A 37-year-old Caucasian man presents to clinic to establish care. At age 18 years, he was diagnosed with homozygous familial hypercholesterolemia (HoFH) after his father died suddenly of a massive myocardial infarction at age 42 years. Two paternal uncles also died suddenly at ages 39 and 45 years. At that time, his low-density lipoprotein cholesterol (LDL-C) was 530 mg/dL, and he was started on a statin and advised to initiate LDL-C apheresis. He notes that he stopped the statin after seven months because "he did not like the way it made him feel." He also discontinued apheresis because it required a 3.5-hour drive each way to reach an academic medical center and his health insurance only covered approximately 30% of the cost. Despite much encouragement, he rejected the possibility of liver transplantation. He stopped following up with a physician. At age 35 years, he sustained an inferior wall myocardial infarction. On cardiac catheterization, he was found to have diffuse multivessel disease with an 80% obstruction in his left main coronary artery, a 75% obstruction in his proximal circumflex artery, and a completely occluded right coronary artery at approximately the middle portion of the vessel. He underwent a three-vessel coronary artery bypass without complication.
The patient is not currently experiencing any symptoms of myocardial ischemia or heart failure. He does not smoke and is walking for 45 minutes daily. He is on an American Heart Association Heart Healthy diet with particular care focused on avoiding saturated and trans fats. His current medications include rosuvastatin 40 mg po qd, ezetimibe 10 mg po qd, colesevelam 3.75 g po qd, aspirin 81 mg po qd, ramipril 10 mg po qd, and carvedilol 12.5 po qd. Vital signs are normal. A physical examination reveals multiple abnormalities. On the current pharmacologic regimen, the patient's fasting lipid profile shows LDL-C 230 mg/dL, HDL-C 67 mg/dL, and triglycerides 97 mg/dL.
Which of the following are reasonable adjuvant therapeutic choices in this patient?
Show Answer
The correct answer is: F. Answer options A and D.
It is quite challenging to normalize the LDL-C of a patient with HoFH with the pharmacologic regimen he is currently receiving. Statins, ezetimibe, and the bile acid binding resins have different, complementary mechanisms of action, but all of these agents have some dependence on being able to upregulate the LDL-R. This is severely or completely attenuated in patients with HoFH. In patients with HoFH, statins will reduce circulating cholesterol by inhibiting 3-hydroxymethyl-3-glutaryl coenzyme A reductase (HMG CoA reductase), ezetimibe will inhibit NPC1L1 in the gut and reduce the absorption of cholesterol from dietary and biliary sources,1 and the bile acid binding resins activate 7-alpha-hydroxylase, the rate limiting step by which cholesterol is converted into bile acids.2
Either mipomersen or lomitapide are appropriate adjuvant therapies in this patient. Both of these agents are indicated for the treatment of HoFH and neither has a dependence on being able to upregulate expression of the LDL-R. Mipomersen is an anti-sense molecule that binds to a specific coding region on the messenger RNA (mRNA) of apoprotein B (APOB).3,4 APOB is the primary apoprotein constituent of very low-density lipoproteins (VLDL). VLDLs are responsible for distributing energy in the form of fatty acids to visceral organs. The enzyme lipoprotein lipase progressively lipolyzes VLDL to form LDL particles. Subsequent to heterodimer formation, the mRNA cannot be translated into APOB, and VLDL production and secretion are reduced, leading to a significant drop in LDL formation.
Lomitapide is an inhibitor of microsomal triglyceride transfer protein (MTTP).5,6 MTTP is the enzyme that lipidates APOB with phospholipid, triglyceride, and cholesteryl ester to form nascent VLDL particles within the endoplasmic reticulum of hepatocytes.7 Lomitapide very specifically inhibits MTTP and the lipidation of APOB, thereby significantly curtailing the production and secretion of VLDL particles.
Omega-3 fish oils are indicated for the treatment of severe hypertriglyceridemia (triglycerides >500 mg/dL). Fenofibrate is not indicated as patient's triglyceride and HDL-C levels are normal. There would be no value in switching the patient to high-dose atorvastatin since rosuvastatin at 40 mg has the highest capacity to reduce serum LDL-C.8 Plasma apheresis would constitute another highly efficacious approach, but the patient has major practical obstacles to this therapy.9
It can be quite challenging to induce clinically meaningful reductions in LDL-C among patients with HoFH. It frequently requires the simultaneous use of three or more medications. For some patients with this disease, attaining LDL-C levels <100 mg/dL may not be realistic. In such cases, driving the LDL-C as low as clinically feasible may be the best and most realistic goal.
References
Toth PP, Davidson MH. Cholesterol absorption blockade with ezetimibe. Curr Drug Targets Cardiovasc Haematol Disord 2005;5:455-62.
Chiang JY, Kimmel R, Stroup D. Regulation of cholesterol 7alpha-hydroxylase gene (CYP7A1) transcription by the liver orphan receptor (LXRalpha). Gene 2001;262:257-65.
Raal FJ, Santos RD, Blom DJ, et al. Mipomersen, an apolipoprotein B synthesis inhibitor, for lowering of LDL cholesterol concentrations in patients with homozygous familial hypercholesterolaemia: a randomised, double-blind, placebo-controlled trial. Lancet 2010;375:998-1006.
Toth PP. Emerging LDL therapies: Mipomersen-antisense oligonudeotide therapy in the management of hypercholesterolemia. J Clin Lipidol 2013;7:S6-S10.
Cuchel M, Bloedon LT, Szapary PO, et al. Inhibition of microsomal triglyceride transfer protein in familial hypercholesterolemia. N Engl J Med 2007;356:148-56.
Cuchel M, Meagher EA, du Toit et al. Efficacy and safety of a microsomal triglyceride transfer protein inhibitor in patients with homozygous familial hypercholesterolaemia: a single-arm, open-label, phase 3 study. Lancet 2013;381:40-6.
Toth PP, Shah PK, Wilkinson MJ, Davidson MH, McCullough PA. Use of microsomal triglyceride transfer protein inhibitors in patients with homozygous familial hypercholesterolemia: translating clinical trial experience into clinical practice. Rev Cardiovasc Med 2014;15:1-10.
Jones PH, Davidson MH, Stein EA, et al. Comparison of the efficacy and safety of rosuvastatin versus atorvastatin, simvastatin, and pravastatin across doses (STELLAR* Trial). Am J Cardiol 2003;92:152-60.
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