Lipid Luminations: Lipid Management in Chronic Kidney Disease

Introduction

Chronic kidney disease (CKD) ranks among the top five causes of global mortality, affecting approximately 35.5 million people in the United States (US).^1,2 Despite being preventable and treatable, the prevalence of CKD and related mortality are on the rise, making it an important global health issue. According to the Global Burden of Disease (GBD) study, CKD is projected to become the fifth leading cause of global mortality by 2040, and the years of life lost due to CKD are expected to double.³ One of the most critical adverse outcomes associated with CKD is cardiovascular disease (CVD), which remains the leading cause of death, accounting for 40%-50% of deaths in individuals with advanced CKD, including in patients with renal transplantation.⁴

Traditional cardiovascular (CV) risk factors, including dyslipidemia, hypertension, diabetes, and smoking, are highly prevalent in CKD patients. These contribute to the development of atherosclerotic CVD (ASCVD) as well as play a role in CKD progression by affecting both large and small renal arteries.⁵ Managing these shared modifiable risk factors is essential for preventing CV complications and slowing the progression of CKD. Dyslipidemia is particularly common in CKD, manifesting as hypertriglyceridemia and atherogenic changes in lipoproteins.⁵ However, the optimal management of dyslipidemia in CKD - especially its advanced stages - remains under some debate, despite evidence suggesting that lipid abnormalities also influence the progression of CKD. With a recent renewed focus on the cardiovascular kidney metabolic syndrome (CKM) that involves crosstalk between these three shared areas, we highlight the importance of lipid management in CKD.⁶

Renal Disease and Cardiovascular Risk

There is a graded direct correlation between the stage of CKD and CVD, independent of traditional CV risk factors, and this relationship becomes evident even in mild renal impairment.^5,7 According to the US Renal Data System (USRDS) 2020, heart failure and myocardial infarction were roughly four times more prevalent in individuals with CKD compared to those without.⁸ Furthermore, percutaneous coronary intervention (PCI) and coronary artery bypass grafting (CABG) were approximately three times higher in CKD patients.⁸ The risk of developing CVD in CKD exceeds the risk of advancing to end-stage renal disease (ESRD). CKD should thus be recognized as one of the most significant risk factors for the development of CVD.

Dyslipidemia in Chronic Kidney Disease

CKD significantly alters the composition and quality of blood lipids, resulting in a very atherogenic profile. CKD patients typically exhibit dyslipidemia characterized by elevated triglycerides (TGs), reduced high-density lipoprotein (HDL), and varying levels of low-density lipoprotein cholesterol (LDL-C) and total cholesterol.⁹ Hypertriglyceridemia is an early manifestation of CKD and is due to reduced breakdown of triglyceride-rich lipoproteins (TRL), because of lower activity of lecithin–cholesterol acyltransferase (LCAT) and increased apolipoprotein (Apo) CIII levels.¹⁰ Elevated Apo CIII levels inhibit lipoprotein lipase (LPL) activity, leading to increased hepatic low-density lipoprotein (VLDL) secretion and reduced clearance of TRL.^5,11 Cumulatively, these lead to an increased risk of atherosclerosis and CV events.^5,11 Although LDL-C and total cholesterol levels are usually within normal limits, CKD patients often have a higher prevalence of atherogenic small dense LDL-C particles that can contribute to arterial plaque formation.^5,12 HDL-mediated reverse cholesterol transport, which clears excess cholesterol from arterial walls, is impaired in CKD due to reduced ApoAI synthesis, decreased LCAT activity, and increased cholesteryl ester transfer protein (CETP) activity.¹³ Plasma lipoprotein (a) [Lp(a)] levels, one of the strongest genetically determined risk factors for CVD, increase as kidney function declines.¹⁴ 

Lipid Management in Chronic Kidney Disease

Despite mounting evidence suggesting that CKD is equivalent to high CVD risk, the utilization of lipid-lowering therapy (LLT) in CKD has not increased over the past decade.¹³ The 2013 
Kidney Disease: Improving Global Outcomes (KDIGO) clinical practice guideline for lipid management in CKD advocated the use of statins in most CKD patients (Table 1).¹⁵ The American Heart Association (AHA) and American College of Cardiology (ACC) categorized CKD as a risk enhancer rather than a high-risk condition in their 2018 guidelines.¹⁶ These guidelines were endorsed by the National Lipid Association (NLA), which recommended the treatment goal for CKD patients (with eGFR 30-59 ml/min/1.73 m²) of achieving non-HDL cholesterol levels below 130 mg/dL and LDL-C levels below 100 mg/dL.¹⁷ The 2019 guidelines for the management of dyslipidemias from the European Society of Cardiology (ESC) categorized CKD as high risk of CVD and recommended statin therapy in all patients with reduced eGFR regardless of calculated CV risk.¹⁸ Thus, all of these guidelines recommend the initiation of statin therapy or statin-ezetimibe combination therapy for CKD patients who are not on dialysis, and maintaining lipid-lowering therapy (if the patient is already on it) for those on dialysis. At this time, there is insufficient RCT data of benefit for the initiation of statins for patients for CV outcome reduction for patients already on dialysis (Table 1).^15,16,19 The KDIGO guidelines also recommend statin therapy for renal transplant recipients.^15,16,19 The 2022 ACC Expert Consensus Decision Pathway (ECDP) recommends adding non-statin therapy for secondary prevention in patients with clinical ASCVD, including those with underlying CKD but not on dialysis, and those at very high-risk if they do not achieve a ≥ 50% reduction in LDL-C or if their LDL-C remains ≥ 55 mg/dL (or non-HDL-C is ≥ 85 mg/dL) despite taking the maximum tolerated statin therapy.²⁰ For patients not classified as very high risk, non-statin therapy is suggested if there is < 50% LDL-C reduction or LDL-C remains ≥ 70 mg/dL (or non–HDL-C is ≥ 100 mg/dL) on maximally tolerated statin therapy.²⁰ The use of a proprotein convertase subtilisin/kexin type 9 (PCSK9) monoclonal antibody is the preferred option for initial non-statin therapy, although bempedoic acid or inclisiran may also be considered.²⁰

