Network meta-analysis

HbA1c below 7 percent

Type 2 diabetes (adults); background therapy: no glucose lowering drug (lifestyle only)

weeks 20 to 36 (target week 26)Not stated by the trialsEach dose separatelyOdds ratio

Randomized trials

Treatments

2,937

Participants

1,596

Events

In plain language

Across 7 trials with 2,937 participants, 11 of 13 treatments had a clearly better result than placebo on HbA1c below 7 percent, and for 2 the evidence could not tell them apart from placebo. The most favorable estimate was for Dulaglutide 0.75 mg subcutaneous once weekly: odds ratio 15.86 (95% credible interval 3.40 to 58.48).

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	Frequentist OR (95% CI)	Verdict
Dulaglutide 0.75 mg subcutaneous once weekly DULA_SC_0p75MG_QW	15.86 (3.40 to 58.48)	1.68 to 115	22.89 (4.96 to 106)	Better
Albiglutide 50 mg subcutaneous once weekly ALBI_SC_50MG_QW	14.70 (3.10 to 57.09)	1.69 to 106	22.30 (4.75 to 105)	Better
Semaglutide 14 mg oral once daily (original tablet) SEMA_PO_14MG_QD	12.26 (3.55 to 34.10)	1.70 to 72.62	15.89 (5.15 to 48.99)	Better
Liraglutide 0.9 mg injection once daily LIRA_SC_0p9MG_QD	11.20 (4.03 to 26.04)	1.64 to 58.96	14.82 (5.49 to 40.03)	Better
Albiglutide 30 mg subcutaneous once weekly ALBI_SC_30MG_QW	10.32 (2.15 to 37.66)	1.19 to 73.05	15.31 (3.28 to 71.47)	Better
Semaglutide 7 mg oral once daily (original tablet) SEMA_PO_7MG_QD	8.73 (2.76 to 24.91)	1.28 to 58.72	11.25 (3.68 to 34.43)	Better
Semaglutide 0.5 mg subcutaneous once weekly SEMA_SC_0p5MG_QW	7.12 (1.33 to 26.82)	0.74 to 48.40	8.73 (1.79 to 42.59)	Better
Efpeglenatide 6 mg subcutaneous once weekly EFPE_SC_6MG_QW	6.58 (1.28 to 24.54)	0.62 to 48.09	8.23 (1.65 to 41.11)	Better
Semaglutide 1.0 mg subcutaneous once weekly SEMA_SC_1p0MG_QW	6.45 (1.22 to 25.26)	0.68 to 45.65	7.91 (1.63 to 38.52)	Better
Visepegenatide 150 µg injection once weekly VISEPE_SC_150UG_QW	5.58 (1.19 to 23.50)	0.66 to 42.90	6.25 (1.27 to 30.79)	Better
Semaglutide 3 mg oral once daily (original tablet) SEMA_PO_3MG_QD	4.53 (1.41 to 12.75)	0.68 to 27.52	5.79 (1.90 to 17.59)	Better
Efpeglenatide 4 mg subcutaneous once weekly EFPE_SC_4MG_QW	4.44 (0.86 to 16.70)	0.48 to 30.76	5.51 (1.11 to 27.33)	Unclear
Efpeglenatide 2 mg subcutaneous once weekly EFPE_SC_2MG_QW	3.58 (0.67 to 13.06)	0.35 to 25.20	4.38 (0.89 to 21.68)	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	DULA_SC_0p75MG_QW	ALBI_SC_50MG_QW	SEMA_PO_14MG_QD	LIRA_SC_0p9MG_QD	ALBI_SC_30MG_QW	SEMA_PO_7MG_QD	SEMA_SC_0p5MG_QW	EFPE_SC_6MG_QW	SEMA_SC_1p0MG_QW	VISEPE_SC_150UG_QW	SEMA_PO_3MG_QD	EFPE_SC_4MG_QW	EFPE_SC_2MG_QW
PLACEBO	PLACEBO	0.06 0.02 to 0.29	0.07 0.02 to 0.32	0.08 0.03 to 0.28	0.09 0.04 to 0.25	0.10 0.03 to 0.47	0.11 0.04 to 0.36	0.14 0.04 to 0.75	0.15 0.04 to 0.78	0.15 0.04 to 0.82	0.18 0.04 to 0.84	0.22 0.08 to 0.71	0.23 0.06 to 1.16	0.28 0.08 to 1.50
DULA_SC_0p75MG_QW	15.86 3.40 to 58.48	DULA_SC_0p75MG_QW	1.07 0.16 to 6.72	1.30 0.24 to 7.14	1.42 0.35 to 5.53	1.53 0.23 to 10.62	1.80 0.32 to 9.42	2.23 0.31 to 18.61	2.39 0.35 to 19.34	2.42 0.35 to 19.35	2.89 0.35 to 20.92	3.51 0.58 to 18.82	3.55 0.51 to 27.94	4.45 0.63 to 38.56
