Case Study: A Patient with Familial Hypercholesterolemia and Statin-Associated Muscle Effects: Pharmacotherapy and Lifestyle

Introduction

Atherosclerotic cardiovascular disease (ASCVD) is an umbrella term for atherosclerotic conditions that affect the cardiovascular system, including ischemic heart disease, peripheral artery disease, and ischemic stroke. The public health impact of ASCVD is hard to overstate, it is currently the number one cause of death in both men and women in the United States.¹ 

Decades of research have shown that low-density lipoprotein cholesterol (LDL-C) and other apo-B-containing particles play a causal role in the development of ASCVD.² Further, we know that cardiovascular risk is reduced proportional to LDL-C reduction, regardless of what lifestyle interventions or pharmacotherapy are used to achieve the reduction.³ Though the relative risk of adverse atherosclerotic events decreases in proportion to LDL-C and non-HDL-cholesterol, the absolute reduction in adverse cardiovascular events depends on the risk of ASCVD. Therefore, even small reductions in atherogenic lipoproteins can benefit high-risk patients.^4-6 The joint American College of Cardiology/American Heart Association (ACC/AHA) and the European Society of Cardiology (ESC) guidelines recommend lifestyle therapy, such as a healthy diet and physical activity for all patients regardless of age or LDL-C.^7-9 

We present a case of a 75-year-old female with familial hypercholesterolemia (FH) who achieved dramatic LDL-C reduction through lifestyle and pharmacotherapy and summarize the effect of both interventions on lipoprotein reduction. 

Clinical Case

A 75-year-old female with a history of phenotypic heterozygous FH, subclinical coronary artery disease via a coronary artery calcium (CAC) scan with a calcium score of 77, paroxysmal atrial fibrillation, hypertension well controlled on 10 mg of amlodipine and 100 mg of losartan, and prediabetes (A1C of 6.4%) presented to the preventive cardiology clinic for primary prevention of ASCVD. She had a family history of premature ASCVD, with her mother having a myocardial infarction in her late 40s. Her paternal history was unknown, and she had no siblings.

She was diagnosed with FH in 2017 at the age of 69 after moving out of state. At the time of her initial appointment, she had no known medical history, but routine lab work found an LDL-C of 396, triglycerides of 178, HDL of 65, and total cholesterol of 497. She was started on 20 mg of rosuvastatin but developed thigh pain, headache, and malaise and stopped taking her medications. She started consuming a Mediterranean diet (rich in fibers, whole grains, and reduced red meat consumption) and began moderate-intensity physical activity (a thirty-minute exercise class three times per week). Three months later, her weight had decreased from 205 pounds to 195 pounds, and her LDL-C had decreased from 396 to 343. At this appointment, we stressed that lifestyle therapy alone was necessary but not sufficient to achieve adequate lipoprotein reduction, and she was re-challenged with 10 mg of rosuvastatin. In three months, her LDL-C and non-HDL-C were 227 and 263, respectively. She was agreeable to 10 mg of Ezetimibe; her follow-up lipid panel three months later showed a total cholesterol of 243 and an LDL-C of 158. We again emphasized escalation of pharmacotherapy but given her prior statin-associated muscle symptoms she opted to instead escalate her exercise program to five days a week. Over the following year, her weight decreased from 205 to 185 lbs. Her cholesterol panel at her most recent appointment showed an LDL-C of 99 with a non-HDL cholesterol of 121. 

Discussion

Primary Prevention of Atherosclerotic Cardiovascular Disease

Familial Hypercholesterolemia (FH) is a genetic disorder caused by various genetic mutations leading to severely impaired LDL-C metabolism.² This clinical syndrome is characterized by severely elevated LDL-C levels and a significantly increased risk of ASCVD. Patients with heterozygous FH commonly have an elevated CAC score by the second decade of life and present with atherosclerotic cardiovascular events such as myocardial infarction in early middle age.^3,10

Primary ASCVD prevention aims to reduce the risk of ASCVD in patients with no previous adverse cardiovascular events. It consists primarily of lifestyle modification, management of comorbidities, and lipid-lowering therapy. In patients with FH, atherogenic lipoproteins and subsequent cardiovascular risk are sufficiently high to warrant joint lifestyle and pharmacotherapy as the initial management option. 

Lifestyle Modification

In our patient, lifestyle therapy was an essential component of lipoprotein and risk reduction. However, up-front pharmacotherapy in addition to lifestyle modification is essential in high-risk patients. In all patients, regardless of age, LDL-C, and comorbid conditions, the ACC/AHA and ESC recommend lifestyle therapy, including a healthy diet, increased physical activity, and management of comorbidities to reduce ASCVD risk. Expected LDL-C reductions with various lifestyle and pharmacologic interventions can be found in Table 1.

