Network meta-analysis
Diabetic retinopathy complications
Type 2 diabetes (adults)
longest follow-upRecorded harmsDoses of a drug pooledHazard ratio (from event counts)
10
Randomized trials
9
Treatments
26,376
Participants
530
Events
In plain language
Across 10 trials with 26,376 participants, 0 of 8 treatments had a clearly better result than placebo on diabetic retinopathy complications, and for 8 the evidence could not tell them apart from placebo. The most favorable estimate was for Ecnoglutide injection: hazard ratio (from event counts) 0.38 (95% credible interval 0.00 to 29.91).
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
Hazard ratio (from event counts). Lower values favor the treatment.
| Treatment | Bayesian HR (95% CrI) | 95% prediction interval | Frequentist HR (95% CI) | Verdict |
|---|---|---|---|---|
| Ecnoglutide injection ECNO_SC | 0.38 (0.00 to 29.91) | 0.00 to 30.05 | Unclear | |
| Tirzepatide injection TIRZ_SC | 0.41 (0.00 to 25.53) | 0.00 to 27.90 | Unclear | |
| Liraglutide injection LIRA_SC | 0.87 (0.19 to 3.88) | 0.15 to 5.05 | Unclear | |
| Albiglutide injection ALBI_SC | 0.88 (0.35 to 2.23) | 0.24 to 3.24 | Unclear | |
| Dulaglutide injection DULA_SC | 1.19 (0.49 to 2.49) | 0.30 to 3.61 | Unclear | |
| Semaglutide tablet SEMA_PO | 1.73 (0.57 to 5.37) | 0.40 to 6.87 | Unclear | |
| Semaglutide injection SEMA_SC | 1.96 (0.92 to 5.14) | 0.64 to 8.10 | Unclear | |
| Sitagliptin SITAGLIPTIN | 2.37 (0.54 to 9.57) | 0.40 to 12.19 | 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: hazard ratio (from event counts) 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 | ECNO_SC | TIRZ_SC | LIRA_SC | ALBI_SC | DULA_SC | SEMA_PO | SEMA_SC | SITAGLIPTIN |
|---|---|---|---|---|---|---|---|---|---|
| PLACEBO | PLACEBO | 2.64 0.03 to 200 | 2.45 0.04 to 217 | 1.16 0.26 to 5.38 | 1.14 0.45 to 2.83 | 0.84 0.40 to 2.03 | 0.58 0.19 to 1.75 | 0.51 0.19 to 1.09 | 0.42 0.10 to 1.86 |
| ECNO_SC | 0.38 0.00 to 29.91 | ECNO_SC | 0.98 0.00 to 475 | 0.44 0.00 to 42.95 | 0.43 0.01 to 36.76 | 0.33 0.00 to 27.89 | 0.22 0.00 to 19.63 | 0.19 0.00 to 16.07 | 0.16 0.00 to 15.06 |
| TIRZ_SC | 0.41 0.00 to 25.53 | 1.02 0.00 to 504 | TIRZ_SC | 0.45 0.00 to 36.56 | 0.47 0.01 to 31.25 | 0.35 0.00 to 23.99 | 0.24 0.00 to 16.77 | 0.20 0.00 to 14.27 | 0.17 0.00 to 15.57 |
| LIRA_SC | 0.87 0.19 to 3.88 | 2.26 0.02 to 226 | 2.20 0.03 to 228 | LIRA_SC | 1.00 0.16 to 5.84 | 0.74 0.15 to 3.88 | 0.50 0.11 to 1.98 | 0.44 0.07 to 2.32 | 0.37 0.07 to 2.03 |
| ALBI_SC | 0.88 0.35 to 2.23 | 2.33 0.03 to 183 | 2.14 0.03 to 197 | 1.00 0.17 to 6.14 | ALBI_SC | 0.73 0.24 to 2.78 | 0.50 0.12 to 2.20 | 0.45 0.11 to 1.42 | 0.37 0.07 to 2.15 |
| DULA_SC | 1.19 0.49 to 2.49 | 3.07 0.04 to 263 | 2.84 0.04 to 257 | 1.34 0.26 to 6.78 | 1.36 0.36 to 4.23 | DULA_SC | 0.68 0.21 to 2.00 | 0.61 0.15 to 1.69 | 0.49 0.12 to 2.07 |
| SEMA_PO | 1.73 0.57 to 5.37 | 4.55 0.05 to 403 | 4.25 0.06 to 400 | 1.99 0.51 to 8.81 | 2.01 0.46 to 8.13 | 1.48 0.50 to 4.67 | SEMA_PO | 0.89 0.20 to 3.37 | 0.72 0.28 to 2.09 |
| SEMA_SC | 1.96 0.92 to 5.14 | 5.14 0.06 to 432 | 4.93 0.07 to 462 | 2.25 0.43 to 14.00 | 2.22 0.70 to 8.73 | 1.65 0.59 to 6.50 | 1.13 0.30 to 5.03 | SEMA_SC | 0.82 0.17 to 5.44 |
| SITAGLIPTIN | 2.37 0.54 to 9.57 | 6.37 0.07 to 601 | 5.88 0.06 to 607 | 2.71 0.49 to 15.06 | 2.74 0.46 to 14.19 | 2.03 0.48 to 8.49 | 1.39 0.48 to 3.51 | 1.22 0.18 to 5.84 | SITAGLIPTIN |
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.
