AntiHyperlipidemic

Aka: AntiHyperlipidemic, Anti-hyperlipidemic, Hypercholesterolemia Management, Hyperlipidemia Management, Lipid Reduction

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II. Indications

  1. Hyperlipidemia
  2. Prevention of Ischemic Stroke
  3. CAD Risk Management

III. Management: General Measures

  1. See Low Fat Diet
  2. Aerobic Exercise for at least 120 minutes per week (900 kcal expended per week)
    1. Raises HDL Cholesterol linearly with cummulative amount of aerobic Exercise
    2. Lowers Total Cholesterol 3.9%, LDL Cholesterol 3.9% and Serum Triglycerides 7.1%
    3. Halbert (1999) Eur J Clin Nutr 53(7):514-22 [PubMed]
  3. Weight loss in Obesity (11 kg or 24 lb)
    1. Lowers LDL 10%, Triglycerides 24%, raises HDL 8%
    2. Katzel (1995) Metabolism 44:307-14 [PubMed]

IV. Management: Approach (ACC/AHA 2013, as well as USPTF 2016, 2023)

  1. Approach
    1. Recheck LDL Cholesterol 4 to 12 weeks after starting Statin, and then recheck yearly
    2. Readdress Statin compliance periodically
  2. ACC/AHA Guidelines as of 2013 changes
    1. Statins are the preferred AntiHyperlipidemic and combinations are not recommended in most cases
    2. Patients are risk stratified to high or low risk Statin dose without the chasing of specific LDL Cholesterol goals
    3. Framingham calculator is replaced with more predictive calculators
      1. Pooled Cohort Equation (ACC/AHA Guideline)
        1. New 10 year Cardiovascular Risk calculator to help risk stratify (including Statin dosing)
        2. http://www.cvriskcalculator.com/
      2. QRisk2 (NICE 2014 Guideline)
        1. Includes Renal Function in risk calculation
        2. https://www.qrisk.org/2016/
    4. Young adults (age <40 years old) may benefit from Cholesterol lowering
      1. LDL Cholesterol >190 mg/dl (esp. if premature coronary disease Family History)
      2. Multiple Cardiovascular Risk Factors
      3. Diabetes Mellitus for more than 20 years (type 1 DM) or 10 years (type 2 DM)
      4. Navar-Bogan (2015) Circulation 131:451-8 [PubMed]
    5. Indications to continue treatment with Statin agent in age over 75 years
      1. Coronary Artery Disease
      2. High Coronary Calcium Score
      3. Ankle brachial index <0.9
      4. hs-CRP >2 mg/L
      5. Consider continuing agent even without other indications (NNT 83 to avoid 1 MI in 3-4 years)
        1. Savarese (2013) J Am Coll Cardiol 62(22):2090-9 [PubMed]
      6. Balance Cardiovascular Risk with quality of life (e.g. Statin induced myalgias) and Drug Interactions
    6. Non-Statins are not recommended unless Statins are not tolerated (or not at goal despite Statin)
      1. Precautions
        1. Most agents aside from Statins do not lower Cardiovascular Risk significantly
        2. Only indicated in highest risk patients (e.g. with CAD) if LDL not at goal (<70 mg/dl)
      2. Alternative agents when Statins are not tolerated (or adjunctive when not at goal despite Statin)
        1. Ezetimibe (Zetia)
