_140MG_QD vs LOTI_PO_200MG_QD vs LOTI_PO_260MG_QD vs LOTI_PO_80MG_QD vs PLACEBO) to 100.0 (DULA_SC_0p75MG_QW vs SEMA_PO_3MG_QD) percent Asian; threshold 30
- NoteOutcome assessment, time point: selected time points span 20 to 30 weeks
- NoteOutcome assessment, analysis set: mixed: full_analysis 5, modified_itt 1
- NoteOutcome assessment, intercurrent events (discontinuation): mixed: hypothetical 5, not stated 1
- NoteOutcome assessment, intercurrent events (rescue): mixed: hypothetical 5, not stated 1
- NoteRisk of bias, blinding: mixed: double_blind 5, single_blind 1
- NoteData handling, input conversions: arms_combined 1
| Trial | time weeks | analysis set | definition | instrument | adjudicated | proportion method | intercurrent events (discontinuation) | intercurrent events (rescue) | blinding | funding | start year | Eligibility |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| PIONEER 4 | 26 | full_analysis | not stated | not stated | not stated | not stated | hypothetical | hypothetical | 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 | 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 |
| NCT05579977 | 20 | modified_itt | not stated | not stated | not stated | not stated | hypothetical | hypothetical | double_blind | industry | 2022 | age 18 to 75; T2D cohort on metformin, HbA1c 7.0 to 10.0, BMI 23 or more; obesity cohort BMI 30 or more without diabetes |
| SUSTAIN 9 | 30 | full_analysis | not stated | not stated | not stated | not stated | not stated | not stated | double_blind | industry | 2017 | adults 18 or older (20 in Japan); HbA1c 7.0 to 10.5 percent; stable SGLT2i with or without metformin or SU |
| 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 |
| 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 |
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 | 26 | contrast, md | -1.800 | 0.357 | R0015836:Supplement Table S3 | ||
| PIONEER 4 | A2 | LIRA_SC_1p8MG_QD | 26 | contrast, md | R0015836:Supplement Table S3 | ||||
| PIONEER 10 | A1 | SEMA_PO_3MG_QD | 26 | contrast, md | -0.500 | 0.587 | R0018421:Supplement Table S5 | ||
| PIONEER 10 | A4 | DULA_SC_0p75MG_QW | 26 | contrast, md | R0018421:Supplement Table S5 | ||||
| NCT05579977 | A10 | LOTI_PO_140MG_QD | 20 | arm, percent_change | -6.210 | 0.657 | 37 | R0004106:Supplement Table S2 | |
| NCT05579977 | A11+A12 | LOTI_PO_200MG_QD | 20 | arm, percent_change | -7.205 | 0.448 | 69 | arms_combined | R0004106:Supplement Table S2 |
| NCT05579977 | A13 | LOTI_PO_260MG_QD | 20 | arm, percent_change | -7.260 | 0.666 | 28 | R0004106:Supplement Table S2 | |
| NCT05579977 | A8 | PLACEBO | 20 | arm, percent_change | -1.840 | 0.614 | 45 | R0004106:Supplement Table S2 | |
| NCT05579977 | A9 | LOTI_PO_80MG_QD | 20 | arm, percent_change | -4.280 | 0.626 | 44 | R0004106:Supplement Table S2 | |
| SUSTAIN 9 | A1 | SEMA_SC_1p0MG_QW | 30 | contrast, md | -4.380 | 0.503 | R0021710:Figure 3a | ||
| SUSTAIN 9 | A2 | PLACEBO | 30 | contrast, md | R0021710:Figure 3a | ||||
| PIONEER 12 | A1 | SEMA_PO_3MG_QD | 26 | arm, percent_change | -2.000 | 0.223 | 322 | registry:outcomes | |
| PIONEER 12 | A2 | SEMA_PO_7MG_QD | 26 | arm, percent_change | -4.000 | 0.224 | 319 | registry:outcomes | |
| PIONEER 12 | A3 | SEMA_PO_14MG_QD | 26 | arm, percent_change | -5.000 | 0.289 | 300 | registry:outcomes | |
| PIONEER 12 | A4 | SITAGLIPTIN | 26 | arm, percent_change | -1.000 | 0.164 | 335 | registry:outcomes | |
| SUSTAIN | A2 | SEMA_SC_1p0MG_QW | 30 | contrast, md | -5.280 | 0.390 | R0014802:Table 2 | ||
| SUSTAIN | A3 | SITAGLIPTIN | 30 | contrast, md | R0014802: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.