IP3 Dyslipidemia 2025 Final PDF

Dyslipidemia Part 1 RHCHP School of Pharmacy Integrated Pharmacotherapy 3 Spring 2025 Facilitators Reading and References Chris Malarkey, Ph.D. Re...

Dyslipidemia Part 1 RHCHP School of Pharmacy Integrated Pharmacotherapy 3 Spring 2025 Facilitators Reading and References Chris Malarkey, Ph.D. Required [email protected] Integrated Pharmacotherapy 3 Dyslipidemia course notes 303-625-1244 Optional Emily Clemens, Pharm.D., BCACP Harper’s Illustrated Biochemistry chapter 25 & 26 [email protected] 303-964-3641 Dyslipidemia RAT 1: Learning Objectives 1 - 29 *The objectives that are starred will not be covered on the RATs, but may be covered in application exercises and exams. 1. In general terms, describe the incidence and impact of CVD in the United States, including the current trends in event and death rates 2. Describe the steps in triglyceride and cholesterol digestion and absorption 3. Describe the difference between cholesterol and cholesteryl ester 4. Define a lipoprotein, and describe the role of each component in a lipoprotein particle 5. *Understand the role of cholesterol in cell membrane fluidity/stability 6. Define apolipoprotein and describe its structure and function in lipoproteins 7. Differentiate between the major groups of lipoproteins (chylomicrons, chylomicron remnants, VLDL, IDL, LDL, and HDL) 8. Identify the major apolipoproteins and lipids associated with each lipoprotein, the biological role of each lipoprotein, and the metabolic fate of each lipoprotein 9. Describe the role of the liver in lipid transport and metabolism 10. Describe the steps of apoE- and apoB-mediated receptor endocytosis 11. Describe the reverse cholesterol transport pathway 12. Describe the role of cholesteryl ester transfer protein in cholesterol transport from HDL 13. Explain how the body acquires cholesterol 14. Summarize the biochemical steps for the synthesis of cholesterol 15. Distinguish the role of HMG-CoA reductase in the synthesis of cholesterol 16. Define the role of the following apolipoproteins: apoAI, apoB, apoCII, apoCIII, apoE 17. Describe how cholesterol is transported in the blood and excreted from the body 18. Outline the synthesis of bile acids 19. Describe the structure and function of a bile acid 20. Differentiate between hypercholesterolemia, hypertriglyceridemia, and combined hypercholesterolemia and hypertriglyceridemia 21. Differentiate between primary and secondary dyslipidemia 22. Recognize common causes of secondary dyslipidemia 23. Summarize the steps involved in atherosclerosis formation and identify the role of LDL-C in this process 24. Identify the steps of TG and cholesterol synthesis or absorption affected by each pharmacologic class of dyslipidemia medications 25. Describe the mechanisms by which each dyslipidemia drug or drug class changes LDL-C, HDL-C, and TG levels 26. When given a generic drug name, recognize the pharmacologic classification of HMG-CoA reductase inhibitors, fibrates, bile acid sequestrants, apoB inhibitors, and PCSK9 inhibitors (both types) 27. Identify drugs that alter lipoprotein lipase activity and predict their pharmacologic effect on lipid levels 28. Describe the general effect of HMG-CoA reductase inhibitors, fibrates, bile acid sequestrants, niacin, ezetimibe, omega-3 fatty acids, PCSK9 inhibitors, and bempedoic acid on LDL-C, HDL-C, and TG 29. Predict likely adverse effects in patients taking dyslipidemia medications  Dyslipidemia RAT 2 : Learning Objectives 30-73 (objectives 1-29 may be included) 30. Using the Friedewald equation, calculate LDL-C (memorize this equation, you also must know when this equation is not valid) [Page 12] 31. Describe first-pass metabolism and discuss its effect on the oral bioavailability of HMG-CoA reductase inhibitors 32. Differentiate between HMG-CoA reductase inhibitor metabolism and excretion pathways and apply this information to the assessment of potential drug-drug interactions 33. Describe the bioactivation of lovastatin, simvastatin and fenofibrate 34. When given the chemical structure of a bile acid sequestrant and a bile acid, depict the anion-exchange process leading to increased excretion of bile acids 35. Differentiate between nicotinic acid and nicotinamide, and describe the pharmacologic activity of each with regard to vitamin supplementation and dyslipidemia 36. Differentiate between the various formulations of niacin 37. Describe how the metabolism of different niacin products relates to the risk of adverse drug events 38. Identify the two active components of fish oil useful for management of dyslipidemia 39. Summarize the FDA-approved indications for the PCSK9 inhibitors, specifically the approved patient populations 40. Discuss the similarities and differences between the mechanisms and effects of the PCSK9 mAbs and the siRNA PCSK9 therapy 41. Compare and contrast the mechanisms of action and clinical impact between bempedoic acid and statins 42. Differentiate between phase I and phase II drug metabolism pathways 43. Describe the drug metabolism profiles of dyslipidemia drugs 44. Identify contraindications to dyslipidemia medications 45. Identify mechanisms by which dyslipidemia drugs interact with other medications 46. *When given a patient drug profile, identify potential drug-drug, drug-food and drug-disease interactions involving dyslipidemia medications 47. Differentiate between Primary Prevention and Secondary Prevention of ASCVD 48. Identify and describe the forms of clinical ASCVD 49. Identify the primary goal/reason for treating patients with dyslipidemia 50. Describe the relationship between LDL-C and ASCVD 51. Describe the four patient management groups who benefit from lipid-modifying therapy, per the 2018 AHA/ACC Cholesterol Guideline 52. Define low-intensity, moderate-intensity, and high-intensity statin therapy based on the anticipated LDL-C percent reduction 53. *Classify a given statin/dosage as low-intensity, moderate-intensity, or high-intensity 54. Describe the system utilized to grade recommendations based on strength & evidence in the ACC/AHA Cholesterol Guideline 55. For Secondary Prevention management, categorize patients as ‘Very high-risk’ or ‘ASCVD not very high-risk’ and state the LDL-C target/goals 56. Identify the recommended treatment/intensity for Secondary Prevention, and *recommend appropriate additional therapies to reduce ASCVD outcomes 57. Describe the evidence-based approach to treat patients with severe hypercholesterolemia 58. Explain the recommended treatment of patients with diabetes (Class I), *and the personalization of therapy based on age, 10-year ASCVD risk, and diabetes-specific risk enhancers 59. List the risk factors used in the Pooled Cohort Equations to estimate 10-year ASCVD risk 60. *Calculate the 10-year ASCVD risk for patients to inform evidence-based treatment decisions 61. For Primary Prevention, classify a patient into the appropriate risk category, according to 10-year ASCVD risk 62. Recommend an evidence-based treatment/intensity for patients at Low-Risk, *Borderline Risk, *Intermediate Risk, and High Risk 63. *Discuss limitations with the Pooled Cohort Equations for ASCVD risk assessment 64. Explain why statins are the first-line therapies for dyslipidemia, and *identify other pharmacologic agents with evidence to reduce ASCVD risk/events in clinical trials 65. Recommend the evidence-based treatment for patients with differing severities of hypertriglyceridemia 66. Create a plan to monitor the effectiveness and adverse effects of the therapeutic agents used to treat dyslipidemia 67. Calculate the anticipated therapeutic response to statin therapy using the definitions of low-, moderate-, or high-intensity statin, AND calculate the achieved LDL-C percent reduction when given a baseline and follow-up value 68. Evaluate laboratory findings and signs/symptoms to identify effectiveness, side effects, and adverse events of lipid lowering medications 69. Explain strategies for minimizing the risk of adverse effects resulting from various agents used alone or in combination to treat dyslipidemia 70. Summarize the non-pharmacologic therapies that are recommended to improve lipids and reduce cardiovascular risk 71. *Formulate an evidence-based therapeutic plan that includes pharmacologic and non-pharmacologic therapies to treat dyslipidemia and prevent ASCVD events 72. Use LDL-C, HDL-C or TG percent decrease or increase data for dyslipidemia drugs to make appropriate drug therapy decisions 73. *Explain the rationale used in selecting each pharmacologic and non-pharmacologic intervention used to treat dyslipidemia INTRODUCTION Selected Abbreviations Cardiovascular disease (CVD) continues to be the leading cause of morbidity and mortality ASCVD- Atherosclerotic Cardiovascular Disease in the United States. According to the American Heart Association’s 2024 Statistical Update, CVD – Cardiovascular Disease the prevalence of CVD (including coronary heart disease [CHD], heart failure [HF], stroke, CAD – Coronary Artery Disease and hypertension) in adults ≥ 20 years of age is 48.6% (127.9 million in 2020), and CVD CHD – Coronary Heart Disease prevalence excluding hypertension (CHD, HF, and stroke only) is 9.9% (28.6 million in IHD – Ischemic Heart Disease 2020). Overall CVD accounts for ~31% of all deaths (~1 of every 3 deaths). Approximately AAA – Abdominal Aortic Aneurysm 2,552 Americans die each day from CVD, which translates to one CVD-related death every CVA – Cerebrovascular Accident, Stroke 34 seconds. CHD remains the #1 cause of death in the U.S., accounting for 13% of deaths MI – Myocardial Infarction (~1 of every 7.7 deaths), and stroke is responsible for ~1 of every 19 deaths. PAD – Peripheral Artery Disease CVD and heart disease deaths in the U.S. increased steadily during the 1900s to the 1980s FLP – Fasting Lipoprotein/Lipid Profile/Panel and then declined into the 2010s. However, CVD deaths have actually increased over the TC – Total cholesterol past 10 years. Dyslipidemia is a significant contributor to CVD and cardiovascular (CV) LDL-C – Low–Density Lipoprotein Cholesterol events, so the recent event trend reaffirms the critical importance of cholesterol management VLDL-C – Very Low-Density Lipoprotein Cholesterol and optimal utilization of dyslipidemia pharmacotherapy. HDL-C – High-Density Lipoprotein Cholesterol Dyslipidemia, along with smoking, hypertension, and diabetes mellitus, has been shown to TG – Triglycerides (aka Triacylglycerol) be an independent risk factor for cardiovascular events. Dyslipidemia consists of a variety of LPL – Lipoprotein Lipase plasma lipid disorders that are characterized by any one or a combination of the following: HL – Hepatic Lipase elevated total cholesterol (TC), elevated low-density lipoprotein cholesterol (LDL-C), TSH – Thyroid Stimulating Hormone elevated triglycerides (TG), and decreased high-density lipoprotein cholesterol (HDL-C). CBC – Complete Blood Count Note, the term “hyperlipidemia” does not encompass the presence of low HDL-C, and it LFT – Liver Function Test generally has been replaced with the term dyslipidemia. AST – Aspartate aminotransferase ALT – Alanine aminotransferase In November of 2018, the American Heart Association and American College of Cardiology (AHA/ACC) published the Guideline on the Management of Blood Cholesterol (often CK – Creatine kinase referred to as the “2018 AHA/ACC Cholesterol Guideline” in this document). These ACC – American College of Cardiology recommendations are the most widely used guidelines for management of lipid disorders in AHA – American Heart Association clinical practice. The 2018 Guideline updates the previous 2013 Guideline and emphasizes a NCEP – National Cholesterol Education Program more comprehensive approach based on recent evidence and expert consensus. ATP III – Adult Treatment Panel III TLC – Therapeutic Lifestyle Changes Figure 1. Digestion and absorption of TG in the small intestine. PHYSIOLOGY/BIOCHEMISTRY Digestion, Absorption, and Transport of Lipids Digestion/Absorption of Lipids TG Digestion and Absorption As you previously learned, lipid digestion and absorption predominantly occurs in the small intestine as a result of emulsification and micelle formation mediated by bile salts/acids, and pancreatic lipase activity (Figure 1). Lipases hydrolyze water- insoluble substrates such as triglycerides (TG) and phospholipids. A TG is hydrolyzed to a monoglyceride and two free fatty acids and all three molecules are absorbed by the intestinal cells (enterocytes). Inside the cell, fatty acids and monoglycerides are reformed to TG. TG are packaged with other lipids and proteins into droplets known as chylomicrons, which are then released into the lymphatic system (a drainage system that removes a clear fluid from tissues). Lymphatic fluid then passes through lymph nodes before it enters into the venous system. Chylomicrons eventually enter the blood stream where the body metabolizes the lipid/protein particle. Intestinal cholesterol is actively absorbed into the brush border of enterocytes. Transport across the membrane is ATP-dependent. Once inside the intestinal cell, free cholesterol is esterified by acyl coenzyme:cholesterol acyltransferase 2 (ACAT) to cholesteryl esters (Figure 2). The structure of cholesteryl esters is more hydrophobic Integrated Pharmacotherapy 3 3 Dyslipidemia than free cholesterol. Cholesteryl esters are then assembled with Figure 2. Cholesterol ester synthesis TG into chylomicron particles. Lipid Transport Lipoproteins Because lipids (TG, cholesterol, phospholipids and fat-soluble vitamins) are not water soluble, they are packaged in the blood into macromolecular structures called lipoproteins (Figure 3). It is important to point out that fatty acids can also be transported in the Figure 3. Structure of a lipoprotein blood bound to albumin. Lipoproteins are distinct spherical particles that contain aggregates of proteins and lipids. Each lipoprotein contains a lipid core consisting of TG and cholesteryl esters. This hydrophobic core is surrounded by a single phospholipid layer, free cholesterol, and protein. The nonpolar tails of the phospholipids are directed toward the hydrophobic core and the polar, charged heads are on the surface which enables the lipoprotein to dissolve in blood. Free cholesterol resides in the layer of phospholipids, playing a similar role as it does in the lipid bilayer of cells, maintaining membrane stability and decreasing membrane permeability (Figure 4). We previously covered this topic in Biochemical Concepts in IP1. The protein components of lipoproteins are called apolipoproteins (apo). Apolipoproteins are amphipathic (having both lipophilic and hydrophilic domains) and have an alpha-helical structure. They may be either integral components of the phospholipids or they may be peripheral to the phospholipids. Apolipoproteins are produced by the liver and serve as ligands Figure 4. Cholesterol in the lipid bilayer for cell receptors and cofactors for enzymes in lipoprotein metabolism. There are at least nine apolipoproteins differentially distributed among the lipoproteins. Some apolipoproteins are released tightly bound to a specific lipoprotein particle and some apolipoproteins are released individually and once in the blood, become associated with a specific lipoprotein particle. Keeping track of the apolipoproteins can be challenging, so Table 1 on page 5 has been included to help you study. There are five classes of lipoproteins; each is distinguished by its density which is a result of a specific protein and lipid makeup. Low density lipoproteins have a higher percentage of lipids and a lower percentage of proteins. In contrast, high density lipoproteins contain higher percentages of protein and low lipid content (Figure 5). Figure 5. Relative number of cholesterol, cholesteryl ester, Chylomicrons are a class of TG-rich lipoprotein that are the largest phospholipid, and protein molecules in four major classes of in volume and have the lowest density. These very large lipoproteins lipoproteins (IDLs not shown) have high fat content (98 to 99%), of which >85% is dietary TG. As previously mentioned, chylomicrons are released by intestinal cells into the lymphatic system. After chylomicrons enter the blood, they acquire a variety of apolipoproteins, including apoE, apoCII, and apoCIII. Chylomicrons transport dietary TG and dietary cholesterol (in the form of cholesteryl esters) from the intestines to various tissues that utilize TG for energy, such as adipose tissue, skeletal muscle, cardiac muscle, and, in lactating women, breast tissue. Lipoprotein lipases (LPL) that reside on cell membranes of the vascular endothelium of the aforementioned tissues hydrolyze TG from chylomicrons. The released fatty acids are taken up by the cells of the tissues and utilized for energy metabolism or storage. ApoCII associated with the chylomicron activates LPL (Figure 6) and hepatic lipase (HL). ApoCIII inhibits LPL and HL. In a healthy individual, chylomicrons enter the bloodstream 1 to 2 hours after the start of a fat-containing Integrated Pharmacotherapy 3 4 Dyslipidemia meal and are present in plasma for up to 12 hours Figure 6. Lipoprotein Synthesis after consuming the meal. Following removal of most of the dietary TG, the remaining, smaller chylomicron particle is now called a chylomicron remnant. The chylomicron remnant still contains most of the dietary cholesterol as only the dietary TG has been removed. The chylomicron remnants are removed from the blood by the liver through apoE-receptor- mediated endocytosis. The liver contains apoE receptors that bind to the apoE located on the surface of the chylomicron remnants, resulting in endocytosis of the chylomicron remnant. Lysosomes (intracellular vesicles containing enzymes) fuse with the endocytic vesicle and the chylomicron remnants are degraded by lysosomal enzymes. The products of lysosomal digestion including fatty acids, amino acids, glycerol, cholesterol, and phosphate are reused by the cell. Very low density lipoproteins (VLDL) are synthesized by the liver and released into the blood. They are much smaller than chylomicrons and their primary function is to transport lipids from the liver to peripheral tissues. This is important because VLDL transport endogenous Chylomicrons are converted to chylomicron remnants by the hydrolysis of their triglycerides by LPL. Chylomicron remnants are rapidly cleared from the plasma by the liver. “Remnant receptors” include TG while chylomicrons transport dietary TG. the LDL receptor–related protein (LRP), LDL receptors, and perhaps other receptors. Free fatty acid Production of VLDL is stimulated by an influx of (FFA) released by LPL is used by muscle tissue as an energy source or taken up and stored by adipose free fatty acids into the liver (in part by diet and tissue. HL, hepatic lipase; IDL, intermediate-density lipoproteins; LDL, low-density lipoproteins; LPL, hormones) or as a result of de novo synthesis of lipoprotein lipase; VLDL, very-low-density lipoproteins. fatty acids by the liver (lipogenesis). Lipogenesis Table 1. Apolipoproteins and their locations and functions is an insulin-mediated process which synthesizes free fatty acids Apolipoprotein Lipoprotein Function from glucose. Newly synthesized free fatty acids are subsequently converted to TG and packaged into VLDL and released into the ApoAI HDL Stabilizes HDL and keeps it in the blood. blood VLDL contain high amounts of TG, but only about 60% of that ApoB LDL, VLDL Facilitates LDL endocytosis by the liver is found in chylomicrons. They also contain more cholesterol ApoCII Chylomicron, Activates HL and LPL and cholesteryl esters than chylomicrons. VLDL contain apoCII, VLDL apoCIII, apoB, and apoE. As these lipoproteins move throughout the body, TG and some phospholipids and apolipoproteins, ApoCIII Chylomicron, Inhibits HL and LPL VLDL are removed and utilized by tissues. In a similar fashion to chylomicrons, apolipoproteins may be released individually and ApoE Chylomicron Facilitates IDL and chylomicron once in the blood, become associated with a specific lipoprotein remnants, remnant endocytosis by the liver VLDL, IDL particle. Depletion of TG reduces the size of VLDL and increases their density. The TG depletion results in formation of intermediate-density lipoproteins (IDLs). IDL either continues to lose TG (because of lipoprotein lipase activity) to form a higher density lipoprotein called low density lipoprotein (LDL) or is removed from the blood by the liver (through apoE-mediated endocytosis). LDL is mostly produced from the catabolism