Network meta-analysis
HbA1c change
Type 2 diabetes (adults); background therapy: basal insulin with or without non insulin drugs
weeks 20 to 36 (target week 26)Not stated by the trialsEach dose separatelyMean difference
7
Randomized trials
9
Treatments
1,999
Participants
16
Trial arms
In plain language
Across 7 trials with 1,999 participants, 5 of 8 treatments had a clearly better result than placebo on HbA1c change, and for 3 the evidence could not tell them apart from placebo. The most favorable estimate was for Semaglutide 1.0 mg subcutaneous once weekly: mean difference -1.74 percentage points (95% credible interval -2.32 to -1.06).
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 1.0 mg subcutaneous once weekly SEMA_SC_1p0MG_QW | -1.74 (-2.32 to -1.06) | -2.55 to -0.75 | -1.76 (-2.01 to -1.51) | Better |
| Semaglutide 0.5 mg subcutaneous once weekly SEMA_SC_0p5MG_QW | -1.34 (-1.91 to -0.67) | -2.16 to -0.37 | -1.36 (-1.61 to -1.11) | Better |
| Liraglutide 1.8 mg subcutaneous once daily LIRA_SC_1p8MG_QD | -1.18 (-1.76 to -0.46) | -1.99 to -0.21 | -1.19 (-1.39 to -0.99) | Better |
| Lixisenatide 20 ug subcutaneous once daily LIXI_SC_20UG_QD | -0.88 (-1.51 to -0.23) | -1.75 to 0.01 | -0.88 (-1.11 to -0.65) | Better |
| Dulaglutide 1.5 mg subcutaneous once weekly DULA_SC_1p5MG_QW | -0.76 (-1.37 to -0.08) | -1.61 to 0.20 | -0.77 (-1.02 to -0.52) | Better |
| Exenatide 10 ug subcutaneous twice daily EXEN_SC_10UG_BID | -0.67 (-1.19 to 0.09) | -1.39 to 0.36 | -0.70 (-0.95 to -0.45) | Unclear |
| Insulin lispro (prandial) INS_LISPRO | -0.64 (-1.26 to 0.29) | -1.47 to 0.50 | -0.68 (-0.96 to -0.40) | Unclear |
| Standard care or no added treatment STANDARD_CARE | -0.54 (-1.26 to 0.56) | -1.45 to 0.75 | -0.59 (-0.94 to -0.24) | 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_SC_1p0MG_QW | SEMA_SC_0p5MG_QW | LIRA_SC_1p8MG_QD | LIXI_SC_20UG_QD | DULA_SC_1p5MG_QW | EXEN_SC_10UG_BID | INS_LISPRO | STANDARD_CARE |
|---|---|---|---|---|---|---|---|---|---|
| PLACEBO | PLACEBO | 1.74 1.06 to 2.32 | 1.34 0.67 to 1.91 | 1.18 0.46 to 1.76 | 0.88 0.23 to 1.51 | 0.76 0.08 to 1.37 | 0.67 -0.09 to 1.19 | 0.64 -0.29 to 1.26 | 0.54 -0.56 to 1.26 |
| SEMA_SC_1p0MG_QW | -1.74 -2.32 to -1.06 | SEMA_SC_1p0MG_QW | -0.40 -1.03 to 0.27 | -0.56 -1.45 to 0.34 | -0.87 -1.68 to 0.08 | -0.98 -1.86 to -0.02 | -1.08 -2.02 to -0.24 | -1.10 -2.14 to -0.20 | -1.20 -2.36 to -0.23 |
| SEMA_SC_0p5MG_QW | -1.34 -1.91 to -0.67 | 0.40 -0.27 to 1.03 | SEMA_SC_0p5MG_QW | -0.16 -1.04 to 0.73 | -0.47 -1.32 to 0.47 | -0.58 -1.46 to 0.37 | -0.68 -1.65 to 0.15 | -0.70 -1.81 to 0.20 | -0.80 -2.02 to 0.14 |
| LIRA_SC_1p8MG_QD | -1.18 -1.76 to -0.46 | 0.56 -0.34 to 1.45 | 0.16 -0.73 to 1.04 | LIRA_SC_1p8MG_QD | -0.30 -1.18 to 0.67 | -0.41 -1.29 to 0.48 | -0.51 -1.48 to 0.30 | -0.54 -1.63 to 0.36 | -0.64 -1.82 to 0.33 |
| LIXI_SC_20UG_QD | -0.88 -1.51 to -0.23 | 0.87 -0.08 to 1.68 | 0.47 -0.47 to 1.32 | 0.30 -0.67 to 1.18 | LIXI_SC_20UG_QD | -0.11 -1.03 to 0.73 | -0.21 -1.23 to 0.56 | -0.24 -1.37 to 0.60 | -0.34 -1.58 to 0.56 |