          1. Underwhelming benefitL, but now generic at $10/month
            1. NNT 50 for one less event in 7 years
            2. Lowers LDL an additional 20% when added to a Statin
        2. PCSK9 Inhibitor
          1. Biologic at very high cost ($550/month in 2023)
          2. Medications in class include Alirocumab (Praluent) and Evolocumab (Repatha)
        3. Bempedoic Acid or Nexletol (ATP-Citrate Lyase Inhibitor)
          1. Lowers LDL Cholesterol as a Statin adjunct or alternative (but does not effect Triglycerides, HDL)
          2. Unknown effect on longterm cardiovascular outcomes
          3. Costs $330/month
          4. Feng (2020) Prog Lipid Res +PMID:31499095 [PubMed]
      3. Other measures (generally not recommended)
        1. Fibrates may be considered for very high Triglycerides (>500-1000 mg/dl)
        2. Bile Acid Sequestrant
      4. References
        1. Ip (2015) Int J Cardiol 191:138-48 [PubMed]
  3. High Intensity Protocol
    1. Goal LDL Cholesterol decrease of >50% AND
      1. LDL Cholesterol <70 mg/dl OR
      2. LDL Cholesterol <55 mg/dl (if very high risk)
        1. Multiple cardiovascular events OR
        2. One cardiovascular event and multiple major risk factors (e.g. diabates mellitus, Tobacco Abuse)
    2. Indications
      1. LDL Cholesterol > 190 mg/dl OR
      2. Known cardiovascular disease or other serious risk factors (10 year Cardiovascular Risk >20%) OR
      3. Diabetes Mellitus and age 40-75 years old and 10 year Cardiovascular Risk >7.5%
    3. Preparations
      1. Atorvastatin (Lipitor) 40 to 80 mg daily
      2. Rosuvastatin (Crestor) 20 to 40 mg daily
    4. Efficacy
      1. Treating to target LDL 50 to 70 mg/dl is non-inferior to high intensity protocol
        1. Hong (2023) JAMA 329(13): 1078-87 [PubMed]
  4. Moderate Intensity Protocol (with goal LDL Cholesterol decrease of >50%)
    1. Indications
      1. 10 year Cardiovascular Risk >7.5%
        1. USPTF recommends at least 1 CAD risk and >10% ten year risk (optional if >7.5%)
        2. Mangione (2022) JAMA 328(8): 746-53 [PubMed]
      2. Diabetes Mellitus AND age 40-75 years old AND 10 year Cardiovascular Risk <7.5%
        1. Use high intensity if Diabetes Mellitus and 10 year Cardiovascular Risk >7.5%
        2. Consider in other Diabetes Mellitus patients outside this age range
      3. Age over 75 years old
        1. May continue on high intensity protocol if tolerating without adverse effects
    2. Preparations (with goal LDL Cholesterol decrease of >50%)
      1. Atorvastatin (Lipitor) 10 to 20 mg daily
      2. Rosuvastatin (Crestor) 5 to 10 mg daily
      3. Simvastatin (Zocor) 20 to 40 mg daily
      4. Pravastatin (Pravachol) 40 to 80 mg daily
      5. Lovastatin (Mevacor) 40 mg daily
      6. Fluvastatin (Lescol) 80 mg daily
      7. Pitavastatin (Livalo) 2 to 4 mg daily
  5. References
    1. (2014) Presc Lett 21(1): 1-2
    2. Stone (2014) J Am Coll Cardiol 63(25 pt B): 2889-2934 +PMID:24239923 [PubMed]

