EVOLOCUMAB LOWERS LOW DENSITY LIPOPROTEIN CHOLESTEROL AND LIPOPROTEIN (A) LEVELS IN NEPHROTIC SYNDROME. Ramarao Pradeep

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1 AACE Clinical Case Reports Rapid Electronic Articles in Press Rapid Electronic Articles in Press are preprinted manuscripts that have been reviewed and accepted for publication, but have yet to be edited, typeset and finalized. This version of the manuscript will be replaced with the final, published version after it has been published in the print edition of the journal. The final, published version may differ from this proof. Case Report ACCR EVOLOCUMAB LOWERS LOW DENSITY LIPOPROTEIN CHOLESTEROL AND LIPOPROTEIN (A) LEVELS IN NEPHROTIC SYNDROME Ramarao Pradeep From: Endocrine Associates of Quad Cities Running title: Evolocumab lowers Lp(a) in nephrotic syndrome Corresponding address: Dr. Ramarao Pradeep, Endocrine Associates of Quad Cities, 612, 35th Avenue, Moline,Illinois

2 Abstract Objectives: To present a patient with nephrotic syndrome and elevated Low density lipoprotein cholesterol secondary to increased Lipoprotein (a) levels and to demonstrate a decrease in Lp(a) levels secondary to Evolocumab therapy. Methods: Lp(a) was measured by immunoturbidimetric assay. The elevated Lp(a) level was treated with Evolocumab. Results: A 56-year-old man with coronary artery disease and peripheral vascular disease presented with elevated LDL cholesterol. Physical examination revealed grade 4+ pitting pedal edema. Twenty-four-hour urine protein collection revealed proteinuria in the nephrotic range. The fasting LDL cholesterol level on a combination of high intensity statins,ezetimibe and lifestyle changes was 156 mg/dl (4.04mmol/L), and the fasting Lp(a) level was 130 mg/dl(4.641µmol/l). Treatment with Evolocumab resulted in a 73 % reduction in Lp(a) and a concomitant 76.9% reduction in LDL -cholesterol. Conclusions: Nephrotic syndrome increases the Lp(a) level. Lp(a) contains cholesterol that is not differentiated from LDL cholesterol by current LDL- cholesterol measurement methods. Hence, Lp(a)-corrected LDL cholesterol should be used in patients with increased Lp(a). Evolocumab decreased the Lp(a) levels by 73% thereby providing the correct estimation of LDL-C. Abbreviations: LDL-C = LDL cholesterol; Lp(a) = lipoprotein(a); PCSK9 = proprotein convertase subtilisin/kexin type 9; HDL = high density lipoprotein; ASCVD = atherosclerotic vascular disease; CETP = cholesteryl ester transfer protein.

3 Introduction Low density lipoprotein- cholesterol accounts for 75% of the cholesterol carried by non-high density lipoprotein cholesterol particles (Intermediate density lipoprotein, LDL-C, Very low density lipoprotein- cholesterol, Chylomicron remnants, and Lipoprotein(a)). LDL-C can be calculated using Friedewald equation (LDL = total cholesterol - (HDL + triglycerides / 5), which include the cholesterol carried by Lp(a). Similarly, direct LDL-C measurements do notdifferentiate cholesterol derived from Lp(a). Patients with nephrotic syndrome have high concentrations of Lp(a) (1). Overall, 45% of Lp(a) is cholesterol, and current LDL measurement methods do not separately report cholesterol derived from Lp(a). We report a case of a 56-year-old man with elevated Lp(a) that resulted in pseudo-elevation of LDL-C that was corrected with Evolocumab. The degree of decrease in Lp(a) following treatment with Evolocumab observed in our patient has not been previously reported. Case Presentation The patient was a 56-year-old man with a history of type 2 diabetes, coronary artery Disease and peripheral vascular disease who presented for lipid evaluation. He was using 5 units of insulin aspart with dinner, glipizide with breakfast and insulin detemir (23 units daily). His blood sugar levels ranged from to 6.05 mmol/l (75 to 110 mg/dl). The patient did not have diabetic retinopathy. The nephrotic syndrome was likely secondary to hypertensive nephrosclerosis. His cardiac history was significant for inferior wall myocardial infarction 4 years prior to presentation. An angiogram one year prior showed a 50-60% occlusion of the right coronary artery and chronic occlusion of the left anterior descending artery. He also had a history of peripheral vascular disease with an aortofemoral bypass. His family history was negative for coronary artery disease and peripheral vascular disease. He was taking aspirin 325 mg, atorvastatin 80 mg daily and ezetimibe. In addition, he used 2 gm of plant sterols and stanols and was on a less than 10% saturated fat diet. He could not

