Network meta-analysis

Serious adverse events

Chronic kidney disease with diabetes

longest follow-upRecorded harmsDoses of a drug pooledHazard ratio (from event counts)Separate part 2 of a disconnected network

Randomized trials

Treatments

1,132

Participants

105

Events

In plain language

Across 6 trials with 1,132 participants, 0 of 6 treatments had a clearly better result than placebo on serious adverse events, and for 6 the evidence could not tell them apart from placebo. The most favorable estimate was for Liraglutide injection: hazard ratio (from event counts) 0.91 (95% credible interval 0.25 to 3.10).

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
Liraglutide injection LIRA_SC	0.91 (0.25 to 3.10)	0.16 to 4.51	0.92 (0.43 to 1.98)	Unclear
Cotadutide injection COTA_SC	0.97 (0.11 to 8.78)	0.08 to 11.41		Unclear
Semaglutide tablet SEMA_PO	0.99 (0.30 to 3.64)	0.18 to 5.25	0.99 (0.48 to 2.01)	Unclear
Semaglutide injection SEMA_SC	1.42 (0.34 to 6.09)	0.25 to 8.72	1.47 (0.48 to 4.48)	Unclear
Lixisenatide injection LIXI_SC	1.60 (0.31 to 9.61)	0.22 to 12.52	1.70 (0.38 to 7.54)	Unclear
HRS-7535 tablet HRS7535_PO	2.21 (0.40 to 16.37)	0.30 to 19.32		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: 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	LIRA_SC	COTA_SC	SEMA_PO	SEMA_SC	LIXI_SC	HRS7535_PO
PLACEBO	PLACEBO	1.09 0.32 to 3.93	1.04 0.11 to 9.32	1.01 0.27 to 3.35	0.71 0.16 to 2.94	0.62 0.10 to 3.20	0.45 0.06 to 2.48
LIRA_SC	0.91 0.25 to 3.10	LIRA_SC	0.94 0.08 to 11.26	0.93 0.15 to 5.01	0.64 0.10 to 4.17	0.56 0.07 to 4.15	0.41 0.04 to 3.25
COTA_SC	0.97 0.11 to 8.78	1.07 0.09 to 13.24	COTA_SC	0.97 0.08 to 11.78	0.67 0.05 to 9.90	0.60 0.04 to 9.80	0.43 0.02 to 7.52
SEMA_PO	0.99 0.30 to 3.64	1.07 0.20 to 6.77	1.03 0.08 to 12.45	SEMA_PO	0.69 0.11 to 4.62	0.62 0.07 to 5.39	0.44 0.05 to 3.60
SEMA_SC	1.42 0.34 to 6.09	1.57 0.24 to 10.38	1.50 0.10 to 20.52	1.45 0.22 to 9.24	SEMA_SC	0.90 0.09 to 7.71	0.63 0.06 to 6.20
LIXI_SC	1.60 0.31 to 9.61	1.77 0.24 to 14.85	1.67 0.10 to 28.04	1.62 0.19 to 13.93	1.12 0.13 to 10.80	LIXI_SC	0.71 0.06 to 8.72
HRS7535_PO	2.21 0.40 to 16.37	2.42 0.31 to 24.76	2.31 0.13 to 44.83	2.28 0.28 to 21.66	1.59 0.16 to 16.51	1.41 0.11 to 17.96	HRS7535_PO

Heterogeneity, fit and convergence

Bayesian random effects (primary)

Heterogeneity (tau): 0.353 (95% CrI 0.085 to 1.301), log scale
Residual deviance: 11.9 for 12 data points
DIC: 23.8 (pD 11.9)
Largest R-hat: 1.001
Smallest ESS: bulk 3,718, tail 3,167
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.

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 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, severe hypoglycemia 1
NoteData handling, input conversions: arms_combined 1

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	severe hypoglycemia	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	57	arm, events	14 / 71		R0007381:Extended Data Table 5
REMODEL	A2	PLACEBO	57	arm, events	5 / 35		R0007381:Extended Data Table 5
SOLID-DKD	A1+A2	HRS7535_PO	18	arm, events	9 / 187	arms_combined	R0004355:Table 2
SOLID-DKD	A3	PLACEBO	18	arm, events	2 / 94		R0004355:Table 2
NCT01620489	A1	LIRA_SC	27	arm, events	14 / 140		registry:adverse_events
NCT01620489	A2	PLACEBO	27	arm, events	15 / 139		registry:adverse_events
PIONEER 5	A1	SEMA_PO	31	arm, events	17 / 163		registry:adverse_events
PIONEER 5	A2	PLACEBO	31	arm, events	17 / 161		registry:adverse_events
NCT03550378	A1	COTA_SC	8.43	arm, events	2 / 21		R0019218:Table 2
NCT03550378	A2	PLACEBO	8.43	arm, events	2 / 20		R0019218:Table 2
S002858	A1	LIXI_SC	24	arm, events	5 / 51		R0001573:Supplement Table S2
S002858	A2	PLACEBO	24	arm, events	3 / 50		R0001573:Supplement Table S2

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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