LivingGLP1
Network meta-analysis

Percent body weight change

Type 2 diabetes (adults); background therapy: one or more non insulin glucose lowering drugs

weeks 40 to 104 (target week 68)Treatment policyDoses of a drug pooledMean differenceConvergence criteria not all met
8
Randomized trials
9
Treatments
6,897
Participants
17
Trial arms

In plain language

Across 8 trials with 6,897 participants, 2 of 8 treatments had a clearly better result than placebo on percent body weight change, and for 6 the evidence could not tell them apart from placebo. The most favorable estimate was for tirzepatide injection: mean difference -10.49 percentage points (95% credible interval -14.05 to -6.28).

  • Tirzepatide injection: better than placebo but not among the most effective (certainty pending).
  • Semaglutide injection: better than placebo but not among the most effective (certainty pending).
  • Semaglutide tablet: not convincingly different from placebo (certainty pending).
  • Empagliflozin: not convincingly different from placebo (certainty pending).
  • Standard care or no added treatment: not convincingly different from placebo (certainty pending).
  • Liraglutide injection: not convincingly different from placebo (certainty pending).
  • Sitagliptin: not convincingly different from placebo (certainty pending).
  • Dulaglutide injection: not convincingly different from placebo (certainty pending).

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.
DULA_SCEMPAGLIFLOZINLIRA_SCPLACEBOSEMA_POSEMA_SCSITAGLIPTINSTANDARD_CARETIRZ_SC
Node area shows participants; line width shows trials comparing two treatments directly. Blue: GLP-1 receptor agonist containing treatments; grey: comparators. Hover over or tab to a node or line for details.

Effects compared with Placebo

Mean difference in percentage points. Lower values favor the treatment.
-15-10-505← favors treatmentfavors reference →Tirzepatide injectionSemaglutide injectionSemaglutide tabletEmpagliflozinStandard care or no added treatm…Liraglutide injectionSitagliptinDulaglutide injection
Versus Placebo. Blue: Bayesian random effects posterior median with 95% credible interval (thick) and 95% prediction interval (dashed). Amber diamond: frequentist estimate with 95% confidence interval. Hover over or tab to a row for its values.
Effects of each treatment versus Placebo
TreatmentBayesian MD (95% CrI)95% prediction intervalFrequentist MD (95% CI)VerdictConfidence
Tirzepatide injection
TIRZ_SC
-10.49 (-14.05 to -6.28)-15.69 to -4.47-10.55 (-11.79 to -9.30)Betterpending
Semaglutide injection
SEMA_SC
-5.27 (-8.90 to -1.54)-10.83 to 0.37-5.29 (-6.04 to -4.54)Betterpending
Semaglutide tablet
SEMA_PO
-3.91 (-7.39 to 0.04)-9.22 to 1.68-3.95 (-4.95 to -2.95)Unclearpending
Empagliflozin
EMPAGLIFLOZIN
-3.61 (-8.79 to 1.97)-9.83 to 3.01-3.66 (-4.90 to -2.42)Unclearpending
Standard care or no added treatment
STANDARD_CARE
-3.38 (-8.67 to 2.05)-10.23 to 3.45-3.38 (-4.88 to -1.88)Unclearpending
Liraglutide injection
LIRA_SC
-2.23 (-5.98 to 1.99)-7.27 to 3.24-2.26 (-3.10 to -1.42)Unclearpending
Sitagliptin
SITAGLIPTIN
-2.05 (-6.49 to 2.70)-7.68 to 4.26-2.15 (-3.25 to -1.05)Unclearpending
Dulaglutide injection
DULA_SC
-1.41 (-6.54 to 4.28)-7.71 to 5.72-1.47 (-2.95 to 0.00)Unclearpending

