Dyslipidemia, Cholesterol and Bile Acids

• Dyslipidemia is important for the health of cells and tissues including the brain

Cholesterol

• Cholesterol is a structural component of cell walls
• Cholesterol is a precursor in hormone and bile acid synthesis
• Cholesterol is used to produce bile acids

Bile Acids

• Bile acids play a crucial role in the digestion and absorption of fats and fat-soluble vitamins
• Bile acids are needed to absorb lipids
• Enterohepatic recycling occurs when bile acids are produced in the liver and travel through the bile ducts with free cholesterol and waste products into the small intestine and are converted from bile acids to bile salts and returned back to the liver
• Cholesterol exits the body as free cholesterol or as bile acid

Atherosclerosis and ASCVD

• Atherosclerosis is the formation of plaque buildup of fats, cholesterol, and other substances on the inner walls of the arteries
• If atherosclerosis is present somewhere, it is present everywhere
• Atherosclerosis is asymptomatic
• Atherosclerosis leads to Atherosclerotic Cardiovascular Disease (ASCVD), which includes:
  • Myocardial infarction
  • Stroke/TIA
  • Stable angina
  • Peripheral arterial disease (PAD) in the legs, arms, and extremities

Cholesterol Effect on AVSCD Risk

• Statins decrease or reduce the formation of cholesterol
• Ezetimibe blocks cholesterol absorption
• Bile Acid Sequestrants block the enterohepatic recirculation of bile salts

Cholesterol Types and Normal Values

• Total Cholesterol (TC) = LDL + HDL + (Triglycerides/5)
• High-density lipoprotein (HDL) is considered "good cholesterol" and lowers ASCVD risk by taking cholesterol from the blood and delivering it to the liver for removal from the body
• Non-HDL lipoproteins contribute to atherosclerosis and are a good predictor of ASCVD
  • Non-HDL = TC - HDL
  • LDL is low-density lipoprotein
  • VLDL is very low-density lipoprotein
• High triglycerides or hypertriglyceridemia are associated with high ASCVD risk
  • Triglycerides (TGs) >500 mg/dL can cause acute pancreatitis

Determining LDL Cholesterol

• Lipid panels are usually done after a 9-12 hour fast, which is needed for TG primarily
• Friedewald equation: LDL = TC - HDL - (TG/5)
  • Equation is not used when TG >500
  • A falsely high TG level can result in a falsely low LDL

Cholesterol Values

• Non-HDL: <130
• LDL: < 100, >190 = Very High
• HDL: Men: >40, Women: >50
• Triglycerides: <150, >500 = Very High

Classification of Dyslipidemia

• Primary (Familial): genetic defects that cause severe cholesterol elevations
• Secondary (Acquired): mostly due to poor diet or lack of physical activity
  • Severe cholesterol elevations present as LDL: >190 mg/dL, and TG: >500 mg/dL

Medications that Increase LDL and TG

• Diuretics
• Efavirenz
• Immunosuppressants like Cyclosporine and tacrolimus
• Atypical antipsychotics
• Protease Inhibitors

Medications that Increase LDL Only

• Fibrates
• Fish Oils except Vascepa

Medications that Increase TG Only

• IV Lipid Emulsions
• Propofol
• Clevidipine
• Bile Acid Sequestrants(~5%)

Conditions that Increase TG

• Obesity
• Poor diet
• AUD
• Hypothyroidism
• Smoking
• Diabetes
• Renal/liver disease
• Nephrotic syndrome

Calculating ASCVD Risk

• Used to provide an estimate of an individual's risk of having a first cardiovascular event during the next 10 years using:
  • Gender
  • Age
  • Race
  • Smoking status
  • TC, HDL, LDL
  • If statin is used
  • Blood pressure
  • If antihypertensive treatment is used
  • Diabetes history
  • Aspirin use
• The calculation should be repeated every 4-6 years
• Risk score is not needed in patients who had a clinical ASCVD, diabetes, or LDL >190 as they should already be on a statin
• High coronary artery calcium score (CAC) is helpful in deciding if statins should be initiated in those with 10-year ASCVD risk of 7.5-19.9%
  • CAC score >100 = statins should be initiated

