> Table of Contents > Hypercholesterolemia
Sebastian T. Tong, MD, MPH
Wendy Brooks Barr, MD, MPH, MSCE
image BASICS
  • Serum total cholesterol >240 mg/dL
  • Lipoprotein subtypes:
    • Low-density lipoproteins (LDL): primary target of therapy, atherogenic
    • High-density lipoproteins (HDL): atheroprotective
    • Triglycerides (TG)
  • High cholesterol is a significant risk factor for atherosclerotic cardiovascular disease (ASCVD).
  • System(s) affected: cardiovascular (CV)
Age: increases with age
27.9% of men and 27.5% of women in the United States with total cholesterol >240 mg/dL
  • Pathophysiology
    • Deposition of cholesterol in vascular walls creating fatty streaks that become fibrous plaques
    • Inflammation causes plaque instability, leading to plaque rupture.
  • Etiology
    • Primary: diet, lack of physical activity, obesity
    • Secondary: excessive alcohol intake, hypothyroidism, diabetes, nephrotic syndrome, liver disease, chronic renal failure, medications (thiazide diuretics, carbamazepine, cyclosporine, progestins, anabolic steroids, corticosteroids, protease inhibitors)
  • Familial hypercholesterolemia (FH)
    • Elevated LDL levels from birth
    • Prevalence = 1/500 in the United States
    • Predisposed to atherosclerotic disease in early adulthood and high coronary heart disease (CHD) risk in 40s to 50s
    • Tendon xanthomas on Achilles and extensor tendons of hands are common.
    • Early lipid-lowering drug therapy is shown to reduce ASCVD risk.
  • Early cholesterol testing of first-degree relatives is beneficial.
Obesity (BMI >30 kg/m2), physical inactivity, heredity. Traditionally, diet rich in saturated fat and cholesterol is considered to be risk factors for hypercholesterolemia and vascular disease. This has become somewhat controversial, with emphasis now on trans-fats as more atherogenic. Relationship of diet to disease is very complex.
  • Reduced intakes of saturated fat and cholesterol
  • Regular physical activity
  • Weight control (see “Ongoing Care”)
Hypertension, diabetes mellitus (DM), obesity
Screening recommendations:
  • U.S. Preventive Services Task Force (USPSTF): total cholesterol and HDL cholesterol (HDL-C) every 5 years
    • All men age ≥35 years
    • Women ≥45 years if at increased risk for ASCVD
    • Men aged 20 to 35 years and women aged 20 to 45 years if at increased risk for ASCVD (1)[A]
  • American Diabetic Association: yearly dyslipidemia screening for diabetics
Pediatric Considerations
National Heart, Lung, and Blood Institute (NHLBI): recommended lipid screening on all children between 9 and 11 years. However, these recommendations are highly controversial and not supported by most other organizations (2)[C].
Nonspecific findings
Initial Tests (lab, imaging)
  • Fasting lipid panel: total cholesterol (TC), LDL, HDL, TG: LDL is usually a calculated value and is accurate if TG <350 mg/dL.
  • If elevated LDL or other form of hyperlipidemia, clinical/laboratory assessment before initiating lipid-lowering therapy: ALT, diabetes screening
  • Consider genetic etiology in very high LDL (>190 mg/dL).
United States: ACC/AHA cholesterol guidelines (3)[C]
  • Four groups benefit from statin therapy:
    • Clinical ASCVD
      • <75 years old: high-intensity statin
      • >75 years old or not candidate for high-intensity statin: moderate-intensity statin
    • Primary elevation of LDL-C >190 mg/dL: high-intensity statin
    • Diabetes (type 1 or 2) ages 40 to 75 years with LDL-C 70 to 189 mg/dL:
      • 10-year ASCVD risk <7.5%: moderate-intensity statin
      • 10-year ASCVD risk >7.5%: high-intensity statin
    • Without above but estimated 10-year ASCVD risk >7.5% based on Pooled Cohort Equations (http://my.americanheart.org/professional/StatementsGuidelines/PreventionGuidelines/Prevention-Guidelines_UCM_457698_SubHomePage.jsp): Consider moderate- to high-intensity statin.
  • Definition of clinical ASCVD:
    • Acute coronary syndrome or history of MI
    • Stable or unstable angina
    • Coronary or other arterial revascularization
    • Stroke or TIA
    • Peripheral arterial disease
  • Significant controversy over recommendation to treat patients with >7.5% 10-year ASCVD risk:
    • Concern that Pooled Cohort Equations significantly overestimate ASCVD risk.