Confidence in the results

How much each comparison can be trusted, rated with CINeMA in six domains and summarized with GRADE.
Confidence in each comparison with Placebo
ComparisonWithin study biasReporting biasIndirectnessImprecisionHeterogeneityIncoherenceConfidence
Dulaglutide injection versus Placebopendingsomependingmajornonesomepending
Empagliflozin versus Placebopendingsomependingsomesomesomepending
Liraglutide injection versus Placebopendingsomependingsomesomesomepending
Semaglutide tablet versus Placebopendingsomependingsomenonesomepending
Semaglutide injection versus Placebopendingsomependingsomenonesomepending
Sitagliptin versus Placebopendingsomependingmajornonesomepending
Standard care or no added treatment versus Placebopendingsomependingsomesomesomepending
Tirzepatide injection versus Placebopendingsomependingnonenonesomepending
Every other comparison (28)
Confidence in the other comparisons
ComparisonWithin study biasReporting biasIndirectnessImprecisionHeterogeneityIncoherenceConfidence
Dulaglutide injection versus Empagliflozinpendingsomependingmajornonesomepending
Dulaglutide injection versus Liraglutide injectionpendingsomependingmajornonesomepending
Empagliflozin versus Liraglutide injectionpendingsomependingmajornonesomepending
Dulaglutide injection versus Semaglutide tabletpendingsomependingsomesomesomepending
Empagliflozin versus Semaglutide tabletpendingsomependingmajornonesomepending
Liraglutide injection versus Semaglutide tabletpendingsomependingsomesomesomepending
Dulaglutide injection versus Semaglutide injectionpendingsomependingsomesomesomepending
Empagliflozin versus Semaglutide injectionpendingsomependingmajornonesomepending
Liraglutide injection versus Semaglutide injectionpendingsomependingsomesomesomepending
Semaglutide tablet versus Semaglutide injectionpendingsomependingmajornonesomepending
Dulaglutide injection versus Sitagliptinpendingsomependingmajornonesomepending
Empagliflozin versus Sitagliptinpendingsomependingmajornonesomepending
Liraglutide injection versus Sitagliptinpendingsomependingmajornonesomepending
Semaglutide tablet versus Sitagliptinpendingsomependingsomesomesomepending
Semaglutide injection versus Sitagliptinpendingsomependingmajornonesomepending
Dulaglutide injection versus Standard care or no added treatmentpendingsomependingmajornonesomepending
Empagliflozin versus Standard care or no added treatmentpendingsomependingmajornonesomepending
Liraglutide injection versus Standard care or no added treatmentpendingsomependingmajornonesomepending
Semaglutide tablet versus Standard care or no added treatmentpendingsomependingmajornonesomepending
Semaglutide injection versus Standard care or no added treatmentpendingsomependingsomesomesomepending
Sitagliptin versus Standard care or no added treatmentpendingsomependingmajornonesomepending
Dulaglutide injection versus Tirzepatide injectionpendingsomependingsomenonesomepending
Empagliflozin versus Tirzepatide injectionpendingsomependingsomenonesomepending
Liraglutide injection versus Tirzepatide injectionpendingsomependingnonesomesomepending
Semaglutide tablet versus Tirzepatide injectionpendingsomependingsomenonesomepending
Semaglutide injection versus Tirzepatide injectionpendingsomependingsomenonesomepending
Sitagliptin versus Tirzepatide injectionpendingsomependingsomenonesomepending
Standard care or no added treatment versus Tirzepatide injectionpendingsomependingsomenonesomepending

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.

Rank probabilities

Probability of each rank for each treatment
TreatmentRank 1Rank 2Rank 3Rank 4Rank 5Rank 6Rank 7Rank 8Rank 9Mean rank
TIRZ_SC94%3%2%1%1.1
SEMA_SC2%69%12%7%4%3%2%1%2.6
SEMA_PO8%36%35%16%4%1%3.8
EMPAGLIFLOZIN2%10%17%29%24%9%5%3%2%4.4
STANDARD_CARE2%5%26%14%23%10%9%8%5%4.8
LIRA_SC2%3%6%13%34%24%14%3%6.2
SITAGLIPTIN1%2%4%12%25%34%15%5%6.5
DULA_SC2%2%3%6%11%19%42%14%7.2
PLACEBO1%2%3%6%17%71%8.5