4 exercise regularly due to shortness of breath.the laboratory data showed an a1c of 6.7 %(50 mmol/mol). His fasting LDL-C level was 156 mg/dl(4.04mmol/l). His non- HDL cholesterol was 254 mg/dl (6.56 mmol/l).the Lp(a) was 130 mg/dl(4.641µmol/l). His thyroid stimulating hormone was 0.89 U/L. The 24 hour urine protein collection equaled 6.6 grams/24 hours. The glomerular filtration rate was 23 ml/min. The serum albumin was 2.9 grams/l. He was started on Evolocumab at 140 mg every 2 weeks. After 3 months of Evolocumab therapy, LDL- C decreased to 36 mg/dl(0.93 mmol/l). Lp(a) had decreased to 35 mg/dl(1.25 µmol/l). Non HDL cholesterol decreased to 57 mg/dl(1.47 mmol/l) Physical Examination The physical examination showed the following: height: 59 inches, weight: 168 lbs., BMI: kg/m2, blood pressure: 120/80 mmhg and waist circumference: 104 cm. Periorbital edema was present. A neck exam showed no goiter. The lungs were clear upon auscultation. He had normal heart sounds without murmurs and grade 4+ pitting pedal edema.there was no evidence of palmar xanthomas or tendon xanthomas. Peripheral vascular examination showed 2+ dorsalis pedis and posterior tibial pulses. Discussion On atorvastatin 80 mg and ezetimibe 10 mg daily, the patient had an LDL cholesterol of 156 mg/dl(4.04g/l). Hypothyroidism was ruled out. Lack of familial history of cardiovascular diseases meant that proteinuria was the most likely cause of mixed hyperlipidemia and elevated Lp(a). Obesity with visceral adiposity may explain the increased LDL-C levels. However, it does not contribute to the elevated Lp(a). Additionally, while chronic kidney disease is an important cause of cardiovascular disease, it did not cause his elevated Lp(a). Lipoprotein (a) consists of apolipoprotein A attached to LDL by a disulfide bond to apolipoprotein B. Lp(a) carries a load of oxidized phospholipids. It inhibits the

5 conversion of plasminogen to plasmin, thereby increasing thrombogenesis and atherogenicity. Based on the number of Kringle IV repeats, the molecular weight of Lp(a) can vary from 300,000 to 800,000 Daltons. The low molecular weight phenotype is associated with a greater number of Lp(a) particles and correlates with increased cardiovascular disease risk (1). A preponderance of the low molecular weight phenotype exists in patients with nephrotic syndrome (1). It is the low molecular weightphenotype that is associated with elevated LDL-C (1). Forty-five percent of Lp (a) is composed of cholesterol. In a classic example from the literature, if the Lp(a) level is 200 mg/dl (7.14 µmol/l) and the measured LDL level is 200 mg/dl (5.18 mmol/l), the actual LDL-C would be 110 mg/dl(2.85 mmol/l) (1). Therefore, if Lp(a) is elevated, 45% of the Lp(a) level needs to be subtracted from the LDL-C value to obtain the true LDL-C level (1) A low serum albumin level results in low plasma oncotic pressure. The low oncotic pressure stimulates apolipoprotein B gene transcription (2). Hence, patients with nephrotic syndrome have elevated total cholesterol, LDL-C, triglycerides, and Lp(a) levels. This patient did not have any family history of cardiovascular or peripheral vascular disease. Hence, the most likely cause of elevated Lp(a) in this patient was nephrotic syndrome. The effect of lowering LDL-C and the risk improvement in ASCVD have been well documented in genetic studies and after pharmacological intervention. Individuals with loss-of-function mutations in the proprotein convertase subtilisin kexin type 9 (PCSK9) gene have low levels of LDL-C and a markedly reduced risk for ASCVD events (3, 4). The Cholesterol Treatment Trialist metaanalysis demonstrated that for every 1 mmol/l (38.7 mg/dl) decrease in LDL-C, there was a 22% relative risk reduction for major ASCVD events. Larger reductions on the order of 2-3 mmol/l ( mg/dl) resulted in a 40-50% relative risk reduction for ASCVD (5). Unfortunately, neither diet nor commonly used anti-lipid agents such as statins, bile acid binding resins and ezetimibe affect Lp(a) levels. Drugs that decrease the Lp(a) level include aspirin and lipid lowering agents- such as niacin, mipomersen, lomitapide, CETP inhibitors and PCSK9 inhibitors. Niacin was not used in this patient because of its tolerability and safety profile. The CETP inhibitor anacetrapib decreases Lp (a) by approximately 40-50% (7). However,