of IDL. LDLs are approximately 2% the size of VLDL and 0.02% the volume of a chylomicron. The LDL particles contains high amounts of cholesterol and cholesteryl esters, are bound to only apoB and have a half-life of 1.5 to 3 days. LDLs are the major means of cholesterol transport and delivery to tissues. Approximately 65% of total serum cholesterol is present in LDL. LDL can vary in density and size (small and dense particles are associated with higher TG levels and are highly atherogenic – involved in the progression of atherosclerosis). LDL levels are monitored in patients and are often refered to as the “bad” cholesterol. Much of the clinical focus of this unit will be on decreasing LDL-C levels because reductions in CV events and mortality are most associated with decreased LDL-C levels. ApoB associated with LDL binds to LDL receptors located on the cell membranes of liver cells (hepatocytes) causing both the LDL Integrated Pharmacotherapy 3 5 Dyslipidemia particle and the receptor to be internalized (Figure 7). The LDL particle is Figure 7. LDL-C-mediated receptor endocytosis. degraded (similar to chylomicron remnant removal by the liver) and the LDL receptor is recycled and positioned back in the plasma membrane of the hepatocyte. This process is targeted clinically by PCSK9 inhibitors and will be discussed below and in applications in class. All cells contain LDL receptors but the liver contains the highest levels of LDL receptors, and consequently is the primary site of removal of LDL from the blood. Inside cells, cholesteryl esters are hydrolyzed by a lysosomal lipase to free cholesterol, which is either incorporated into cell membranes or reesterified by ACAT for storage as cholesteryl esters droplets. The liver also produces high-density lipoproteins (HDL) which are protein-rich lipoproteins. The HDL particle is relatively small and dense and has a volume approximately 0.12% of the VLDL particle. The major apolipoprotein associated with HDL is apoAI. ApoAI wraps around the particle serving as a primary structural component and a recognition molecule for most proteins that interact with HDL. ApoAI also stabilizes the HDL particle and reduces HDL removal from the blood. Both LDL-C and its receptor (in purple, green and blue) are HDLs scavenge extra cholesterol and cholesteryl esters from cell membranes, internalized into the hepatocyte. The receptor is then recycled VLDL and LDL. HDL then transports cholesterol and cholesteryl esters to the back to the cell membrane. LDL-C is broken down and its cholesterol made available for use in the cell. Int. J. Biol. Sci. 5(5): liver for use or excretion. Increased numbers of HDL particles are associated with 474-488, 2009. reduced atherosclerosis and decreased coronary events, strokes, and death. Hence, HDL is often referred to as “good” cholesterol. Reverse Cholesterol Transport HDL mediated transport of cholesterol to the liver is referred to reverse cholesterol transport (Figure 8). Reverse cholesterol transport is a major Figure 8. Reverse cholesterol transport pathway. component of lipid homeostasis and is particularly beneficial in vascular tissue. This process reduces cellular cholesterol levels in the walls of blood vessels and cells such as macrophages residing in the arterial walls (this is an important concept: macrophages + lipids = bad). The exchange of cholesterol from cells to HDL-C is facilitated by the cell membrane shuttle protein adenosine triphosphate (ATP)-binding cassette 1A (ABCA1). To trap cholesterol within the HDL core, free cholesterol is then esterified by lecithin:cholesterol acyltransferase (LCAT). HDL containing cholesteryl esters have at least 2 metabolic fates. The first pathway is the direct pathway which includes direct removal of cholesteryl esters from HDL through selective uptake by hepatocytes and steroid hormone-producing cells via the scavenger receptor type B1 (SR-B1). The interaction between SR-B1 and HDL is mediated by apoAI. HDL can quickly recycle back into the blood to scavenge more cholesterol. HDL particles are primarily removed by the liver through a SR-B1-mediated receptor endocytosis. The indirect pathway is more complex and uses LDL receptor-mediated endocytosis of LDL particles. Cholesteryl esters in HDL can be exchanged ABCA1 moves cholesterol from cells to HDL. Once inside HDL, LCAT converts the cholesterol to cholesteryl esters (CE). The CEs for triglycerides found in VLDL and LDL (see left half of Figure 9). Transfer are either transported directly to the liver by binding to SR-B1, or of cholesteryl esters to VLDL and LDL is mediated through the action of are transferred to VLDL and LDL by CETP. The CE rich LDLs are then cholesteryl ester transfer protein (CETP), which accounts for removal of the transported to the liver by binding directly to LDL receptors. majority of cholesterol associated with HDL. The addition of cholesteryl esters Int. J. Biol. Sci. 5(5): 474-488, 2009. to VLDL and LDL ultimately results in cholesteryl ester-laden LDL particles (remember VLDL metabolism results in LDL). LDL particles are taken up by the liver through LDL receptor-mediated endocytosis resulting in the accumulation of cholesteryl esters in the liver. Integrated Pharmacotherapy 3 6 Dyslipidemia Cholesterol Metabolism Figure 9. Cholesterol synthesis take place in the Cholesterol is a ubiquitous and essential component of cell membranes. mitochondria, cytoplasm, and endoplasmic reticulum. Total body cholesterol is estimated to be in excess of 125 grams, of which >90% is in cell membranes. Recall, cholesterol plays an important role in membrane structure and function. It is also abundant in bile which aids in the absorption of lipids and fat-soluble vitamins. Cholesterol is also a precursor in the biosynthesis of steroid hormones such as progesterone, corticosteroids, aldosterone, and sex steroids (testosterone and estrogen). Lastly, cholesterol is also a precursor to vitamin D. Cholesterol is derived from either diet or de novo synthesis. Dietary intake can vary from 0 to 1000 mg/day. For reference, a McDonald’s Quarter Pounder™ contains approximately 65 mg of cholesterol and one egg has 213 mg. Approximately 30-75% of dietary cholesterol is absorbed by the intestines. Cholesterol biosynthesis takes place in all cells but occurs most extensively in the liver and adrenal cortex. The normal rate of cholesterol synthesis is approximately 600 to 1000 mg/day. As you can see, endogenous production of cholesterol constitutes a major source of cholesterol for the body. Total cholesterol levels vary with diet, stress, and the level of McKee and McKee, Biochemistry: The Molecular Basis of Life. endogenous cholesterol synthesis. Approximately one-third of plasma cholesterol exists in the free (or unesterified) form. The other two-thirds of plasma cholesterol exists as cholesteryl esters. Remember cholesteryl esters have a long-chain fatty acid attached to cholesterol by ester linkage to the hydroxyl group (Figure 2 on page 4). Figure 10. Cholesterol Biosynthesis Cholesterol Biosynthesis As the complex structure of cholesterol suggests, synthesis involves many multimolecular interactions. All 27 carbons are derived from one precursor, acetyl-CoA. An abbreviated pathway of the synthesis of cholesterol is illustrated in Figure 10. Synthesis starts with acetyl CoA, which is a key intermediate for glycolysis, the citric acid cycle, and fatty acid degradation (beta- oxidation) (Figure 9 and Figure 10). The first step is the condensation of two acetyl-CoA molecules to form acetoacetyl-CoA. In the second reaction, acetoacetyl-CoA + acetyl-CoA, formation of β-hydroxy-β-methylglutaryl-CoA (HMG-CoA) occurs. Integrated Pharmacotherapy 3 7 Dyslipidemia  Figure 11. HMG-CoA Reductase- Figure 12. Bile Acid Synthesis Catalyzed Reaction. The next reaction is the rate-limiting reaction for the synthesis of cholesterol and involves the irreversible conversion of HMG-CoA to mevalonic acid by HMG-CoA reductase (Figure 10 on page 7 and Figure 11). This reaction can be controlled by several factors, including time of day (predominantly at night), diet composition and quantity, or obesity. Increased intracellular cholesterol levels lead to reduced cellular content of HMG-CoA, which enables cells to adjust cholesterol concentrations as needed. Inhibition of the HMG- CoA reductase enzyme is the target of statin drugs and leads to decreased LDL-C levels. The second phase in the synthesis of cholesterol is the conversion of mevalonic acid to squalene. This involves several consecutive head-to-tail condensations with each newly formed product. During the last phase, squalene forms cholesterol through more than 20 reactions via several intramolecular ring closures, oxidation, and several condensation reactions. Cholesterol biosynthesis and transport are controlled by the activity of HMG-CoA reductase, the rate of LDL receptor synthesis, and the rate of esterification of cholesterol. Bile Acid Synthesis Cholesterol plays an important role in bile acid which aids in the absorption of lipids and fat-soluble vitamins. It is delivered to the liver via reverse cholesterol transport and enters the bile acid synthesis pathway. The liver is the only organ that can dispose of excess cholesterol. Recall that bile acids are amphipathic molecules with a hydrophilic side and a hydrophobic side. Bile acids also have a negative charge at the end of the molecule. In an aqueous solution, bile acids have the ability to solubilize lipids to form mixed micelles. Bile acid synthesis begins with the enzymatic hydroxylation of cholesterol to 7-α- hydroxycholesterol by cholesterol 7-α- hydroxylase (CYP7A1). This is the rate-limiting step in the synthesis of bile acids. The remaining steps in the conversion of cholesterol into conjugated bile acids involves at least 16 enzymes. During this process, hydrophilic structures such as taurine and glycine are conjugated to the cholesterol metabolites forming conjugated bile acids such as taurocholic and glycocholic acid (Figure 12). Bile acids are then secreted and briefly stored in the gallbladder and ultimately released into the duodenum of the small intestine. Bile acids have a pKa of between 2 and 4. Therefore, they are more ionized with a negative charge in the contents of the intestinal lumen (pH is