#308 The impact of multimorbidity on the effects of empagliflozin in chronic kidney disease (CKD): exploratory analyses from the EMPA-KIDNEY trial
Authors: Mayne Kaitlin 
Published: May 2024

Abstract

Background and Aims
Sodium-glucose co-transporter-2 (SGLT2) inhibitors slow kidney disease progression and reduce cardiovascular risk in patients with CKD. Multimorbidity is common in CKD and associated with poor prognosis. Multimorbidity may identify patients with most to gain from, or at increased risk of adverse effects of, such treatment, so uncertainty exists around the risk-benefit profile. We assessed the effects of empagliflozin according to baseline multimorbidity, polypharmacy and health-related quality of life in EMPA-KIDNEY trial participants.

Method
EMPA-KIDNEY was a double-blind, placebo-controlled randomised trial which compared empagliflozin 10 mg once daily versus placebo among 6609 patients with CKD (Clinicaltrials.gov: NCT03594110). Eligible patients had an eGFR of 20 to &lt;45; or 45 to &lt;90 ml/min/1.73 m2 with a urinary albumin-to-creatinine ratio (uACR) ≥200 mg/g.
Multimorbidity was defined by the presence or absence of eight self-reported conditions at randomisation (diabetes, heart failure, ischaemic heart disease [any history of myocardial infarction or angina], cerebrovascular disease [any history of stroke or transient ischaemic attack], peripheral arterial disease, atrial fibrillation, peripheral neuropathy and gout), in addition to CKD. Polypharmacy was derived from the number of concomitant medications recorded at randomisation. Health-related quality of life at randomisation was assessed using the EuroQoL EQ-5D-5L tool.
To enable subgroup analyses, participants were categorised into approximate thirds of each variable's distribution. The relative effects of allocation to empagliflozin versus placebo on the trial's pre-specified efficacy and safety outcomes were assessed using Cox regression models adjusted for age, sex, region, eGFR, uACR and diabetes status. Tests for heterogeneity across subgroups were used to assess for any evidence that multimorbidity modifies relative treatment effects, and used to inform approaches to estimate absolute benefits.

Results
The median (Q1-Q3) number of comorbid conditions (other than CKD) recorded at randomisation was 1 (0-2); range 0-7. At randomisation, the median (Q1-Q3) number of concomitant medications recorded was 7 (5-10), range 0-36, and polypharmacy (≥5 medications) was prevalent in 5044/6609 (76%) of participants. There was considerable overlap between multimorbidity, polypharmacy and deficits in health-related quality of life (Fig. 1).
Empagliflozin reduced the risk of the primary composite outcome of kidney disease progression or cardiovascular death by 28% (hazard ratio 0.72, 95% CI 0.64-0.82). There was no evidence of heterogeneity relative effects by categories reflecting multimorbidity, nor by level of polypharmacy or self-reported quality of life at randomisation (P value for heterogeneity all &gt;0.05; Fig. 2). Absolute benefits for the primary outcome were at least as large in the highest categories of multimorbidity or polypharmacy versus the lowest (and for those with poorer versus greater health-related quality of life). Safety outcomes were infrequent with no evidence of a difference in effect by baseline levels of multimorbidity, polypharmacy or quality of life, including no excess of symptomatic dehydration or fractures.

Conclusion
In EMPA-KIDNEY, the estimated absolute benefits of empagliflozin on kidney disease progression or cardiovascular death substantially outweigh potential for harm, irrespective of multimorbidity, polypharmacy or quality of life. The analyses encourage safe widespread use of SGLT2 inhibitors in CKD.