    • Concern for significant overtreatment: one study showing 96% of men and 66% of women >55 years of age on statins based on recommendations
  • Many more patients treated and medications used in the United States than elsewhere in the world without substantial evidence for improved outcomes
United Kingdom: National Institute for Health and Care Excellence (NICE) cholesterol guidelines (4)[C]
  • No history of CV disease: if 10-year risk of CVD >10%, start atorvastatin 20 mg
  • If eGFR <60 or type I diabetes, start atorvastatin 20 mg regardless of risk.
  • History of CV disease: Start atorvastatin 80 mg.
  • 10-year risk to be calculated using QRISK2: http://www.qrisk.org/
  • Nonfasting lipid panel before treatment initiation and at 3 months of treatment: goal reduction of 40% in non-HDL cholesterol
European: European Society of Cardiology/European Atherosclerosis Society (ESC/EAS) cholesterol guidelines (5)[C]
  • Risk stratification to low, moderate, high, and very high risk based on SCORE charts
  • High- and very high-risk patients should be offered drug therapy.
  • If >500, TG lowering becomes primary target until TG <500 to prevent acute pancreatitis.
    • Therapeutic life changes + statin + fibrate
  • Therapeutic lifestyle changes are cornerstone therapies to be attempted before drug therapy (diet and regular exercise; see “Ongoing Care”).
  • Check fasting lipoprotein profile 4 to 12 weeks after starting medication to evaluate response/compliance.
    • High-intensity statin: should lower LDL-C >50%
    • Moderate-intensity statin: should lower LDL-C 30-50%
First Line
HMG-CoA reductase inhibitors (statins)
  • Categorized based on intensity
    • High intensity
      • Atorvastatin 40 to 80 mg/day
      • Rosuvastatin 20 to 40 mg/day
    • Moderate intensity
      • Atorvastatin 10 to 20 mg/day
      • Rosuvastatin 5 to 10 mg/day
      • Simvastatin 20 to 40 mg/day
      • Pravastatin 40 to 80 mg/day
      • Lovastatin 40 mg/day
      • P.505

      • Fluvastatin XL 80 mg/day
      • Fluvastatin 40 mg BID
      • Pitavastatin 2 to 4 mg/day
    • Low intensity
      • Simvastatin 10 mg/day
      • Pravastatin 10 to 20 mg/day
      • Lovastatin 20 mg/day
      • Fluvastatin 20 to 40 mg/day
      • Pitavastatin 1 mg/day
  • To be taken in the evening or at bedtime for best effect (exception: atorvastatin, rosuvastatin)
  • Effect is greatest in lowering LDL-C; shown to decrease CHD incidence and all-cause mortality, although number needed to treat may be high in primary prevention.
  • Contraindications: pregnancy, lactation, or active liver disease
  • Drug interactions: cyclosporine, macrolide antibiotics, various antifungal agents, HIV protease inhibitors, fibrates/nicotinic acid (to be used with caution)
  • Adverse reactions:
    • Mild myalgia is common.
    • Liver transaminase elevations: ALT before therapy to establish baseline; if ALT >3 times upper limit of normal, do not start statin; routine monitoring is not recommended; reasonable to measure hepatic function if symptoms suggesting hepatotoxicity occur.
    • Association with increased cases of diabetes: 0.1 excess cases of diabetes per 100 persons on moderate-intensity statin and 0.3 excess cases per 100 persons on high-intensity statin
    • Myopathies (considered rare but not well studied):
      • Creatine kinase (CK) baseline reasonable for those at increased risk for adverse muscle events; routine monitoring not needed unless muscle symptoms occur
      • Instruct patients to report immediately any muscle pain, muscle weakness, or brown urine.
      • If myopathy or rhabdomyolysis is suspected, discontinue statin use and draw serum CK, creatinine, urine analysis.
      • Can rechallenge statin at lower dose or different type after resolution of symptoms
  • Do not exceed simvastatin 10 mg/day with amiodarone, verapamil, and diltiazem.
  • Do not exceed simvastatin 20 mg/day with amlodipine and ranolazine.
Pregnancy Considerations
  • Statins contraindicated during pregnancy: class X
  • Lactation: possibly unsafe
Second Line
  • Second-line drugs are no longer recommended in any guidelines.
  • Ezetimibe
    • Can be taken by itself or in combination with a statin: monotherapy (Zetia 10 mg/day) or ezetimibe/simvastatin (Vytorin 10/10, 10/20, 10/40)
    • Effect: Lowers LDL-C; one recent RCT shows combination therapy with statin has small benefit in reducing CV events and CV-related mortality after acute coronary syndromes (6).
