dyslipidemia
DYSLIPIDEMIA
Dyslipidemia is having an abnormal amount of lipids or fats in the blood.
Lipid profile is obtained from an individual with diabetes mellitus, coronary heart disease, cerebrovascular disease, peripheral arterial disease or other coronary heart disease risk factors or from an individual with family history or clinical evidence of familial hypercholesterolemia.
Plasma lipids are total cholesterol, high-density lipoprotein cholesterol, trigylcerides, and low-density lipoprotein cholesterol.
Evaluation of lipid profile must be performed in parallel with the risk assessment of coronary heart disease.

Pharmacotherapy

LDL-C-Lowering Pharmacological Therapy

LDL-C is the primary target of lipid management

  • The greater the LDL-C level is reduced, the more significant is the amount of CV risk reduction
  • Assess patient’s response to LDL-C-lowering therapy and lifestyle modifications with a repeat lipid profile 4-12 weeks after starting statin therapy or dose adjustment then every 3-12 months as needed
Statins [Beta-hydroxy-beta-methylglutaryl-Coenzyme A (HMG-CoA) Reductase Inhibitors]
  • Reduce risk for acute coronary syndromes, coronary procedures and other coronary outcomes in both primary and secondary coronary heart disease prevention
  • Recommended for the following:
    • Adults ≥21 years old with clinical atherosclerotic cardiovascular disease (ASCVD)
    • Adults ≥21 years old with LDL-C ≥190 mg/dL
    • Adults 40-75 years of age without ASCVD but with diabetes mellitus (especially type 2 diabetes mellitus) and LDL-C levels of 70-189 mg/dL
    • Adults 40-75 years of age without ASCVD and diabetes mellitus but with LDL-C levels of 70-189 mg/dL and estimated 10-year risk of ≥7.5% for ASCVD
      • If decision to start statin therapy is uncertain, measure coronary artery calcium (CAC); statin therapy is favored with a CAC score of 1-99 and is indicated with a CAC score of ≥100 Agatston units or ≥75th percentile
    • Adults 40-75 years of age without diabetes mellitus but with risk-enhancing factors and estimated 10-year ASCVD risk of 7.5-19.9%
  • Effective in patients with nephrotic syndrome
  • Inhibit HMG-CoA reductase which is the rate-limiting step in cholesterol biosynthesis
  • Most effective class of drugs at lowering LDL-C levels, with moderate effects on lowering triglycerides and elevating HDL-C: Decreases LDL-C by 18-55%, increases HDL-C by 2-15%, decreases triglycerides by 6-30%
  • The drugs of choice for LDL lowering in patients with diabetes mellitus and hypertriglyceridemia
    • Dose may be increased or non-statin drug (eg Ezetimibe, fibrates, or Nicotinic acid) may be added if LDL levels remain at >2 mmol/L (177 mg/dL) after achieving the LDL-C target level
  • High-intensity statins: Atorvastatin (80 mg), Rosuvastatin (20 mg)
    • Statin regimen that helps lower LDL-C by 30-50%
    • Recommended as 1st-line treatment for patients <75 years old with clinical ASCVD
    • May be used for patients >21 years old with LDL-C >190 mg/dL or TG >500 mg/dL especially those trying to achieve at least 50% LDL-C level reduction
      • A non-statin drug may be added if LDL-C goal has not been achieved with high-intensity regimen
    • For >75-year-old patients with ASCVD without contraindications
    • For 40-75-year-old patients with diabetes mellitus with >7.5% 10-year ASCVD risk1
    • For 40-75-year-old patients with diabetes mellitus or LDL-C >190 mg/dL
  • Moderate-intensity statins: Atorvastatin (10 mg), Rosuvastatin (10 mg), Simvastatin (20-40 mg), Pravastatin (40 mg), Lovastatin (40 mg), Fluvastatin (40 mg 12 hrly), Pitavastatin (1-4 mg)
    • Daily dose helps lower LDL-C by 30-49% 
    • Alternative treatment for patients with clinical ASCVD with contraindications against high-intensity statins or with side effects from statin therapy
    • For >75-year-old patients with ASCVD with contraindications/intolerance to high-intensity statins
    • For 40-75-year-old patients with diabetes mellitus with or without 5-<7.5% 10-year ASCVD risk
    • For 40-75-year-old patients with diabetes mellitus and LDL-C 70-189 mg/dL
    • For 40-75-year-old patients with diabetes mellitus or LDL-C >190 mg/dL with contraindications/intolerance to high-intensity statins
    • For 40-75-year-old patients without diabetes mellitus but LDL-C ≥70 mg/dL and  ≥7.5% 10-year ASCVD risk
  • Low-intensity statins: Simvastatin (10 mg), Pravastatin (10-20 mg), Lovastatin (20 mg), Fluvastatin (20-40 mg)
    • Daily dose helps lower LDL-C by <30%

