Network meta-analysis

Nausea

Chronic kidney disease with diabetes

longest follow-upRecorded harmsEach dose separatelyHazard ratio (from event counts)Separate part 2 of a disconnected network

Randomized trials

Treatments

1,132

Participants

163

Events

In plain language

Across 6 trials with 1,132 participants, 0 of 7 treatments had a clearly better result than placebo on nausea, 3 a clearly worse one, and for 4 the evidence could not tell them apart from placebo. The most favorable estimate was for Semaglutide 1.0 mg subcutaneous once weekly: hazard ratio (from event counts) 1.00 (95% credible interval 0.15 to 8.15).

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
Semaglutide 1.0 mg subcutaneous once weekly SEMA_SC_1p0MG_QW	1.00 (0.15 to 8.15)	0.11 to 10.29	0.99 (0.17 to 5.66)	Unclear
Lixisenatide 20 ug subcutaneous once daily LIXI_SC_20UG_QD	1.17 (0.27 to 5.59)	0.17 to 7.96	1.20 (0.34 to 4.22)	Unclear
Cotadutide 300 ug subcutaneous once daily COTA_SC_300UG_QD	2.48 (0.54 to 11.83)	0.37 to 15.23		Unclear
Semaglutide 14 mg oral once daily (original tablet) SEMA_PO_14MG_QD	2.63 (0.77 to 8.25)	0.48 to 12.65	2.92 (1.44 to 5.91)	Unclear
Liraglutide 1.8 mg subcutaneous once daily LIRA_SC_1p8MG_QD	5.08 (1.27 to 18.34)	0.76 to 27.26	6.05 (2.43 to 15.05)	Worse
HRS-7535 30 mg tablet once daily HRS7535_PO_30MG_QD	5.27 (1.17 to 23.35)	0.69 to 32.96		Worse
HRS-7535 90 mg tablet once daily HRS7535_PO_90MG_QD	10.53 (2.24 to 46.61)	1.41 to 63.77		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	SEMA_SC_1p0MG_QW	LIXI_SC_20UG_QD	COTA_SC_300UG_QD	SEMA_PO_14MG_QD	LIRA_SC_1p8MG_QD	HRS7535_PO_30MG_QD	HRS7535_PO_90MG_QD
PLACEBO	PLACEBO	1.00 0.12 to 6.50	0.85 0.18 to 3.77	0.40 0.08 to 1.85	0.38 0.12 to 1.30	0.20 0.05 to 0.79	0.19 0.04 to 0.86	0.09 0.02 to 0.45
SEMA_SC_1p0MG_QW	1.00 0.15 to 8.15	SEMA_SC_1p0MG_QW	0.85 0.07 to 10.92	0.41 0.04 to 5.31	0.38 0.04 to 4.22	0.20 0.02 to 2.52	0.19 0.02 to 2.69	0.09 0.01 to 1.35
LIXI_SC_20UG_QD	1.17 0.27 to 5.59	1.17 0.09 to 13.68	LIXI_SC_20UG_QD	0.48 0.06 to 4.10	0.45 0.07 to 3.39	0.23 0.03 to 1.90	0.22 0.03 to 1.97	0.11 0.01 to 1.00
COTA_SC_300UG_QD	2.48 0.54 to 11.83	2.45 0.19 to 26.83	2.09 0.24 to 17.64	COTA_SC_300UG_QD	0.94 0.14 to 6.28	0.49 0.07 to 3.80	0.47 0.06 to 4.02	0.23 0.03 to 2.01
SEMA_PO_14MG_QD	2.63 0.77 to 8.25	2.62 0.24 to 22.99	2.23 0.30 to 14.36	1.06 0.16 to 7.03	SEMA_PO_14MG_QD	0.51 0.09 to 3.22	0.50 0.08 to 3.41	0.25 0.04 to 1.71
LIRA_SC_1p8MG_QD	5.08 1.27 to 18.34	5.07 0.40 to 48.50	4.33 0.53 to 29.47	2.05 0.26 to 13.62	1.95 0.31 to 10.88	LIRA_SC_1p8MG_QD	0.96 0.13 to 6.57	0.48 0.07 to 3.27
HRS7535_PO_30MG_QD	5.27 1.17 to 23.35	5.30 0.37 to 55.66	4.47 0.51 to 35.20	2.14 0.25 to 16.98	2.01 0.29 to 13.14	1.04 0.15 to 7.53	HRS7535_PO_30MG_QD	0.50 0.15 to 1.64
HRS7535_PO_90MG_QD	10.53 2.24 to 46.61	10.63 0.74 to 106	9.07 1.00 to 70.90	4.31 0.50 to 32.47	4.06 0.59 to 24.98	2.10 0.31 to 14.54	2.01 0.61 to 6.45	HRS7535_PO_90MG_QD

