Managing Lipid Therapy in CKD Patients

Chronic kidney disease (CKD), defined by at least 3 months of impaired kidney function or albuminuria, is a well-established risk factor for cardiovascular disease (CVD).¹

In a large meta-analysis, a linear increase in cardiovascular mortality was seen with decreasing estimated glomerular filtration rate (eGFR) below a threshold eGFR of 75 mL/min/1.73 m², with mortality rates twice as high in stage 3 CKD (eGFR 30-59 mL/min/1.73 m²) and 3 times as high in stage 4 CKD (eGFR 15-29 mL/min/1.73 m²).

Patients with CKD have also been shown to have similar rates of myocardial infarction (MI) or coronary heart disease (CHD) compared to those with diabetes, which is why I consider CKD a CHD equivalent risk factor.

Dyslipidemia is common in CKD. Because of chronic inflammation and malnutrition, many patients with advanced CKD may even have low levels of serum lipoproteins in the absence of lipid-lowering drug therapy. As a result, even though patients with CKD should be considered part of the highest risk group for CVD, they’re often underdiagnosed and undertreated with cholesterol-lowering agents.

To address this key deficiency in the care of these patients, the Kidney Disease: Improving Global Outcomes (KDIGO) organization updated their clinical practice guidelines in 2013 to summarize evidence and recommend lipid management for all forms of CKD. This set of 13 recommendations spearheaded by prominent nephrologists, lipid specialists, and epidemiologists abandons lipid targets and focuses more on risk assessment driven mainly by age and eGFR.¹

Pharmacotherapy in CKD Patients Not on Hemodialysis

The KDIGO committee doesn’t use specific low-density lipoprotein cholesterol (LDL-C) targets; instead, it focuses on statin therapy for managing dyslipidemia. It recommends statin therapy in all adults 50 years or older with CKD who aren’t on chronic dialysis. In this same age group with more advanced stages of CKD (Stage 3-5, eGFR <60 mL/min/1.73 m²), combination statin and ezetimibe treatment is recommended. ^1-3

The recommendation for this combination comes from the SHARP trial, which randomized 9270 patients older than 40 years with CKD to simvastatin 20 mg plus ezetimibe 10 mg daily regardless of baseline LDL-C levels. The primary outcome of combined MI, coronary death, stroke, or arterial revascularization was reduced by 17% in the treatment group, with a 32% mean reduction seen in LDL-C levels. This came at the expense of a minor excess risk of myopathy without any increased risk of hepatitis, gallstones, or excess death from nonvascular causes.⁴

In younger adults (18-49 years) with CKD who aren’t on chronic dialysis, the KDIGO group recommends statin treatment only for those with 1 of the following: 1) known coronary disease (MI or coronary revascularization), 2) diabetes, 3) prior ischemic stroke, or 4) estimated 10-year incidence of coronary death or nonfatal MI of ≥10% based on the Framingham risk score used in the Adult Treatment Panel III Guidelines. However, using risk estimators to predict individual risk in this age group is difficult because they’re generally not validated in adults younger than 40 years and often underestimate risk in CKD patients.

Pharmacists caring for patients with CKD need to be aware that this population is at higher risk for side effects from lipid medications because of reduced renal excretion, polypharmacy, and multiple comorbidities. Given the risk of toxicity with high-dose statins, KDIGO recommends statin dosing based on regimens that have been studied and shown to be beneficial in randomized trials performed specifically in patients with eGFR <60 mL/min/1.73 m². This includes moderate-intensity statins, such as daily atorvastatin 20 mg, rosuvastatin 10 mg, simvastatin 40 mg, pravastatin 40 mg, or fluvastatin 80 mg.

Similar to patients without CKD, fibrates should be avoided in combination with statins, and ezetimibe monotherapy isn’t recommended. Baseline transaminase levels should be measured in all CKD patients prior to starting statin therapy, although routine transaminase for CK levels isn’t recommended in the absence of clinical evidence for hepatotoxicity or myopathy.

Other lipid guidelines have some similarities to KDIGO but differ on their approach to treating CKD patients. The National Lipid Association (NLA) 2015 guidelines recommend a step-wise approach to risk management, first identifying the highest ASCVD risk category, and then treating to specific non-HDL-C and LDL-C goals based on the risk category. ^2,5 Per the NLA approach, all patients with stage 3B (eGFR 30-44 mL/min/1.73 m²) or stage 4 CKD are considered high risk and would be treated to a goal non-HDL-C <130 mg/dL and LDL-C <100 mg/dL.