1Risk of developing a first ASCVD event, defined as nonfatal myocardial infarction or coronary heart disease (CHD) death or fatal or nonfatal stroke, over a 10-year period among people free from ASCVD at the beginning of the period.

Anti-sense Apoliporotein B Oligonucleotides

  • Eg Mipomersen
  • May be used for patients with homozygous familial hypercholesterolemia unresponsive to PCSK9 inhibitor therapy; may also be considered in patients with ASCVD and baseline LDL-C ≥190 mg/dL who had inadequate response to statin therapy (with or without Ezetimibe and PCSK9 inhibitors)
  • Hybridization to mRNA results to RNase H-mediated degradation of mRNA used for translation of apo B-100
  • Lowers LDL-C levels by 21%, total cholesterol by 19%, apo B by 24%, and non-HDL-C by 22%

Bile Acid Sequestrants

  • Have been shown to reduce risk for CVD; considered in patients who have contraindications or intolerance to statin therapy
  • Also effective in LDL lowering in patients with diabetes mellitus
  • Bind bile acids in the intestine through anion exchange
  • Cause moderate reduction in LDL-C levels
    • LDL-lowering potential increases when combined with other agents (eg statins)
    • May raise triglycerides levels in some patients
    • Decrease LDL-C by 15-30%
    • Increase HDL-C by 3-5%

Microsomal Triglyceride Transfer Protein (MTP) Inhibitor

  • Eg Lomitapide
  • May be used for patients with homozygous familial hypercholesterolemia unresponsive to PCSK9 inhibitor therapy; may also be considered in patients with ASCVD and baseline LDL-C ≥190 mg/dL who had inadequate response to statin therapy (with or without Ezetimibe and PCSK9 inhibitors)  
  • Inhibits chylomicron and VLDL synthesis by direct binding and inhibition of the microsomal triglyceride transferprotein (MTP)
  • Lowers LDL-C levels by 40%, TC by 36%, apo B by 39%, TG by 45%, and non-HDL-C by 40%

Nicotinic Acid

  • Favorably affects all lipid and lipoproteins when given in the proper dosage
    • Lower doses increase HDL-C
    • 2-3 g/day are needed to lower LDL-C
  • Moderate reduction in CVD risk
  • Alter lipid levels by inhibiting lipoprotein synthesis and decreasing the production of very low-density lipoprotein (VLDL) particles by the liver
  • Most effective at raising HDL levels among lipid-modifying drugs
    • Decrease LDL-C by 5-25%
    • Increase HDL-C by 10-35%
    • Decrease TG by 20-50%
  • May be combined with statins in managing DM patients with hypertriglyceridemia
  • May increase blood glucose levels

