A 38-year-old white man is referred to the lipid clinic for optimization of his cardiovascular (CV) health. He has history of obesity and hypertension (HTN). He has no known history of CV disease. His family history is significant for premature coronary artery disease (CAD) in multiple family members: his father had a myocardial infarction (MI) at 47 years of age, his paternal grandfather had an MI and revascularization with coronary artery bypass grafting at 50 years of age, and his uncle had an MI in his 40s. Most recently, his older brother had an MI at 45 years of age. In this setting, he was diagnosed with heterozygous familial hypercholesterolemia (HeFH) approximately 6 months earlier. His current medications include lisinopril 10 mg daily and atorvastatin 40 mg daily.
His lipid profile at the time of his HeFH diagnosis was significant for elevated cholesterol levels, with low-density lipoprotein (LDL) level 220 mg/dL. He also underwent noncontrast cardiac computed tomography, which revealed coronary artery calcium (CAC) score 88 (>99th percentile for age and sex).
His physical examination findings are notable for body mass index (BMI) 34 kg/m2 but are otherwise unremarkable, without tendon xanthomas or arcus cornealis. His blood pressure is 120/80 mm Hg.
A recent fasting lipid panel on his current therapy showed total cholesterol level 242 mg/dL, triglyceride level 100 mg/dL, high-density lipoprotein cholesterol (HDL-C) level 42 mg/dL, and low-density lipoprotein cholesterol (LDL-C) level 170 mg/dL. His creatinine, liver enzyme, lipoprotein(a) (Lp[a]), thyroid-stimulating hormone, and vitamin D levels are within the reference ranges. Genetic testing confirms a mutation in the LDL receptor.
He is working on a regular exercise regimen with 50 min of moderate aerobic exercise daily, and has been referred to a weight-loss counselor. He has good exercise capacity at baseline and denies any chest pain, shortness of breath, palpitations, leg swelling, dizziness, or syncope. He notes that he was alerted about elevated LDL-C (or "bad cholesterol") levels in the 250s mg/dL range 10 years earlier, but at that time had decided to focus on modifying his diet and exercise pattern rather than starting medications. He was lost to follow-up until 6 months earlier; after his brother's heart attack, he re-engaged with medical care and started atorvastatin. He would like to keep his risk of future adverse CV events as low as possible.
What are the next steps to consider in optimal management of atherosclerotic cardiovascular disease (ASCVD) risk in this patient?
Show Answer
The correct answer is: D. Both B and C.
Answer choice D is the correct choice because "lower LDL-C level for longer is better" and "getting to LDL-C goal sooner is better." Answer choice A is an incorrect choice because this patient had no symptoms of angina. Hence, he did not need a nuclear stress test for evaluation.
Familial hypercholesterolemia (FH) is a relatively common (estimated prevalence 1:250-300 individuals globally) yet underdiagnosed genetic disorder with an autosomal-dominant pattern of inheritance that is characterized by lifelong cumulative exposure to high levels of LDL-C from birth. This exposure leads to the development of premature ASCVD, with an increased risk (up to 30-50% higher than that of the general population) of fatal or nonfatal cardiac events and reduced lifespans, if untreated. HeFH is mainly diagnosed by a combination of phenotypic criteria that include history of significantly elevated LDL-C levels (>190 mg/dL), known history of premature ASCVD or family history of premature CAD, and genetic testing. Commonly used tools to diagnosis FH include the Dutch Lipid Clinic Network (DLCN) and the Simon Broome criteria.
This patient had severe HeFH with multiple significant ASCVD risk factors, including male sex, family history of premature CAD, HTN, elevated BMI, and advanced subclinical atherosclerosis (>99th age/sex percentile); he therefore had a very high risk of future ASCVD events. The International Atherosclerosis Society (IAS) has described three phenotypes that would be classified as severe FH1:
FH with subclinical atherosclerosis (CAC score >100 Agatston units or >75th percentile for age and sex); and
FH without ASCVD (untreated LDL-C level >400 mg/dL, LDL-C level >310 mg/dL, and one risk factor or LDL-C level >190 mg/dL and two risk factors [risk factors include age >40 years, smoking, male sex, HTN, diabetes mellitus, chronic kidney disease, BMI >30 kg/m2, Lp[a] level >125 nmol/L, HDL-C level <40 mg/dL, and family history of premature CAD]).
In this context, an earlier, intensive risk factor treatment approach is the most effective primary-prevention strategy.