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.
Every treatment in a row compared with every treatment in a column
Row versus columnPLACEBOTIRZ_SCSEMA_SCSEMA_POEMPAGLIFLOZINSTANDARD_CARELIRA_SCSITAGLIPTINDULA_SC
PLACEBOPLACEBO10.49
6.28 to 14.05		5.27
1.54 to 8.90		3.91
-0.04 to 7.39		3.61
-1.97 to 8.79		3.38
-2.05 to 8.67		2.23
-1.99 to 5.98		2.05
-2.70 to 6.49		1.41
-4.28 to 6.54
TIRZ_SC-10.49
-14.05 to -6.28		TIRZ_SC-5.21
-10.21 to 0.41		-6.57
-11.80 to -1.08		-6.86
-13.53 to -0.32		-7.12
-13.43 to 0.18		-8.26
-13.48 to -2.77		-8.41
-14.34 to -2.37		-9.05
-15.53 to -2.41
SEMA_SC-5.27
-8.90 to -1.54		5.21
-0.41 to 10.21		SEMA_SC-1.37
-6.95 to 3.87		-1.67
-8.73 to 4.91		-1.92
-5.92 to 2.31		-3.04
-8.72 to 2.32		-3.24
-9.59 to 2.63		-3.87
-10.79 to 2.35
SEMA_PO-3.91
-7.39 to 0.04		6.57
1.08 to 11.80		1.37
-3.87 to 6.95		SEMA_PO-0.29
-4.23 to 3.59		-0.52
-7.05 to 6.33		-1.67
-5.64 to 2.44		-1.84
-4.75 to 0.91		-2.49
-6.43 to 1.33
EMPAGLIFLOZIN-3.61
-8.79 to 1.97		6.86
0.32 to 13.53		1.67
-4.91 to 8.73		0.29
-3.59 to 4.23		EMPAGLIFLOZIN-0.25
-8.02 to 7.63		-1.37
-7.04 to 4.41		-1.55
-6.36 to 3.34		-2.21
-7.92 to 3.35
STANDARD_CARE-3.38
-8.67 to 2.05		7.12
-0.18 to 13.43		1.92
-2.31 to 5.92		0.52
-6.33 to 7.05		0.25
-7.63 to 8.02		STANDARD_CARE-1.14
-8.20 to 5.51		-1.32
-8.79 to 5.79		-1.96
-9.94 to 5.44
LIRA_SC-2.23
-5.98 to 1.99		8.26
2.77 to 13.48		3.04
-2.32 to 8.72		1.67
-2.44 to 5.64		1.37
-4.41 to 7.04		1.14
-5.51 to 8.20		LIRA_SC-0.18
-5.28 to 4.70		-0.83
-6.62 to 4.49
SITAGLIPTIN-2.05
-6.49 to 2.70		8.41
2.37 to 14.34		3.24
-2.63 to 9.59		1.84
-0.91 to 4.75		1.55
-3.34 to 6.36		1.32
-5.79 to 8.79		0.18
-4.70 to 5.28		SITAGLIPTIN-0.64
-5.43 to 4.22
DULA_SC-1.41
-6.54 to 4.28		9.05
2.41 to 15.53		3.87
-2.35 to 10.79		2.49
-1.33 to 6.43		2.21
-3.35 to 7.92		1.96
-5.44 to 9.94		0.83
-4.49 to 6.62		0.64
-4.22 to 5.43		DULA_SC

Heterogeneity, fit and convergence

Bayesian random effects (primary)

Heterogeneity (tau)
0.866 (95% CrI 0.037 to 4.846)
Residual deviance
15.6 for 16 data points
DIC
31.2 (pD 15.6)
Largest R-hat
1.008
Smallest ESS
bulk 833, tail 1,244
Divergent transitions
1
Convergence
Not all met; read with caution
Priors
PR01 N(0, 35^2); PR03 N(0, 17.5^2); PR07 half normal(0, 3.5^2) on tau

Frequentist check (netmeta)

Method
inverse variance, REML, MD
Tau
0.000
I squared
0%
Q (total)
0.20 on 1 df, P = 0.656
Q (between designs)
0.00

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.