Selective Cholesterol-Absorption Inhibitor

  • Eg Ezetimibe
  • First optional non-statin to consider for patients with poor tolerance to statins
  • First option to add onto maximally tolerated statin therapy in patients who are less responsive to statins and failed to reach LDL-C goals
    • May be added to a maximally tolerated statin therapy in patients with very high-risk ASCVD when LDL-C level remains ≥70 mg/dL 
    • Combination is a strategy to prevent side effects associated with statin monotherapy
    • Combination products of selective cholesterol-absorption inhibitor + statin, eg Ezetimibe/Simvastatin, Ezetimibe/Atorvastatin, are available and may be used to reduce LDL-C, apo B, triglycerides and non-HDL-C and to increase HDL-C
      • The IMPROVE-IT trial in patients with recent acute coronary syndrome (ACS) showed further decrease in LDL-C and reduction in cardiovascular events with the addition of Ezetimibe to a moderate-intensity statin (Simvastatin) over 6 years of follow-up
      • The SHARP trial demonstrated reductions in LDL-C and primary endpoint of 1st major ASCVD event with Ezetimibe plus Simvastatin when compared to placebo over 4.9 years of follow-up
    • If the addition of Ezetimibe to a statin achieved therapy
  • Beneficial in patients with homozygous familial hypercholesterolemia
  • Selective potent inhibitor of cholesterol absorption in the intestinal lumen and reduces the overall delivery of cholesterol to the liver
  • Causes moderate reduction in LDL-C levels
    • When used alone, Ezetimibe decreases LDL by 10-20% with favorable effects on HDL and triglycerides
    • When used in combination with statins there is an additional reduction in LDL-C by 18-25% with favorable effects on HDL and triglycerides, with Fenofibrate 20-22% reduction in LDL-C
PCSK9 Inhibitors
  • Eg Alirocumab, Evolocumab
  • As human monoclonal PCSK9 antibody, it binds to PCSK9 which then increases LDL receptor density
  • Adjunct to diet and maximally tolerated statin therapy for the treatment of heterozygous familial hypercholesterolemia or clinical ASCVD that needs further reduction of LDL-C
  • Given also to patients with very high and high CV risk with intolerance to statin therapy
  • It is reasonable to add a PCSK9 inhibitor to patients with very high-risk ASCVD or severe primary hypercholesterolemia with multiple risk factors for ASCVD events if the LDL-C level remains above goal on maximally tolerated statin and Ezetimibe therapy
  • Evolocumab may also be given in combination with other LDL-lowering agents (eg statins, Ezetimibe, LDL apheresis) to treat homozygous familial hypercholesterolemia needing further reduction of LDL-C
  • Lowers LDL-C levels by 48-71%, total cholesterol by 36-42%, apo B by 42-55%, and non-HDL-C by 49-58%

Intensified LDL-C-Lowering Pharmacotherapy

  • Dose increase
  • Combination therapy

Triglyceride-Lowering and HDL-C-Raising Pharmacological Therapy

Fibrates

  • Primary use is for lowering triglycerides
    • Decrease triglycerides by 20-50%
    • May be combined with statins in managing diabetes mellitus patients with hypertriglyceridemia and low HDL-C
    • If triglycerides are not elevated, fibrates may lower LDL-C by 5-20%
  • Also useful in combined/mixed dyslipidemia and in increasing HDL-C by 6-35%
  • Recommended for patients with very high triglycerides who are at risk for pancreatitis
  • Moderately reduce risk for CHD
  • Favorably lower LDL in patients with diabetes mellitus
  • Down-regulate the apolipoprotein C-III gene and up-regulate genes for apolipoprotein A-1, fatty acid transport protein, fatty acid oxidation and possibly lipoprotein lipase
  • Primarily target atherogenic dyslipidemia including diabetic dyslipidemia
    • Fenofibrate with or without statin therapy reduces progression of diabetic retinopathy
  • When used in combination with LDL-lowering drugs, it improved the overall lipoprotein compared to either agent alone
  • Provide an alternative treatment in statin-intolerant patients with mild to moderate hypercholesterolemia
  • In patients in whom a fibrate is recommended, Nicotinic acid can also be considered

