Network meta-analysis

HbA1c below 7 percent

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

weeks 36 to 64 (target week 52)Treatment policyEach dose separatelyOdds ratio

Randomized trials

Treatments

3,677

Participants

1,498

Events

In plain language

Across 4 trials with 3,677 participants, 4 of 7 treatments had a clearly better result than placebo on HbA1c below 7 percent, and for 3 the evidence could not tell them apart from placebo. The most favorable estimate was for Semaglutide oral once daily (original tablet), flexible dose: 3, 7 or 14 mg adjusted by HbA1c and tolerability: odds ratio 7.78 (95% credible interval 1.40 to 22.25).

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
Semaglutide oral once daily (original tablet), flexible dose: 3, 7 or 14 mg adjusted by HbA1c and tolerability SEMA_PO_FLEX_QD	7.78 (1.40 to 22.25)	1.05 to 26.60	11.08 (4.95 to 24.80)	Better
Semaglutide 14 mg oral once daily (original tablet) SEMA_PO_14MG_QD	6.83 (2.50 to 13.89)	1.74 to 17.74	8.74 (4.83 to 15.80)	Better
Liraglutide 1.8 mg subcutaneous once daily LIRA_SC_1p8MG_QD	5.81 (2.13 to 12.43)	1.56 to 16.25	6.91 (3.82 to 12.49)	Better
Semaglutide 7 mg oral once daily (original tablet) SEMA_PO_7MG_QD	3.75 (1.08 to 8.46)	0.82 to 10.60	4.90 (2.51 to 9.57)	Better
Dulaglutide 0.75 mg subcutaneous once weekly DULA_SC_0p75MG_QW	2.89 (0.75 to 7.85)	0.57 to 9.59	3.91 (1.68 to 9.14)	Unclear
Sitagliptin SITAGLIPTIN	2.49 (0.66 to 5.74)	0.50 to 7.34	3.43 (1.72 to 6.84)	Unclear
Semaglutide 3 mg oral once daily (original tablet) SEMA_PO_3MG_QD	1.76 (0.51 to 3.94)	0.37 to 4.87	2.39 (1.22 to 4.68)	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	SEMA_PO_FLEX_QD	SEMA_PO_14MG_QD	LIRA_SC_1p8MG_QD	SEMA_PO_7MG_QD	DULA_SC_0p75MG_QW	SITAGLIPTIN	SEMA_PO_3MG_QD
PLACEBO	PLACEBO	0.13 0.04 to 0.71	0.15 0.07 to 0.40	0.17 0.08 to 0.47	0.27 0.12 to 0.93	0.35 0.13 to 1.34	0.40 0.17 to 1.52	0.57 0.25 to 1.95
SEMA_PO_FLEX_QD	7.78 1.40 to 22.25	SEMA_PO_FLEX_QD	1.14 0.31 to 2.91	1.35 0.28 to 4.21	2.10 0.60 to 5.74	2.69 0.66 to 8.92	3.10 1.20 to 6.82	4.43 1.29 to 12.28
SEMA_PO_14MG_QD	6.83 2.50 to 13.89	0.87 0.34 to 3.18	SEMA_PO_14MG_QD	1.19 0.50 to 2.51	1.83 1.07 to 3.45	2.35 1.01 to 5.79	2.72 1.43 to 6.22	3.89 2.23 to 7.66
LIRA_SC_1p8MG_QD	5.81 2.13 to 12.43	0.74 0.24 to 3.53	0.84 0.40 to 2.00	LIRA_SC_1p8MG_QD	1.54 0.63 to 4.57	1.98 0.68 to 6.89	2.29 0.92 to 7.48	3.25 1.37 to 10.15
SEMA_PO_7MG_QD	3.75 1.08 to 8.46	0.48 0.17 to 1.67	0.55 0.29 to 0.94	0.65 0.22 to 1.59	SEMA_PO_7MG_QD	1.28 0.53 to 3.10	1.48 0.74 to 3.28	2.12 1.16 to 3.95
DULA_SC_0p75MG_QW	2.89 0.75 to 7.85	0.37 0.11 to 1.52	0.43 0.17 to 0.99	0.50 0.15 to 1.48	0.78 0.32 to 1.88	DULA_SC_0p75MG_QW	1.16 0.44 to 3.41	1.66 0.69 to 3.96
SITAGLIPTIN	2.49 0.66 to 5.74	0.32 0.15 to 0.83	0.37 0.16 to 0.70	0.44 0.13 to 1.09	0.68 0.30 to 1.36	0.86 0.29 to 2.30	SITAGLIPTIN	1.42 0.66 to 2.88
SEMA_PO_3MG_QD	1.76 0.51 to 3.94	0.23 0.08 to 0.77	0.26 0.13 to 0.45	0.31 0.10 to 0.73	0.47 0.25 to 0.86	0.60 0.25 to 1.44	0.70 0.35 to 1.51	SEMA_PO_3MG_QD