ALBI_SC_50MG_QW	14.70 3.10 to 57.09	0.94 0.15 to 6.10	ALBI_SC_50MG_QW	1.20 0.22 to 6.56	1.31 0.32 to 5.49	1.45 0.32 to 6.94	1.67 0.29 to 8.62	2.11 0.28 to 16.45	2.26 0.30 to 18.19	2.30 0.31 to 18.96	2.70 0.33 to 18.91	3.32 0.54 to 16.73	3.32 0.48 to 24.32	4.20 0.58 to 32.90
SEMA_PO_14MG_QD	12.26 3.55 to 34.10	0.77 0.14 to 4.25	0.83 0.15 to 4.65	SEMA_PO_14MG_QD	1.09 0.33 to 3.68	1.19 0.22 to 7.27	1.40 0.43 to 4.26	1.73 0.30 to 11.76	1.87 0.32 to 12.88	1.90 0.33 to 13.18	2.23 0.35 to 13.66	2.70 0.83 to 8.38	2.74 0.47 to 18.68	3.42 0.59 to 24.53
LIRA_SC_0p9MG_QD	11.20 4.03 to 26.04	0.70 0.18 to 2.83	0.76 0.18 to 3.14	0.91 0.27 to 2.99	LIRA_SC_0p9MG_QD	1.09 0.28 to 4.84	1.28 0.36 to 4.28	1.59 0.31 to 9.88	1.69 0.33 to 10.44	1.75 0.33 to 10.94	2.00 0.35 to 11.04	2.47 0.70 to 8.40	2.53 0.49 to 15.09	3.14 0.61 to 19.53
ALBI_SC_30MG_QW	10.32 2.15 to 37.66	0.65 0.09 to 4.31	0.69 0.14 to 3.12	0.84 0.14 to 4.58	0.91 0.21 to 3.57	ALBI_SC_30MG_QW	1.17 0.20 to 5.96	1.45 0.19 to 11.06	1.56 0.21 to 12.94	1.60 0.21 to 13.14	1.85 0.22 to 13.10	2.27 0.38 to 11.71	2.35 0.31 to 18.87	2.87 0.37 to 23.96
SEMA_PO_7MG_QD	8.73 2.76 to 24.91	0.56 0.11 to 3.16	0.60 0.12 to 3.48	0.71 0.23 to 2.31	0.78 0.23 to 2.77	0.86 0.17 to 5.12	SEMA_PO_7MG_QD	1.25 0.22 to 8.57	1.34 0.23 to 9.53	1.37 0.25 to 9.74	1.58 0.26 to 10.06	1.94 0.62 to 5.95	1.97 0.35 to 13.23	2.46 0.43 to 17.62
SEMA_SC_0p5MG_QW	7.12 1.33 to 26.82	0.45 0.05 to 3.25	0.47 0.06 to 3.61	0.58 0.09 to 3.35	0.63 0.10 to 3.25	0.69 0.09 to 5.20	0.80 0.12 to 4.54	SEMA_SC_0p5MG_QW	1.08 0.13 to 8.81	1.09 0.23 to 4.95	1.26 0.14 to 10.11	1.58 0.23 to 8.34	1.62 0.20 to 12.84	2.00 0.24 to 16.60
EFPE_SC_6MG_QW	6.58 1.28 to 24.54	0.42 0.05 to 2.84	0.44 0.05 to 3.34	0.54 0.08 to 3.15	0.59 0.10 to 3.06	0.64 0.08 to 4.85	0.75 0.10 to 4.38	0.92 0.11 to 7.72	EFPE_SC_6MG_QW	1.01 0.13 to 8.11	1.19 0.13 to 8.20	1.44 0.20 to 8.30	1.48 0.32 to 6.86	1.85 0.41 to 8.42
SEMA_SC_1p0MG_QW	6.45 1.22 to 25.26	0.41 0.05 to 2.87	0.44 0.05 to 3.21	0.53 0.08 to 2.99	0.57 0.09 to 2.99	0.63 0.08 to 4.65	0.73 0.10 to 3.99	0.91 0.20 to 4.35	0.99 0.12 to 7.54	SEMA_SC_1p0MG_QW	1.16 0.13 to 9.09	1.43 0.21 to 7.56	1.45 0.19 to 10.79	1.80 0.24 to 14.81
VISEPE_SC_150UG_QW	5.58 1.19 to 23.50	0.35 0.05 to 2.89	0.37 0.05 to 3.06	0.45 0.07 to 2.84	0.50 0.09 to 2.82	0.54 0.08 to 4.54	0.63 0.10 to 3.81	0.79 0.10 to 7.16	0.84 0.12 to 7.91	0.86 0.11 to 7.65	VISEPE_SC_150UG_QW	1.22 0.20 to 7.52	1.24 0.18 to 10.71	1.59 0.23 to 13.44
SEMA_PO_3MG_QD	4.53 1.41 to 12.75	0.29 0.05 to 1.73	0.30 0.06 to 1.87	0.37 0.12 to 1.20	0.40 0.12 to 1.43	0.44 0.09 to 2.63	0.52 0.17 to 1.63	0.63 0.12 to 4.32	0.69 0.12 to 4.93	0.70 0.13 to 4.74	0.82 0.13 to 4.94	SEMA_PO_3MG_QD	1.02 0.19 to 7.13	1.28 0.22 to 8.99
EFPE_SC_4MG_QW	4.44 0.86 to 16.70	0.28 0.04 to 1.94	0.30 0.04 to 2.09	0.36 0.05 to 2.13	0.40 0.07 to 2.05	0.42 0.05 to 3.25	0.51 0.08 to 2.85	0.62 0.08 to 5.03	0.68 0.15 to 3.12	0.69 0.09 to 5.19	0.81 0.09 to 5.51	0.99 0.14 to 5.41	EFPE_SC_4MG_QW	1.25 0.27 to 5.69
EFPE_SC_2MG_QW	3.58 0.67 to 13.06	0.22 0.03 to 1.59	0.24 0.03 to 1.73	0.29 0.04 to 1.70	0.32 0.05 to 1.63	0.35 0.04 to 2.71	0.41 0.06 to 2.33	0.50 0.06 to 4.21	0.54 0.12 to 2.44	0.55 0.07 to 4.11	0.63 0.07 to 4.34	0.78 0.11 to 4.47	0.80 0.18 to 3.68	EFPE_SC_2MG_QW