Statins

Evidence from randomized controlled trials (RCTs) supports using statins for both primary and secondary prevention of CVD in individuals with CKD who are not on dialysis. The Pravastatin Pooling Project (PPP) analyzed data from three RCTs involving 4,491 patients with moderate CKD (eGFR 30–59 ml/min/1.73 m2) and found that pravastatin significantly reduced CV events and overall mortality, similar to its effect in those with normal kidney function.²¹ A sub-analysis of the Treating to New Targets (TNT) study in patients with stable coronary artery disease (CAD) revealed that intensive lipid-lowering with atorvastatin 80 mg reduced the risk of major CV events by 32% compared to a lower dose (10 mg) in patients with moderate CKD and CAD.²² Similarly, in the Study of Heart and Renal Protection (SHARP) trial involving 9,270 CKD patients, including 3,023 on dialysis, simvastatin plus ezetimibe reduced major atherosclerotic events (MACE) by 17% in primary prevention, although this benefit was not observed in patients on dialysis.²³ A recent meta-analysis of 63 RCTs also demonstrated that statins reduce major CV events and CV mortality by approximately 20%, as compared to placebo in CKD patients not requiring dialysis.²⁴ In 2 RCTs focused on end-stage renal disease (ESRD) patients on dialysis, statins did not reduce MACE, such as in the Die Deutsche Diabetes Dialyse Studie (4D) and A study to evaluate the Use of Rosuvastatin in subjects On Regular hemodialysis: an Assessment of survival and cardiovascular events (AURORA) trials.^25,26 Nonetheless, a post-hoc analysis of the 4D study did show benefits in the subgroup with high LDL-C (> 145 mg/dL) levels.²⁷ Additionally, a retrospective study among 47,200 veterans showed that when statin therapy was initiated 12 months before the onset of ESRD, there was a reduction in CV mortality, MACE, and CV hospitalization.²⁸

In kidney transplant recipients, the Fluvastatin 40 - 80 mg in the Assessment of Lescol in Renal Transplantation (ALERT) trial showed a 17% reduction in MACE in patients randomized to fluvastatin compared to placebo.²⁹ In the ALERT extension study, participants who were continued on fluvastatin 80 mg/day for 2 more years showed a 29% reduction in cardiac death or non-fatal myocardial infarction, indicating sustained benefits and safety of statin therapy in this cohort.³⁰ Thus, statin therapy is recommended for kidney transplant recipients by the KDIGO guidelines.

The recognized adverse effects of statins, including myopathy, liver injury, and new onset diabetes mellitus, have been linked to statin-induced mitochondrial dysfunction. Many CKD patients already have underlying mitochondrial dysfunction and insulin resistance, so they may be more susceptible to these statin-related adverse effects.⁵ Most statins are primarily metabolized through the liver, and for individuals with mild to moderate CKD (eGFR > 30 ml/min/1.73 m²), dose adjustments are typically not needed. In general, the amount of statin dependence on renal elimination is small, with pravastatin having the highest at 20% and atorvastatin being the lowest at < 2%.³¹ No adjustment is necessary for atorvastatin and fluvastatin regardless of the stage of CKD.³² However, for those with severe CKD (eGFR < 30 ml/min/1.73 m²), the KDIGO guidelines recommend that the maximal daily dose of simvastatin be ≤ 40 mg, pravastatin 40 mg, rosuvastatin 10 mg, and pitavastatin 2 mg.¹⁵ 

Ezetimibe

Ezetimibe is an appealing option for patients with CKD because it is not renally excreted and does not require dosage adjustments. When combined with statins, it can reduce LDL-C cholesterol by 25%, and as monotherapy, it lowers LDL-C by 15%. While combining ezetimibe with statins has shown CV benefits in CKD patients, its precise impact as monotherapy on MACE in CKD patients is uncertain.^23,33 In more advanced stages of CKD (Stage 3-5, eGFR < 60 mL/min/1.73 m2), the 2013 KDIGO guidelines recommend treatment with a combination of statin and ezetimibe.¹⁴

