Network meta-analysis

Nausea

Polycystic ovary syndrome

longest follow-upRecorded harmsEach dose separatelyHazard ratio (from event counts)

Randomized trials

Treatments

380

Participants

156

Events

In plain language

Across 7 trials with 380 participants, 0 of 6 treatments had a clearly better result than placebo on nausea, 1 a clearly worse one, and for 5 the evidence could not tell them apart from placebo. The most favorable estimate was for Metformin: hazard ratio (from event counts) 0.52 (95% credible interval 0.08 to 2.89).

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.

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

Hazard ratio (from event counts). Lower 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 HR (95% CrI)	95% prediction interval	Frequentist HR (95% CI)	Verdict
Metformin METFORMIN	0.52 (0.08 to 2.89)	0.07 to 3.53		Unclear
Liraglutide and metformin 1.2 to 0.85 mg injection once daily LIRAMETF_SC_1p2-0p85MG_QD	1.01 (0.14 to 6.70)	0.13 to 8.19		Unclear
Liraglutide 1.2 mg subcutaneous once daily LIRA_SC_1p2MG_QD	1.12 (0.19 to 6.20)	0.16 to 7.23		Unclear
Liraglutide plus metformin 1.2 to 1000 mg injection once daily LIRAMETF_SC_1p2-1000MG_QD	1.71 (0.36 to 7.90)	0.30 to 9.71		Unclear
Liraglutide 3.0 mg subcutaneous once daily LIRA_SC_3p0MG_QD	2.54 (0.73 to 9.53)	0.56 to 11.92	2.73 (0.71 to 10.48)	Unclear
Liraglutide 1.8 mg subcutaneous once daily LIRA_SC_1p8MG_QD	10.66 (3.95 to 29.47)	2.73 to 40.01	23.55 (8.85 to 62.67)	Worse

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: hazard ratio (from event counts) 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	METFORMIN	LIRAMETF_SC_1p2-0p85MG_QD	LIRA_SC_1p2MG_QD	LIRAMETF_SC_1p2-1000MG_QD	LIRA_SC_3p0MG_QD	LIRA_SC_1p8MG_QD
PLACEBO	PLACEBO	1.93 0.35 to 11.79	0.99 0.15 to 6.97	0.89 0.16 to 5.30	0.59 0.13 to 2.81	0.39 0.10 to 1.38	0.09 0.03 to 0.25
METFORMIN	0.52 0.08 to 2.89	METFORMIN	0.51 0.15 to 1.68	0.47 0.18 to 1.11	0.30 0.08 to 1.16	0.20 0.04 to 1.05	0.05 0.01 to 0.36
LIRAMETF_SC_1p2-0p85MG_QD	1.01 0.14 to 6.70	1.97 0.60 to 6.72	LIRAMETF_SC_1p2-0p85MG_QD	0.91 0.28 to 2.87	0.60 0.12 to 2.99	0.39 0.06 to 2.52	0.09 0.01 to 0.83
LIRA_SC_1p2MG_QD	1.12 0.19 to 6.20	2.13 0.90 to 5.44	1.10 0.35 to 3.55	LIRA_SC_1p2MG_QD	0.65 0.18 to 2.44	0.44 0.09 to 2.16	0.10 0.01 to 0.76
LIRAMETF_SC_1p2-1000MG_QD	1.71 0.36 to 7.90	3.32 0.86 to 13.25	1.67 0.33 to 8.51	1.54 0.41 to 5.67	LIRAMETF_SC_1p2-1000MG_QD	0.67 0.19 to 2.36	0.16 0.02 to 0.98
LIRA_SC_3p0MG_QD	2.54 0.73 to 9.53	4.92 0.96 to 27.47	2.54 0.40 to 16.72	2.30 0.46 to 11.73	1.49 0.42 to 5.24	LIRA_SC_3p0MG_QD	0.24 0.05 to 1.27
LIRA_SC_1p8MG_QD	10.66 3.95 to 29.47	20.89 2.76 to 166	10.65 1.20 to 94.32	9.72 1.32 to 76.13	6.22 1.02 to 40.26	4.20 0.79 to 21.07	LIRA_SC_1p8MG_QD

Heterogeneity, fit and convergence

Bayesian random effects (primary)

Heterogeneity (tau): 0.288 (95% CrI 0.068 to 0.963), log scale
Residual deviance: 16.4 for 16 data points
DIC: 29.7 (pD 13.2)
Largest R-hat: 1.001
Smallest ESS: bulk 2,295, tail 3,213
Divergent transitions: 0
Convergence: All criteria met
Priors: PR02 N(0, 5^2); PR05 N(0, 2.5^2); PR09 log normal(-2.1, 1.58^2) on tau^2 (Adverse events, pharm vs pharm)

Frequentist check (netmeta)

Method: inverse variance, REML, OR
Tau: 0.000
I squared: 0%
Q (total): 0.00 on 1 df, P = 1.000
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.