Heterogeneity, fit and convergence

Bayesian random effects (primary)

Heterogeneity (tau): 0.360 (95% CrI 0.082 to 1.257), log scale
Residual deviance: 12.8 for 13 data points
DIC: 25.3 (pD 12.6)
Largest R-hat: 1.001
Smallest ESS: bulk 3,945, tail 3,710
Divergent transitions: 0
Convergence: All criteria met
Priors: PR02 N(0, 5^2); PR05 N(0, 2.5^2); PR09 log normal(-1.87, 1.52^2) on tau^2 (Adverse events, pharm vs placebo control)

Frequentist check (netmeta)

Method: inverse variance, REML, OR
Tau: 0.000
Q (total): 0.00 on 0 df
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 6
REMODEL S000395	23.56
SOLID-DKD S001370	26.07
NCT01620489 S001504	49.1
PIONEER 5 S002025	51.85
NCT03550378 S002039	48.8
S002858 S002858	35.35

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, Sex: design means range from 23.6 (PLACEBO vs SEMA_SC_1p0MG_QW) to 51.9 (PLACEBO vs SEMA_PO_14MG_QD) percent female; threshold 15
NoteOutcome assessment, time point: selected time points span 8.43 to 57 weeks
NoteOutcome assessment, analysis set: mixed: randomized 2, safety 4
NoteOutcome assessment, definition: mixed: level 3 severe hypoglycemia 1, not stated 4, serious acute kidney injury 1
NoteData handling, input conversions: nonserious_only 6

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
REMODEL	57	randomized	serious acute kidney injury	not stated	not stated	not stated	not stated	not stated	double_blind	industry	2021	T2D with HbA1c 9.0 percent or less; eGFR 30 to 75; UACR 20 to under 5000 mg/g
SOLID-DKD	18	safety	level 3 severe hypoglycemia	not stated	not stated	not stated	not stated	not stated	double_blind	industry	2024	age 18 to 75; T2D with UACR 300 to below 3000 mg/g; eGFR 30 or more; HbA1c 6.5 to 10; BMI 20 to 40
NCT01620489	27	safety	not stated	not stated	not stated	not stated	not stated	not stated	double_blind	industry	2012	type 2 diabetes; eGFR 30 to 59 mL/min/1.73m2 (MDRD); oral drugs and/or insulin
PIONEER 5	31	safety	not stated	not stated	not stated	not stated	not stated	not stated	double_blind	industry	2016	type 2 diabetes; HbA1c 7.0 to 9.5 percent; moderate renal impairment
NCT03550378	8.43	safety	not stated	not stated	not stated	not stated	not stated	not stated	double_blind	industry	2018	age 18 to 84; BMI 25 to 45; eGFR 30 to 59; HbA1c 6.5 to 10.5 percent
S002858	24	randomized	not stated	not stated	not stated	not stated	not stated	not stated	double_blind	industry		T2D age over 35; clinical CKD; eGFR above 30 mL/min; stable ACE inhibitor or ARB

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
REMODEL	A1	SEMA_SC_1p0MG_QW	57	arm, events	4 / 71	nonserious_only	registry:adverse_events
REMODEL	A2	PLACEBO	57	arm, events	2 / 35	nonserious_only	registry:adverse_events
SOLID-DKD	A1	HRS7535_PO_30MG_QD	18	arm, events	18 / 93		R0004355:Table 2
SOLID-DKD	A2	HRS7535_PO_90MG_QD	18	arm, events	33 / 94		R0004355:Table 2
SOLID-DKD	A3	PLACEBO	18	arm, events	3 / 94		R0004355:Table 2
NCT01620489	A1	LIRA_SC_1p8MG_QD	27	arm, events	30 / 140	nonserious_only	registry:adverse_events
NCT01620489	A2	PLACEBO	27	arm, events	6 / 139	nonserious_only	registry:adverse_events
PIONEER 5	A1	SEMA_PO_14MG_QD	31	arm, events	31 / 163	nonserious_only	registry:adverse_events
PIONEER 5	A2	PLACEBO	31	arm, events	12 / 161	nonserious_only	registry:adverse_events
NCT03550378	A1	COTA_SC_300UG_QD	8.43	arm, events	9 / 21		R0019218:Table 2
NCT03550378	A2	PLACEBO	8.43	arm, events	4 / 20		R0019218:Table 2
S002858	A1	LIXI_SC_20UG_QD	24	arm, events	6 / 51		R0001573:Supplement Table S1
S002858	A2	PLACEBO	24	arm, events	5 / 50		R0001573:Supplement Table S1

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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