Network meta-analysis

Discontinuation due to adverse events

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

529

Participants

Events

In plain language

Across 4 trials with 529 participants, 0 of 5 treatments had a clearly better result than placebo on discontinuation due to adverse events, and for 5 the evidence could not tell them apart from placebo. The most favorable estimate was for Lixisenatide 20 ug subcutaneous once daily: hazard ratio (from event counts) 1.39 (95% credible interval 0.22 to 9.73).

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
Lixisenatide 20 ug subcutaneous once daily LIXI_SC_20UG_QD	1.39 (0.22 to 9.73)	0.19 to 11.41	1.50 (0.24 to 9.38)	Unclear
HRS-7535 90 mg tablet once daily HRS7535_PO_90MG_QD	1.61 (0.08 to 26.36)	0.08 to 29.44		Unclear
Cotadutide 300 ug subcutaneous once daily COTA_SC_300UG_QD	1.75 (0.18 to 20.43)	0.15 to 22.47		Unclear
Semaglutide 1.0 mg subcutaneous once weekly SEMA_SC_1p0MG_QW	3.99 (0.70 to 38.23)	0.60 to 44.47	4.94 (0.60 to 40.62)	Unclear
HRS-7535 30 mg tablet once daily HRS7535_PO_30MG_QD	6.29 (0.58 to 94.77)	0.52 to 109		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	LIXI_SC_20UG_QD	HRS7535_PO_90MG_QD	COTA_SC_300UG_QD	SEMA_SC_1p0MG_QW	HRS7535_PO_30MG_QD
PLACEBO	PLACEBO	0.72 0.10 to 4.51	0.62 0.04 to 11.96	0.57 0.05 to 5.55	0.25 0.03 to 1.43	0.16 0.01 to 1.73
LIXI_SC_20UG_QD	1.39 0.22 to 9.73	LIXI_SC_20UG_QD	0.87 0.03 to 27.02	0.78 0.04 to 15.58	0.34 0.02 to 4.70	0.22 0.01 to 5.02
HRS7535_PO_90MG_QD	1.61 0.08 to 26.36	1.15 0.04 to 32.12	HRS7535_PO_90MG_QD	0.90 0.02 to 32.60	0.39 0.01 to 9.99	0.27 0.01 to 2.72
COTA_SC_300UG_QD	1.75 0.18 to 20.43	1.29 0.06 to 28.24	1.11 0.03 to 49.28	COTA_SC_300UG_QD	0.42 0.02 to 8.37	0.28 0.01 to 9.29
SEMA_SC_1p0MG_QW	3.99 0.70 to 38.23	2.96 0.21 to 50.84	2.60 0.10 to 98.50	2.39 0.12 to 57.77	SEMA_SC_1p0MG_QW	0.66 0.03 to 15.46
HRS7535_PO_30MG_QD	6.29 0.58 to 94.77	4.53 0.20 to 122	3.77 0.37 to 69.69	3.61 0.11 to 124	1.51 0.06 to 38.19	HRS7535_PO_30MG_QD

Heterogeneity, fit and convergence

Bayesian random effects (primary)

Heterogeneity (tau): 0.219 (95% CrI 0.041 to 1.017), log scale
Residual deviance: 8.8 for 9 data points
DIC: 16.3 (pD 7.5)
Largest R-hat: 1.001
Smallest ESS: bulk 5,858, tail 4,300
Divergent transitions: 0
Convergence: All criteria met
Priors: PR02 N(0, 5^2); PR05 N(0, 2.5^2); PR09 log normal(-2.99, 1.74^2) on tau^2 (Withdrawals/drop-outs, 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; 4 of 4	Asian ancestry or region (percent Asian) effect modifier, prognostic factor; 4 of 4
REMODEL S000395	23.56	14.15
SOLID-DKD S001370	26.07	100
NCT03550378 S002039	48.8	0
S002858 S002858	35.35	5.35

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 48.8 (COTA_SC_300UG_QD vs PLACEBO) percent female; threshold 15
FlagBaseline, Asian ancestry or region: design means range from 0.0 (COTA_SC_300UG_QD vs PLACEBO) to 100.0 (HRS7535_PO_30MG_QD vs HRS7535_PO_90MG_QD vs PLACEBO) percent Asian; threshold 30
NoteOutcome assessment, time point: selected time points span 8.43 to 57 weeks
NoteOutcome assessment, analysis set: mixed: randomized 2, safety 2
NoteOutcome assessment, definition: mixed: level 3 severe hypoglycemia 1, not stated 2, severe hypoglycemia 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
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	Source
REMODEL	A1	SEMA_SC_1p0MG_QW	57	arm, events	9 / 71	R0007381:Extended Data Table 5
REMODEL	A2	PLACEBO	57	arm, events	1 / 35	R0007381:Extended Data Table 5
SOLID-DKD	A1	HRS7535_PO_30MG_QD	18	arm, events	3 / 93	R0004355:Table 2
SOLID-DKD	A2	HRS7535_PO_90MG_QD	18	arm, events	1 / 94	R0004355:Table 2
SOLID-DKD	A3	PLACEBO	18	arm, events	0 / 94	R0004355:Table 2
NCT03550378	A1	COTA_SC_300UG_QD	8.43	arm, events	2 / 21	R0019218:Results
NCT03550378	A2	PLACEBO	8.43	arm, events	1 / 20	R0019218:Results
S002858	A1	LIXI_SC_20UG_QD	24	arm, events	3 / 51	R0001573:Supplement Table S1
S002858	A2	PLACEBO	24	arm, events	2 / 50	R0001573:Supplement Table S1

Rerun this analysis yourself

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