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.
- NoteOutcome assessment, time point: selected time points span 25 to 365.26 weeks
- NoteOutcome assessment, analysis set: mixed: full_analysis 1, other 1, randomized 1, safety 7
- NoteOutcome assessment, definition: mixed: EAC confirmed acute pancreatitis 1, EAC confirmed retinopathy complications: photocoagulation, intravitreal agents, vitreous hemorrhage or diabetes related blindness 1, in trial adverse events related to diabetic retinopathy by MedDRA search 1, not stated 6, severe hypoglycemic events, adverse event of special interest 1
- NoteOutcome assessment, adjudicated: mixed: no 1, not stated 4, yes 5
- NoteOutcome assessment, intercurrent events (discontinuation): mixed: not stated 8, treatment_policy 1, while_on_treatment 1
- NoteOutcome assessment, intercurrent events (rescue): mixed: not stated 9, treatment_policy 1
- NoteRisk of bias, blinding: mixed: double_blind 9, single_blind 1
- NoteData handling, input conversions: arms_combined 7, count_from_percent 1, printed_denominator 1
| Trial | proportion method | time weeks | analysis set | definition | instrument | adjudicated | intercurrent events (discontinuation) | intercurrent events (rescue) | blinding | funding | start year | Eligibility |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| NCT03131687 | not stated | 30 | safety | not stated | not stated | not stated | not stated | not stated | double_blind | industry | 2017 | age 18 to 75; T2D at least 6 months; HbA1c 7.0 to 10.5%; BMI 23 to 50; diet and exercise or metformin |
| PIONEER 4 | not stated | 57 | safety | in trial adverse events related to diabetic retinopathy by MedDRA search | not stated | not stated | not stated | not stated | 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 |
| REWIND | not stated | 365.26 | randomized | not stated | not stated | yes | treatment_policy | not stated | double_blind | industry | 2011 | age 50 or older with T2D; HbA1c 9.5 percent or less; BMI 23 or more; CV disease or risk factors |
| PIONEER 10 | not stated | 57 | safety | not stated | not stated | yes | while_on_treatment | 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 |
| PIONEER 12 | not stated | 31 | other | EAC confirmed acute pancreatitis | not stated | yes | not stated | not stated | double_blind | industry | 2019 | adults with type 2 diabetes on metformin, HbA1c 7.0 to 10.5 percent |
| NCT02465515 | not stated | 140.89 | safety | severe hypoglycemic events, adverse event of special interest | not stated | not stated | not stated | not stated | double_blind | industry | 2015 | type 2 diabetes with established cardiovascular disease |
| NCT05486065 | not stated | 49 | safety | not stated | not stated | not stated | not stated | not stated | double_blind | industry | 2022 | age 18 to 64; HbA1c 7.0 to 10.5; BMI 27 or more; on metformin |
| SUSTAIN™ 6 | not stated | 109 | full_analysis | EAC confirmed retinopathy complications: photocoagulation, intravitreal agents, vitreous hemorrhage or diabetes related blindness | not stated | yes | not stated | not stated | double_blind | industry | 2013 | T2D HbA1c 7.0 or more; age 50 or more with CVD, CHF or CKD stage 3 or more, or age 60 or more with CV risk factor |
| SUSTAIN™ 5 | not stated | 35 | safety | not stated | not stated | yes | not stated | not stated | double_blind | industry | 2014 | age 18 or older (20 in Japan); HbA1c 7.0 to 10.0 percent; stable basal insulin with or without metformin; eGFR 30 or more |
| S002947 | not stated | 25 | safety | not stated | not stated | no | not stated | not stated | double_blind | industry | 2021 | age 18 to 65; HbA1c 7.0 to 10.5 percent; BMI 20 to 35; diet or one oral agent washed out |
Trial data
What each trial contributes. Arm rows give the arm value with its standard error, or events over participants; contrast rows give the hazard ratio (from event counts) on the analysis scale (log) against the trial's first row. Flags mark converted, combined or approximated inputs.