approximately 6) making them very efficient detergents. Approximately 750 to 1250 mg of cholesterol are secreted in bile daily. One-half to two-thirds of biliary cholesterol is reabsorbed, and the remainder is excreted in the stool. Bile is released into the duodenum and predominantly reabsorbed in the ileum (distal portion of the small intestine). Bile acids are actively reabsorbed by a sodium-dependent bile acid transporter located in the brush border of the intestinal cells. They are then secreted into the portal vein where they are reabsorbed and reused by the hepatocyte. Bile acids are recycled approximately 6 to 8 times per day. Bacterial flora resident in the small intestines (also known as “normal flora”) can biotransform bile acids through deconjugation and dehydroxylation reactions forming secondary bile acids. Secondary bile acids are less soluble and, therefore, are less readily reabsorbed from the intestines. Integrated Pharmacotherapy 3 8 Dyslipidemia PATHOPHYSIOLOGY Dyslipidemia is a major health issue because it predisposes persons to an array of Abbreviations coronary, cerebrovascular, and peripheral vascular arterial disease. Evidence suggests The abbreviation “LDL” refers to a globule which is com- that elevated cholesterol and LDL-C, and low HDL-C levels are associated with posed of apolipoprotein, TGs, phospholipids, cholesterol, morbidity and mortality. and cholesteryl esters. The abbreviation “LDL-C” generally refers to only the cholesterol and cholesteryl ester compo- Dyslipidemia can be broadly characterized as primary or secondary. Primary nent of LDL globules in the blood, however, you will com- dyslipidemia is a genetic disorder and secondary dyslipidemia results from certain monly hear these abbreviations used interchangeably. drugs and other health disorders. Basically, dyslipidemia can be characterized by one or more or any combination of the following: elevated total cholesterol, LDL-C, or TG levels, or low HDL-C levels. Primary Lipoprotein Disorders Primary lipoprotein disorders basically fall into one of the following categories: hypercholesterolemia, hypertriglyceridemia, and combined hypercholesterolemia and hypertriglyceridemia. It is important to point out that the following list is not an all inclusive disease list. Hypercholesterolemia Familial Hypercholesterolemia (FH) FH is characterized by increased plasma levels of total and LDL-C. FH can result from a mutation in the LDL receptor. A dysfunctional LDL receptor prevents the uptake and removal of LDL-C from the blood. There are over 800 mutations in the LDL receptor gene and patients with a mutation in both genes (homozygous) is the most severe form of FH (HoFH). These patients are characterized by premature atherosclerosis and coronary artery disease, and without treatment may die around age 30 with cholesterol levels typically greater than 600 mg/dL. Excess cholesterol is also deposited in the skin and tendons in the form of yellow nodules called xanthomas. Heterozygous FH (HeFH) patients typically have total cholesterol levels from 350 mg/dL to 450 mg/dL, and most patients will have a major coronary event at some point in their life. Polygenic Hypercholesterolemia Another cause of hypercholesterolemia is polygenic (many genes) as a result of interactions between a number of genetic defects and the environment leading to an overproduction of VLDL-C and conversion to LDL-C. This is associated with the accumulation of LDL-C overwhelming the ability of the body to clear LDL-C. Hypertriglyceridemia Familial Hypertriglyceridemia Primary hypertriglyceridemia can result from an apoCII deficiency or a defect in LPL, both of which lead to a reduction in chylomicron and VLDL-C removal from blood. Patients can present in childhood with TG levels greater than 1000 mg/dL and is associated with pancreatitis. Total cholesterol levels are typically less than 200 mg/dL. Familial hypertriglyceridemia can also be characterized by excess TG enrichment of VLDL-C, chylomicrons or both in the presence of normal apoB production. This leads to large, TG-rich VLDL particles. Serum TG levels are usually in the 200-500 mg/dL range. HDL-C is decreased and LDL-C levels are near normal. Combined Hypercholesterolemia and Hypertriglyceridemia Familial Combined Hyperlipidemia (FCHL) FCHL is the most common form of hyperlipidemia, occurring in 1-2% of the population. A typical lipoprotein profile consists of elevated TC and TG levels, elevated apoB, smaller, denser LDL-C particles (which can be atherogenic), and reduced HDL-C. Variations in the FCHL phenotype include elevated VLDL-C particles and decreases in HDL-C and apoAI. FCHL is a genetically heterogeneous disease (lots of mutations in many different genes can lead to this disease). FCHL is related to increased apoB secretion contributing to increased production of VLDL-C, defects in the expression of the LDL-C receptor, and impaired clearance of TG-rich lipoproteins. Integrated Pharmacotherapy 3 9 Dyslipidemia Secondary Lipoprotein Disorders Table 2. Common Secondary Causes of Lipoprotein Abnormalities Dyslipidemias can also occur as a consequence of other disorders such Health Medications Other as diabetes mellitus, hypothyroidism, and obesity. Specific drugs classes Disorders including, but not limited to β-adrenergic antagonists, thiazide diuretics, Protease Inhibitors Hypothyroidism Alcohol retinoic acid derivatives, estrogens, androgens, and glucocorticoids may Glucocorticoids Diabetes Mellitus Consumption also cause secondary dyslipidemia. Immunosuppressive Liver Disease Pregnancy drugs (cyclosporine, Nephrotic Smoking Moderate hypertriglyceridemia is associated with diabetes mellitus, excess sirolimus, tacrolimus) Syndrome alcohol intake, and excess consumption of products with a high glycemic Isotretinoin Systemic Lupus index (e.g. non-diet soda, fruit juice). Obesity and consumption of a diet Anti-psychotics Erythematous high in cholesterol and saturated fat are associated with an accumulation Estrogens Obesity of LDL-C. Tobacco use can also cause secondary dyslipidemia by lowering Progestins HDL-C. When evaluating a patient with abnormal lipid levels, secondary Tamoxifen, raloxifene causes of dyslipidemias should also be considered. Common secondary Beta-blockers causes for abnormal lipoprotein levels are included in Table 2. Thiazide Diuretics Mirtazapine Atherosclerosis The number of LDL receptors present, the binding of LDL-C to its receptors, and the post-receptor binding process can be dysregulated by a variety of factors, leading to an accumulation of LDL-C in the blood. Saturation of LDL receptors as a result of high levels of LDL-C particles also leads to an overabundance of LDL-C in the blood. The major issue with increased cholesterol and LDL-C is the formation of atherosclerosis. Atherosclerosis is a progressive pathologic process that begins when high plasma levels of LDL-C lead to increased transport into the intima layer (the layer of the blood vessel just below the endothelial cells) of artery walls. Macrophages follow LDL-C into the intima where they bind and internalize excess LDL-C particles. Unfortunately, macrophages are stupid and they think they are doing a good thing by eating LDL-C particles. The accumulation of lipid-laden macrophages (called foam cells) in the inner arterial wall forms a fatty streak (Figure 13). The accumulation of macrophages and cholesterol can continue, causing smooth muscle cell expansion and artery narrowing. Formation of foam cells also initiates an inflammatory response associated with fibrous deposition and endothelial cell damage. Ultimately, this leads to fibrous, calcified, cholesteryl ester-rich plaques. This cascade of events can lead to the complete occlusion of the vessel if the fibrous plaque ruptures and initiates a clotting event (Figure 15 on page 11). The formation of this thrombus can result in an infarction of tissues distal to the occlusion. Certain vessels are at increased risk for atherosclerosis and are therefore more commonly seen with plaques (Figure 14). Figure 13. Early Phases of Atherosclerosis Figure 14. Sites of severe atherosclerosis in order of frequency Intima A B C D A= Excess LDL particles infiltrate the artery intima B= LDL undergoes oxidative & enzymatic modification C= Inflammatory lipids activate signaling for leukocyte migration and are taken up by macrophages D= Macrophages evolve into foam cells within the intima Hansson GK. N Eng J Med. 2005;352:1685-95. From Pathophysiology, by Porth and Matfin Integrated Pharmacotherapy 3 10 Dyslipidemia  Figure 15. Development of atherosclerosis (A) The vascular endothelium normally protects subendothelial layers from interaction with blood cells and other blood components. Elevated LDL levels can cause endothelial cell injury, leading to adhesion of platelets and monocytes. (B) Damaged endothelial cells express adhesion molecules that bind monocytes. These monocytes migrate between endothelial cells into the intima (yellow in the image) layer, transforming into macrophages that engulf LDL. (C) The macrophages release toxic oxygen species that oxidize LDL. As the macrophages engulf the oxidized LDL in the intima layer, they become foam cells. The foam cells produce growth factors that lead to smooth muscle cell proliferation and migration into the intima layer. (D) The fully formed atherosclerotic plaque has a fibrous cap consisting of smooth muscle cells and extracellular matrix. Beneath this cap are foam cells, macrophages, lymphocytes and a nectrotic core, consisting of dead cellular debris and lipids. This plaque puts a patient at risk for vessel occlusion along with other complications. Adapted from Parth and Matfin, Pathophysiology 8th edition, 2009. Many lipoproteins are involved in atherogenesis (the formation of atherosclerosis), and LDL-C has a focal role in this process. Many early studies measured only total cholesterol, but subsequent research revealed that LDL-C is the most abundant and atherogenic lipoprotein. Atherosclerotic plaques can begin to develop in patients with an LDL-C level between 100 mg/dL and 130 mg/dL and plaque formation can increase as the LDL-C concentration increases. Figure 16. Relationship of LDL-C and CHD Atherosclerosis is the underlying pathophysiology in nearly all types of coronary heart disease (CHD) and other cardiovascular (CV) events. Due to their prominent role in atherogenesis, evidence has clearly established that elevated levels of TC and LDL-C and low levels of HDL-C are major risk factors for CHD and CV events. Epidemiologic and clinical studies have established a direct relationship between LDL-C levels and CHD risk (Figure 16). As shown in this graphic, a 1 mg/dL increase in LDL-C correlates with a 1% increase in the relative risk of CHD. This principle also demonstrates the importance of modifying lipoproteins; a reduction in LDL-C of 1 mg/dL correlates with a 1% reduction in the relative risk of CHD. Accordingly, when LDL-C is reduced by 30 mg/dL, a patient’s relative risk of CHD is reduced by 30%. Circulation. 