Comparing rosuvastatin and atorvastatin on cardiovascular and kidney outcomes in patients with diabetes across chronic kidney disease stages: an emulated target trial in China.

Abstract

Statins are the cornerstone of lipid-lowering therapies in diabetes and chronic kidney disease (CKD). Rosuvastatin, compared with atorvastatin, is associated with higher risk of kidney impairment in Western populations with diabetes and CKD. However, whether its effects on cardiorenal outcomes can generalise to East Asians remains unknown especially given ethnic differences in statin metabolism. We aimed to compare the risk associations of rosuvastatin versus atorvastatin for cardiovascular-renal outcomes in Chinese people with diabetes across CKD stages. For this target trial emulation, we included a propensity-score overlap-weighted cohort of 106,677 patients (aged 18+ years) with diabetes (type 1 or type 2) in Hong Kong in 2002-2019, comprising 13,737 new-atorvastatin users and 92,940 new-rosuvastatin users. Patients with missing estimated glomerular filtration rate (eGFR) or diagnosed with end-stage kidney disease (ESKD) at baseline, or aged <18 years were excluded. Propensity scores were estimated via multivariate logistic regression based on demographics, clinical characteristics, medication use, and index year. The primary outcome was the incidence of ESKD, defined as dialysis, kidney-replacement therapy, or eGFR <15 ml/min/1.73 m²on two occasions (≥90 days apart). We employed Cox-model adjusted for time-fixed and time-varying exposure and covariates to estimate hazard ratios (HRs) for ESKD, major-adverse cardiovascular events (MACE), all-cause mortality, and new-onset albuminuria in the propensity-score overlap-weighted cohort. Follow-up began at the index date (first prescription) and ended at the earliest occurrence of outcomes, death, or Dec 31, 2019. Among 106,677 patients, 75.80% (n = 80,866), 20.47% (n = 21,842), and 3.72% (n = 3969) had CKD stages of G1-2, G3, and G4 respectively. During a median follow-up of 2.33 years, 3.45% (n = 3685) had incident ESKD; 5.78% (n = 6169) reported MACE and 10.13% (n = 10,809) died. Initial (time-fixed) exposure to rosuvastatin was associated with similar risks of ESKD, MACE, and all-cause mortality compared with atorvastatin; whereas, accounting for time-varying exposure revealed a lower risk of MACE (HR = 0.85 [0.77-0.93]) and all-cause mortality (HR = 0.88 [0.81-0.96]) with rosuvastatin. Notably, rosuvastatin was associated with a higher, dose-dependent risk of new-onset albuminuria than atorvastatin in both time-fixed and time-varying Cox models. Our findings support similar effects of atorvastatin and rosuvastatin on ESKD, while more favourable cardiovascular effects and dose-dependent association with albuminuria were observed with rosuvastatin in East Asians with diabetes. Careful monitoring for albuminuria is needed in rosuvastatin users, and longer-term studies are required to fully assess the renal safety of rosuvastatin, especially in patients on high-intensity regimens. CUHK Impact Research Fellowship Scheme.