Network meta-analysis

Weight loss of 5 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

3,283

Participants

794

Events

In plain language

Across 5 trials with 3,283 participants, 7 of 12 treatments had a clearly better result than placebo on weight loss of 5 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 49.28 (95% credible interval 11.14 to 220).

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	49.28 (11.14 to 220)	8.90 to 252	Better
Tirzepatide 15 mg subcutaneous once weekly TIRZ_SC_15MG_QW	34.08 (8.12 to 147)	6.49 to 165	Better
Tirzepatide 5 mg subcutaneous once weekly TIRZ_SC_5MG_QW	18.54 (4.51 to 81.36)	3.48 to 92.14	Better
Semaglutide 14 mg oral once daily (original tablet) SEMA_PO_14MG_QD	8.91 (3.28 to 21.69)	2.26 to 27.41	Better
Dulaglutide 1.5 mg subcutaneous once weekly DULA_SC_1p5MG_QW	5.89 (1.32 to 26.80)	1.06 to 30.47	Better
Semaglutide 7 mg oral once daily (original tablet) SEMA_PO_7MG_QD	4.85 (1.45 to 13.31)	1.05 to 16.30	Better
Liraglutide 1.8 mg subcutaneous once daily LIRA_SC_1p8MG_QD	4.21 (1.50 to 11.16)	1.07 to 14.19	Better
Tirzepatide 1 mg subcutaneous once weekly TIRZ_SC_1MG_QW	3.14 (0.64 to 14.82)	0.52 to 17.01	Unclear
Semaglutide 3 mg oral once daily (original tablet) SEMA_PO_3MG_QD	1.65 (0.43 to 4.48)	0.33 to 5.31	Unclear
Lixisenatide 20 ug subcutaneous once daily LIXI_SC_20UG_QD	1.61 (0.65 to 4.08)	0.47 to 5.39	Unclear
Dulaglutide 0.75 mg subcutaneous once weekly DULA_SC_0p75MG_QW	1.42 (0.27 to 5.70)	0.23 to 6.80	Unclear
Sitagliptin SITAGLIPTIN	0.83 (0.21 to 2.57)	0.17 to 3.07	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	TIRZ_SC_5MG_QW	SEMA_PO_14MG_QD	DULA_SC_1p5MG_QW	SEMA_PO_7MG_QD	LIRA_SC_1p8MG_QD	TIRZ_SC_1MG_QW	SEMA_PO_3MG_QD	LIXI_SC_20UG_QD	DULA_SC_0p75MG_QW	SITAGLIPTIN
PLACEBO	PLACEBO	0.02 0.00 to 0.09	0.03 0.01 to 0.12	0.05 0.01 to 0.22	0.11 0.05 to 0.31	0.17 0.04 to 0.76	0.21 0.08 to 0.69	0.24 0.09 to 0.67	0.32 0.07 to 1.56	0.61 0.22 to 2.32	0.62 0.25 to 1.55	0.70 0.18 to 3.70	1.20 0.39 to 4.65
TIRZ_SC_10MG_QW	49.28 11.14 to 220	TIRZ_SC_10MG_QW	1.45 0.48 to 4.32	2.64 0.88 to 7.70	5.52 1.02 to 32.72	8.41 2.74 to 25.58	10.32 1.88 to 64.92	11.72 2.13 to 69.39	15.58 4.69 to 54.84	30.80 5.52 to 209	30.77 5.37 to 173	35.39 4.52 to 305	59.25 9.53 to 391
TIRZ_SC_15MG_QW	34.08 8.12 to 147	0.69 0.23 to 2.07	TIRZ_SC_15MG_QW	1.81 0.62 to 5.28	3.84 0.71 to 21.82	5.75 1.86 to 17.59	7.17 1.30 to 45.06	8.17 1.47 to 45.56	10.84 3.26 to 38.26	21.34 3.84 to 138	21.00 3.72 to 117	23.75 3.30 to 222	41.36 6.97 to 272
