Use of lipid‐lowering therapies in patients with chronic kidney disease and atherosclerotic cardiovascular disease: 2‐year results from Getting to an imprOved Understanding of Low‐Density lipoprotein cholesterol and dyslipidemia management (GOULD)

Abstract Background Chronic kidney disease (CKD) is a known risk factor of atherosclerotic cardiovascular disease (ASCVD). Per the 2018 American Heart Association/American College of Cardiology cholesterol guidelines, high‐risk ASCVD patients with CKD and low‐density lipoprotein cholesterol (LDL‐C) levels ≥ 70 mg/dL should take a high‐intensity statin with ezetimibe and/or a proprotein convertase subtilisin/kexin type 9 inhibitor (PCSK9i). Objective/Methods We examined the changes in use of lipid lowering therapies (LLT) over two years in 3304 patients with ASCVD and CKD in the Getting to an imprOved Understanding of Low‐Density Lipoprotein Cholesterol and Dyslipidemia Management (GOULD) observational cohort study. Results Of those with eGFR <60 ml/min/1.73 m2, 21.6% (171/791) had intensification of LLT while 10.4% (82/791) had de‐escalation of LLT. Notably, 61.6% (487/791) had no change in LLT regimen over 2 years. Statin use was 83.2% (785/944) at baseline and 80.1% (634/791) at 2 years. Statin/ezetimibe use increased from 2.9% (27/944) to 4.9% (39/791). Statin discontinuation at 2 years was greater with lower eGFR levels across all cohorts. Conclusion Despite the recommendations of multiscociety guidelines, statin use, while high, is not ubiquitous and rates of high‐intensity statin and ezetimibe use remain low in patients with CKD. There remains a significant opportunity to optimize LLT and achieve atheroprotective cholesterol levels in the CKD population.


| INTRODUCTION
Chronic kidney disease (CKD) is an independent risk factor for cardiovascular disease (CVD) and is therefore considered a risk enhancer for the use of lipid-lowering therapies (LLT). 1 In the United States, CKD affects about 15% of adults, or 37 million people. 2 The prevalence of atherosclerotic CVD (ASCVD) rises with worsening kidney disease. 3 Adults with end-stage renal disease (ESRD) have 10-20 times higher risk of CVD than the general population and 50% of all deaths in patients with ESRD are due to CVD. 4,5 Dyslipidemia is present in even early stages of CKD and progresses as renal function worsens. Patients with CKD have elevated triglyceride levels, decreased high-density lipoprotein cholesterol levels, and varying low-density lipoprotein cholesterol (LDL-C) levels. 6 Advanced lipoprotein testing and vascular ultrasound examination for atheromatosis in patients without diabetes and with or without CKD (not on statins) in the Observatorio Nacional de Atherosclerosis en NEFrologia (NEFRONA) study demonstrated that CKD patients had a higher prevalence of atheromatosis and increased triglyceride-rich LDL-C particles, which was independently and positively associated with atheromatosis. 7 The Chronic Renal Insufficiency Cohort (CRIC) study demonstrated that adults with CKD and ASCVD taking moderate-to high-intensity statins still had high ASCVD event rates, suggesting that additional LLT may be beneficial in reducing ASCVD risk. 8 Alirocumab, a proprotein convertase subtilisin/kexin type 9 inhibitor (PCSK9i), and icosapent ethyl were both reported to be associated with fewer cardiovascular events across a broad range of renal function categories in the ODYSSEY OUTCOMES and REDUCE-IT RENAL studies respectively. 9 need to be included in lipid lowering trials. 14 The primary objective of the GOULD multicenter observational registry (NCT02993120) is to evaluate changes in use of evidencebased lipid-lowering therapies and, secondarily, trends in LDL-C levels over time in patients with ASCVD in the United States. Patients were enrolled between 2017 and 2018 and followed prospectively for 2 years. 15 Only 17.1% of all patients with ASCVD had intensification of LLT and two-thirds of patients continued to have suboptimal LDL-C levels after 2 years. 16 This report describes the change in LLT usage and LDL-C levels in patients with both ASCVD and CKD.

| METHODS
The design of the GOULD study has previously been reported.
Eligible patients were at least 18 years of age, on stable LLT for at least four weeks, and with established ASCVD. 15 (Table 2). Statin discontinuation was a primary driver of de-escalation in all cohorts (Table 3).   .715 Other LLT Added .429 Note: Intensification in lipid-lowering therapies (LLT) was most common among the LDL-C ≥ 100 mg/dL cohort and least among the PCSK9i cohort. Intensification was primarily driven by statin uptitration and the addition of ezetimibe. In the LDL-C 70-99 mg/dL cohort, rates of statin uptitration were higher with worsening eGFR. Otherwise, there was no significant change in LLT use across eGFR groups among any cohort.
T A B L E 3 De-escalation of lipid-lowering therapies over 2 years by cohort and eGFR .43 Note: De-escalation in lipid-lowering therapies (LLT) was most common among the PCSK9i cohort and least among the LDL-C 70-99 mg/dL cohort. De-escalation was primarily driven by statin discontinuation.
In the PCSK9i cohort, rates of statin discontinuation were higher with worsening eGFR. In the LDL-C 70-99 mg/dL cohort, rates of statin down-titration were highest with eGFR <30. Otherwise, there was no significant change in LLT use across eGFR groups among any cohort.  20 While this survey was focused on ASCVD overall and did not further examine views among patients with CKD, patient education about the efficacy and safety of statins is likely still a major contributor to the suboptimal prevalence of statin use among this population. The latter is particularly evident in the rates of statin discontinuation due to concerns about muscle pain. It is also possible that there is not widespread implementation of the KDIGO and ACC/AHA guidelines by physicians due to a lack of awareness or clinical inertia. There may also be some concern for the safety or efficacy of statins in patients with CKD, though multiple studies have demonstrated benefit and safety in this population. These results present an opportunity and a need for increased education of clinicians and patients regarding the role of statins in patients with CKD.

| CONCLUSION
While overall statin use among patients with CKD is high, there have only been modest increases in the use of high-intensity statin, ezetimibe, and PCSK9i over the course of this prospective 2-year study. The use of ezetimibe and PCSK9i did not differ by CKD stage, but unfortunately, statin use was lower in those with lower eGFR.
Studies of PCSK9i and ezetimibe have shown similar benefits in cardiovascular outcomes across eGFR groups in this high-risk population. 21 Despite ASCVD being a major cause of morbidity and mortality in patients with CKD, a majority of patients in this study did not achieve an atheroprotective LDL-C goal of <70 mg/dL. This highlights a key opportunity to improve quality of care and outcomes in the CKD population.

ACKNOWLEDGMENT
The GOULD study is funded by Amgen.