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	Sex (percent female) effect modifier, prognostic factor; 6 of 7
S003101 S003101	100
NCT02909933 S000499	100
SAXAPCOS S000534	100
NCT01911468 S000723	100
LIPT S000948	100
NCT02187250 S001782	100
S003022 S003022	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.

NoteOutcome assessment, time point: selected time points span 12 to 36 weeks
NoteOutcome assessment, analysis set: mixed: completers 2, other 2, randomized 1, safety 2
NoteOutcome assessment, definition: mixed: nausea 1, not stated 6
NoteRisk of bias, blinding: mixed: double_blind 3, open_label 4
NoteRisk of bias, funding: mixed: industry 1, mixed 2, non_industry 4
NoteData handling, input conversions: nonserious_only 2, printed_denominator 5

Comparability items per trial
Trial	analysis set	time weeks	definition	instrument	adjudicated	proportion method	intercurrent events (discontinuation)	intercurrent events (rescue)	blinding	funding	start year	Eligibility
S003101	other	26	not stated	not stated	not stated	not stated	not stated	not stated	double_blind	mixed	2014	premenopausal women 18 or older; Rotterdam PCOS; BMI 25 or more and/or C-peptide above 0.6 nmol/L; no diabetes
NCT02909933	completers	12	not stated	not stated	not stated	not stated	not stated	not stated	open_label	non_industry	2015	women 18 to menopause, PCOS phenotype A by Rotterdam criteria, BMI 30 or higher
SAXAPCOS	safety	36	not stated	not stated	not stated	not stated	not stated	not stated	double_blind	industry	2018	premenopausal women 18 to 45 years; PCOS by modified NIH 1990; BMI 30 or more; no diabetes
NCT01911468	randomized	12	not stated	not stated	not stated	not stated	not stated	not stated	open_label	non_industry	2011	premenopausal women over 18; BMI 30 or more; metformin 6 months or longer with under 5 percent weight loss; no diabetes
LIPT	safety	26	not stated	not stated	not stated	not stated	not stated	not stated	double_blind	mixed	2014	Rotterdam PCOS; BMI over 25 or insulin resistance; non hormonal contraception; no diabetes or CVD
NCT02187250	other	12	not stated	not stated	not stated	not stated	not stated	not stated	open_label	non_industry	2014	women with PCOS (Rotterdam phenotype A), age 18 to menopause, BMI 30 or higher
S003022	completers	12	nausea	not stated	not stated	not stated	not stated	not stated	open_label	non_industry	2018	women with PCOS (Rotterdam); age over 18; premenopausal; BMI 24 or more

Trial data

What each trial contributes. Arm rows give the arm value with its standard error, or events over participants; contrast rows give the hazard ratio (from event counts) 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
NCT02909933	A1	LIRA_SC_3p0MG_QD	12	arm, events	8 / 15		R0022935:Results
NCT02909933	A2	LIRAMETF_SC_1p2-1000MG_QD	12	arm, events	6 / 15		R0022935:Results
SAXAPCOS	A1	LIRA_SC_3p0MG_QD	36	arm, events	14 / 55		R0022023:Table 4
SAXAPCOS	A2	PLACEBO	36	arm, events	3 / 27		R0022023:Table 4
NCT01911468	A1	METFORMIN	12	arm, events	1 / 14	printed_denominator	R0018103:Results
NCT01911468	A2	LIRA_SC_1p2MG_QD	12	arm, events	6 / 11	printed_denominator	R0018103:Results
NCT01911468	A3	LIRAMETF_SC_1p2-1000MG_QD	12	arm, events	6 / 11	printed_denominator	R0018103:Results
LIPT	A1	LIRA_SC_1p8MG_QD	26	arm, events	37 / 48	nonserious_only	registry:adverse_events
LIPT	A2	PLACEBO	26	arm, events	3 / 24	nonserious_only	registry:adverse_events
NCT02187250	A1	METFORMIN	12	arm, events	4 / 14	printed_denominator	R0023497:Results
NCT02187250	A2	LIRA_SC_1p2MG_QD	12	arm, events	4 / 14	printed_denominator	R0023497:Results
S003022	A1	METFORMIN	12	arm, events	6 / 20		R0015954:Results
S003022	A2	LIRA_SC_1p2MG_QD	12	arm, events	9 / 20		R0015954:Results
S003022	A3	LIRAMETF_SC_1p2-0p85MG_QD	12	arm, events	9 / 20		R0015954:Results
S003101	A1	LIRA_SC_1p8MG_QD	26	arm, events	37 / 48		R0025661:Table 2
S003101	A2	PLACEBO	26	arm, events	3 / 24		R0025661:Table 2

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