Heterogeneity within designs (decomp.design)
DesignQdfP
SEMA_PO:SITAGLIPTIN0.2010.656

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.
0.000.390.77-1.59-0.790.000.791.59Centered effectStandard error
Comparisons ordered as DULA_SC, EMPAGLIFLOZIN, LIRA_SC, SEMA_PO, SEMA_SC, SITAGLIPTIN, STANDARD_CARE, TIRZ_SC, PLACEBO; the shaded triangle is where 95% of points would fall without small study effects. Egger type test P = 0.060.

Contribution of direct evidence

Percent contribution of each direct comparison (columns) to each network estimate (rows), from netcontrib.

Contribution of direct comparisons to network estimates
Network estimateDULA_SC:SEMA_POEMPAGLIFLOZIN:SEMA_POLIRA_SC:PLACEBO:SEMA_POPLACEBO:SEMA_SCPLACEBO:TIRZ_SCSEMA_PO:SITAGLIPTINSEMA_SC:STANDARD_CARE
DULA_SC:PLACEBO4258
EMPAGLIFLOZIN:PLACEBO4258
LIRA_SC:PLACEBO100
PLACEBO:SEMA_PO100
PLACEBO:SEMA_SC100
PLACEBO:SITAGLIPTIN5842
PLACEBO:STANDARD_CARE5050
PLACEBO:TIRZ_SC100