2004;110:227-39. Integrated Pharmacotherapy 3 11 Dyslipidemia CLINICAL PRESENTATION Atherosclerotic cardiovascular disease (ASCVD) is generally asymptomatic, unless it becomes severe enough to restrict the perfusion of target organs/tissues, either from severe arterial narrowing or by thrombus formation from a plaque rupture (these occurrences would be classified as an ASCVD event). Asymptomatic atherosclerosis may be detected by imaging suspected arteries, but such imaging is not part of routine management. ASCVD encompasses all forms of atherosclerotic accumulation in any vasculature of the body, with the most common types being coronary heart disease (CHD), cerebrovascular disease, and peripheral artery disease (PAD). A further description of ASCVD and events is provided in the ‘Evidence Based Clinical Management’ section on page 31. Severely elevated TGs are associated with the development of pancreatitis. Pancreatitis is a serious, sometimes fatal, complication of hypertriglyceridemia in which patients present with severe abdominal pain, nausea/vomiting, fever, hypotension, and/or tachycardia, and it is most commonly seen when TGs are significantly greater than 1,000 mg/dL. The 2018 AHA/ACC Cholesterol Guideline recommends that all adults over the age of 20 should be screened for dyslipidemia. In patients who do not require drug therapy for cholesterol lowering and/or ASCVD, traditional risk factors (including a lipid profile) should be assessed every 4 to 6 years. ASCVD risk factors and risk estimation will be presented in ‘Evidence Based Clinical Management’ section. Laboratory tests The lipid profile/panel is a laboratory test used to evaluate for dyslipidemia and consists of TC, LDL-C, TG, and HDL-C. Historically, laboratories do not measure the LDL-C directly, rather, LDL-C is often calculated and reported using one of several methods. The traditional method is the Friedewald equation, which was developed in 1972. The “(TG÷5)” term serves as an estimate for VLDL-C. Friedewald Equation: LDL-C = TC - HDL-C - (TG÷5) The TG component can be impacted directly by food, so TGs may be elevated when a nonfasting lipid profile is collected. The dietary impact on TG is variable and is related to the fat and carbohydrate content recently consumed. When TGs are elevated due to a recent high-fat meal (from excess chylomicrons), then the calculated LDL-C can appear falsely low. “Normal” food intake has a more modest impact, thus a more reliable LDL-C can be calculated. The 2018 AHA/ACC Cholesterol Guideline states: “nonfasting samples can be used for risk assessment in primary prevention and for assessment of baseline LDL-C levels before the initiation of a statin in primary and secondary prevention. If more precision is necessary, fasting lipids can be measured, but a nonfasting sample is reasonable for most situations.” The 2018 AHA/ACC Cholesterol Guideline states: if “initial nonfasting lipid profile reveals a triglycerides level of 400 mg/dL or higher, a repeat lipid profile in the fasting state should be performed for assessment of fasting triglyceride levels and baseline LDL-C.” Fasting is generally considered to be 8-12 hours without food consumption. If TG are greater than 400 mg/dL in the fasting state, then the TG value indicates endogenous hypertriglyceridemia, without confounding from of dietary chylomicrons. Elevated TGs are an independent risk factor for CHD because some TG-rich lipoproteins are atherogenic. These atherogenic TG-rich lipoproteins are partially degraded VLDL, called remnant lipoproteins. The VLDL-C level is generally estimated as TG ÷ 5, due to the high TG content in VLDL. To estimate the total burden of atherogenic lipids, a non-HDL cholesterol value can be calculated: non-HDL cholesterol = TC - HDL-C. This value represents a sum of the major atherogenic components LDL-C and VLDL-C. The Friedewald equation becomes less accurate for estimating LDL-C when TGs are high (either endogenously or from a nonfasting state) and when patients’ have naturally lower LDL-C. In both circumstances, LDL-C can be underestimated. To address the issues, the Martin/Hopkins equation was developed in 2013. Martin/Hopkins method uses the same formula as the Friedewald equation, except the fixed factor of 5 to estimate VLDL-C (TG÷5) is replaced with a variable factor between 3 and 10. The specific variable factor is determined by the patient’s non-HDL-C and TG values. The calculation can be performed via computer program, smartphone app, or manually using a reference table. The Martin/Hopkins method was found to be more accurate in estimating LDL-C compared to Friedewald (92% accuracy vs. 85% accuracy; p upper limit of normal [ULN]) Rhabdomyolysis: muscle symptoms with elevated CK >10x ULN), AND evidence of renal injury (e.g. increased SCr, reduced CrCl/ eGFR, reduced urine output, etc.) Across various publications, the definitions for SAMS are not standardized, and some of the terms used interchangeably. For the purposes of IP3, the 2018 AHA/ACC Cholesterol Guideline definitions (stated above) will be used. When evaluating for SAMS, a thorough assessment of symptoms is recommended, in addition to evaluation for nonstatin etiologies, assessment of predisposing factors, and a physical exam. The 2018 AHA/ACC Cholesterol Guideline identifies predisposing factors for SAMS as: age, female sex, low body mass index, high-risk medications (CYP3A4 inhibitors, OATP1B1 inhibitors), comorbidities (HIV, renal, liver, thyroid, preexisting myopathy), Asian ancestry, excess alcohol, high levels of physical activity, and trauma. Based on the severity of symptoms, laboratory testing for CK elevations and evidence of renal injury may be warranted. The frequency of myalgia reported from randomized controlled trials is low (1%-5%), but observational cohort studies have reported rates as high as 10%-30%. Rhabdomyolysis is a very RARE but potentially life-threatening condition. The incidence of true rhabdomyolysis caused by statins is extremely low, with an estimated risk of 0.01%. One cohort study estimated the risk to be 0.44 per 10,000 patients per year for statin monotherapy. Rhabdomyolysis is a serious form of muscle toxicity where there is substantial breakdown of muscle tissue that leads to the release of muscle fiber contents into the blood. These substances are harmful to the kidney and often cause kidney damage. Initial symptoms include intense myalgia (muscle pain/weakness similar to that experienced with influenza) beginning in the arms and legs and spreading to the whole body. When muscle breakdown of any type occurs, the enzyme creatine kinase (CK), normally found in high levels in muscle tissue, is released into the blood. If rhabdomyolysis occurs, serum CK levels will be elevated (> 10-fold over the upper limit of normal [ULN]), and if therapy continues, myoglobinurea, renal failure, and death may result. Patients should be advised to report any muscle aching to their health care provider, but muscle aching in combination with changes in urine color to a dark red-brown signifies an emergency in which the patient will need to stop their statin therapy immediately and seek medical attention. Patients with CK levels > 10x ULN should not initiate or continue statin therapy; those with severe muscle pain and an elevation between 3-10x ULN should also temporarily discontinue therapy. Another RARE but potentially serious SASE is hepatotoxicity. Statins can cause a dose-related increase in hepatic transaminases of 3x ULN (a marker of hepatotoxicity) in 50%) approximately 0.3 excess cases of diabetes will be diagnosed for every 100 patients receiving treatment for one year compared to placebo. As above, most patients who develop new-onset DM are those who are already at high risk. Statins have been reported to cause memory/cognitive impairment, but the frequency is reported to be very low. This SASE has been reported in case reports, but 3 large-scale randomized controlled trials demonstrated no increase in memory/cognition problems. When reported, memory/cognitive impairment appears to be reversible upon discontinuation of the statin. Finally, some data has linked statins to an increased risk for hemorrhagic stroke. The reported excess risk of hemorrhagic stroke per year is approximately 0.01 per 100 patients treated with statin compared to placebo. However, the 2018 AHA/ACC Cholesterol Guideline concludes that the SASE of hemorrhagic stroke is “Unfounded.” Overall, while the potential SASE may seem significant, the ability of statins to significantly reduce ASCVD events (CHD, ischemic stroke) clearly outweigh the potential risks in many patient populations. Cholesterol is essential for healthy development of the fetus. Historically, all statins were FDA contraindicated in pregnancy, but a major change has altered this regulation. Based on a comprehensive review of available data, the FDA requested that all statin manufacturers remove the contraindication for use in pregnant patients. Statins should Figure 20. Simvastatin Activation and CYP450 Metabolism be discontinued in most pregnant patients, but certain patients, especially HO O HO those with HoFH or those with established cardiovascular disease/ H H CO H 2 O OH ASCVD, may benefit from statin therapy to mitigate the risk of CV events O O during pregnancy. Breastfeeding is still not recommended in patients O O taking a statin. H H Hydrolysis Drug Elimination The liver plays an important role in the elimination of all statins (both by Simvastatin Active form metabolism and biliary excretion). Most