Heterogeneity, fit and convergence

Bayesian random effects (primary)

Heterogeneity (tau): 0.639 (95% CrI 0.252 to 1.349), log scale
Residual deviance: 26.3 for 25 data points
DIC: 49.5 (pD 23.1)
Largest R-hat: 1.001
Smallest ESS: bulk 1,850, tail 3,670
Divergent transitions: 0
Convergence: All criteria met
Priors: PR02 N(0, 5^2); PR05 N(0, 2.5^2); PR09 log normal(-2, 1.58^2) on tau^2 (Biological markers (dichotomised), pharm vs pharm)

Frequentist check (netmeta)

Method: inverse variance, REML, OR
Tau: 0.756
I squared: 78%
Q (total): 22.40 on 5 df, P = 0.000
Q (between designs): 22.40, P = 0.000

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.

Baseline effect modifiers and prognostic factors per trial
Trial	Baseline HbA1c (percent) effect modifier, prognostic factor; 6 of 7	Background glucose lowering therapy (stratum S0 to S4) effect modifier, prognostic factor; 7 of 7	Diabetes duration (years) effect modifier, prognostic factor; 6 of 7
PB119 S000217	8.5	S0	2.18
NCT01558271 S000837	8.14	S0	6.59
SUSTAIN™1 S000878	8.05	S0	4.2
NCT01733758 S001075	8.11	S0	6.65
PIONEER 1 S001741	not reported	S0	not reported
PIONEER 9 S001943	8.2	S0	7.6
AMPLITUDE-M S002081	8.07	S0	5.1

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, Diabetes duration: design means range from 2.2 (PLACEBO vs VISEPE_SC_150UG_QW) to 7.6 (LIRA_SC_0p9MG_QD vs PLACEBO vs SEMA_PO_14MG_QD vs SEMA_PO_3MG_QD vs SEMA_PO_7MG_QD) years; threshold 3
NoteOutcome assessment, time point: selected time points span 24 to 30 weeks
NoteOutcome assessment, analysis set: mixed: full_analysis 5, modified_itt 1, randomized 1
NoteOutcome assessment, definition: mixed: HbA1c below 7.0 percent 1, not stated 6
NoteOutcome assessment, proportion method: mixed: not stated 4, not_stated 3
NoteData handling, input conversions: count_from_percent 9