6 anacetrapib is not currently approved for the treatment of elevated Lp(a). Mipomersen and Lomitapide are approved for the treatment of familial hypercholesterolemia only. In a patient with ischemic stroke and elevated Lp(a), aspirin reduced the Lp(a) levels by 15% (8). Our patient had been taking 325mg aspirin for four years. Hence, it was unlikely that aspirin contributed to the acute decrease in the Lp(a) level. The decrease in Lp(a) cholesterol was likely due to the addition of Evolocumab. The magnitude of decrease in Lp(a) observed in this patient has not been previously reported in the literature and it is similar to the reduction in Lp(a) levels by LDL apheresis. PCSK9 is a protein secreted by the liver that binds to the LDL receptor and targets it for lysosomal degradation (6). Therefore, inhibition of PCSK9 is an important target in the treatment of elevated LDL-C. In the FOURIER trial, patients with diabetes at baseline whoreceived Evolocumab demonstrated an absolute reduction of 56 mg/dl(1.44 mmol/l)in the level of LDL-C. In the subgroup with diabetes at baseline, a 16% reduction in triglycerides and a 49.5% reduction in non-hdl cholesterol level were observed (9). In addition, a 17% decrease was observed in the primary efficacy endpoint of major cardiovascular events. Defined as a composite of cardiovascular deaths, myocardial infarction, stroke, and hospitalization due to unstable angina or coronary revascularization. In this trial, Evolocumab reduced Lp(a) by 26.9%. This patient demonstrated a robust reduction in Lp(a) due to Evolocumab therapy Postulated mechanisms by which PCSK9 inhibitors decrease Lp(a) include decreased synthesis of apolipoprotein B-100 particles, increased expression of SRB1 scavenger receptors and clearance of Lp(a) by SRB1 scavenger receptors or increased degradation of Lp receptor-related proteins (10) This case has important implications for statin use. First, statins do not affect Lp(a) levels.second, the American Heart Association divides patients into statin benefit groups (11). In such a case, statin effectiveness is decided by the percentage decrease in LDL-C. A patient with an LDL-C level that is not corrected for elevated Lp(a) will be recommended higher doses of statins, addition of non-statins, or both. In patients with chronic kidney disease,higher doses of stains can increase the risk of

7 statin-related myalgia/myositis, thereby increasing the potential for statin noncompliance in a group of patients in need of statins. In conclusion,it is important to recognize that patients with nephrotic syndrome have elevated levels of Lp(a). Lp(a)- corrected LDL-cholesterol needs to be used in cardiovascular risk assessment in patients with Nephrotic syndrome. Evolocumab lowers Lp(a) and helps in an accurate assessment of LDL-C.. Funding: None Conflict of Interest: None

8 References 1. Kronenberg, F, Lingenhel A, Lhotta K, et al. Lipoprotein(a) and lowdensity lipoprotein-derived cholesterol innephrotic syndrome: Impact on lipid-lowering therapy. Kidney Int. 2004;66: Yamaguchi, A, Fukuhara Y, Yamamoto S, et al. Oncotic pressure regulates gene transcriptions of albumin and apolipoprotein B in cultured rat hepatoma cells. Am J Physiol. 1992;263:C397-C Cohen JC, Boerwinkle E, Mosley TH Jr, Hoobs HH. Sequence variations in PCSK9, low LDL, and protection against coronary heart disease. N Engl J Med. 2006;354: Seidah NG, Awan Z, Chretien M, Mbikay M. PCSK9: A key modulator of cardiovascular health. Circ Res. 2014;114: Cholesterol Treatment Trialists (CTT) Collaboration, Baigent C, Blackwell L, Emberson J. Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials. Lancet. 2010;376: Seidah NG, Awan Z, Chretien M, Mbikay M. PCSK9: A key modulator of cardiovascular health. Circ Res. 2014;114: Bloomfield D, Carlson GL, Sapre A, et al. Efficacy and safety of the cholesteryl ester transfer protein inhibitor anacetrapib as monotherapy and coadministered with atorvastatin in dyslipidemic patients. Am Heart J. 2009; 157: e 8. Lakshminarayan D, Elajami TK, Devabhaktuni S, Welty FK. Ischemic Stroke in young Adult with elevated lipoprotein (a): A case report and review of literature. J Clin Lipidol. 2016;10:

9 9. MS Sabatine, LA Leiter, SD Wiviott, RP Giugliano, P Deedwania, GM De Ferrari, SA Murphy, JF Kuder, AC Keech, PS Sever, and TR Pedersen, for the FOURIER Steering Committee & Investigators. Cardiovascular efficacy and safety of evolocumab in diabetes, and risk of development of diabetes. In: European Association of Diabetes- 53rd Annual Meeting. Clinical Trial Update. September 15th, Kotani K, Banach M. Lipoprotein(a) and inhibitors of proprotein convertase subtilisin/kexin type 9. J Thorac Dis. 2017;9:E78-E Stone NJ, Robinson JG, Lichtenstein AH, et al 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:

Drug Class Monograph

Drug Class Monograph Class: Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) Inhibitor Drugs: Praluent (alirocumab), Repatha (evolocumab) Line of Business: Medi-Cal Effective Date: February 17, 2016