Hypercholesterolemia

Background

• Hypercholesterolemia is a condition characterized by elevated serum levels of total cholesterol, low-density lipoprotein (LDL) cholesterol, non-high-density lipoprotein (HDL) cholesterol, and apolipoprotein B (apo B).
• Elevated non-HDL cholesterol and LDL cholesterol are associated with increased risk of cardiovascular disease and mortality.
• Causes of hypercholesterolemia may include primary genetic disorders or may be secondary to obesity, type 2 diabetes, metabolic syndrome, chronic kidney disease, nephrotic syndrome, hypothyroidism, cholestatic liver disease, and selected medications (such as anabolic steroids).

Evaluation

• Consider lipid screening as part of cardiovascular risk assessment in men > 40 and women > 50 years old (or if postmenopausal) without known cardiovascular risk factors, and in patients with cardiovascular risk factors such as established cardiovascular disease, diabetes, smoking, severe chronic kidney disease, family history of premature cardiovascular disease, or familial hypercholesterolemia.
• In adults aged 40-75 years with LDL cholesterol 70-189 mg/dL (1.8-4.8 mmol/L) and without cardiovascular disease or diabetes, estimate 10-year risk of ASCVD using risk scores such as Pooled Cohort Equations or QRISK2.
• Assessment of cardiovascular risk that are in part based on values from a lipid panel appears to be similar in fasting and nonfasting patients as long as the triglyceride level is < 500 mg/dL (< 5.65 mmol/L).
• Suspect familial hypercholesterolemia in patients with:
  • Severe hypercholesterolemia in absence of secondary causes, such as diabetes, hypothyroidism, hepatic disease, and renal disease;
  • Family history of familial hypercholesterolemia with elevated LDL cholesterol;
  • Early-onset (< 50 years old) cardiovascular disease (particularly premature myocardial infarction), particularly in the absence of other risk factors;
  • Corneal arcus prior to age 45 years or presence of xanthomas (particularly tendon xanthomas).
• To rule out secondary causes of hypercholesterolemia, obtain a fasting blood glucose or hemoglobin A1c, thyroid-stimulating hormone, alkaline phosphatase (to detect biliary obstruction), and urinalysis to assess for proteinuria.

Management

• Lifestyle modifications:
  • Use dietary changes that include reducing intake of saturated fats (< 7% of kcals) and reducing percent of calories from trans fat and saturated fat to lower LDL and non-high-density lipoprotein cholesterol levels (Strong recommendation).
  • Consider increased physical activity such as 40 minutes of moderate to vigorous intensity exercise 3 or 4 times per week (Weak recommendation).
• When prescribing pharmacotherapy for cholesterol use statins (3-hydroxy-3-methyl-glutaryl-coenzyme A [HMG Co-A] reductase inhibitors) as drugs of first choice to lower LDL and non-high-density lipoprotein cholesterol levels.
• Secondary prevention in patients with clinical atherosclerotic cardiovascular disease (ASCVD):
  • Prescribe high-intensity statin with goal LDL cholesterol reduction ≥ 50% in patients ≤ 75 years old; consider moderate- or high-intensity statin in patients > 75 years old after evaluating risks and benefits of therapy (Weak recommendation).
  • Consider adding ezetimibe to maximally-tolerated statin therapy in patients with LDL-C ≥ 70 mg/dL (≥ 1.8 mmol/L) who are at very high risk (Weak recommendation).
  • Consider adding PCSK9 inhibitor after evaluating risks and benefits of therapy in patients at very high risk with LDL-C ≥ 70 mg/dL (≥ 1.8 mmol/L) or non-HDL-C level ≥ 100 mg/dL (≥ 2.6 mmol/L) despite maximally tolerated combination therapy of a statin with ezetimibe (Weak recommendation).
• Primary prevention of ASCVD:
  • Discuss the risks and benefits of cholesterol-lowering therapy, based on 10-year risk of ASCVD and taking into account patient preferences using shared decision making (Strong recommendation).
  • For high-risk patients (10-year ASCVD risk ≥ 20%), give a high-intensity statin with a goal of reducing LDL-C by ≥ 50% (Strong recommendation).
  • Give moderate-intensity statin to patients with diabetes aged 40-75 years regardless of estimated ASCVD risk (); consider high-intensity statin in patients with diabetes who have multiple ASCVD risk factors (Weak recommendation).
  • Prescribe maximally tolerated statin therapy in patients aged 20-75 years with primary severe hypercholesterolemia (LDL-C ≥ 190 mg/dL [≥ 4.9 mmol/L]) (); consider addition of ezetimibe if LDL-C ≥ 190 mg/dL (≥ 4.9 mmol/L) with < 50% reduction in LDL-C while on maximally tolerated statin therapy and/or if LDL-C ≥ 100 mg/dL (≥ 2.6 mmol/L) (Weak recommendation).
  • For intermediate-risk patients (10-year ASCVD risk ≥ 7.5% to < 20%), give a moderate-intensity statin with a goal of reducing LDL cholesterol by ≥ 30%.
    • Give a moderate-intensity statin with a goal of reducing LDL cholesterol by ≥ 30% (Strong recommendation);
    • Consider obtaining coronary artery calcium (CAC) score if decision about statin use remains uncertain (Weak recommendation):
      • If the CAC score is 0, consider withholding statin therapy and reassess in 5 to 10 years, providing that higher risk conditions are absent (diabetes mellitus, family history of premature coronary heart disease, and/or cigarette smoking);
      • If the CAC score is 1 to 99, consider initiating statin therapy for patients ≥ 55 years old;
      • If the CAC score is ≥ 100 or ≥ 75th percentile, consider initiating statin therapy.
• Measure fasting lipid profiles and appropriate safety indicators to assess adherence to lifestyle modifications and effects of LDL-C-lowering medications 4 to12 weeks after initiation or dose-adjustment, and every 3 to 12 months thereafter as needed (Strong recommendation).