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
PB119	24	full_analysis	not stated	not stated	not stated	not_stated	not stated	not stated	double_blind	industry	2020	age 18 to 75; HbA1c 7.5 to 11.0 at screening and 7.0 to 10.5 at randomization; BMI 18.5 to 40; eGFR 60 or more; drug naive
NCT01558271	26	full_analysis	HbA1c below 7.0 percent	not stated	not stated	not stated	not stated	not stated	double_blind	industry	2012	Japanese; age 20 or more; BMI 18.5 to 35; HbA1c 7.0 to 10.0 percent; OAM naive or OAM stopped
SUSTAIN™1	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; drug naive on diet and exercise; eGFR 30 or more
NCT01733758	24	modified_itt	not stated	not stated	not stated	not stated	not stated	not stated	double_blind	industry	2013	Japanese adults; diet and exercise with or without one oral drug; HbA1c 7 to 10 percent after washout
PIONEER 1	26	full_analysis	not stated	not stated	not stated	not stated	not stated	not stated	double_blind	industry	2016	adults with type 2 diabetes on diet and exercise only; HbA1c 7.0 to 9.5 percent
PIONEER 9	26	full_analysis	not stated	not stated	not stated	not stated	not stated	not stated	double_blind	industry	2017	Japanese adults 20 y or older; HbA1c 6.5 to 9.5 on one oral drug washed out, or 7.0 to 10.0 on diet and exercise
AMPLITUDE-M	30	randomized	not stated	not stated	not stated	not_stated	not stated	not stated	double_blind	industry	2017	type 2 diabetes on diet and exercise, HbA1c 7 to 10 percent, no glucose lowering drug in prior 3 months

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
PB119	A1	VISEPE_SC_150UG_QW	24	arm, responders	69 / 137	count_from_percent	R0011471:Table 2
PB119	A2	PLACEBO	24	arm, responders	19 / 136	count_from_percent	R0011471:Table 2
NCT01558271	A1	DULA_SC_0p75MG_QW	26	arm, responders	200 / 280		R0011901:Results
NCT01558271	A2	LIRA_SC_0p9MG_QD	26	arm, responders	94 / 136		R0011901:Results
NCT01558271	A3	PLACEBO	26	arm, responders	4 / 68		R0011901:Results
SUSTAIN™1	A1	SEMA_SC_0p5MG_QW	30	arm, responders	95 / 128	count_from_percent	registry:outcomes
SUSTAIN™1	A2	SEMA_SC_1p0MG_QW	30	arm, responders	94 / 130	count_from_percent	registry:outcomes
SUSTAIN™1	A3	PLACEBO	30	arm, responders	32 / 129	count_from_percent	registry:outcomes
NCT01733758	A1	PLACEBO	24	arm, responders	4 / 77		registry:outcomes
NCT01733758	A2	ALBI_SC_30MG_QW	24	arm, responders	92 / 159		registry:outcomes
NCT01733758	A3	ALBI_SC_50MG_QW	24	arm, responders	100 / 150		registry:outcomes
NCT01733758	A4	LIRA_SC_0p9MG_QD	24	arm, responders	66 / 103		registry:outcomes
PIONEER 1	A1	SEMA_PO_3MG_QD	26	arm, responders	92 / 167		registry:outcomes
PIONEER 1	A2	SEMA_PO_7MG_QD	26	arm, responders	110 / 160		registry:outcomes
PIONEER 1	A3	SEMA_PO_14MG_QD	26	arm, responders	123 / 160		registry:outcomes
PIONEER 1	A4	PLACEBO	26	arm, responders	52 / 168		registry:outcomes
PIONEER 9	A1	SEMA_PO_3MG_QD	26	arm, responders	24 / 49		registry:outcomes
PIONEER 9	A2	SEMA_PO_7MG_QD	26	arm, responders	33 / 49		registry:outcomes
PIONEER 9	A3	SEMA_PO_14MG_QD	26	arm, responders	35 / 48		registry:outcomes
PIONEER 9	A4	LIRA_SC_0p9MG_QD	26	arm, responders	24 / 48		registry:outcomes
PIONEER 9	A5	PLACEBO	26	arm, responders	6 / 49		registry:outcomes
AMPLITUDE-M	A1	EFPE_SC_2MG_QW	30	arm, responders	60 / 100	count_from_percent	R0007136:Results
AMPLITUDE-M	A2	EFPE_SC_4MG_QW	30	arm, responders	66 / 101	count_from_percent	R0007136:Results
AMPLITUDE-M	A3	EFPE_SC_6MG_QW	30	arm, responders	76 / 103	count_from_percent	R0007136:Results
AMPLITUDE-M	A4	PLACEBO	30	arm, responders	26 / 102	count_from_percent	R0007136:Results

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