A 60-year-old asymptomatic, diabetic, overweight woman with Familial Hypercholesterolemia (FH) has been under my care for one year. LDL-C levels have ranged between 250 and 300 mg/dL. She has had side effects (myalgias, headaches, and fatigue) from six of the seven statins. Vitamin D has been repleted and CoQ10 has been tried. Dietary changes, weight loss, and daily exercise have had an inconsequential impact on her lipids.
Past Medical History:
Small Inferior Myocardial Infarction at age 50.
Coronary artery bypass grafting at age 53.
Stents to the saphenous vein graft to the right coronary artery and native left circumflex coronary artery at age 57 and 59 respectively.
Hypothyroidism
Hypertension
Non-valvular Paroxysmal Atrial Fibrillation
ECHO documentation of moderate valvular and mild supravalvular Aortic Stenosis1
Medications:
Rivaroxaban
Levothyroxine
ASA
Metoprolol
Ramapril
Vitamin D
Eicosapentaenoic acid and docosahexaenoic acid
Physical Exam:
BP 125/78 mm Hg
HR 58 BPM
BMI 30.02 Kg/m2
Waist circumference at the top of the iliac crest at end-expiration 37"
2/6 crescendo-decrescendo systolic murmur
Bilateral carotid bruits
Intact peripheral pulses
Corneal arcus (present by history since age 20)
Small bilateral Achilles tendon xanthomas
Data:
Labs:
Total cholesterol 350 mg/dL
LDL-C 265 mg/dL
HDL-C 45 mg/dL
TG 200 mg/dL
ECG: Normal sinus rhythm with old IMI. Borderline LVH.
What are her current treatment options?
Show Answer
The correct answer is: F. All of the above
Answers:
(a.) FH is most commonly a consequence of impaired function or diminished numbers of LDL receptors. Therefore, as statins' mechanism of action (MOA) is predominantly the upregulation of these receptors one can conjecture that such medications would be ineffective. The opposite is true. FH is not an absolute condition — typically receptors do exist and do maintain some function, albeit significantly diminished. Therefore statins are actually the mainstay of therapy in such patients and their use diminishes not only cardiovascular morbidity, but mortality as well2,3. Since statin-induced side effects can be idiosyncratic, it would be worthwhile in this high-risk patient to try the remaining drug in this class. It is important to recognize that combination therapy is advised in FH patients. The shared MOA of these agents is upregulation of LDL receptors.
(b.) LDL apheresis is a weekly or bi-weekly procedure during which the patient's blood is "cleansed" of LDL. Two venous lines are used; the procedure typically takes two to three hours; and it is extraordinarily safe and well-tolerated. Two machines are currently FDA-approved, Heparin Extracorporeal LDL Precipitation (HELP), and Dextran Sulfate Adsorption (DSA). FH patients are approved for LDL apheresis through Medicare and most commercial insurance carriers. LDL apheresis has been shown to significantly reduce cardiovascular events4.
(c.) Lomitapide is the first drug in the Microsomal Triglyceride Transfer Protein (MTP) inhibition class. The drug works by blocking MTP, a protein required for building hepatocyte-derived VLDL and enterocyte-derived chylomicron lipoprotein particles. As VLDL is the precursor for LDL particles, Lomitapide can drastically reduce these levels. The drug is indicated only for homozygous FH (HoFH), not heterozygous FH (HeFH). In this patient, although her LDL-C runs between 250 and 300 mg/dL, she is a woman with premature aggressive coronary artery disease and other manifestations of FH – tendon xanthomas, corneal arcus prior to age 45 (by history), and early valvular and supravalvular aortic stenosis. The diagnosis of HoFH is currently made on clinical grounds and one could certainly make the case that this patient qualifies.
(d.) Mipomersen is the first in class of antisense drugs. It is administered through subcutaneous injection on a weekly basis and works by binding and thereby blocking hepatic mRNA for apoB, a protein required for building VLDL particles. As with Lomitapide, blocking the production of VLDL results in a downstream diminution of LDL particles and LDL-C. Mipomersen, like Lomitapide is indicated in HoFH patients. In this case the most relevant distinction between these two drugs is that Lomitapide can be used with LDL apheresis while Mipomersen cannot.
(e.) PCSK9 inhibitors are a novel drug class that may be effective in FH patients. Their MOA is blocking PCSK9 a proprotein responsible for degrading LDL receptors. The inhibitors are antibodies administered bi-weekly. They are currently not FDA approved but a number of phase three clinical trials are ongoing. If the patient were to choose this option, within the context of current placebo controlled clinical trials drug would not be guaranteed.
References
Saito S, Usui A, Akita T, Ueda Y. Surgery for calcific aortic root stenosis in homozygous familial hypercholesterolemia. Eur J Cardiothorac Surg 2006;29:114-6.
Raal FJ, Pilcher GJ, Panz VR, et al. Reduction in mortality in subjects with homozygous familial hypercholesterolemia associated with advances in lipid-lowering therapy. Circulation 2011;124:2202-7.
Versmissen J ,Oosterveer DM ,Yazdanpanah M ,Defesche JC ,Basart DCG ,Liem AH ,et al. Efficacy of statins in familial hypercholesterolaemia: a long term cohort study. Br Med J 2008;337:a2423
Mabuchi H, Koizumi J, Shimizu M, et al. Long-term efficacy of low-density lipoprotein apheresis on coronary heart disease in familial hypercholesterolemia. Hokuriku-FH-LDL-Apheresis Study Group. Am J Cardiol 1998;82:1489-95.
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