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.
Baseline effect modifiers and prognostic factors per trial
TrialBaseline BMI or body weight (kg/m2)
effect modifier, prognostic factor; 6 of 8
Sex (percent female)
effect modifier, prognostic factor; 8 of 8
Asian ancestry or region (percent Asian)
effect modifier, prognostic factor; 7 of 8
Kidney function (eGFR) (mL/min/1.73 m2)
prognostic factor, effect modifier; 6 of 8
Treatment duration (weeks)
effect modifier; 8 of 8
Lifestyle co-intervention intensity (none standard intensive)
effect modifier, prognostic factor; 8 of 8
PIONEER 4
S000133
32.944813.495.852not_reported
PIONEER 10
S000234
26.2625.7410096.5752not_reported
PIONEER 2
S000251
32.8549.395.9695.552not_reported
NCT03596450
S000545
not reported45.77not reportednot reported104.36not_reported
PIONEER 7
S001153
31.1943.4515.0894.36104not_reported
SURMOUNT-2
S001712
36.150.7313.3395.1972standard
STEP 2
S001740
35.750.926.295.4368standard
PIONEER 3
S002267
not reported47.1613.14not reported78not_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: not reported by 2 of 8 trials
  • FlagBaseline, Baseline BMI or body weight: design means range from 26.3 (DULA_SC vs SEMA_PO) to 36.1 (PLACEBO vs TIRZ_SC) kg/m2; threshold 3
  • FlagBaseline, Sex: design means range from 25.7 (DULA_SC vs SEMA_PO) to 50.9 (PLACEBO vs SEMA_SC) percent female; threshold 15
  • FlagBaseline, Asian ancestry or region: design means range from 6.0 (EMPAGLIFLOZIN vs SEMA_PO) to 100.0 (DULA_SC vs SEMA_PO) percent Asian; threshold 30
  • FlagBaseline, Kidney function (eGFR): not reported by 2 of 8 trials
  • FlagBaseline, Treatment duration: design means range from 52.0 (DULA_SC vs SEMA_PO) to 104.4 (SEMA_SC vs STANDARD_CARE) weeks; threshold 26
  • NoteOutcome assessment, time point: selected time points span 52 to 78 weeks
  • NoteOutcome assessment, analysis set: mixed: completers 1, full_analysis 6, randomized 1
  • NoteOutcome assessment, intercurrent events (discontinuation): mixed: not stated 2, treatment_policy 6
  • NoteOutcome assessment, intercurrent events (rescue): mixed: not stated 3, treatment_policy 5
  • NoteRisk of bias, blinding: mixed: double_blind 4, open_label 2, single_blind 2
  • NoteData handling, input conversions: arms_combined 4
Comparability items per trial
Trialtime weeksanalysis setdefinitioninstrumentadjudicatedproportion methodintercurrent events (discontinuation)intercurrent events (rescue)blindingfundingstart yearEligibility
PIONEER 452full_analysisnot statednot statednot statednot statedtreatment_policytreatment_policydouble_blindindustry2016Age 18 or older; T2D on metformin with or without SGLT2i; HbA1c 7.0 to 9.5 percent; eGFR 60 or more
PIONEER 1052full_analysisnot statednot statednot statednot statedtreatment_policytreatment_policysingle_blindindustry2017Japanese adults 20 or older; T2D; HbA1c 7.0 to 10.5 percent on one oral glucose lowering drug
PIONEER 252full_analysisnot statednot statednot statednot statedtreatment_policytreatment_policysingle_blindindustry2016type 2 diabetes on metformin; HbA1c 7.0 to 10.5 percent; eGFR 60 or more
NCT0359645052.18completersnot statednot statednot statednot statedtreatment_policynot statedopen_labelindustry2018adults with type 2 diabetes on metformin, later up to 2 oral drugs, needing intensification
PIONEER 752randomizednot statednot statednot statednot statednot statednot statedopen_labelindustry2016age 18 or more; HbA1c 7.5 to 9.5 percent; one or two oral glucose lowering drugs
SURMOUNT-272full_analysisnot statednot statednot statednot statedtreatment_policytreatment_policydouble_blindindustry2021age 18 or older; BMI 27 or more; type 2 diabetes with HbA1c 7 to 10 percent on diet or oral drugs
STEP 268full_analysisnot statednot statednot statednot statednot statednot stateddouble_blindindustry2018age 18 or older; BMI 27 or more; HbA1c 7 to 10 percent; T2D on diet or up to 3 oral agents
PIONEER 378full_analysisnot statednot statednot statednot statedtreatment_policytreatment_policydouble_blindindustry2016adults 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 data entering this analysis
TrialArmTreatmentWeekDataValueSEEvents / NFlagsSource
PIONEER 4A1SEMA_PO52arm, percent_change-4.9400.377285registry:outcomes
PIONEER 4A2LIRA_SC52arm, percent_change-3.2500.257284registry:outcomes
PIONEER 4A3PLACEBO52arm, percent_change-0.9900.346142registry:outcomes
PIONEER 10A1+A2+A3SEMA_PO52arm, percent_change-1.2270.221393arms_combinedregistry:outcomes
PIONEER 10A4DULA_SC52arm, percent_change1.2500.50465registry:outcomes
PIONEER 2A1SEMA_PO52arm, percent_change-4.3800.284411registry:outcomes
PIONEER 2A2EMPAGLIFLOZIN52arm, percent_change-4.0900.236410registry:outcomes
NCT03596450A1SEMA_SC52.18arm, percent_change-3.9300.518458registry:outcomes
NCT03596450A2STANDARD_CARE52.18arm, percent_change-2.0200.416461registry:outcomes
PIONEER 7A3SEMA_PO52contrast, md-2.1000.714R0023369:Supplement Table S10
PIONEER 7A4SITAGLIPTIN52contrast, mdR0023369:Supplement Table S10
SURMOUNT-2A1+A2TIRZ_SC72arm, percent_change-13.7480.392623arms_combinedR0008662:Table 2
SURMOUNT-2A3PLACEBO72arm, percent_change-3.2000.500315R0008662:Table 2
STEP 2A1+A2SEMA_SC68arm, percent_change-8.5910.267784arms_combinedregistry:outcomes
STEP 2A3PLACEBO68arm, percent_change-3.3000.274403registry:outcomes
PIONEER 3A1+A2+A3SEMA_PO78arm, percent_change-2.7530.1431,396arms_combinedregistry:outcomes
PIONEER 3A4SITAGLIPTIN78arm, percent_change-0.9900.203467registry:outcomes

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