Network meta-analysis

Nausea

Polycystic ovary syndrome

longest follow-upRecorded harmsDoses of a drug pooledHazard ratio (from event counts)

Randomized trials

Treatments

450

Participants

160

Events

In plain language

Across 8 trials with 450 participants, 0 of 4 treatments had a clearly better result than placebo on nausea, 2 a clearly worse one, and for 2 the evidence could not tell them apart from placebo. The most favorable estimate was for Cyproterone ethinylestradiol: hazard ratio (from event counts) 0.20 (95% credible interval 0.00 to 3.83).

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
Cyproterone ethinylestradiol OTHER_ACTIVE_cyproterone_ethinylestradiol	0.20 (0.00 to 3.83)	0.00 to 4.27		Unclear
Metformin METFORMIN	2.80 (0.81 to 8.22)	0.59 to 10.77		Unclear
Liraglutide and metformin injection LIRAMETF_SC	6.24 (2.08 to 17.45)	1.42 to 22.52		Worse
Liraglutide injection LIRA_SC	6.88 (3.08 to 15.30)	2.01 to 21.45	11.38 (2.76 to 46.90)	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	OTHER_ACTIVE_cyproterone_ethinylestradiol	METFORMIN	LIRAMETF_SC	LIRA_SC
PLACEBO	PLACEBO	4.88 0.26 to 289	0.36 0.12 to 1.23	0.16 0.06 to 0.48	0.15 0.07 to 0.33
OTHER_ACTIVE_cyproterone_ethinylestradiol	0.20 0.00 to 3.83	OTHER_ACTIVE_cyproterone_ethinylestradiol	0.08 0.00 to 1.61	0.03 0.00 to 0.71	0.03 0.00 to 0.56
METFORMIN	2.80 0.81 to 8.22	13.29 0.62 to 890	METFORMIN	0.45 0.17 to 1.13	0.40 0.16 to 0.90
LIRAMETF_SC	6.24 2.08 to 17.45	30.44 1.40 to 1955	2.22 0.89 to 6.01	LIRAMETF_SC	0.89 0.41 to 1.89
LIRA_SC	6.88 3.08 to 15.30	33.73 1.77 to 2119	2.49 1.11 to 6.18	1.12 0.53 to 2.43	LIRA_SC

Heterogeneity, fit and convergence

Bayesian random effects (primary)

Heterogeneity (tau): 0.301 (95% CrI 0.069 to 0.942), log scale
Residual deviance: 18.9 for 18 data points
DIC: 31.5 (pD 12.5)
Largest R-hat: 1.001
Smallest ESS: bulk 2,399, tail 3,435
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: 1.037
I squared: 69%
Q (total): 6.44 on 2 df, P = 0.040

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	Sex (percent female) effect modifier, prognostic factor; 7 of 8
NCT02909933 S000499	100
SAXAPCOS S000534	100
NCT01911468 S000723	100
LIPT S000948	100
NCT03151005 S001582	85.71
NCT02187250 S001782	100
S003022 S003022	not reported
S003101 S003101	100

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 3, other 2, randomized 1, safety 2
NoteOutcome assessment, definition: mixed: nausea 1, not stated 7
NoteRisk of bias, blinding: mixed: double_blind 3, open_label 5
NoteRisk of bias, funding: mixed: industry 1, mixed 2, non_industry 5
NoteData handling, input conversions: nonserious_only 2, printed_denominator 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
NCT02909933	12	completers	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	36	safety	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	12	randomized	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	26	safety	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
NCT03151005	12	completers	not stated	not stated	not stated	not stated	not stated	not stated	open_label	non_industry	2017	Rotterdam PCOS, BMI 24 kg/m2 or more, age 18 to 50 years
NCT02187250	12	other	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	12	completers	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
S003101	26	other	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

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	12	arm, events	8 / 15		R0022935:Results
NCT02909933	A2	LIRAMETF_SC	12	arm, events	6 / 15		R0022935:Results
SAXAPCOS	A1	LIRA_SC	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	12	arm, events	6 / 11	printed_denominator	R0018103:Results
NCT01911468	A3	LIRAMETF_SC	12	arm, events	6 / 11	printed_denominator	R0018103:Results
LIPT	A1	LIRA_SC	26	arm, events	37 / 48	nonserious_only	registry:adverse_events
LIPT	A2	PLACEBO	26	arm, events	3 / 24	nonserious_only	registry:adverse_events
NCT03151005	A1	OTHER_ACTIVE_cyproterone_ethinylestradiol	12	arm, events	0 / 35		R0007146:Supplement Table 1
NCT03151005	A2	LIRA_SC	12	arm, events	4 / 35		R0007146:Supplement Table 1
NCT02187250	A1	METFORMIN	12	arm, events	4 / 14	printed_denominator	R0023497:Results
NCT02187250	A2	LIRA_SC	12	arm, events	4 / 14	printed_denominator	R0023497:Results
S003022	A1	METFORMIN	12	arm, events	6 / 20		R0015954:Results
S003022	A2	LIRA_SC	12	arm, events	9 / 20		R0015954:Results
S003022	A3	LIRAMETF_SC	12	arm, events	9 / 20		R0015954:Results
S003101	A1	LIRA_SC	26	arm, events	37 / 48		R0025661:Table 2
S003101	A2	PLACEBO	26	arm, events	3 / 24		R0025661:Table 2

Rerun this analysis yourself

Remove treatments or trials and refit the frequentist and Bayesian models in your browser, with the same methods as the published analysis.

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