Heterogeneity, fit and convergence

Bayesian random effects (primary)

Heterogeneity (tau): 0.268 (95% CrI 0.067 to 0.873), log scale
Residual deviance: 12.9 for 13 data points
DIC: 25.2 (pD 12.2)
Largest R-hat: 1.002
Smallest ESS: bulk 1,979, tail 2,166
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: 0.132
I squared: 28%
Q (total): 2.77 on 2 df, P = 0.250
Q (between designs): 2.77, P = 0.250

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; 4 of 4	Background glucose lowering therapy (stratum S0 to S4) effect modifier, prognostic factor; 4 of 4	Diabetes duration (years) effect modifier, prognostic factor; 3 of 4
PIONEER 4 S000133	7.98	S1	7.6
PIONEER 10 S000234	8.31	S1	9.36
PIONEER 7 S001153	7.93	S1	8.71
PIONEER 3 S002267	8.33	S1	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, Diabetes duration: not reported by 1 of 4 trials
NoteOutcome assessment, analysis set: mixed: full_analysis 3, randomized 1
NoteOutcome assessment, definition: mixed: HbA1c below 7.0 percent 2, not stated 2
NoteOutcome assessment, proportion method: mixed: not stated 3, observed 1
NoteOutcome assessment, intercurrent events (discontinuation): mixed: hypothetical 2, not stated 2
NoteOutcome assessment, intercurrent events (rescue): mixed: hypothetical 2, not stated 2
NoteRisk of bias, blinding: mixed: double_blind 2, open_label 1, single_blind 1
NoteData handling, input conversions: arms_combined 2, count_from_percent 3

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
PIONEER 4	52	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	52	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 7	52	randomized	not stated	not stated	not stated	not stated	not stated	not stated	open_label	industry	2016	age 18 or more; HbA1c 7.5 to 9.5 percent; one or two oral glucose lowering drugs
PIONEER 3	52	full_analysis	HbA1c below 7.0 percent	not stated	not stated	not stated	not stated	not stated	double_blind	industry	2016	adults 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 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
PIONEER 4	A1	SEMA_PO_14MG_QD	52	arm, responders	167 / 275	count_from_percent	R0015836:Figure 2C
PIONEER 4	A2	LIRA_SC_1p8MG_QD	52	arm, responders	148 / 269	count_from_percent	R0015836:Figure 2C
PIONEER 4	A3	PLACEBO	52	arm, responders	20 / 133	count_from_percent	R0015836:Figure 2C
PIONEER 10	A1	SEMA_PO_3MG_QD	52	arm, responders	43 / 126		R0018421:Table 4
PIONEER 10	A2	SEMA_PO_7MG_QD	52	arm, responders	77 / 129		R0018421:Table 4
PIONEER 10	A3	SEMA_PO_14MG_QD	52	arm, responders	90 / 127		R0018421:Table 4
PIONEER 10	A4	DULA_SC_0p75MG_QW	52	arm, responders	32 / 63		R0018421:Table 4
PIONEER 7	A1+A3	SEMA_PO_FLEX_QD	52	arm, responders	178 / 345	arms_combined	registry:outcomes
PIONEER 7	A2+A4	SITAGLIPTIN	52	arm, responders	86 / 347	arms_combined	registry:outcomes
PIONEER 3	A1	SEMA_PO_3MG_QD	52	arm, responders	113 / 466		registry:outcomes
PIONEER 3	A2	SEMA_PO_7MG_QD	52	arm, responders	168 / 465		registry:outcomes
PIONEER 3	A3	SEMA_PO_14MG_QD	52	arm, responders	238 / 465		registry:outcomes
PIONEER 3	A4	SITAGLIPTIN	52	arm, responders	138 / 467		registry:outcomes

Rerun this analysis yourself

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