Kaitlin Mayne, MBChB: Impact of Multimorbidity, Polypharmacy on Benefits of SGLT2i in CKD

An analysis of the landmark EMPA-Kidney trial underlines the need for urgency when prescribing SGLT2 inhibitors in patients at risk of chronic kidney disease progression, with benefits outweighing harms irrespective of multimorbidity, polypharmacy, or quality of life.

A double-blind, placebo-controlled, phase 3 randomized clinical trial, EMPA-Kidney was launched in 2019, published in 2022, and served as the basis for a September 2023 label expansion for empagliflozin for reducing the risk of sustained decline in estimated glomerular filtration rate (eGFR), end-stage kidney disease, cardiovascular death, and hospitalization in adults with chronic kidney disease at risk of progression.^1,2

The trial included a population of 6609 patients with chronic kidney disease who had an eGFR of at least 20 but less than 45 mL/min/1.73m2 of body-surface area, or who had an eGFR of at least 45 but less than 90 mL/min/1.73m2 with a UACR of at least 200. The primary outcome of interest for the trial was the progression of kidney disease or death from cardiovascular causes, which occurred among 13.1% of the empagliflozin group and 16.9% of the placebo group (Hazard Ratio [HR], 0.72; 95% Confidence Interval [CI], 0.64 to 0.82; P <.001).²

In the current analysis, Kaitlin Mayne, MBChB, of the Nuffield Department of Health at Oxford University, and a team of colleagues sought to determine how the presence of multimorbidity might influence the benefit-risk profile of empagliflozin use among patients from the trial. With this in mind, investigators designed a series of subgroup analyses assessing the relative effects of allocation to empagliflozin on the trial’s primary outcomes based on multimorbidity, polypharmacy, and quality of life at randomization.¹

For the purpose of analysis, multi morbidity was defined by the presence or absence of 8 self-reported conditions at randomization, which included diabetes, heart failure, ischemic heart disease, history of myocardial infarction or angina, history of stroke or transient ischemic attack, atrial fibrillation, peripheral neuropathy, or gout. Of note, investigators used Cox regression models adjusted for age, sex, region, eGFR, UACR and diabetes status to estimate treatment effects on risk of the primary outcome.¹

Initial analysis revealed the median number of comorbid conditions recorded at randomization was 1 (IQR, 0 to 2) and the median number of concomitant medications was 7 (IQR, 5 to 10), with 76% reporting receiving 5 medications or more. Investigators pointed out considerable overlap existed between multimorbidity, polypharmacy, and deficits in health-related quality of life.¹

Results of the primary analysis suggested there was no evidence of heterogeneity relative effects according to multimorbidity, level of polypharmacy, or self-reported quality of life at randomization (P value for heterogeneity all > .05) Additional analysis indicated the absolute benefits for the trial’s primary outcome were at least as large, if not greater, among those in the highest categories of multimorbidity or polypharmacy relative to the lowest. Analysis of safety endpoints suggested there was no evidence of a difference in effect by baseline levels of multimorbidity, polypharmacy, or quality of life, with no excess of symptomatic dehydration or fractures.¹

For more on the study and its implications, check out our interview with Mayne from the 61st European Renal Association Congress.

References:

1. Mayne K. #308 the impact of multimorbidity on the effects of Empagliflozin in chronic kidney disease (CKD): Exploratory analyses from the EMPA-Kidney Trial. Nephrology Dialysis Transplantation. 2024;39(Supplement_1). doi:10.1093/ndt/gfae069.062
2. Campbell P. Empagliflozin (Jardiance) receives CKD approval from US FDA. HCP Live. September 28, 2023. Accessed June 7, 2024. https://www.hcplive.com/view/empagliflozin-jardiance-receives-ckd-approval-from-us-fda.