Network meta-analysis

Weight loss of 10 percent or more

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 separatelyOdds ratio

Randomized trials

Treatments

2,618

Participants

192

Events

In plain language

Across 4 trials with 2,618 participants, 6 of 11 treatments had a clearly better result than placebo on weight loss of 10 percent or more, and for 5 the evidence could not tell them apart from placebo. The most favorable estimate was for Tirzepatide 10 mg subcutaneous once weekly: odds ratio 19.01 (95% credible interval 4.08 to 94.30).

Higher 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.

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

Odds ratio. Higher values favor the treatment.

Versus Placebo, log scale. 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
Treatment	Bayesian OR (95% CrI)	95% prediction interval	Verdict
Tirzepatide 10 mg subcutaneous once weekly TIRZ_SC_10MG_QW	19.01 (4.08 to 94.30)	3.10 to 109	Better
Tirzepatide 15 mg subcutaneous once weekly TIRZ_SC_15MG_QW	18.13 (3.88 to 88.70)	2.78 to 100	Better
Semaglutide 14 mg oral once daily (original tablet) SEMA_PO_14MG_QD	12.97 (3.24 to 55.34)	2.57 to 71.24	Better
Semaglutide 7 mg oral once daily (original tablet) SEMA_PO_7MG_QD	6.35 (1.30 to 30.38)	1.04 to 36.40	Better
Tirzepatide 5 mg subcutaneous once weekly TIRZ_SC_5MG_QW	5.65 (1.15 to 28.23)	0.90 to 33.33	Better
Liraglutide 1.8 mg subcutaneous once daily LIRA_SC_1p8MG_QD	5.00 (1.12 to 25.69)	0.90 to 30.58	Better
Dulaglutide 1.5 mg subcutaneous once weekly DULA_SC_1p5MG_QW	2.90 (0.53 to 15.42)	0.44 to 18.40	Unclear
Dulaglutide 0.75 mg subcutaneous once weekly DULA_SC_0p75MG_QW	1.82 (0.11 to 18.75)	0.10 to 20.68	Unclear
Tirzepatide 1 mg subcutaneous once weekly TIRZ_SC_1MG_QW	1.69 (0.24 to 10.03)	0.20 to 11.83	Unclear
Semaglutide 3 mg oral once daily (original tablet) SEMA_PO_3MG_QD	0.96 (0.16 to 5.19)	0.12 to 5.93	Unclear
Sitagliptin SITAGLIPTIN	0.44 (0.05 to 2.95)	0.05 to 3.39	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: odds ratio 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 column	PLACEBO	TIRZ_SC_10MG_QW	TIRZ_SC_15MG_QW	SEMA_PO_14MG_QD	SEMA_PO_7MG_QD	TIRZ_SC_5MG_QW	LIRA_SC_1p8MG_QD	DULA_SC_1p5MG_QW	DULA_SC_0p75MG_QW	TIRZ_SC_1MG_QW	SEMA_PO_3MG_QD	SITAGLIPTIN
PLACEBO	PLACEBO	0.05 0.01 to 0.25	0.06 0.01 to 0.26	0.08 0.02 to 0.31	0.16 0.03 to 0.77	0.18 0.04 to 0.87	0.20 0.04 to 0.89	0.34 0.06 to 1.88	0.55 0.05 to 9.08	0.59 0.10 to 4.19	1.04 0.19 to 6.21	2.29 0.34 to 18.73