Fibrates

Fibrates can lower TGs and increase HDL-C, but their CV benefits are inconsistent in the general population. Concerns arise in using fibrates in CKD patients due to their potential to increase serum creatinine levels and the risk of myopathy and rhabdomyolysis when combined with statins.⁵ While fibrates have been linked to reduced CV events in CKD patients, the recent Pemafibrate to Reduce Cardiovascular Outcomes by Reducing Triglycerides in Patients with Diabetes (PROMINENT) trial showed overall negative CV outcomes, even in CKD subgroups.^34–36 Fibrates may potentially delay the need for dialysis, but more research in CKD patients is needed, with careful consideration of dosage adjustments.

Bile Acid Sequestrants

Bile acid sequestrants can reduce LDL-C levels when used alone, but they have minimal effects on HDL-C and often increase TG levels.^37,38 While generally safe due to minimal systemic absorption, they have not been well studied in patients with CKD. The insufficient evidence of their CV benefits and the potential to raise TG may limit their suitability in CKD patients.

Omega-3 Fatty Acids

Omega-3 fatty acids (FAs) can lower TG levels by 30% - 45%, potentially benefiting CKD patients.^39,40 However, RCTs have conflicting results on their CV effects in the general population, and data is limited for CKD patients.^41–43 A post-hoc analysis of the Reduction of Cardiovascular Events with EPA-Intervention Trial (REDUCE-IT) showed that the use of omega-3 FAs was more effective than a placebo in reducing TGs, CV events, and CV mortality in patients with high TG levels who were already taking statin therapy, including those with CKD.⁴¹ Further research is needed to provide stronger support for the use of omega-3 FAs in CKD patients at this time.

Niacin

Niacin can raise HDL-C levels while reducing LDL-C and TGs, but it is rarely prescribed due to significant side effects.⁴⁴ Some interest exists in using niacin for CKD and ESRD patients because it is not renally cleared and may lower phosphate levels.⁴⁵ However, RCTs investigating the use of niacin have not shown CV benefit beyond statin therapy and even a potential signal of harm, thus its use has been mostly abandoned now.^46,47

Bempedoic Acid 

Bempedoic acid helps further lower LDL-C by inhibiting ATP citrate lyase, upstream of where statins act in the cholesterol biosynthesis pathway.⁴⁸ The Cholesterol Lowering via Bempedoic Acid [ECT1002], an ACL-Inhibiting Regimen (CLEAR) trial demonstrated a 13% reduction in MACE at 40 months in patients intolerant to statins.⁴⁹ Bempedoic acid undergoes hepatic metabolism and is considered safe in CKD with no dosage adjustments needed for mild or moderate renal impairment.⁵⁰ 

PCSK9 Inhibitors

Due to the compelling evidence from RCTs (DESCARTES, ODYSSEY OUTCOMES, and FOURIER) involving monoclonal antibodies targeting proprotein convertase subtilisin/kexin type 9 (PCSK9), these agents have been granted approval for use in patients with ASCVD who do not achieve their lipid level goals despite receiving the maximally tolerated statin therapy.^51–53 PCSK9 inhibitors are both safe and effective, even in patients with established CKD. An analysis of pooled data from eight phase 3 trials from the Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment with Alirocumab (ODYSSEY) program revealed a 46.1% to 62.2% reduction in LDL-C levels after 24 weeks of treatment with alirocumab in patients with underlying CKD.⁵⁴ The efficacy and safety of these treatments were comparable to those in patients with normal kidney function, although individuals with an eGFR < 30 ml/min/1.73 m2 were excluded from the analysis.⁵⁴ Similarly, a post hoc analysis of the Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk (FOURIER) trial demonstrated that the effectiveness of evolocumab in lowering LDL-C levels and the ensuing CV benefits was similar in CKD patients compared to those with preserved renal function.⁵⁵ However, the effectiveness of PCSK9 inhibitors in dialysis and transplant patients is still under investigation, and ongoing studies are evaluating their impact on mortality and CV outcomes specifically in those with advanced CKD.^56,57

Conclusion

Patients with all stages of CKD, including those on dialysis and after kidney transplant have an increased risk of CVD. Paradoxically, these patients are less likely to receive LLT, either for primary or secondary prevention of ASCVD, likely due to concerns about its safety and efficacy in this population, as well as the limited adoption of guidelines in patients with CKD due to misperceptions of futility. Statins have demonstrated safety and effectiveness in CKD, with documented reduction of CVD events including in post-renal transplant patients, although their benefit in ESRD on dialysis needs further longer-term studies. With newer, more potent lipid-lowering combination therapy being available as well as drugs that delay the progression of CKD to ESRD, further trials are needed to better define the optimal LLT, LDL-C goals and thresholds, and residual risk markers in CKD.

 

Dr. Sagheer has no financial relationships to disclose. Dr. Kalra has no financial relationships to disclose. 

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