V. Management: Approach - Older

  1. These guidelines are replaced as of 2013 by guidelines described above
  2. Left here for historical reasons
  3. General
    1. Guidelines push for lower LDL Cholesterol
      1. LDL Cholesterol <70 mg/dl in coronary disease and Diabetes Mellitus
      2. Guidelines updated in 2014 to risk stratify to high intensity or low intensity management as above
      3. LDL Cholesterol may be decreased to very low levels (<40 mg/dl) without safety concerns
        1. In fact, very high risk patients (multiple CV events) target LDL Cholesterol decrease >50% to <55 mg/dl
    2. Guidelines may require high dose
      1. Most potent agents: Zocor, Lipitor, Crestor
        1. Doubling dose lowers LDL Cholesterol 6%
      2. Guidelines of 2014 de-emphasize adding other agents to Statins (due to lack of efficacy)
        1. Agents typically combined with Statins: Niacin, Cholestyramine, Ezetimibe
        2. However Niacin has not shown added benefit beyond Statin alone
        3. Of these additional agents, only Ezetimibe further lowers Cardiovascular Risk (NNT 50) in high risk patients
          1. Lowers LDL Cholesterol additional 20%
    3. Old age should not be a sole reason to not prescribe a Statin
      1. Statins are associated with a 30% reduction in cardiovascular events
      2. If a patient is considered a candidate for revascularization, they should be a candidate for Statin use
    4. References
      1. (2004) Prescriber's Letter 11(8):43
      2. Kopecky (2012) Mayo POIM, Rochester
  4. Serum Triglyceride <150 mg/dl (Primarily LDL Disorder)
    1. First-line
      1. HMG-CoA Reductase Inhibitors (Statins) are the mainstays of therapy
    2. Second-line agents (not recommended as of 2013 ACC/AHA guidelines)
      1. Second: Niacin or Ezitimibe
        1. However neither has been shown to improve outcomes over Statin alone
      2. Third: Bile Binding Resin (Cholestyramine)
        1. Consider adding Colesevelam (Welchol) in Diabetes Mellitus
    3. Adjunctive agents
      1. Plant Sterols and stanols
  5. Serum Triglyceride 150 to 400-500 mg/dl (Mixed lipid disorder)
    1. First-line
      1. HMG-CoA Reductase Inhibitors (Statins) are the mainstays of therapy
    2. Second-line agents (not recommended as of 2014 ACC/AHA guidelines)
      1. Second: Niacin (not recommended as of 2014 ACC/AHA guidelines)
      2. Third: Cholesterol absorption inhibitor (Ezitimibe)
      3. As noted above, neither Niacin nor Ezetimibe have been shown to improve outcomes over Statin alone
  6. Serum Triglyceride >400-500 mg/dl: See Hypertriglyceridemia
    1. HMG-CoA Reductase Inhibitors (Statins) are still the mainstays of therapy
    2. Some specific Triglyceride management agents may be used with Statins with caution (due to Rhabdomyolysis risk)
      1. Tricor may be used with Statins with caution
      2. Do not use Gemfibrozil with Statins
      3. Nicotinic Acid (Niacin) may be used with Statins with caution (however see lack of efficacy data above)
    3. Adjuncts
      1. Fish oil
  7. Coronary Artery Disease Prevention
    1. HMG-CoA Reductase Inhibitor (Statin)
  8. Medication not recommended if only HDL Cholesterol low
    1. Raise HDL Cholesterol with non-medication measures
    2. Focus medication use on lowering LDL Cholesterol
    3. Birjmohun (2005) J Am Coll Cardiol 45:185-97 [PubMed]
  9. Hyperlipidemia in age over 65 years
    1. Low HDL increases MI risk in age over 65 years
    2. Other Hyperlipidemia does not predict MI risk age >65
    3. Psaty (2004) J Am Geriatr Soc 52:1639-47 [PubMed]

VI. Management: Adjuvant Therapy

  1. Garlic
    1. Stevinson (2000) Ann Intern Med 133:420-9 [PubMed]
  2. Plant Sterols and stanols (e.g. Benecol, Promise Activ)
    1. Dose 2 grams daily lowers LDL by 10%
  3. Fish oils (Omega-3 Fatty Acids)
    1. Lowers Triglycerides (4%: 1 g/day, 10-40%: 2-4g/day)
    2. Unfortunately raises LDL Cholesterol 5-10%
    3. Marginal effect on HDL Cholesterol
    4. Not proven to reduce cardiovascular events
  4. Soluble Dietary Fiber
    1. Lowers LDL Cholesterol 7% for 10 grams of fiber
    2. Sources
      1. Psyllium, Barley, Beans
      2. Oat bran (e.g. cheerios, oatmeal)
    3. Brown (1999) Am J Clin Nutr 69:30-42 [PubMed]
  5. Dietary Soy Proteins 25 grams per day (4% lowering)
    1. Anderson (1995) N Engl J Med 333:276-82 [PubMed]
  6. Unsaturated fat nuts (pistachios, almonds)
  7. Glucophage (Metformin)
  8. Rosiglitazone or Pioglitazone
  9. Orlistat (Xenical)
  10. Policosanol (sugar cane derivative)
  11. Red-yeast rice
    1. Contains natural HMG-CoA reductase agent (similar to Lovastatin)
      1. Produced when rice ferments with yeast
    2. Currently unregulated and dose not standardized
    3. Not recommended until standardized dosing available
    4. May be an alternative for patients not tolerant to Statin medications
      1. Example Monocolin K 5-10 mg daily
  12. Lactobacillus reuteri (Cardioviva)
    1. Probiotic may decrease fat and Cholesterol gastrointestinal absorption
    2. May lower LDL 10% (similar effect to fiber, Benecol)
    3. Jones (2012) Eur J Clin Nutr 66: 1234-41 [PubMed]