Nicotinic Acid

  • Please see discussion under LDL-C-Lowering Pharmacological Therapy

Treatment of Specific Dyslipidemias

Very High LDL Cholesterol (≥4.9 mmol/L or ≥190 mg/dL)

  • Usually caused by genetic forms of hypercholesterolemia
  • Treatment of mild cases
    • Statin or bile acid sequestrant
  • Treatment of more severe cases
    • Statin + bile acid sequestrant or selective cholesterol-absorption inhibitor
    • Combination product of selective cholesterol-absorption inhibitor + statin is available and may be used
    • May need to add Nicotinic acid

Elevated Triglycerides

  • Strong association between high triglyceride levels and CHD risk
  • Triglyceride levels ≥2.3 mmol/L (200 mg/dL) indicate the need to identify non-HDL-C level, which is the secondary target of lipid-lowering therapy in these patients (LDL-C is still the primary goal of therapy)
    • Non-HDL-C is more representative of all atherogenic lipoproteins than LDL-C
      • Non-HDL-C (mmol/L) = TC-HDL-C
      • (Non-HDL-C levels can be calculated from non-fasting serum)
  • Acquired causes: Obesity, physical inactivity, excess alcohol intake, high carbohydrate diet
    • Secondary causes (eg diabetes mellitus, chronic renal failure, nephrotic syndrome, chronic liver disease, hypothyroidism, Cushing’s disease, various medications, etc)
    • Genetic causes
  • Elevated triglycerides can often be effectively treated through lifestyle changes; however, fibrates, niacin, and combination therapy with statins may be appropriate options for many patients
  • Borderline Hypertriglyceridemia (150-199 mg/dL)
    • For borderline increase in triglycerides associated with elevated serum cholesterol or low HDL-C, 1st-line therapy includes lifestyle changes (eg weight control, physical activity, smoking cessation)
  • Very high triglycerides [>5.6 mmol/L (>500 mg/dL)]
    • Treatment should be likened to an emergency to avoid acute pancreatitis
    • Fibrate or Nicotinic acid should be started
    • Lifestyle modifications
    • Fish oils can replace some long-chain TG in diet
  • If LDL-C is still elevated despite a fibrate, consider adding a statin
    • Decision must be individualized
    • Must be started only when it is strongly indicated
    • The recommended fibrate to be combined with a statin is Fenofibrate
  • High triglycerides [2.3-5.6 mmol/L (200-499 mg/dL)]
    • Lifestyle modifications
    • If LDL-C or non-HDL-C levels are high: Start statin
      • Consider combination therapy with Fenofibrate if unresponsive to statin monotherapy
  • Borderline high triglycerides [1.7-2.3 mmol/L (150-199 mg/dL)]
    • Lifestyle modifications
    • Medications are rarely required unless LDL-C is elevated above target level

Low HDL-C [<1 mmol/L (40 mg/dL)]

  • Low HDL-C is a strong, independent predictor of CHD
  • Excluding secondary causes of low HDL-C and in the presence of other risk factors (eg borderline LDL-C, personal history of CAD, or a family history of premature CAD, HDL-C levels should be raised by as much as possible to levels of at least >40 mg/dL in both men and women
  • Raising HDL-C levels alone in patients without accompanying risk factors is not recommended

Low HDL-C without Hypertriglyceridemia

  • Causes: Obesity, physical inactivity, cigarette smoking, type 2 DM, certain drugs, etc
  • Treatment in patients with CHD or CHD-risk equivalents when lifestyle modifications fail to increase HDL include fibrates or Nicotinic acid

Low HDL-C with Hypertriglyceridemia

  • HDL-C is low and triglycerides is high and LDL-C is not significantly elevated: Start fibrates or Nicotinic acid

