PRESENTED BY
CHARLES FERRO

Presentation Summary

Written by Jasna Trbojevic-Stankovic
Reviewed by Charles Ferro

Dyslipidemia represents a disorder of lipoprotein metabolism, including lipoprotein overproduction or deficiency. It contributes to the development of atherosclerosis and cardiovascular and cerebrovascular adverse events. Serum cholesterol levels have first been linked to the risk of coronary heart disease forty years ago in the Framingham Study (1). However, the observed relationship has been widely disputed for a considerable period after. The statin therapy for hypercholesterolemia remained controversial until the mid-nineties mainly because of insufficient clinical trial evidence for improved survival. Finally, in 1994 the Scandinavian Simvastatin Survival Study undeniably proved the positive effect of simvastatin on survival in patients with angina pectoris or previous myocardial infarction by lowering total cholesterol, low-density –lipoprotein (LDL) cholesterol and high-density lipoprotein (HDL) cholesterol (2).

Hemodialysis (HD) patients exhibit a higher risk of death attributed to arteriosclerotic complications – myocardial infarction, stroke and congestive heart failure. The incidence of these complications is multiple times higher in this population than in healthy and hypertensive individuals of comparable age, and similar to the rates found in Type 2 hyperlipoproteinemia (3, 4). Non-dialysis chronic kidney disease (CKD) patients also have a higher risk of death and cardiovascular events which is strongly associated with declining estimated glomerular filtration rate (5). The excess risk of cardiovascular disease in this population has been attributed to a higher prevalence of older age, hypertension, diabetes, physical inactivity and hyperlipidemia (4).

Lipid metabolism and the role of statins in CKD patients
Lipid metabolism is complex and involves multiple organs, tissues and cells, all of which can be affected by declining kidney function. Renal dysfunction changes the level, composition and quality of blood lipids towards a uremic lipid profile, characterized by raised triglycerides, low HDL cholesterol and variable levels of LDL-cholesterol (6). The typical derangements in lipoprotein metabolism in CKD is presented in Figure 1.

Figure 1. Mechanisms of lipid metabolism disorder in CKD patients (6, 7)

Beneficial effects of statin therapy on lowering LDL cholesterol and reducing major vascular events and vascular mortality has been shown in a wide range of individuals. However, its effects on individuals with more advanced CKD are not that impressive. The relative reduction in major vascular events with statin-based treatment decreases as eGFR declines, with little benefit in dialyzed patients (8). Statins increase the levels of proprotein convertase subtilisin/kexin type 9 (PCSK9), as well as lipoprotein (a) (9, 10). PCSK9 is an extracellular protein that binds directly to LDL receptors and induces its internalization and degradation, thus reducing LDL uptake in the cells that leads to increased concentrations of circulating LDL-cholesterol (6). Inhibiting PCSK9 prevents the breakdown of LDL-receptor, thus increasing its cellular uptake and lowering circulating LDL-cholesterol. The role of PCSK9 in cholesterol transport is shown in Figure 2.

 

Figure 2. Role of PCSK9 in cholesterol transport (6, 7)

Lipoprotein (a) is a highly atherogenic variant of LDL and its elevated levels are independently associated with the risk of atherosclerosis, myocardial infarction, aortic valve calcification and death in CKD patients (6, 13). Lp(a) levels are mainly genetically determined, but since it is cleared by the kidney, among other clearance mechanisms, Lp(a) may increase in CKD and in response to statins (13). The measured LDL-cholesterol includes the cholesterol content of Lp(a), which can contribute approximately 30-45% to measured LDL-cholesterol levels as a percentage of its mass (14). In CKD patients, the lower the measured LDL-cholesterol, the higher the content of Lp(a), which may explain the limited efficacy of statin therapy on cholesterol-lowering in advanced CKD.