of the statin dose is eliminated (inactive prodrug) fecally, either as parent drug or as metabolites. Most statins also have 10- CYP3A4 20% renal elimination, with the exception of atorvastatin which has atorvastatin). CYP3A4 inhibitors are relatively common as compared with inhibitors of other drug metabolizing enzymes, and this risk should be considered when evaluating patient drug profiles. Statins that are metabolized by CYP3A4 should not be used in combination with medications that are strong inhibitors of CYP3A4 which include: Azole antifungals (ketoconazole, itraconazole, fluconazole), erythromycin, clarithromycin, HIV protease inhibitors, and large quantities of grapefruit juice (> 1 quart per day). However, the use of statins metabolized by CYP3A4 is not always contraindicated when a patient is taking medications that inhibit CYP3A4. Rather, some statins require a dose adjustment when used in combination with weaker 3A4 inhibitors to avoid over- accumulation of statin concentration in the serum. The package insert for each statin and other drug information resources (e.g. Lexicomp) can provide the statin dose limit when used in combination with various drugs. For example, the daily dose of simvastatin should not exceed 10 mg when concomitantly administered with verapamil due to CYP3A4 inhibition by verapamil. The package inserts for these agents are edited periodically as new information about safety and drug-drug interactions is discerned, and it is prudent to stay current with these changes. In addition, statins that are metabolized by CYP3A4 will compete with other CYP3A4 substrate drugs, and possibly decrease the metabolism of those drugs. See the section on Drug Interactions of Fibrates and Statins on page 20 for a detailed discussion on specific interactions between statins and fibrates. Dose Adjustments Although the majority of statin elimination occurs fecally, some statins do have a portion of the administered dose eliminated via the kidneys. Therefore, some statins do require dose adjustment for impaired renal function. For rosuvastatin a maximum of 10 mg/day is recommended when CrCL < 30 ml/min, and the dose of pitavastatin should be limited to 2 mg/day for a GFR between 15-59 ml/ min. Other agents have recommended dose adjustments only for severe renal impairment (fluvastatin, lovastatin, pravastatin), and it is suggested to initiate the medication at the lowest starting dose and cautiously increase the dose. However, these statins do not carry limits for the maximum dose in patients with severe renal impairment. Simvastatin and atorvastatin do not require a dose adjustment for renal impairment. Integrated Pharmacotherapy 3 18 Dyslipidemia Finally, pharmacokinetic studies demonstrate a two-fold increase in AUC and Cmax of rosuvastatin in Asian patients compared to Caucasian controls. For this reason, the initial dose of rosuvastatin should be limited to 5 mg daily in Asian patients. The dose may be titrated upward in patients who tolerate rosuvastatin and do not achieve therapeutic goals. Fibrates (Fibric Acid Derivatives) Table 7. Fenofibrate and Fenofibric Acid Dosage Forms Drug Formulation, Delivery and Absorption Fenofibrate Products Available Doses (mg) Fibrates are only marketed as solid oral dosage forms. Fenofibrate is available as Standard Fenofibrate Formulations multiple formulations and products, which are listed in Table 7. A micronized Fenoglide® 40, 120 formulation has been developed, which reduces particle size resulting in enhanced drug dissolution and greater bioavailability. Several products deliver Lipofen® 50, 150 fenofibric acid, which is the active metabolite of fenofibrate. These products Tricor® 48, 145 deliver the active drug product and do not require activation in the body Triglide® 50, 160 after administration. Trilipix® is a delayed-release fenofibric acid product. It is 40, 120; 48, 145; 54, 160; supplied as a gelatin capsule containing small enteric coated tablets. Fenofibrate (generic) 50, 150 The various brand names and inconsistent dosing across products are a result Micronized Fenofibrate Formulations of the many different formulations of fenofibrate and fenofibric acid. Several Antara® (micronized) 30, 90 generic products are now available (Table 7). All products are available in Lofibra® capsules (micronized) 67, 134, 200 two or three dose strengths, and most patients should receive the highest Fenofibrate (micronized, generic) 43, 130; 67, 134, 200 dose of a selected product; the lowest dose is reserved for patients with renal Fenofibric Acid Formulations impairment. Regardless of the product and dose selected, the medication Fibricor® (fenofibric acid) 35, 105 should be given once daily, without regard to food. Trilipix® Gemfibrozil is available as a generic product and as the brand Lopid®. It is 45, 135 (fenofibric acid, delayed release) dosed as follows: 600 mg twice daily, 30 minutes before the morning and Fenofibric acid (generic) 35, 105; 45, 135 evening meal. It is recommended to administer the medication before meals in order to maximize the rate and extent of absorption. Both fenofibrate and gemfibrozil are well absorbed and have high oral bioavailability (> 90%). Drug Distribution, Action, Effects and Therapeutic Considerations Gemfibrozil and fenofibrate are derivatives of a drug formerly marketed for hyperlipidemia called clofibric acid (clofibrate), and are therefore also called fibric acid derivatives. Gemfibrozil and fenofibrate are structurally similar; of note, gemfibrozil is active while fenofibrate is an inactive prodrug that is activated by ester hydrolysis via plasma esterases to fenofibric acid (Figure 22). Fibrates bind extensively to plasma albumin (about 95% of blood Figure 22. Fibrate Chemistry and Bioactivation O concentration is bound). Despite being highly protein bound, fibrates distribute extensively to nearly all tissues due to their O OH lipophilicity and relatively low molecular mass. O O Cl O O The most important pharmacologic effect of the fibrates is to Fenofibrate (inactive) Gemfibrozil (active) lower plasma TG levels (Table 3 on page 13). Fibrates are Antara®, Fenoglide®, Lipofen®, Lofibra®, TriCor®, Triglide® 1st-line medications to lower very elevated TGs. Fibrates also modestly raise HDL-C and have variable effects on LDL-C. Due Plasma esterases to their mechanism of action of altering lipoprotein metabolism, fibrates may increase LDL-C when TGs are very elevated (>500 mg/dL). When TGs are not excessively elevated, fibrates can O produce a moderate LDL-C reduction of 5%-20%. HO The exact mechanism for these effects is not fully elucidated, O Cl but involves the activation of peroxisome proliferator-activated O receptors (PPARs) found in liver and adipose tissue (and to a Fenofribric acid (active) Fribricor®, Trilipix® lesser extent cardiac, kidney and muscle tissue). Specifically, fibrates bind to and activate PPAR-α receptors which, once activated, behave as transcription factors. Activation of PPAR receptors causes a change in the expression of genes that code for proteins important to lipid and TG regulation. Integrated Pharmacotherapy 3 19 Dyslipidemia The following are effects believed to result from activation of PPAR-α by fibrates: Increased expression of lipoprotein lipase (LPL), which promotes the removal of TG from VLDL-C via hydrolysis, resulting in lowered plasma TG levels Decreased expression of apoCIII, a lipoprotein that inhibits lipoprotein lipase activity, increasing the action of lipoprotein lipase in #1 above Increase in oxidation of fatty acids (remember TG are comprised of three fatty acids, and lipoprotein lipase hydrolysis of TG produces two free fatty acid molecules) An increase in apoA1 expression, which probably contributes to the increase in HDL caused by fibrates The mechanism of the effect of fibrates on VLDL-C and plasma TG levels is also depicted in Figure 23. For comparative dosing between the different fenofibrate products, the minimum doses are Figure 23. Effect of fibrates on VLDL-C and TG approximately equivalent to each other, and the same is generally true for the maximum Fibrates doses. For example, Fenoglide® 40 mg = Lofibra® 67 mg, and generic fenofibrate 160 mg = Tricor® 145 mg. PPAR-α Receptors Fibrates are usually well tolerated, with the most common adverse effects being gastrointestinal-related. Muscle adverse effects may occur in patients taking fibrates, but apoCIII the risk is relatively low. When combined with a statin, the risk for muscle adverse effects is increased. This increased risk is particularly true for gemfibrozil, and this interaction Lipoprotein Lipase is further explained in the drug interaction section below. Fibrates can cause LFT (liver Hydrolysis and removal of TG in VLDL function test) elevations, and may rarely cause cholelithiasis (gall stone formation). Data has also indicated that fibrates, particularly fenofibrate can infrequently cause a VLDL IDL mild-moderate elevation in serum creatinine which is often transient. The fibrates are contraindicated in patients with gallbladder disease, active liver disease, hypersensitivity to fenofibrate products, nursing mothers, and patients with severe renal dysfunction. Plasma triglyceride levels decrease Drug Elimination Gemfibrozil and fenofibrate are primarily metabolized via glucuronidation (phase II metabolism) via the UDP-glucuronosyltransferase UGT2B7, though both drugs are also substrates for other UGT isoforms. In particular, gemfibrozil is a substrate for (and inhibitor of) UGT1A1 and UGT1A3, while fenofibrate is metabolized to a great extent by UGT1A9. The drugs are excreted renally as unchanged drug (fenofibric acid) or in the glucuronide conjugated form. Gemfibrozil is a minor substrate for CYP3A4, but it is a strong inhibitor of CYP2C8 and a strong inhibitor of specific organic anion transporters (OATP) in liver cells- OATP1B1/1B3 and OATP2B1. Fenofibrate is a weak inhibitor of CYP2C8, CYP2C19, and a mild/moderate inhibitor of CYP2C9. The fibrates’ metabolism, excretion, and enzyme/transporter inhibition are important for dosing adjustments and drug-drug interactions. Dose Adjustments After metabolism, both gemfibrozil and fenofibrate are eliminated from the body primarily via the renal route. Accordingly, their excretion is impaired in patients with