TIRZ_SC_5MG_QW	18.54 4.51 to 81.36	0.38 0.13 to 1.13	0.55 0.19 to 1.60	TIRZ_SC_5MG_QW	2.11 0.40 to 12.23	3.17 1.05 to 9.78	3.90 0.69 to 24.01	4.45 0.78 to 25.48	5.97 1.76 to 20.40	11.66 2.10 to 73.73	11.57 2.02 to 63.32	13.52 1.85 to 122	22.64 3.75 to 149
SEMA_PO_14MG_QD	8.91 3.28 to 21.69	0.18 0.03 to 0.98	0.26 0.05 to 1.40	0.47 0.08 to 2.49	SEMA_PO_14MG_QD	1.52 0.25 to 8.18	1.83 1.06 to 3.62	2.12 0.85 to 4.72	2.86 0.44 to 16.89	5.48 3.00 to 11.90	5.57 1.31 to 19.42	6.25 1.96 to 24.71	10.61 4.98 to 25.01
DULA_SC_1p5MG_QW	5.89 1.32 to 26.80	0.12 0.04 to 0.36	0.17 0.06 to 0.54	0.32 0.10 to 0.95	0.66 0.12 to 4.05	DULA_SC_1p5MG_QW	1.22 0.22 to 8.01	1.40 0.24 to 8.37	1.86 0.55 to 6.73	3.61 0.65 to 24.67	3.64 0.63 to 21.16	4.20 0.57 to 39.06	7.04 1.15 to 49.29
SEMA_PO_7MG_QD	4.85 1.45 to 13.31	0.10 0.02 to 0.53	0.14 0.02 to 0.77	0.26 0.04 to 1.44	0.55 0.28 to 0.95	0.82 0.12 to 4.55	SEMA_PO_7MG_QD	1.16 0.36 to 2.94	1.55 0.22 to 9.69	2.97 1.58 to 6.06	2.98 0.61 to 11.42	3.37 1.02 to 13.40	5.76 2.52 to 13.17
LIRA_SC_1p8MG_QD	4.21 1.50 to 11.16	0.09 0.01 to 0.47	0.12 0.02 to 0.68	0.22 0.04 to 1.29	0.47 0.21 to 1.17	0.71 0.12 to 4.15	0.86 0.34 to 2.81	LIRA_SC_1p8MG_QD	1.34 0.22 to 8.27	2.57 1.03 to 9.01	2.64 0.67 to 9.59	2.94 0.75 to 15.15	4.99 1.71 to 18.36
TIRZ_SC_1MG_QW	3.14 0.64 to 14.82	0.06 0.02 to 0.21	0.09 0.03 to 0.31	0.17 0.05 to 0.57	0.35 0.06 to 2.26	0.54 0.15 to 1.83	0.65 0.10 to 4.51	0.75 0.12 to 4.48	TIRZ_SC_1MG_QW	1.93 0.30 to 14.09	1.94 0.31 to 11.68	2.21 0.27 to 21.75	3.76 0.57 to 27.65
SEMA_PO_3MG_QD	1.65 0.43 to 4.48	0.03 0.00 to 0.18	0.05 0.01 to 0.26	0.09 0.01 to 0.48	0.18 0.08 to 0.33	0.28 0.04 to 1.55	0.34 0.16 to 0.63	0.39 0.11 to 0.97	0.52 0.07 to 3.28	SEMA_PO_3MG_QD	1.01 0.19 to 3.79	1.12 0.32 to 4.57	1.94 0.78 to 4.42
LIXI_SC_20UG_QD	1.61 0.65 to 4.08	0.03 0.01 to 0.19	0.05 0.01 to 0.27	0.09 0.02 to 0.49	0.18 0.05 to 0.77	0.28 0.05 to 1.58	0.34 0.09 to 1.64	0.38 0.10 to 1.49	0.52 0.09 to 3.18	0.99 0.26 to 5.35	LIXI_SC_20UG_QD	1.13 0.22 to 7.73	1.93 0.47 to 10.24
DULA_SC_0p75MG_QW	1.42 0.27 to 5.70	0.03 0.00 to 0.22	0.04 0.00 to 0.30	0.07 0.01 to 0.54	0.16 0.04 to 0.51	0.24 0.03 to 1.77	0.30 0.07 to 0.99	0.34 0.07 to 1.34	0.45 0.05 to 3.68	0.89 0.22 to 3.08	0.88 0.13 to 4.58	DULA_SC_0p75MG_QW	1.71 0.37 to 6.68
SITAGLIPTIN	0.83 0.21 to 2.57	0.02 0.00 to 0.10	0.02 0.00 to 0.14	0.04 0.01 to 0.27	0.09 0.04 to 0.20	0.14 0.02 to 0.87	0.17 0.08 to 0.40	0.20 0.05 to 0.59	0.27 0.04 to 1.74	0.52 0.23 to 1.29	0.52 0.10 to 2.12	0.59 0.15 to 2.68	SITAGLIPTIN

Heterogeneity, fit and convergence

Bayesian random effects (primary)