Although the NLA guidelines include those with CKD as high risk for ASCVD, the highly controversial ACC/AHA 2013 guidelines don’t specifically address CKD. These guidelines use a risk-based approach for individuals without clinical ASCVD, LDL ≥190 mg/dL, or diabetes. Moderate- or high-intensity statin treatment should be considered if 10-year risk is ≥7.5% in those 40 to 75 years with LDL-C 70 mg/dL to 189 mg/dL.⁶

Pharmacotherapy in CKD Patients on Hemodialysis

In adults with dialysis-dependent CKD, KDIGO recommends avoiding initiation of statins or statin-ezetimibe combinations These recommendations are based on several trials, including 4D and AURORA, as well as sub-group analysis of SHARP. However, there’s no recommendation to stop therapy in dialysis patients who are already receiving such treatment.

In all 3 trials looking at treating hemodialysis patients with statins or a statin plus ezetimibe versus placebo, the primary outcome of CVD death, MI, or stroke wasn’t different between the treatment and placebo arms. When taken together, however, there seemed to be an uncertain benefit of statins in this population, likely due to high competing risk. Other pathophysiologic mechanisms may be at play in these patients, such as coronary artery calcification. Nevertheless, the NLA and ACC/AHA guidelines don’t have specific treatment goals for patients on dialysis because of the lack of clear evidence supporting statin therapy.

Summary

Patients with CKD have a substantially increased risk of CVD, and lipid assessment and treatment is an important aspect of their care. Although statin therapy has clear benefit in stage 1-4 CKD and kidney transplant patients, that doesn’t seem to be the case for those on chronic dialysis, likely due to the unique mechanism of atherosclerosis in this population.

I agree with the recommendations to consider CKD as a CHD risk equivalent and to treat all of these patients with statin-based drug therapy for primary prevention. However, I can’t support the recommendation to use the combination of eztimibe/simvastatin over other therapies. In the SHARP trial, this regimen was compared with placebo, and recently, the FDA refused to grant it an indication for reduction in cardiovascular events in the non-CKD population.

I also agree with the recommendation to avoid fibrates in CKD patients, as these agents haven’t proven beneficial in combination with statin therapy. I’d therefore advocate a regimen of statin monotherapy at the doses previously suggested for all patients 50 years and older with CKD, and I wouldn’t eliminate those on hemodialysis from this recommendation.^7,8

Although the evidence for those on hemodialysis has failed to show benefit, the trials had limitations, and the risk of appropriately based statin treatment is very low. For younger patients with CKD, I agree with following a risk-based statin monotherapy strategy. I’d also not aim for a specific LDL-C value in any patients with CKD, given the known derangement of lipid levels in this population.

References

• KDIGO Lipid Work Group. KDIGO Clinical Practice Guideline for Lipid Management in Chronic Kidney Disease. Kidney Inter. 2013; 3:259-305.
• Colantonio LD, Baber U, Banach M, et al. Contrasting cholesterol management guidelines for adults with CKD. J Am Soc Nephrol. 2015;26:1173-1180.
• Baigent C, Landray MJ, Reith C, et al. The effects of lowering LDL cholesterol with simvastatin plus ezetimibe in patients with chronic kidney disease (study of heart and eenal protection): a randomised placebo-controlled trial. Lancet. 2011;377:2181-2192.
• Sarnak MJ, Bloom R, Muntner P, et al. KDOQI US commentary on the 2013 KDIGO Clinical Practice Guideline for Lipid Management in CKD. Am J Kidney Dis. 2015;65:354-366.
• Jacobson TA, Ito MK, Maki KC, et al. National lipid association recommendations for patient-centered management of dyslipidemia: part 1--full report. J Clin Lipidol. 2015;9:129-169.
• Stone NJ, Robinson JG, Lichtenstein AH, et al. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2014;63:2889-2934.
• Wanner C, Krane V, März W, et al. Atorvastatin in patients with type 2 diabetes mellitus undergoing hemodialysis. N Engl J Med. 2005;353:238-248.
• Fellström BC, Jardine AG, Schmieder RE, et al. Rosuvastatin and cardiovascular events in patients undergoing hemodialysis. N Engl J Med. 2009;360:1395-1407.