A heart-healthy diet with an increased intake of vegetables, fruits, nuts, whole grains, lean animal protein and decreased trans-fat-rich foods, red meat, processed meat, refined carbohydrates, and sweetened beverages is recommended. The Mediterranean diet is endorsed by the American Heart Association (AHA)¹¹ due to their positive impact on cardiovascular health and are associated with a significant reduction^12,13 of LDL (17-29%).

The ACC/AHA also recommend at least 150 minutes of moderate-intensity aerobic exercise weekly. Exercise is an important factor in reducing hypercholesterolemia. For example, a single exercise period can reduce postprandial triacylglycerol for up to two days.¹⁴ Both aerobic exercise and resistance training¹⁵ have been shown to reduce LDL-C, non-HDL-C, and triglycerides independent of weight by 4-6%. Similarly, even modest reductions in weight loss can result in significant improvements in hypercholesterolemia. For example¹⁶, a 5-10% reduction in weight can reduce LDL-C by ~15% and triglycerides by up to 30%. One meta-analysis¹⁷ found that for every kilogram of weight lost, LDL-C decreased by 0.7%, and triglycerides decreased by 1.9%. The Healthy Aging: A Longitudinal Study in Europe (HALE) was a longitudinal study of over 1500 patients in 11 European countries investigating the effects of multiple lifestyle factors on cardiovascular and all-cause mortality. Over ten years, there was significantly lower mortality in patients that consumed a Mediterranean diet (HR 0.77, 95% confidence interval [CI] 0.68-0.88), had low or moderate alcohol use (HR 0.78; 95% CI 0.67–0.91), were physically active (HR 0.63; 95% CI, 0.55–0.72), and who did not smoke (HR 0.65; 95% CI 0.57–0.75). The combination of all four risk factors dramatically reduced mortality (OR 0.35, 95% CI 0.28-0.44). In contrast, non-adherence to this low-risk pattern was associated with a population-attributable risk of 60% of all deaths and 61% from cardiovascular diseases.

Management of Comorbidities and Lipid-Lowering Therapy

The strict control of medical comorbidities is an essential component of ASCVD prevention. Hypertension, diabetes, and tobacco-use disorder have additive effects on the risk of ASCVD. All patients should be counseled on a regular basis to quit smoking and adhere to regular physical activity. For example, patients 40-75 years of age with diabetes are at high enough risk that at least moderate-intensity statin therapy is recommended, regardless of their LDL-C or 10-year ASCVD risk. In addition, achieving an HbA1C level of < 7% has been shown to reduce the risk of macrovascular complications in patients newly diagnosed with type 2 diabetes.¹⁸

Similarly, patients with known ASCVD or LDL-C > 190 mg/dL are at very high risk of future atherosclerotic events and thus should be treated with high-intensity or maximally tolerated statin therapy regardless of the presence of other risk factors. 

Statins reduce hepatic cholesterol synthesis by inhibiting the enzyme HMG-CoA reductase, resulting in the upregulation of LDL receptors on hepatocytes and subsequent clearance of LDL from circulation. The most common side effect of statins is statin-induced muscle pain, as seen in our patient. High-intensity statins (atorvastatin 40 mg or 80 mg, rosuvastatin 20 mg or 40 mg) typically reduce LDL-C by >50%.
 
Ezetimibe reduces LDL by inhibiting cholesterol absorption. It can be given as monotherapy if statins are contraindicated, not tolerated, or combined with statins to augment their lipid-lowering effect. Typically, Ezetimibe reduces LDL-C by 15-25%.

Our patient started with a profoundly elevated LDL-C of 396 mg/dL. She decreased her LDL-C by 14.4% between her first and second visits with increased physical activity and a Mediterranean diet. With the addition of 10 mg of rosuvastatin (moderate-intensity), her LDL-C dropped an additional 34% within three months and an additional 31% with Ezetimibe three months later. After intensifying her exercise regimen and nearly twenty pounds of weight loss, her LDL-C decreased 61% to 99 mg/dL. 

Conclusion

In all patient cohorts, lifestyle therapy, including a healthy diet and increased physical activity, is the mainstay of preventing atherosclerotic events. Our patient had a 114 mg/dL reduction in LDL-C through diet and exercise alone. The combination of improved diet, and increased physical activity, a moderate-intensity dose of rosuvastatin, and Ezetimibe decreased LDL-C and non-HDL-C in our patient by 75%. For patients in high-risk groups, such as those with known ASCVD or LDL-C >190 mg/dL, lifestyle therapy in combination with appropriate pharmacotherapy is necessary to achieve adequate risk reduction.

Dr. Chedid has no financial relationships to disclose. Dr. Buda has no financial relationships to disclose. 

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