Heterogeneity (tau): 0.242 (95% CrI 0.056 to 0.947), log scale
Residual deviance: 22.3 for 19 data points
DIC: 39.0 (pD 16.7)
Largest R-hat: 1.002
Smallest ESS: bulk 2,109, tail 2,466
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; 5 of 5	Sex (percent female) effect modifier, prognostic factor; 5 of 5	Treatment duration (weeks) effect modifier; 5 of 5	Lifestyle co-intervention intensity (none standard intensive) effect modifier, prognostic factor; 5 of 5
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
GETGOAL-M S002188	32.85	58.44	24	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, Treatment duration: design means range from 24.0 (LIXI_SC_20UG_QD vs PLACEBO) to 52.0 (DULA_SC_0p75MG_QW vs SEMA_PO_14MG_QD vs SEMA_PO_3MG_QD vs SEMA_PO_7MG_QD) weeks; threshold 26
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 58.4 (LIXI_SC_20UG_QD vs PLACEBO) percent female; threshold 15
NoteOutcome assessment, time point: selected time points span 24 to 26 weeks
NoteOutcome assessment, analysis set: mixed: full_analysis 3, modified_itt 2
NoteOutcome assessment, definition: mixed: HbA1c below 7.0 percent 1, HbA1c below 7.0 percent, LOCF, mITT on treatment dataset 1, not stated 3
NoteOutcome assessment, proportion method: mixed: imputed 1, not stated 2, not_stated 1, observed 1
NoteRisk of bias, blinding: mixed: double_blind 4, single_blind 1
NoteData handling, input conversions: arms_combined 1, count_from_percent 5

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	observed	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	HbA1c below 7.0 percent	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
GETGOAL-M	24	modified_itt	not stated	not stated	not stated	not_stated	hypothetical	hypothetical	double_blind	industry	2008	type 2 diabetes on metformin 1.5 g/day or more for 3 months; HbA1c 7 to 10 percent; FPG 13.9 mmol/L or less

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	Flags	Source
NCT03131687	A1	PLACEBO	26	arm, responders	0 / 51		R0016215:Supplement Table 4
NCT03131687	A2	TIRZ_SC_1MG_QW	26	arm, responders	7 / 52		R0016215:Supplement Table 4
NCT03131687	A3	TIRZ_SC_5MG_QW	26	arm, responders	26 / 55		R0016215:Supplement Table 4
NCT03131687	A4	TIRZ_SC_10MG_QW	26	arm, responders	36 / 51		R0016215:Supplement Table 4
NCT03131687	A5	TIRZ_SC_15MG_QW	26	arm, responders	33 / 53		R0016215:Supplement Table 4
NCT03131687	A6	DULA_SC_1p5MG_QW	26	arm, responders	12 / 54		R0016215:Supplement Table 4
PIONEER 4	A1	SEMA_PO_14MG_QD	26	arm, responders	110 / 238	count_from_percent	R0015836:Figure 3C
PIONEER 4	A2	LIRA_SC_1p8MG_QD	26	arm, responders	69 / 244	count_from_percent	R0015836:Figure 3C
PIONEER 4	A3	PLACEBO	26	arm, responders	8 / 112	count_from_percent	R0015836:Figure 3C
PIONEER 10	A1	SEMA_PO_3MG_QD	26	arm, responders	6 / 126		R0018421:Table 4
PIONEER 10	A2	SEMA_PO_7MG_QD	26	arm, responders	22 / 124		R0018421:Table 4
PIONEER 10	A3	SEMA_PO_14MG_QD	26	arm, responders	36 / 120		R0018421:Table 4
PIONEER 10	A4	DULA_SC_0p75MG_QW	26	arm, responders	4 / 62		R0018421:Table 4
PIONEER 12	A1	SEMA_PO_3MG_QD	26	arm, responders	51 / 322		R0019776:Table 2
PIONEER 12	A2	SEMA_PO_7MG_QD	26	arm, responders	106 / 319		R0019776:Table 2
PIONEER 12	A3	SEMA_PO_14MG_QD	26	arm, responders	137 / 300		R0019776:Table 2
PIONEER 12	A4	SITAGLIPTIN	26	arm, responders	27 / 335		R0019776:Table 2
GETGOAL-M	A1+A2	LIXI_SC_20UG_QD	24	arm, responders	85 / 497	count_from_percent;arms_combined	registry:outcomes
GETGOAL-M	A3	PLACEBO	24	arm, responders	19 / 168	count_from_percent	registry:outcomes

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