"In patients with severe primary hypercholesterolemia (LDL-C level ≥190 mg/dL [≥4.9 mmol/L]), without calculating 10-year ASCVD risk, begin high-intensity statin therapy." (Class 1, Level of Evidence [LOE] B-R)
"In patients 20 to 75 years of age with an LDL-C level of 190 mg/dL or higher (≥4.9 mmol/L) who achieve less than 50% reduction in LDL-C while receiving maximally tolerated statin therapy and/or have an LDL-C level of 100 mg/dL (≥2.6 mmol/L) or higher, ezetimibe therapy is reasonable." (Class 2a, LOE B-R)
"In patients 30 to 75 years of age with heterozygous FH and with an LDL-C level of 100 mg/dL or higher (≥2.6 mmol/L) while taking maximally tolerated statin and ezetimibe therapy, the addition of a PCSK9 inhibitor may be considered." (Class 2b, LOE B-R)
Patients with severe primary hypercholesterolemia have a high lifetime risk because of cumulative exposure to high levels of LDL-C, along with risk of premature and recurrent events, if underdiagnosed and undertreated. This patient reported an initial test result suggestive of primary hypercholesterolemia 10 years earlier that was not followed up on. The concept of "cholesterol-years," a marker of cumulative exposure to high cholesterol levels over time in the setting of FH, describes the natural history, describes the progression to extensive atherosclerosis in the young, and is directly related to adverse outcomes. In addition, studies support the importance of early intervention to reduce the future risk of ASCVD, as a lifelong decrease in LDL-C levels results in a more dramatic (three to four times greater) reduction in ASCVD events than does short-term LDL-C level lowering with medications later in life.
Hence, the framework of "importance of getting to LDL-C goal sooner" needs to be incorporated into the approach to managing this young patient with already known significant exposure to elevated LDL-C levels. The findings of contemporary trials of lipid-lowering medications (ezetimibe, PCSK9 monoclonal antibody [mAB] inhibitors) in combination with statins—IMPROVE-IT (Improved Reduction of Outcomes: Vytorin Efficacy International Trial), FOURIER (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk), and ODYSSEY Outcomes (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab)—provide the best evidence that "the lower the LDL-C goal the better" to prevent future ASCVD outcomes.
Most guidelines therefore recommend that patients with FH at high risk or very high risk receive intensive LDL-C level lowering therapy to goal <100 mg/dL in a primary-prevention setting.2-4
Since the publication of the 2018 multisociety cholesterol guideline, the Food and Drug Administration (FDA) has approved additional therapies for LDL-C level lowering: bempedoic acid and inclisiran (and evinacumab for homozygous FH). Bempedoic acid is an oral medication approved by the FDA in 2020 as an adjunct to diet and maximally tolerated statin for the treatment of adults with HeFH or established ASCVD who require additional LDL-C level lowering. The CLEAR Outcomes (Cholesterol Lowering via Bempedoic Acid, an ACL-Inhibiting Regimen) trial provided further evidence of benefit of bempedoic acid for reduction of major adverse CV events in patients with ASCVD or at high risk of ASCVD who are unable or unwilling to take statin therapy and maintain LDL-C levels ≥100 mg/dL.5
This patient remained significantly above his LDL-C goal of <100 mg/dL. He was subsequently recommended to increase his atorvastatin to 80 mg/dL and to start ezetimibe 10 mg. His laboratory studies were checked 6 weeks later, and his LDL-C level had further decreased to 129 mg/dL but was still above goal. At that point, additional potential therapies were discussed with him, including initiating PCSK9 mAB inhibitors, bempedoic acid, or inclisiran (in lieu of a PCSK9 mAB).3,6,7 He did not have any children, but other first-degree relatives were recommended for cascade screening for FH.
This patient case quiz is part of an ACC course titled Bempedoic Acid: New Evidence Transforming the LDL-C Treatment Landscape. Educational grant support is provided by Esperion. To visit the Online Course page for the Bempedoic Acid: New Evidence Transforming the LDL-C Treatment Landscape Grant, click here.
References
Santos RD, Gidding SS, Hegele RA, et al.; International Atherosclerosis Society Severe Familial Hypercholesterolemia Panel. Defining severe familial hypercholesterolaemia and the implications for clinical management: a consensus statement from the International Atherosclerosis Society Severe Familial Hypercholesterolemia Panel. Lancet Diabetes Endocrinol 2016;4:850-61.
Grundy SM, Stone NJ, Bailey AL, et al. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA guideline on the management of blood cholesterol: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol 2019;73:e285-e350.
Lloyd-Jones DM, Morris PB, Ballantyne CM, et al.; Writing Committee. 2022 ACC expert consensus decision pathway on the role of nonstatin therapies for LDL-cholesterol lowering in the management of atherosclerotic cardiovascular disease risk: a report of the American College of Cardiology Solution Set Oversight Committee. J Am Coll Cardiol 2022;80:1366-418.
Mach F, Baigent C, Catapano AL, et al.; ESC Scientific Document Group. 2019 ESC/EAS guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk. Eur Heart J 2020;41:111-88.
Nissen SE, Lincoff AM, Brennan D, et al.; CLEAR Outcomes Investigators. Bempedoic acid and cardiovascular outcomes in statin-intolerant patients. N Engl J Med 2023;388:1353-64.
Feingold KR, Chait A. Approach to patients with elevated low-density lipoprotein cholesterol levels. Best Pract Res Clin Endocrinol Metab 2023;Apr 12:[ePub ahead of print].
Wilkinson MJ, Lepor NE, Michos ED. Evolving management of low-density lipoprotein cholesterol: a personalized approach to preventing atherosclerotic cardiovascular disease across the risk continuum. J Am Heart Assoc 2023;Jun 1:[ePub ahead of print].
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