TIRZ_SC_10MG_QW	19.01 4.08 to 94.30	TIRZ_SC_10MG_QW	1.06 0.33 to 3.41	1.47 0.17 to 11.84	3.02 0.32 to 26.73	3.36 0.96 to 11.81	3.78 0.38 to 33.03	6.52 1.70 to 27.25	10.75 0.62 to 260	11.23 2.49 to 64.24	19.94 2.08 to 217	44.49 3.61 to 587
TIRZ_SC_15MG_QW	18.13 3.88 to 88.70	0.94 0.29 to 3.03	TIRZ_SC_15MG_QW	1.38 0.17 to 11.24	2.80 0.33 to 24.75	3.19 0.96 to 11.02	3.57 0.37 to 29.63	6.17 1.61 to 25.21	10.14 0.59 to 246	10.64 2.35 to 58.68	19.12 2.08 to 206	42.47 3.48 to 558
SEMA_PO_14MG_QD	12.97 3.24 to 55.34	0.68 0.08 to 5.91	0.72 0.09 to 6.05	SEMA_PO_14MG_QD	2.03 0.97 to 4.77	2.29 0.28 to 20.10	2.60 0.90 to 6.98	4.52 0.52 to 42.39	6.94 0.97 to 114	7.84 0.83 to 88.17	13.41 4.80 to 50.69	29.28 7.21 to 175
SEMA_PO_7MG_QD	6.35 1.30 to 30.38	0.33 0.04 to 3.10	0.36 0.04 to 3.06	0.49 0.21 to 1.04	SEMA_PO_7MG_QD	1.13 0.12 to 10.69	1.28 0.31 to 4.27	2.19 0.23 to 21.36	3.38 0.45 to 54.76	3.79 0.36 to 45.20	6.62 2.17 to 24.29	14.46 3.27 to 87.48
TIRZ_SC_5MG_QW	5.65 1.15 to 28.23	0.30 0.08 to 1.04	0.31 0.09 to 1.04	0.44 0.05 to 3.63	0.89 0.09 to 8.18	TIRZ_SC_5MG_QW	1.12 0.11 to 10.32	1.94 0.46 to 8.32	3.17 0.18 to 78.68	3.34 0.71 to 19.76	5.89 0.59 to 66.19	13.32 1.08 to 177
LIRA_SC_1p8MG_QD	5.00 1.12 to 25.69	0.26 0.03 to 2.62	0.28 0.03 to 2.71	0.38 0.14 to 1.11	0.78 0.23 to 3.25	0.89 0.10 to 8.87	LIRA_SC_1p8MG_QD	1.73 0.19 to 17.97	2.72 0.30 to 47.59	3.02 0.29 to 36.16	5.19 1.37 to 29.68	11.40 2.18 to 88.62
DULA_SC_1p5MG_QW	2.90 0.53 to 15.42	0.15 0.04 to 0.59	0.16 0.04 to 0.62	0.22 0.02 to 1.92	0.46 0.05 to 4.42	0.51 0.12 to 2.15	0.58 0.06 to 5.33	DULA_SC_1p5MG_QW	1.66 0.09 to 40.47	1.73 0.32 to 10.54	3.06 0.29 to 35.39	6.76 0.53 to 95.85
DULA_SC_0p75MG_QW	1.82 0.11 to 18.75	0.09 0.00 to 1.60	0.10 0.00 to 1.68	0.14 0.01 to 1.03	0.30 0.02 to 2.22	0.32 0.01 to 5.45	0.37 0.02 to 3.30	0.60 0.02 to 11.68	DULA_SC_0p75MG_QW	1.07 0.04 to 21.69	1.97 0.11 to 18.71	4.30 0.20 to 55.92
TIRZ_SC_1MG_QW	1.69 0.24 to 10.03	0.09 0.02 to 0.40	0.09 0.02 to 0.43	0.13 0.01 to 1.21	0.26 0.02 to 2.77	0.30 0.05 to 1.42	0.33 0.03 to 3.41	0.58 0.09 to 3.13	0.93 0.05 to 24.46	TIRZ_SC_1MG_QW	1.76 0.14 to 21.35	3.91 0.24 to 56.98
SEMA_PO_3MG_QD	0.96 0.16 to 5.19	0.05 0.00 to 0.48	0.05 0.00 to 0.48	0.07 0.02 to 0.21	0.15 0.04 to 0.46	0.17 0.02 to 1.69	0.19 0.03 to 0.73	0.33 0.03 to 3.43	0.51 0.05 to 9.03	0.57 0.05 to 6.95	SEMA_PO_3MG_QD	2.17 0.37 to 14.92
SITAGLIPTIN	0.44 0.05 to 2.95	0.02 0.00 to 0.28	0.02 0.00 to 0.29	0.03 0.01 to 0.14	0.07 0.01 to 0.31	0.08 0.01 to 0.92	0.09 0.01 to 0.46	0.15 0.01 to 1.89	0.23 0.02 to 4.98	0.26 0.02 to 4.11	0.46 0.07 to 2.69	SITAGLIPTIN