New advances in lipid-lowering therapies
Two monoclonal antibodies that inhibit PCSK9 and lower LDL-cholesterol are currently available – evolocumab and alirocumab. Both have been tested in randomized, double-blind, placebo-controlled trials on a background of medium to high-intensity statin therapy and were shown to effectively reduce LDL-cholesterol and Lp(a) levels, as well as the risk of cardiovascular events (11, 12). The FOURIER (Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk) trial compared outcomes with evolocumab and placebo according to the level of kidney function, concluding that absolute reduction in the composite of cardiovascular death, myocardial infarction, or stroke with evolocumab was numerically greater with more advanced CKD (15). However, the trial did not include end-stage renal disease patients, therefore the efficacy and safety of this therapeutic regimen in this patient group still need to be addressed.

There are currently no approved medications to specifically lower Lp(a). Pelacarsen, a hepatocyte-directed antisense oligonucleotide targeting the LPA gene mRNA, has been shown to lower Lp(a) levels in several very recent trials, but it has not yet been investigated on patients with glomerular filtration rate <60ml/min or urinary albumin:creatinine ratio >100mg/g (13, 16). Even more so, the upcoming phase 3 Lp(a) HORIZON trial also a priori excludes patients with significant kidney disease (17). Given the increased risk for dyslipidemia and related complications in CKD patients, novel efficient and safe lipid-lowering therapeutics are urgently needed for this population.

References

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2. Randomised Trial of Cholesterol Lowering in 4444 Patients With Coronary Heart Disease: The Scandinavian Simvastatin Survival Study (4S). Lancet 1994;344(8934):1383-1389.

3. Lindner A, Vharra B, Sherrard DJ, Scribner BH. Accelerated Atherosclerosis in Prolonged Maintenance Hemodialysis. N Engl J Med 1974;290(13):697-701.

4. Foley RN, Parfrey PS, Sarnak MJ. Clinical Epidemiology of Cardiovascular Disease in Chronic Renal Disease. Am J Kidney Dis 1998;32(5 Suppl 3):S112-119.

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7. Ferro CJ. Treatment of dyslipidaemia in CKD: where do we stand now? Presented at the 57th European Renal Association – European Dialysis Transplantation Association Congress (fully virtual), June 8, 2020. Available at Virtual Meeting

8. Cholesterol Treatment Trialists Collaboration. Impact of Renal Function on the Effects of LDL Cholesterol Lowering With Statin-Based Regimens: A Meta-Analysis of Individual Participant Data From 28 Randomised Trials. Lancet Diabetes Endocrinol 2016;4(10):829-839.

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10. Kostner GM, Gavish D, Leopold B, Bolzano K, Weintraub MS, Breslow JL. HMG CoA Reductase Inhibitors Lower LDL Cholesterol Without Reducing Lp(a) Levels. Circulation 1989;80(5):1313-1319.

11. Sabatine MS, Giugliano RP, Keech AC, et al. Evolocumab and Clinical Outcomes in Patients With Cardiovascular Disease. N Engl J Med. 2017;376(18):1713-1722.

12. Schwartz GG, Steg PG, Szarek M, et al. Alirocumab and Cardiovascular Outcomes After Acute Coronary Syndrome. N Engl J Med 2018;379(22):2097-2107.

13. Fernandez-Prado R, Perez-Gomez MV, Ortiz A. Pelacarsen for lowering lipoprotein(a): implications for patients with chronic kidney disease. Clin Kidney J 2020 (ahead of print, available at: https://doi.org/10.1093/ckj/sfaa001)

14. Yeang C, Witztum JL, Tsimikas S. ‘LDL-C’ = LDL-C + Lp(a)-C: Implications of Achieved Ultra-Low LDL-C Levels in the Proprotein Convertase subtilisin/kexin Type 9 Era of Potent LDL-C Lowering. Curr Opin Lipidol 2015;26(3):169-178.

15. Charytan DM, Sabatine MS, Pedersen TR, et al. Efficacy and Safety of Evolocumab in Chronic Kidney Disease in the FOURIER Trial. J Am Coll Cardiol 2019;73(23):2961-2970.

16. Tsimikas S, Karwatowska-Prokopczuk E, et al. Lipoprotein(a) Reduction in Persons With Cardiovascular Disease. N Engl J Med. 2020;382(3):244-255.

17. Ferro CJ, Sarafidis P, Ortiz A. Lipoprotein(a) Reduction in Persons With Cardiovascular Disease. N Engl J Med. 2020;382(21):e65.

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