renal dysfunction. The following dose adjustments are recommended (note- GFR is expressed in units of mL/min/1.73 m2): Gemfibrozil: normal dosing= 600 mg twice daily 30 minutes before breakfast and dinner Manufacturer labeling: Mild/Moderate impairment “use with caution;” Severe impairment “use is contraindicated;” consider avoiding if baseline SCr > 2 mg/dL. Due to this ambiguity, alternative recommendations have been suggested: GFR 10-50 = administer 75% of the normal dose (900 mg per day) GFR 30-80 = initiate at the lowest mg strength of a selected product, adjust dose after monitoring for efficacy/toxicity CrCl ≤30 = contraindicated or avoid use Drug Interactions Fibrates and Statins Both the statins and fibrates can cause muscle adverse effects independently, and this risk is increased when the two classes are used together. Clinical evidence reveals a much higher incidence of reported muscle adverse effects with gemfibrozil vs. fenofibrate when used as monotherapy, or in combination with a statin. Compared to monotherapy with either a statin or a fibrate alone, the use of a Integrated Pharmacotherapy 3 20 Dyslipidemia statin plus a fibrate leads to a significant increase in the risk of severe muscle adverse effects. Again, the risk was significantly higher with gemfibrozil than with fenofibrate. The increased risk is likely a result of elevated serum statin concentrations caused by the fibrates, and this effect is more pronounced with gemfibrozil. Gemfibrozil increases the blood concentration of all statins by several mechanisms. First, gemfibrozil blocks the transport of statins into liver cells by inhibiting OATP1B1/1B3 and OATP2B1. This decreases the clearance of statins by the liver. Second, gemfibrozil inhibits the phase I metabolism of some statins by competing for CYP3A4, although gemfibrozil is a minor substrate for this enzyme. Third, gemfibrozil inhibits (via its own metabolism) the same UGT isoforms (UGT1A1 and UGT1A3) that metabolize statins during phase II conjugation metabolism by glucuronidation. In contrast, fenofibrate is not a strong inhibitor of the CYP450 system and is metabolized by UGT isoforms which are not involved in statin metabolism. As a result, gemfibrozil can increase total statin exposure (AUC) 2 to 4.4 fold, while increased statin exposure is not typically seen with fenofibrate. However, these potential interactions do not constitute absolute contraindications for the use of either gemfibrozil or fenofibrate with all statins. Simvastatin is contraindicated in combination with gemfibrozil; the package insert for lovastatin, fluvastatin, pitavastatin and atorvastatin recommend avoiding gemfibrozil use. Rosuvastatin should be limited to 10 mg daily if used in combination with gemfibrozil. All statins should be used with caution in combination with fenofibrate, but the statin doses do not require adjustment when used with fenofibrate. It is important to note that the currently available clinical evidence has failed to demonstrate a benefit in clinical outcomes (e.g. decreased death from cardiovascular causes) when statins and fibrates are used in combination compared to statin monotherapy. Fibrates and Warfarin Figure 24. Bile Acid Sequestrant Anion-Exchange Fibrates displace warfarin from its binding sites on albumin, a protein in the blood that binds many different drugs. Remember that drug bound to proteins in the H2 H H2 CH C C C blood is inactive, in the sense that it is not free to distribute to the site of action in the body. Displacement of warfarin from albumin may result in warfarin having a greater anticoagulant effect, and knowledge of this possibility is important to consider when H2 Cl Repeating Unit monitoring warfarin therapy in patients taking fibrates. C CH2 CH2N n Cholestyramine Resin Bile Acid Sequestrants Exchange of bile acid anions for chloride anions Drug Formulation, Delivery and Absorption Bile Acid Sequestrants (BASs), also known as Bile Acid Resins (BARs), consists of a polymeric resin containing ammonium cations (see Figure 24). These ammonium O cations function as ion exchange agents because the chloride ions administered with OH H NHCH2COO- the BASs can be exchanged with bile acids. The resin is not absorbed from the GI tract, H so the resin, containing bound bile acids, is excreted in the feces. Cholesterol is then metabolized to replenish the lost bile acids, thus reducing cholesterol levels in the blood. H H HO OH The resins (especially with the added suspending agents) have significant GI side H Glycocholate (a bile acid) effects, such as constipation and bloating. To help reduce the side effects, a new cholestyramine formulation was developed, omitting much of the bulkiness added by the suspending agents. In addition to side effects, patient adherence to the regimen can decrease because the suspension is considered unpalatable. Tablet forms of the resins have been developed in response to this issue. Colestipol tablets each contain 1 g of resin, and doses range from 2-16 g/day, given once or in divided doses. Bile acid sequestrant tablets are sustained release, and should not be crushed or chewed. A typical maintenance dose regimen consists of taking 1or 2 packets once to twice daily with meals. The contents of each packet are to be added to 2-6 ounces of non-carbonated liquid and stirred to a uniform consistency before drinking. Available preparations and dosing guidelines for BASs are found in Table 8. Drug Distribution, Action, Effects and Therapeutic Considerations These drugs are anion-exchange resins, containing a positively charged functional group that can ion-pair (form an ionic bond) with an anion. They are formulated with chloride ions which are exchanged with anions that have a greater affinity for forming an ion pair with the resin. Bile acids are anions which have a greater affinity for the positively charged functional group than chloride ion, and are exchanged for chloride to be bound with the anion exchange resin. The net effect is a lowering of bile acid concentration in the gastrointestinal tract as the anion-exchange resin carries the bile acids out of the body in the feces. As shown in Figure 12 on page 8, bile acids are formed by 7α-hydroxylase metabolism of cholesterol. Subsequently, bile acids Integrated Pharmacotherapy 3 21 Dyslipidemia are excreted in the bile from the liver, through the Table 8. Bile Acid Sequestrants Preparations and Dosing gallbladder, and into the intestines. Bile acids in Drug Name the intestine inhibit the conversion of cholesterol Preparations Dosing Generic (Brand) to bile acids (the body’s mechanism for ensuring Available as powder for 4 to 8 gm QDay to TID that too much cholesterol is not metabolized). Bile Cholestyramine (Questran®, suspension; bulk powder Prevalite®) acid sequestrants decrease gastrointestinal bile acid and 4 gm packets concentration and decrease the feedback inhibition Available as powder for Powder is dosed 5 to 30 gm of bile acids on cholesterol metabolism, resulting in suspension; bulk powder (5 QDay or divided BID increased conversion of cholesterol to bile acids. The grams/dose) Colestipol (Colestid®) net pharmacologic action is a lowering of plasma Tablet is dosed 2 to 16 gm Available as 1 gm tablets daily or divided BID cholesterol without a decrease in TG. In fact, BASs can raise TG and should NOT be used when TG are ≥ 300 Available as powder for 1.875 gm powder twice mg/dL. suspension; 1.875gm and daily or 3.75 gm powder The major effect of bile acid sequestrants on plasma 3.75gm powder packets once daily Colesevelam (Welchol®) lipids is to lower LDL-C. This effect is dose-dependent, Available as 625mg tablet 2 tabs TID, 3 tabs BID, or 6 with greater decreases in LDL-C resulting from higher tabs daily; max dose is 7 doses of BAS. However, most patients reach a point tabs/day where a dose increase will be counter-productive due to increased adverse effects. In addition to their LDL-C- lowering effects, BASs produce a modest increase (≤ 5%) in HDL-C. The major adverse effects of bile acid sequestrants are gastrointestinal-related, including dyspepsia, constipation and a bloated feeling. This is to be expected, as BASs are administered in large quantities and are not absorbed or broken down in the gastrointestinal tract. Constipation may be somewhat alleviated by increasing daily water intake and/or use of psyllium. Titrating the dose slowly (in 6 week intervals) also improves tolerability. BASs should also not be used in patients who have history of bowel obstruction or history of TG induced pancreatitis. Drug Elimination Bile acid sequestrants are neither absorbed nor metabolized in the gastrointestinal tract. They are excreted in the feces mostly in their ion-paired form with bile acids. Drug Interactions The mechanism by which bile acid sequestrants may cause drug-drug interactions is to bind with acidic drugs and decrease their oral absorption. Since BASs are anion-exchange resins, they do not appreciably bind with neutral or basic (cationic) drugs. Therefore, their drug-drug interaction potential is limited to drugs which are weak acids. An important example of a weak acid drug class that may be combined with a BAS is the statins. In general, other medications should be taken a minimum of 1 hour before or 4 hours after taking a BAS. BASs may reduce the absorption of fat soluble vitamins (A, D, E, K), likely on account of limiting the amount of bile acids available to assist in the absorption of these lipophilic molecules. Niacin Drug Formulation, Delivery and Absorption Niacin (Figure 25) is available in several formulations by prescription and OTC. It is available as an immediate release (IR) product or as two different delayed release products. The delayed release formulations consist of an extended release (ER) and a sustained-release (SR) product. None of the formulations are evquivalent to each other. IR niacin (crystalline niacin) is readily available and inexpensive as an OTC, with most preparations labeled as dietary supplements. Most have not undergone review by the FDA, and have not received explicit approval as lipid-altering agents. As a result, the free nicotinic acid content of OTC preparations is not guaranteed. Some products are marketed as “no-flush niacin.” These preparations do not contain nicotinic