Heterogeneity, fit and convergence

Bayesian random effects (primary)

Heterogeneity (tau): 0.257 (95% CrI 0.059 to 1.111), log scale
Residual deviance: 21.5 for 17 data points
DIC: 35.0 (pD 13.5)
Largest R-hat: 1.007
Smallest ESS: bulk 1,777, tail 3,074
Divergent transitions: 0
Convergence: All criteria met
Priors: PR02 N(0, 5^2); PR05 N(0, 2.5^2); PR09 log normal(-2.53, 1.58^2) on tau^2 (General physical health indicators, pharm vs pharm)

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.

Baseline effect modifiers and prognostic factors per trial
Trial	Baseline BMI or body weight (kg/m2) effect modifier, prognostic factor; 4 of 4	Sex (percent female) effect modifier, prognostic factor; 4 of 4	Treatment duration (weeks) effect modifier; 4 of 4	Lifestyle co-intervention intensity (none standard intensive) effect modifier, prognostic factor; 4 of 4
NCT03131687 S000010	32.57	46.85	26	standard
PIONEER 4 S000133	32.94	48	52	not_reported
PIONEER 10 S000234	26.26	25.74	52	not_reported
PIONEER 12 S000522	28.58	41.7	26	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_14MG_QD vs SEMA_PO_3MG_QD vs SEMA_PO_7MG_QD) to 32.9 (LIRA_SC_1p8MG_QD vs PLACEBO vs SEMA_PO_14MG_QD) kg/m2; threshold 3
FlagBaseline, Sex: design means range from 25.7 (DULA_SC_0p75MG_QW vs SEMA_PO_14MG_QD vs SEMA_PO_3MG_QD vs SEMA_PO_7MG_QD) to 48.0 (LIRA_SC_1p8MG_QD vs PLACEBO vs SEMA_PO_14MG_QD) percent female; threshold 15
NoteOutcome assessment, analysis set: mixed: full_analysis 3, modified_itt 1
NoteOutcome assessment, definition: mixed: HbA1c below 7.0 percent, LOCF, mITT on treatment dataset 1, not stated 3
NoteOutcome assessment, proportion method: mixed: imputed 1, not stated 3
NoteRisk of bias, blinding: mixed: double_blind 3, single_blind 1

Comparability items per trial
Trial	time weeks	analysis set	definition	instrument	adjudicated	proportion method	intercurrent events (discontinuation)	intercurrent events (rescue)	blinding	funding	start year	Eligibility
NCT03131687	26	modified_itt	HbA1c below 7.0 percent, LOCF, mITT on treatment dataset	not stated	not stated	imputed	hypothetical	hypothetical	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	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
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

Trial data

What each trial contributes. Arm rows give the arm value with its standard error, or events over participants; contrast rows give the odds ratio on the analysis scale (log) against the trial's first row. Flags mark converted, combined or approximated inputs.

Trial data entering this analysis
Trial	Arm	Treatment	Week	Data	Events / N	Source
NCT03131687	A1	PLACEBO	26	arm, responders	0 / 51	R0016215:Supplement Table 4
NCT03131687	A2	TIRZ_SC_1MG_QW	26	arm, responders	3 / 52	R0016215:Supplement Table 4
NCT03131687	A3	TIRZ_SC_5MG_QW	26	arm, responders	9 / 55	R0016215:Supplement Table 4
NCT03131687	A4	TIRZ_SC_10MG_QW	26	arm, responders	20 / 51	R0016215:Supplement Table 4
NCT03131687	A5	TIRZ_SC_15MG_QW	26	arm, responders	20 / 53	R0016215:Supplement Table 4
NCT03131687	A6	DULA_SC_1p5MG_QW	26	arm, responders	5 / 54	R0016215:Supplement Table 4
PIONEER 4	A1	SEMA_PO_14MG_QD	26	arm, responders	36 / 238	R0015836:Table 2
PIONEER 4	A2	LIRA_SC_1p8MG_QD	26	arm, responders	15 / 244	R0015836:Table 2
PIONEER 4	A3	PLACEBO	26	arm, responders	0 / 112	R0015836:Table 2
PIONEER 10	A1	SEMA_PO_3MG_QD	26	arm, responders	0 / 126	R0018421:Supplement Table S5
PIONEER 10	A2	SEMA_PO_7MG_QD	26	arm, responders	5 / 124	R0018421:Supplement Table S5
PIONEER 10	A3	SEMA_PO_14MG_QD	26	arm, responders	8 / 120	R0018421:Supplement Table S5
PIONEER 10	A4	DULA_SC_0p75MG_QW	26	arm, responders	1 / 62	R0018421:Supplement Table S5
PIONEER 12	A1	SEMA_PO_3MG_QD	26	arm, responders	5 / 322	R0019776:Table 2
PIONEER 12	A2	SEMA_PO_7MG_QD	26	arm, responders	23 / 319	R0019776:Table 2
PIONEER 12	A3	SEMA_PO_14MG_QD	26	arm, responders	40 / 300	R0019776:Table 2
PIONEER 12	A4	SITAGLIPTIN	26	arm, responders	2 / 335	R0019776:Table 2

Rerun this analysis yourself

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