| Trial | Arm | Treatment | Week | Data | Value | SE | Events / N | Flags | Source |
|---|---|---|---|---|---|---|---|---|---|
| NCT03131687 | A1 | PLACEBO | 30 | arm, events | 0 / 51 | R0016215:Results | |||
| NCT03131687 | A2+A3+A4+A5 | TIRZ_SC | 30 | arm, events | 0 / 213 | arms_combined | R0016215:Results | ||
| NCT03131687 | A6 | DULA_SC | 30 | arm, events | 0 / 54 | R0016215:Results | |||
| PIONEER 4 | A1 | SEMA_PO | 57 | arm, events | 8 / 285 | R0015836:Supplement Table S7 | |||
| PIONEER 4 | A2 | LIRA_SC | 57 | arm, events | 4 / 284 | R0015836:Supplement Table S7 | |||
| PIONEER 4 | A3 | PLACEBO | 57 | arm, events | 2 / 142 | R0015836:Supplement Table S7 | |||
| REWIND | A1 | PLACEBO | 365.26 | arm, events | 76 / 4,952 | R0018537:Table 2 | |||
| REWIND | A2 | DULA_SC | 365.26 | arm, events | 95 / 4,949 | R0018537:Table 2 | |||
| PIONEER 10 | A1+A2+A3 | SEMA_PO | 57 | arm, events | 28 / 393 | arms_combined | R0018421:Table 2 | ||
| PIONEER 10 | A4 | DULA_SC | 57 | arm, events | 3 / 65 | R0018421:Table 2 | |||
| PIONEER 12 | A1+A2+A3 | SEMA_PO | 31 | arm, events | 42 / 1,082 | arms_combined | R0019776:Results | ||
| PIONEER 12 | A4 | SITAGLIPTIN | 31 | arm, events | 20 / 359 | R0019776:Results | |||
| NCT02465515 | A1 | PLACEBO | 140.89 | arm, events | 89 / 4,732 | registry:outcomes | |||
| NCT02465515 | A2 | ALBI_SC | 140.89 | arm, events | 78 / 4,731 | registry:outcomes | |||
| NCT05486065 | A1+A2+A3 | SEMA_SC | 49 | arm, events | 1 / 185 | arms_combined | R0005510:Table 2 | ||
| NCT05486065 | A4 | PLACEBO | 49 | arm, events | 0 / 60 | R0005510:Table 2 | |||
| SUSTAIN™ 5 | A1+A2 | SEMA_SC | 35 | arm, events | 5 / 264 | count_from_percent;arms_combined | R0012671:Results | ||
| SUSTAIN™ 5 | A3 | PLACEBO | 35 | arm, events | 0 / 133 | R0012671:Results | |||
| SUSTAIN™ 6 | A1+A2 | SEMA_SC | 109 | arm, events | 50 / 1,648 | arms_combined | R0020578:Results | ||
| SUSTAIN™ 6 | A6 | PLACEBO | 109 | arm, events | 29 / 1,649 | printed_denominator | R0020578:Results | ||
| S002947 | A1+A2+A3 | ECNO_SC | 25 | arm, events | 0 / 109 | arms_combined | R0006482:Results | ||
| S002947 | A4 | PLACEBO | 25 | arm, events | 0 / 36 | R0006482: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.