acid, but instead contain nicotinamide, which does not have lipid lowering activity. The ER product (Niaspan®) is a unique extended-release tablet formulation; it is available as prescription only, and does have a generic equivalent. The SR product is a unique niacin formulation available as Slo-Niacin®; it is available OTC only and it does not appear to have a generic equivalent. Slo-niacin® provides sustained serum niacin levels through its polygel formulation, and its dissolution time typically exceeds 12 hours. Integrated Pharmacotherapy 3 22 Dyslipidemia Niacin dosing is complicated because therapy cannot be initiated at doses that provide maximal benefit on lipoproteins and CVD (target dose). The administration of niacin is limited by dose-related adverse effects, including flushing, pruritus, rash, nausea, dyspepsia, abdominal pain, and diarrhea. In order to avoid these negative effects, therapy Figure 25. Niacin analogs must be initiated at a lower dose and slowly increased to the target dose. The delayed- O O release products were developed to reduce some of these effects, but titration is still required for all formulations. Refer to the Niacin Titration Schedules for recommended strategies for each niacin formulation. OH NH2 Drug Distribution, Action, Effects and Therapeutic Considerations N N Niacin (also known as nicotinic acid) is a water-soluble B-complex vitamin (vitamin Nicotinic Acid Nicotinamide B3). Nicotinic acid is only useful as a vitamin after it is converted to NAD or NADP (nicotinamide adenine dinucleotide phosphate). Niacin vitamin requirements may be met by taking nicotinamide, the amide form of nicotinic acid; however, nicotinamide is ineffective as a lipid lowering agent (their respective structures are shown in Extended Release vs. Sustained Release Extended release suggests a product which allows at least a Figure 26). two-fold decrease in dosing frequency as compared to the immediate release formulation. NIACIN FORMULATION KEY POINTS Sustained release products deliver an initial loading dose of the drug, followed by a slow constant release. Nicotinic acid IS effective as a lipid-lowering agent Sustained release formulations are considered a type of ex- Nicotinamide IS NOT effective as a lipid-lowering agent tended release formulation This is important because some OTC preparations labeled as niacin actually contain nicotinamide The daily niacin dose requirement as a vitamin is not sufficient to produce clinically important lipid lowering effects. Much larger doses must be given to patients for management of dyslipidemia, and as a result adverse effects may occur. Niacin lowers TG, VLDL-C and LDL-C levels, and raises HDL-C levels by several mechanisms, none of which affect the biosynthesis or breakdown of cholesterol. Niacin inhibits the action of hormone-sensitive lipase in adipose tissue, inhibiting lipolysis in adipose tissue and triggering a chain of events leading to Niacin Titration Schedules decreased TG, VLDL-C and LDL-C as shown in Figure 27. Immediate Release Niacin Niacin also stimulates lipoprotein lipase, resulting in increased breakdown of TG, decreasing Slowly titrate the dose VLDL-C levels. The increase in HDL-C levels seen with niacin therapy is believed to be due 50 mg BID x 1 week; 100 mg BID x 1 to a decrease in clearance of apoAI, a necessary component of HDL-C. Niacin is the most week; 200 mg BID x 1 week; 300 mg BID x 1 week; 400 mg BID x 1 week; potent medication to raise HDL-C concentrations that is currently available. 500 mg BID x 6 weeks* The effect of niacin on lipoproteins is dose dependent, with additional declines in LDL-C Maximum dose is 3000-4000 mg/day and TG and elevations in HDL-C upon dose escalation. Because of this relationship, Extended Release (Niaspan®) titration maximizing niacin therapy via dose titration is important. When added to statin therapy, Dosing titration niacin can provide additional improvements in all lipoprotein concentrations and is a useful 500 mg QHS x 4 weeks combination. Note that while all 3 niacin preparations (IR, ER, SR) are used to modify 1000 mg QHS x 4 weeks* 2000 mg QHS (target dose) lipoprotein concentrations, only Niaspan® has been FDA approved specifically for this use. Sustained Release (Slo-Niacin®) titration Dosing titration Drug Elimination 500 mg QHS x 4 weeks Niacin has a relatively short half-life of about 1 hour, which requires twice or three-times 1000 mg QHS x 4 weeks* daily dosing of the immediate release preparation. The ER (Niaspan®) and SR (Slo-Niacin®) 2000 mg QHS (target dose) formulations may be administered once-daily. *Return to clinic for evaluation of side Niacin is metabolized by two separate, saturable metabolic pathways (Figure 27). effect and response Pathway 1 consists of hepatic metabolism by conjugation to form nicotinuric acid, which is excreted in the urine along with unchanged niacin. This pathway/metabolite is responsible for the flushing phenomenon associated with niacin. Pathway 2 involves a number of oxidation–reduction reactions that produce nicotinamide and ultimately pyridine metabolites. This pathway/metabolite is associated with the hepatotoxic effects of niacin. Pathway 2 is a high-affinity, low-capacity system, meaning niacin is metabolized initially via this pathway until it becomes saturated (and the saturation occurs rapidly). Pathway 1 is a low-affinity, high-capacity system, meaning niacin is metabolized via this pathway only after Pathway 2 has been saturated. When IR niacin is given, the nicotinamide pathway (pathway 2) is quickly saturated. The remaining niacin, the majority of the dose, Integrated Pharmacotherapy 3 23 Dyslipidemia is metabolized via conjugation (Pathway 1). Therefore, IR niacin has a high incidence of Figure 26. Effect of niacin on lipids flushing but low incidence of hepatotoxicity. Niacin Drug Interactions Other medications that cause vasodilation may enhance the flushing adverse effect of Hormone-Sensitive ↓ apoAI clearance niacin. An example is the dihydropyridine calcium channel antagonists. If you do not Lipase remember why or how these medications cause vasodilation, then please review the calcium channel antagonists in the IP2 Hypertension Part 1 notes. Evidence suggests that niacin in combination with a statin can increase the risk of muscle adverse effects. The ↓ Adipose lipolysis ↑ HDL levels overall risk is very low, but patients and clinicians should monitor for muscle symptoms when these medications are used together. ↓ Transport of free Ezetimibe fatty acids to liver Drug Formulation, Delivery and Absorption The oral bioavailability of ezetimibe (Zetia®) is unknown and somewhat irrelevant, though Liver 35 - 60% of the administered dose is absorbed from the gut and extensively metabolized to ↓ Triglyceride synthesis an active glucuronide conjugate, which is actively secreted back into the intestinal lumen. The site of action of ezetimibe is a cholesterol transporter on mucosal cells in the brush border of the small intestine. Secretion of the active glucuronide conjugate into the gut ↓ VLDL synthesis therefore maintains a high concentration of the drug where it is most effective. Ezetimibe is available as an oral 10 mg tablet and is dosed without regard to food. Ezetimibe is included in several fixed-dose combination products as well. ↓ LDL synthesis Drug Distribution, Action, Effects and Therapeutic Considerations Ezetimibe is chemically unique from other dyslipidemia drugs (Figure 28). Its cholesterol- lowering effects were discovered during a search for a new class of drugs, acyl CoA-cholesterol acetyltransferase (ACAT) inhibitors. Ezetimibe is a weak ACAT inhibitor, but its clinically Figure 27. Pathways of Niacin Metabolism important effects on lowering cholesterol appear to be due to inhibition of cholesterol absorption via blocking a transport protein (NPC1L1) in the brush-border membrane of the gastrointestinal tract. Ezetimibe lowers LDL-C by about 15-18% when used as monotherapy and up to 25% when used in combination with a statin; it is used mostly as an adjunct to statin drug therapy. Ezetimibe is selective for inhibition of cholesterol absorption, and only slightly decreases TG levels. Why might statin therapy be necessary with ezetimibe? (Hint: What compensatory response do you think the body might make if cholesterol absorption is decreased) Ezetimibe appears to be well-tolerated. The most common adverse reaction is GI upset and diarrhea (4%). Myalgia has occurred with the use of ezetimibe both when used as monotherapy and when used in combination with statins. This reaction is extremely rare when ezetimibe is used as monotherapy (500 mg/dL). Available by prescription only, Lovaza® is a liquid-filled gel capsule for oral administration. Each 1 gram capsule contains 900 mg of the ethyl esters of omega-3 fatty acids purified from fish oils. These oils are predominantly a combination of ethyl esters of EPA (~ 465 mg) and DHA (~375 mg). Lovaza® is dosed 4 grams once daily or 2 grams BID, and a generic version is available. Vascepa™ contains > 96% icosapent ethyl, the ethyl ester of EPA, per 1 gram capsule. It is dosed 2 grams BID with meals. Omega-3 fatty acids are also available OTC in many different products and strengths. In general, these products are labeled “fish oil” and do not contain exclusively purified EPA and DHA. They contain many other fish oils (in addition to EPA/DHA), and the total dose of “fish oil” and EPA/DHA varies widely from product to product. Because EPA/DHA have shown the majority of therapeutic benefit, the dose of an OTC omega-3 or fish oil product should be based on the labeled EPA/DHA content and not the milligram strength on the front of the package. Drug Distribution, Action, Effects and Therapeutic Considerations The three major omega-3 polyunsaturated fatty acids EPA, DHA, and ALA are Figure 29. Fish Oil Omega-3 Fatty Acids depicted in Figure 29. The designation of “omega-3” refers to the location of the double bond nearest the methyl end of the fatty acid chain. The carbon of the terminal methyl group is known as the “omega” carbon and the nearest double bond is three carbons away on the “omega minus 3” or “omega-3” carbon. These fatty acids appear to have many beneficial effects on cardiovascular health, but the majority of data is with EPA and DH