Atherogenic Dyslipidemia [Triglycerides ≥1.7 mmol/L (150 mg/dL) and HDL-C <1 mmol/L (40 mg/dL)]

  • The patient likely has metabolic syndrome
  • Attempt adequate trial of lifestyle modification to meet LDL-C goals
    • Add LDL-lowering drug therapy if lifestyle modification fails to reach LDL-C goals
  • Triglycerides <2.3 mmol/L (200 mg/dL): Drug therapy to lower triglycerides is not necessary
    • If patient has CHD or CHD-risk equivalents, consider using drug therapy to raise HDL-C (eg fibrates or Nicotinic acid) 
  • Triglycerides 2.3-5.7 mmol/L (200-499 mg/dL): If non-HDL-C remains elevated after adequate LDL-C lowering therapy: May consider higher dose of statin or statin + Triglycerides-lowering drug (fibrate or Nicotinic acid)

Apolipoproteins

  • Target apo B level at <90 mg/dL for patients at risk of CAD, including those with diabetes mellitus 
  • Target apo B level at <80 mg/dL for patients with established CAD or DM plus ≥1 additional risk factor

Pediatric Dyslipidemia

  • Benefits of developing healthy lifestyle habits in children have been recognized
  • Recommended first-line approach is intensive lifestyle modifications (with emphasis on improved dietary intake and normalization of body weight)
    • It is recommended that lifestyle changes in children should be implemented for at least 6-12 months prior to considering pharmacologic therapy 
  • Studies have shown that high-fiber, low-fat diets are also beneficial in children by helping reduce cholesterol levels
    • However, monitoring of fat-soluble vitamin status in children on low-fat diet is recommended since this may reduce absorption of these vitamins
  • Avoid high carbohydrate diet in children with hypertriglyceridemia
  • Smoking cessation should also be implemented
  • Fish oil supplements are considered to have significant effects on triglyceride levels in children, especially in those with end-stage renal insufficiency
  • Dietary supplementation with plant stanols and sterols (eg orange juice, yogurt drinks, cereal bars, margarines/ spreads, dietary supplements) may be considered for children with severe hypercholesterolemia or those who are at high risk
    • Above supplements may also reduce absorption of fat-soluble vitamins; monitoring of fat-soluble vitamin status is also recommended 
  • Pharmacotherapy is generally reserved for those with severe dyslipidemia or those with genetic lipid disorders
  • Other candidates for pharmacotherapy include children and adolescents >8 years of age who satisfy the following criteria:
    • LDL-C level of ≥190 mg/dL or
    • LDL-C level of ≥160 mg/dL plus
      • Presence of ≥2 CAD risk factors
      • Family history of premature CAD (<55 years of age)
      • Being overweight or obese, or having other elements of insulin resistance syndrome
    • Pediatric diabetic patients with LDL level of ≥130 mg/dL
  • Pharmacotherapeutic options for pediatric dyslipidemia include the following:
    • Based on available evidence, statins are considered safe and effective 
    • Pediatric studies have demonstrated 15-20% reductions in LDL-C level with bile acid sequestrants
      • Cholestyramine is currently approved for hypercholesterolemia in children and should be initiated at <8 g daily
      • Safety and efficacy of Colestipol and Colesevelam have not yet been established in pediatric patients although Colestipol may be started at <10 g daily while Colesevelam is approved for children ≥8 years of age
      • Bile acid may lead to folic acid and cholecalciferol depletion; multivitamins should therefore be used
      • Bile acid sequestrants should not be used in children with hypertriglyceridemia
    • Fibrates may be useful in children with severe hypertriglyceridemia and at increased risk of pancreatitis
      • Use of fibrates in children or adolescents with type I or V hyperlipoproteinemia warrants close monitoring
    • Ezetimibe has only been used in children ≥10 years of age and adolescents with homozygous familial hypercholesterolemia or sitosterolemia
    • Experience with Niacin therapy in children is limited
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