    • Adverse reactions: generally well tolerated
  • Fibrates
    • Types: Gemfibrozil (Lopid) 600 mg BID, fenofibrate (Antara, Lofibra, Tricor, Triglide)
    • Effect: most effective in lowering TG with moderate effect in lowering LDL and raising HDL. More recent studies fail to show benefit in most patients.
    • Contraindications: severe hepatic or renal insufficiency
    • Possible interactions: potentiates effects of warfarin and oral hypoglycemic agents
    • Adverse reactions: GI complaints; increased likelihood of gallstones
  • Nicotinic acid: raises HDL but no evidence for improved outcomes in recent trials and significant potential harms; should no longer be used in routine practice
  • Bile acid sequestrant: causes significant GI side effects, no evidence for improved outcomes, rarely used
  • Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) inhibitors (7):
    • Drug currently in approval process showing significant reduction in all-cause mortality, CV mortality and CV events
    • Requires SC injections every 2 to 4 weeks to administer and will be very expensive
  • Omega-3 fatty acids and fish oil intake: Sources are fish oil (salmon), plant sources (flaxseed, canola oil, soybean oil, nuts); mainly lower TG level but has some benefit in lowering LDL and raising HDL although overall CV benefit and mortality reduction is uncertain. Supplements do not reduce overall or cardiovascular mortality. Patients should be advised to eat a variety of oily fish twice a week.
  • &bgr;-Sitosterols and red yeast rice (contains natural lovastatin-analogue) can reduce total cholesterol and LDL.
  • Garlic: appears to have some lipid-lowering effect, but more studies are needed; effective dose not established but generally 1 to 2 cloves of raw garlic/day, 300 mg dried garlic powder tablet BID or TID, or 7.2 g of aged garlic extract/day
Exercise: sustained exercise for 30 minutes, 3 to 4 times per week: increases HDL, lowers total cholesterol, and helps control weight
Patient Monitoring
  • Initially, lipid panel in 4 to 12 weeks after starting therapy, routine monitoring of LDL levels in patients on statin is not necessary.
  • Routine monitoring of LFTs is no longer recommended if initial ALT is within normal range.
1. U.S. Preventive Services Task Force. Lipid disorders in adults (cholesterol, dyslipidemia): screening. http://www.uspreventiveservicestaskforce.org/Page/Document/UpdateSummaryFinal/lipid-disorders-inadults-cholesterol-dyslipidemia-screening. 2008.
2. National Heart, Lung, and Blood Institute. Integrated guidelines for cardiovascular health and risk reduction in children and adolescents. http://www.nhlbi.nih.gov/health-pro/guidelines/current/cardiovascular-health-pediatric-guidelines. 2011.
3. Stone NJ, Robinson JG, Lichtenstein AH, et al. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology\American Heart Association Task Force on Practice Guidelines. Circulation. 2014;129(25 Suppl 2):S1-S45.
4. National Institute for Health and Care Excellence. NICE Clinical Guideline (CG181): lipid modification: cardiovascular risk assessment and the modification of blood lipids for the primary and secondary prevention of cardiovascular disease. 2014. http://www.nice.org.uk/guidance/cg181
5. Reiner Z, Catapano AL, De Backer G, et al. ESC/EAS guidelines for the management of dyslipidaemias: the Task Force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS). Eur Heart J. 2011;32(14):1769-1818.
6. Cannon CP, Blazing MA, Giugliano RP, et al. Ezetimibe added to statin therapy after acute coronary syndromes. N Engl J Med. 2015;372(25):2387-2397.
7. Navarese EP, Kolodziejczak M, Schulze V, et al. Effects of proprotein convertase subtilisin/kexin type 9 antibodies in adults with hypercholesterolemia: a systematic review and meta-analysis. Ann Intern Med. 2015;163(1):40-51.
Additional Reading
Taylor F, Huffman MD, Macedo AF, et al. Statins for the primary prevention of cardiovascular disease. Cochrane Database Syst Rev. 2013;(1):CD004816.
See Also
  • Hypothyroidism, Adult
  • Algorithm: Hypercholesterolemia
E78.0 Pure hypercholesterolemia
Clinical Pearls
  • Hypercholesterolemia is a significant risk factor for ASCVD, but ASCVD is a multifactorial disease with many different risk factors.
  • Diet and exercise should be tried before pharmaceutical interventions.
  • Statins are considered first-line medications for hypercholesterolemia. Other medications show little evidence of benefit.