| DULA_SC_1p5MG_QW | -0.76 -1.37 to -0.08 | 0.98 0.02 to 1.86 | 0.58 -0.37 to 1.46 | 0.41 -0.48 to 1.29 | 0.11 -0.73 to 1.03 | DULA_SC_1p5MG_QW | -0.10 -1.12 to 0.74 | -0.13 -1.29 to 0.74 | -0.22 -1.49 to 0.70 |
| EXEN_SC_10UG_BID | -0.67 -1.19 to 0.09 | 1.08 0.24 to 2.02 | 0.68 -0.15 to 1.65 | 0.51 -0.30 to 1.48 | 0.21 -0.56 to 1.23 | 0.10 -0.74 to 1.12 | EXEN_SC_10UG_BID | -0.03 -0.51 to 0.41 | -0.12 -0.81 to 0.44 |
| INS_LISPRO | -0.64 -1.26 to 0.29 | 1.10 0.20 to 2.14 | 0.70 -0.20 to 1.81 | 0.54 -0.36 to 1.63 | 0.24 -0.60 to 1.37 | 0.13 -0.74 to 1.29 | 0.03 -0.41 to 0.51 | INS_LISPRO | -0.10 -0.73 to 0.49 |
| STANDARD_CARE | -0.54 -1.26 to 0.56 | 1.20 0.23 to 2.36 | 0.80 -0.14 to 2.02 | 0.64 -0.33 to 1.82 | 0.34 -0.56 to 1.58 | 0.22 -0.70 to 1.49 | 0.12 -0.44 to 0.81 | 0.10 -0.49 to 0.73 | STANDARD_CARE |
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; 7 of 7 | Background glucose lowering therapy (stratum S0 to S4) effect modifier, prognostic factor; 7 of 7 | Diabetes duration (years) effect modifier, prognostic factor; 7 of 7 | Asian ancestry or region (percent Asian) effect modifier, prognostic factor; 6 of 7 | Age (years) prognostic factor; 7 of 7 | Treatment duration (weeks) effect modifier; 7 of 7 |
|---|---|---|---|---|---|---|
| NCT00765817 S000345 | 8.4 | S2 | 12 | 3.06 | 59 | 30 |
| AWARD-9 S000446 | 8.4 | S2 | 13 | 0.33 | 60.4 | 28 |
| GETGOAL-L-ASIA S000488 | 8.53 | S2 | 13.9 | 100 | 58.35 | 24 |
| NCT00960661 S000609 | 8.25 | S2 | 11.5 median | 5 | 59.45 | 30 |
| PREVAIL S000693 | 6.57 | S2 | 3.65 median | 11.84 Asian subgroup rows | 57.66 | 8 |
| NCT01617434 S000926 | 8.25 | S2 | 12.1 | not reported | 58.4 | 26 |
| SUSTAIN™ 5 S001872 | 8.37 | S2 | 13.3 | 16.67 | 58.8 | 30 |
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 6.6 (EXEN_SC_10UG_BID vs INS_LISPRO vs STANDARD_CARE) to 8.5 (LIXI_SC_20UG_QD vs PLACEBO) percent; threshold 0.5
- FlagBaseline, Diabetes duration: design means range from 3.6 (EXEN_SC_10UG_BID vs INS_LISPRO vs STANDARD_CARE) to 13.9 (LIXI_SC_20UG_QD vs PLACEBO) years; threshold 3
- FlagBaseline, Asian ancestry or region: design means range from 0.3 (DULA_SC_1p5MG_QW vs PLACEBO) to 100.0 (LIXI_SC_20UG_QD vs PLACEBO) percent Asian; threshold 30
- NoteOutcome assessment, time point: selected time points span 20 to 30 weeks
- NoteOutcome assessment, analysis set: mixed: full_analysis 3, modified_itt 3, per_protocol 1
- NoteRisk of bias, blinding: mixed: double_blind 5, open_label 2
- NoteRisk of bias, funding: mixed: industry 6, non_industry 1
| Trial | time weeks | analysis set | definition | instrument | adjudicated | proportion method | intercurrent events (discontinuation) | intercurrent events (rescue) | blinding | funding | start year | Eligibility |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| NCT00765817 | 30 | full_analysis | not stated | not stated | not stated | not stated | not stated | not stated | double_blind | industry | 2008 | adults 18 or older; insulin glargine 20 U/d or more alone or with metformin or pioglitazone; HbA1c 7.1 to 10.5 percent; BMI 45 or less |