Non-Drug Treatment

• Lifestyle modifications
• Healthy diet rich in vegetables, fruit, whole grains, and high-fiber foods, as well as fish and limited intake of saturated fats, trans fat, and cholesterol
• Healthy weight (BMI 18.5 - 24.9)
• Physical activity
• Avoiding tobacco

Natural Products

• Red Yeast is effective in lowering LDL and contains naturally-occurring HMG-CoA reductase inhibitors
• OTC fish oils can lower TG but can increase LDL
• Garlic is no longer recommended for dyslipidemia

Drug Treatment

• Statins are the drug of choice for treating high non-HDL and LDL
• Guidelines focus on adding Ezetimibe and/or proprotein convertase subtilisin/kexin type 9 monoclonal antibodies (PCSK9 MAbs) for their effective LDL-lowering effects and cardiovascular benefits
• Many cholesterol-lowering drugs may cause liver damage, which includes niacin, fibrates, sometimes statins and ezetimibe
  • Should not be used if AST/ALT is >3 times the upper limit of normal

Statins

• Inhibit HMG-CoA reductase, which prevents the conversion of HMG-CoA to mevalonate
  • Which is the rate-limiting step in cholesterol synthesis
• Muscle damage from statins is symmetrical and occur within 6 weeks
  • Presents as myalgias (muscle soreness and tenderness)
  • Myopathy (muscle weakness +/- CPK elevations)
  • Myositis (muscle inflammation)
  • Rhabdomyolysis (muscle symptoms with a very high CPK plus muscle protein in the urine, which can lead to acute renal failure)
• It is okay to take Coq10 for mild muscle symptoms
• Treatment:
  • Hold statin
  • Check CPK
  • After 2-4 weeks, rechallenge by restarting at the same or lower dose
  • Can use another statin
  • If myalgias return, discontinue statin
• Prevention:
  • Avoid drug interactions
  • DO NOT USE: Simvastatin 80 mg/day or gemfibrozil + statin

Statin Equivalent Doses

• "Pharmacists Rock At Saving Lives and Preventing Fatty deposits"
  • Pitavastatin 2 mg
  • Rosuvastatin 5 mg
  • Atorvastatin 10 mg
  • Simvastatin 20 mg
  • Lovastatin 40 mg
  • Pravastatin 40 mg
  • Fluvastatin 80 mg

Specific Statins

• Atorvastatin (Lipitor) dose: 10-80 mg
• Rosuvastatin (Crestor) dose: 5-40 mg QD
  • May need to lower dose in asians (Exposures are 2 times higher)
• Pravastatin (Pravachol) dose: 10-80 mg
• Pitavastatin dose: 1-4 mg QD
• Simvastatin (Zocor) dose: 10-40 mg PO QPM
  • Do Not use 80 mg dose (increases risk of myopathy)

Statin Contraindications

• Breast-feeding and liver disease
• Use with CYP34A inhibitors with simvastatin and lovastatin
• Use with cyclosporine

Statin Warnings

• Muscle damage from statins, increased CPK, higher risk with higher doses and advanced age, as well as use with niacin, fibrates
• Lovastatin (Altoprev) and Fluvastatin
  • Do not use with pregnancy unless benefit outweighs risk

Statin Side Effects and Monitoring

• Side effects include myalgia and myopathy
• Monitoring requires lipid panels, checking 4-12 weeks after starting and per year, as well as liver function tests at baseline and if symptoms of hepatotoxicity

Statin Drug Interactions

• Drug interactions INCREASE drug effects through CYP3A4, inlcuding Atorvastatin, lovastatin, and simvastatin
• Rosuvastatin and pravastatin have less drug interactions
• Fibrates and Niacin can increase the risk of myopathies and rhabdomyolysis
• DO NOT USE STATINS WITH GEMFIBROZIL and Amlodipine

Non-Statin Add-On Treatment

• If LDL remains above goal, statin dose should be maximized
• Initial add-on recommendations due to CV benefits is Ezetimibe orally, and PCSK9 inhibitors (MAbs) through injectables
• Other treatments that do NOT have CV data: Bempedoic acid and Inclisiran (inhibitor of PCSK9 production) and do not add with PCSK9-i

Determining Need for Add-On Treatment

• Clinical ASCVD and either very high risk or baseline LDL ≥ 190 mg/dL