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. 2022 Nov 24:55:101751.
doi: 10.1016/j.eclinm.2022.101751. eCollection 2023 Jan.

Clinical outcomes following discontinuation of renin-angiotensin-system inhibitors in patients with type 2 diabetes and advanced chronic kidney disease: A prospective cohort study

Aimin Yang  1   2 , Mai Shi  1   2 , Eric S H Lau  1 , Hongjiang Wu  1 , Xinge Zhang  1 , Baoqi Fan  1 , Alice P S Kong  1   2 , Andrea O Y Luk  1   2   3 , Ronald C W Ma  1   2   4 , Juliana C N Chan  1   2 , Elaine Chow  1   2   3
Affiliations

Clinical outcomes following discontinuation of renin-angiotensin-system inhibitors in patients with type 2 diabetes and advanced chronic kidney disease: A prospective cohort study

Aimin Yang et al. EClinicalMedicine. .

Abstract

Background: Renin-angiotensin-system inhibitors (RASi), that include angiotensin converting enzyme inhibitors (ACEis) and angiotensin receptor blockers (ARBs) reduce proteinuria, delay chronic kidney disease (CKD) progression, protect against cardiovascular events and heart failure hospitalizations. We examined the associations of discontinuation of ACEi/ARBs with risk of clinical outcomes in Chinese patients with type 2 diabetes (T2D) and advanced-CKD (estimated-glomerular filtration rate [eGFR] <30 ml/min/1.73 m2).

Methods: We conducted a prospective, population-based cohort study including 10,400 patients with T2D in Hong Kong stratified by continuation of ACEi/ARBs within 6 months after reaching eGFR <30 ml/min/1.73 m2 from January 01, 2002 to December 31, 2018 and observed until December 31, 2019. The primary outcomes were death, major-adverse cardiovascular events (MACE), heart failure, end-stage kidney disease (ESKD), and all-cause mortality. Cox-model with time-dependent exposure and covariates was used to estimate the hazard ratio (HR) of outcomes in a propensity-score overlap-weighted cohort. The risk of occurrence of hyperkalemia (plasma potassium >5.5 mmol/L) in discontinued-ACEi/ARBs versus continued-ACEi/ARBs users was assessed in a register-based cohort.

Findings: In the population-based cohort of 10,400 ACEi/ARBs users with new-onset eGFR<30 ml/min/1.73 m2, 1766 (17.0%) discontinued ACEi/ARBs and 8634 (83.0%) persisted with treatment. During a median follow-up of 3.6 (interquartile range, IQR: 2.11-5.8) years (41,623 person-years), 13.5%, 12.9%, and 27.6% had incident MACE, heart failure and ESKD respectively, and 35.8% died. Discontinued-ACEi/ARBs use was associated with higher risk of MACE (HR = 1.27, 95% CI: 1.08-1.49), heart failure (HR = 1.85, 95% CI: 1.53-2.25) and ESKD (HR = 1.30, 95% CI: 1.17-1.43), and neutral risk of all-cause mortality (HR = 0.93, 95% CI: 0.86-1.01) compared to counterparts with continued use. In the register-based cohort (583 discontinued-ACEi/ARBs users and 3817 continued-ACEi/ARBs users), discontinued-ACEi/ARBs had neutral risk of hyperkalemia (HR = 0.95, 95% CI: 0.84-1.08).

Interpretation: Discontinuation of ACEi/ARBs was associated with increased risk of cardiovascular-renal events supporting their continued use in patients with T2D and advanced-CKD.

Funding: CUHK Impact Research Fellowship Scheme.

Keywords: Angiotensin receptor antagonists; Angiotensin-converting enzyme inhibitors; Cardiovascular disease; Chronic kidney disease; Diabetes; Mortality; Therapeutics.