| AWARD-9 | 28 | modified_itt | not stated | not stated | not stated | not stated | not stated | not stated | double_blind | industry | 2014 | adults with T2D on basal insulin glargine with or without metformin |
| GETGOAL-L-ASIA | 24 | modified_itt | not stated | not stated | not stated | not stated | not stated | not stated | double_blind | industry | 2009 | age 25 to 81; type 2 diabetes at least 1 year; stable basal insulin at least 10 U/day with or without sulfonylurea; HbA1c 7 to 10 percent |
| NCT00960661 | 30 | per_protocol | not stated | not stated | not stated | not stated | not stated | not stated | open_label | industry | 2009 | age 18 or older; T2D on insulin glargine and metformin with or without sulfonylurea; HbA1c 7.0 to 10.0; BMI 25.0 (23.0 in South Korea) to 45.0; HbA1c above 7.0 after optimization |
| PREVAIL | 20 | modified_itt | not stated | not stated | not stated | not stated | not stated | not stated | open_label | non_industry | 2014 | age 30 to 80; T2D 7 years or less; A1c 6.0 to 9.5 percent off drugs or 5.5 to 9.0 on up to 2 oral drugs |
| NCT01617434 | 26 | full_analysis | not stated | not stated | not stated | not stated | not stated | not stated | double_blind | industry | 2012 | age 18 to 80; HbA1c 7.0 to 10.0 percent; BMI 20 to 45; basal insulin analogue 20 U or more with or without metformin |
| SUSTAIN™ 5 | 30 | full_analysis | not stated | not stated | not stated | not stated | 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 |
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 |
|---|---|---|---|---|---|---|---|---|---|
| NCT00765817 | A1 | EXEN_SC_10UG_BID | 30 | arm, change | -1.740 | 0.089 | 137 | R0027069:Table 2 | |
| NCT00765817 | A2 | PLACEBO | 30 | arm, change | -1.040 | 0.092 | 122 | R0027069:Table 2 | |
| AWARD-9 | A1 | DULA_SC_1p5MG_QW | 28 | arm, change | -1.440 | 0.090 | 150 | registry:outcomes | |
| AWARD-9 | A2 | PLACEBO | 28 | arm, change | -0.670 | 0.090 | 150 | registry:outcomes | |
| GETGOAL-L-ASIA | A1 | LIXI_SC_20UG_QD | 24 | contrast, md | -0.880 | 0.119 | R0022626:Results | ||
| GETGOAL-L-ASIA | A2 | PLACEBO | 24 | contrast, md | R0022626:Results | ||||
| NCT00960661 | A1 | EXEN_SC_10UG_BID | 30 | arm, change | -1.130 | 0.050 | 247 | R0016788:Table 2 | |
| NCT00960661 | A2 | INS_LISPRO | 30 | arm, change | -1.100 | 0.050 | 263 | R0016788:Table 2 | |
| PREVAIL | A1 | STANDARD_CARE | 20 | arm, final | 6.700 | 0.100 | 33 | R0010144:Table 2 | |
| PREVAIL | A2 | INS_LISPRO | 20 | arm, final | 6.600 | 0.090 | 35 | R0010144:Table 2 | |
| PREVAIL | A3 | EXEN_SC_10UG_BID | 20 | arm, final | 6.600 | 0.100 | 34 | R0010144:Table 2 | |
| NCT01617434 | A1 | LIRA_SC_1p8MG_QD | 26 | arm, change | -1.300 | 0.069 | 215 | registry:outcomes | |
| NCT01617434 | A2 | PLACEBO | 26 | arm, change | -0.110 | 0.074 | 217 | registry:outcomes | |
| SUSTAIN™ 5 | A1 | SEMA_SC_0p5MG_QW | 30 | arm, change | -1.450 | 0.090 | 132 | registry:outcomes | |
| SUSTAIN™ 5 | A2 | SEMA_SC_1p0MG_QW | 30 | arm, change | -1.850 | 0.090 | 131 | registry:outcomes | |
| SUSTAIN™ 5 | A3 | PLACEBO | 30 | arm, change | -0.090 | 0.090 | 133 | 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.