Specialty Corner: Lipid Metabolism and Cardiovascular Disease in Patients with Renal Disease

Reduced estimated glomerular filtration rate (GFR) and chronic kidney disease (CKD) are also independently associated with the risk of death and cardiovascular (CV) events in community.(3) When compared to the general population, patients with CKD have a distinct lipid profile which involves alterations in different lipoprotein classes and shows considerable variations depending on the stage of CKD.(4) Although very complex, the most important characteristics of this uremic lipid profile can be simplified as follows: 1) hypertriglyceridemia, 2) elevated remnant lipoproteins including chylomicron remnants and IDL, 3) reduced HDL and 4) increased highly atherogenic small dense LDL (sdLDL), lipoprotein(a) and apolipoprotein A-IV. Although elevated LDL-C levels are not typically seen in CKD patients, it has been reported in patients with nephrotic syndrome and patients on peritoneal dialysis (PD).(4) Therefore, LDL-C levels are not a reliable predictor of CV risk in patients with advanced CKD. Moreover, in end-stage renal disease (ESRD), low cholesterol levels, probably reflecting chronic inflammation and malnutrition, have been paradoxically related to high mortality risk.(5)

Use of Statin Therapy in Renal Disease

U.S. population studies suggest an optimal total cholesterol level in the general population is about 150 mg/dL (3.8 mmol/L), which corresponds to an LDL-C level of approximately 100 mg/dL (2.6 mmol/L). Randomized clinical trials (RCTs) of cholesterol-lowering drugs in high-risk patients confirm that LDL-C lowering results in reductions in atherosclerotic cardiovascular disease (ASCVD).(6) Statins, as the mainstay of LDL lowering therapy, have also been shown to be beneficial in reduction of CV morbidity and mortality in CKD patients. In different RCTs, simvastatin (7,8) pravastatin (9), atorvastatin (10) and rosuvastatin (11) were associated with improvement of CV risk profile in CKD patients. Furthermore, when compared with lower dosage, a higher dosage of atorvastatin (10mg daily versus 80mg daily respectively) was associated with 32% reduction in the relative risk of major cardiovascular events in CKD patients. This effect was twice as large in CKD patients when compared to the population without CKD. The Study of Heart and Renal Protection (SHARP) indicated that simvastatin/ezetimibe combination therapy reduces the risk of major atherosclerotic events (coronary death, MI, non-hemorrhagic stroke or any revascularization) compared with placebo in people with GFR < 60 mL/min per 1.73 m2 (GFR categories G3a–G5).(13) While in renal transplant patients treatment with fluvastatin was associated with better cardiovascular outcomes compared with placebo, however, renal graft survival and all-cause mortality were not influenced.(14,15)

“LDL levels are not a reliable predictor of CV risk in patients with advanced CKD.”

In contrast, the result of lipid lowering strategies and statin therapy in ESRD and hemodialysis (HD) patients are not consistent. For example, when compared with untreated HD patients, the 4D Study (Die Deutsche Diabetes Dialyse Studie) and the AURORA (A Study to Evaluate the Use of Rosuvastatin in Subjects on Regular Hemodialysis: An Assessment of Survival and Cardiovascular Events) trial both failed to demonstrate improvement in cardiovascular endpoints in the group of ESRD patients who were treated with atorvastatin or rosuvastatin respectively, despite the expected decreases in their LDL-C levels. Interestingly, there was a two-fold increase in fatal strokes in the atorvastatin treatment group in the 4D study.(16,17) It is worth noting that many cardiovascular events in dialysis patients were due to arrhythmia or non-ischemic cardiomyopathy. Additionally, the atherosclerosis was so advanced in these patients they were unlikely to benefit from drug therapy.(18)

Guidelines Recommendations

In their 2013 guidelines, the Kidney Disease Improving Global Outcomes (KDIGO) recommended that lipid profile should be evaluated in all adults with newly identified CKD, while follow-up measurements were not required for the majority of patients since therapy was not geared toward a specific cholesterol level. In adults aged 50 years or older with eGFR >60 or <60 mL/min per 1.73 m2 but not treated with chronic dialysis or kidney transplantation, treatment with a statin is recommended. In patients with eGFR>60, the addition of ezetimibe could be considered. In adults aged 18-49 years with CKD but not treated with chronic dialysis or kidney transplantation, statin treatment was found to be beneficial if the person had one or more of the following:

1)    known coronary disease (myocardial infarction or coronary revascularization),
2)    diabetes mellitus,
3)     prior ischemic stroke, and
4)     estimated 10-year incidence of coronary death or non-fatal myocardial infarction >10%. In contrast, lipid lowering therapy was not suggested in dialysis-dependent patients but continuation of these agents was recommended if these patients were already receiving statins or statin/ezetimibe combination at the time of dialysis initiation.(19)

The 2018 Multisociety Guidelines on Management of Blood Cholesterol recognized CKD (eGFR 15-59 mL/min/1.73 m2) as a risk enhancer for atherosclerotic cardiovascular disease (ASCVD) and its presence in adults 40 to 75 years of age without diabetes mellitus and 10-year risk of 5%-19.9% favored a risk discussion regarding initiation of moderate-intensity statin therapy as a primary prevention strategy. In patients with history of previous ASCVD, CKD was considered as a high risk condition. Very high risk patients have multiple ASCVD events, or one ASCVD event and multiple high risk conditions, which warrant using an LDL-C threshold of 70 mg/dL. If patients remain above this treatment threshold despite maximally tolerated statin therapy, addition of nonstatins was recommended.(20)

In the 2019 European Society of Cardiology (ESC) guidelines, patients were categorized with eGFR of < 30 mL/min/1.73 m2 as very-high-risk for ASCVD while eGFR of 30-59 mL/min/1.73 m2 was considered high-risk for future events. Therefore, using risk estimation models in these patients was not required. For people at very high CV risk, whether in secondary prevention or (rarely) in primary prevention, LDL-C reduction of ≥ 50% from baseline and an LDL-C goal of < 55 mg/dL are recommended whereas an LDL-C goal < 70 mg/dL are recommended in high CV risk patients. Similar to the Multisociety guidelines, they did not recommend initiation of lipid lowering agents in patents on dialysis but supported continuations of these medications if patients were taking them before commencement of dialysis.

Disclosure Statement: Dr. Bookani has no financial disclosures to report. Dr. Davidson has received honoraria from Amgen, Sanofi, Regeneron, Akcea, and Esperion. Dr. Koschinsky has received honoraria from Pifzer, Amgen, Eli Lilly, and Ionis.

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