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Conflict of interest statement

JCNC has received research grants and/or honoraria for consultancy or giving lectures, from 10.13039/100004325AstraZeneca, 10.13039/100004326Bayer, Boehringer Ingelheim, 10.13039/100004312Eli Lilly & Co, Hua Medicine, Lee Powder, Merck Serono, 10.13039/100009947Merck Sharp & Dohme, 10.13039/100004319Pfizer, 10.13039/501100011725Servier, 10.13039/100004339Sanofi and Viatris Pharmaceutical. APSK has received research grants and/or speaker honoraria from Abbott, 10.13039/100004325AstraZeneca, 10.13039/100004326Bayer, Boehringer Ingelheim, Eli-Lilly, Kyowa Kirin, Merck Serono, Nestle, 10.13039/501100004191Novo Nordisk, 10.13039/100004319Pfizer and 10.13039/100004339Sanofi. AOYL has served as a member of advisory panel for Amgen, AstraZeneca, Boehringer Ingelheim and Sanofi and received research support from Amgen, Asia Diabetes Foundation, Bayer, Boehringer Ingelheim, Lee's Pharmaceutical, MSD, Novo Nordisk, Roche, Sanofi, Sugardown Ltd, Takeda. None of these relationships had any influence on the content of the present manuscript. RCWM has received research funding from 10.13039/100004325AstraZeneca, 10.13039/100004326Bayer, Merck Sharp & Dohme, 10.13039/501100004191Novo Nordisk, 10.13039/100004319Pfizer and Tricida Inc. for carrying out clinical trials, and has received speaker honorarium or consultancy in advisory boards from AstraZeneca, Bayer and Kyowa Kirin. All proceeds have been donated to the Chinese University of Hong Kong to support diabetes research. Other authors have no conflicts of interest to disclose.

Figures

Fig. 1
Fig. 1
Study design and time frame definitions. Rx = prescription. Censored at the earliest date of outcomes of interest or censor date (31 December 2019). Abbreviations: RASi, renin angiotensin system inhibitor; ACEi, angiotensin converting enzyme inhibitors; ARBs, angiotensin receptor blockers; eGFR, estimated glomerular filtration rate; AKI, acute kidney injury.
Fig. 2
Fig. 2
Flowchart of selection patient with type 2 diabetes.Abbreviations: RASi, renin angiotensin system inhibitor; MACE, major adverse cardiovascular events; ESKD, end-stage kidney disease; eGFR, estimated glomerular filtration rate; AKI, acute kidney injury.
Fig. 3
Fig. 3
Number of clinical events (A) and weighted and adjusted Kaplan–Meier curves of discontinued-RASi versus continued-RASi use for MACE (B), heart failure (C), ESKD (D), and all-cause mortality (E) in patients with type 2 diabetes and advanced chronic kidney disease (eGFR reached 30 mL/min/1.73 m2). Weighted and adjusted hazard ratio (HRs) and 95% CIs of MACE, heart failure, and ESKD were yielded using Cox model with time-varying RASi use, adjusting for time-varying HbA1c, lipids, age, medications, and comorbidities in the overlap-weighted cohort. Results of all-cause mortality was yielded using time-fixed Cox model in the overlap-weighed cohort. Abbreviations: RASi, renin angiotensin system inhibitor; MACE, major adverse cardiovascular events; ESKD, end-stage kidney disease; eGFR, estimated glomerular filtration rate.
Fig. 4
Fig. 4
Subgroup analyses of discontinued-RASi users comparing permanently discontinued (A) and stop-restart (B) groups versus continued-RASi use with risk of clinical events in patients with type 2 diabetes and advanced chronic kidney disease (eGFR reached 30 mL/min/1.73 m2). Weighted and adjusted hazard ratio (HRs) and 95% CIs of MACE, heart failure, and ESKD were yielded using Cox model with time-varying RASi use, adjusting for time-varying HbA1c, lipids, age, medications, and comorbidities in the overlap-weighted cohort. Results of all-cause mortality were yielded using the time-fixed Cox model in the overlap-weighed cohort. Abbreviations: RASi, renin-angiotensin system inhibitor; MACE, major adverse cardiovascular events; ESKD, end-stage kidney disease; eGFR, estimated glomerular filtration rate.
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