VII. Management: Measures that are not effective (not recommended)

  1. Estrogen Replacement Therapy
    1. No longer recommended for CAD prevention
    2. Recent studies suggest increased Cardiovascular Risk
      1. See Hormone Replacement for details
    3. Lipid effects
      1. LDL lowered (15%)
      2. HDL raised (15%)
      3. Triglycerides
        1. Raised: Oral Estrogen Replacement (considerably)
        2. No effect: Transdermal Estrogen
  2. Antioxidants do not affect lipid levels
    1. No benefit with Vitamin E, C, Beta Carotene, Selenium
    2. Brown (2001) N Engl J Med 345:1583-92 [PubMed]
  3. Medications to raise HDL Cholesterol
    1. Adding agents to Statins to raise HDL Cholesterol does not lower Cardiovascular Risk
    2. Keene (2014) BMJ 349:g4379 [PubMed]

VIII. Management: Combination Regimens

  1. General
    1. Combination regimens can lower LDL 40-50%
  2. Combinations without risk
    1. HMG-CoA Reductase Inhibitors and Bile Binding Resin
    2. HMG-CoA Reductase Inhibitors and Ezetimibe (Zetia)
      1. Early studies suggested benefit in lowering LDL with low toxicity
      2. However, subsequent studies questioned Zetia efficacy in vascular disease prevention
      3. Allows lipid control at lower Statin dose
  3. Combinations to use with caution
    1. Statin and Nicotinic Acid (Niacin)
      1. Risk of Myopathy, Hepatitis And Rhabdomyolysis
      2. Zocor + Niacin lowered LDL 42% and raised HDL 26%
      3. Brown (2001) N Engl J Med 345:1583-92 [PubMed]
    2. Advicor (Niacin and Lovastatin)
      1. Appears relatively safe and well tolerated
        1. Limited Myopathy and hepatitis risk
      2. Efficacy in lowering lipid levels
        1. Lowers LDL up to 32-47%
        2. Lowers Triglycerides 24-45%
        3. Raises HDL 18-40%
      3. Efficacy in vascular disease prevention
        1. Does not appear to improve outcomes
  4. Contraindicated combinations
    1. Statin and Gemfibrozil (Lopid)
      1. Risk of severe Myopathy and Rhabdomyolysis
      2. Fenofibrate appears safer with Statins

IX. Management: Severe Familial Hypercholesterolemia

  1. Indications
    1. Severe, high LDL Cholesterol, refractory to high dose Statin
  2. PCSK9 Inhibitors (monoclonal antibodies)
    1. See PCSK9 Inhibitors
    2. Praluent (Alirocumab)
    3. Repatha (Evolocumab)
  3. Small Interfering RNA
    1. Inclisiran (Leqvio)

X. Efficacy

  1. Statin lowering of LDL Cholesterol as primary prevention
    1. Over 3 to 6 years, Statin LDL lowering results in only small reductions in mortality, CVA and MI
    2. Byrne (2022) JAMA Intern Med 182(5): 474-81 [PubMed]

XI. References

  1. (2023) Presc Lett 30(6): 31-2
  2. Last (2017) Am Fam Physician 95(2): 78-87 [PubMed]
  3. McKenney (2002) Am J Cardiol 90(suppl):8K-20K [PubMed]
  4. Stein (2002) Am J Cardiol 89(suppl):50C-57C [PubMed]

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