Drug Therapy for Dyslipidemias PDF

37 Chapter PLASMA LIPOPROTEIN METABOLISM Chylomicrons Chylomicron Remnants Drug Therapy for Dyslipidemias Natalia Ruiz-Negrón and Donald K. Blumenthal...

37 Chapter PLASMA LIPOPROTEIN METABOLISM Chylomicrons Chylomicron Remnants Drug Therapy for Dyslipidemias Natalia Ruiz-Negrón and Donald K. Blumenthal Adverse Effects and Drug Interactions NONSTATIN DRUG THERAPIES Cholesterol Absorption Inhibitor Very Low-Density Lipoproteins Bile Acid Sequestrants Low-Density Lipoproteins Niacin (Nicotinic Acid) High-Density Lipoproteins Fibric Acid Derivatives Lipoprotein (a) Omega-3 Fatty Acid Ethyl Esters ATHEROSCLEROTIC CARDIOVASCULAR DISEASE RISK PCSK9 Inhibitors ASSESSMENT Inhibitor of Microsomal Triglyceride Transfer ATP-Citrate Lyase Inhibitor STATIN DRUG THERAPY Inhibitor of Angiopoietin-Like Protein 3 Mechanism of Action FUTURE DEVELOPMENTS IN MANAGEMENT OF ADME DYSLIPIDEMIAS Therapeutic Effects Dyslipidemia is a disorder of lipoprotein metabolism, including lipopro- known as apolipoproteins or apoproteins, provide structural stability to tein overproduction or deficiency. Dyslipidemia is a major cause of ath- the lipoproteins and may function as ligands in lipoprotein-receptor erosclerotic cardiovascular disease (ASCVD), ischemic cerebrovascular interactions or as cofactors in enzymatic processes that regulate lipopro- disease, and peripheral vascular disease. Cardiovascular disease is the tein metabolism. The major classes of lipoproteins and their properties number one cause of death globally (World Health Organization, 2020). are summarized in Table 37–2. Apoproteins have well-defined roles in Genetic disorders, metabolic diseases such as diabetes mellitus, and life- plasma lipoprotein metabolism (Table 37–3). Mutations in lipoproteins style factors are common causes of dyslipidemias, including hypercholes- or their receptors can lead to familial dyslipidemias and premature death terolemia and low levels of high-density lipoprotein (HDL) cholesterol. due to accelerated atherosclerosis. In 2018, various professional organizations, including the American In all spherical lipoproteins, the most water-insoluble lipids (choles- Heart Association (AHA) and the American College of Cardiology teryl esters and triglycerides) are core components, and the more polar, (ACC), published updated guidelines for the management of blood cho- water-soluble components (apoproteins, phospholipids, and unesterified lesterol (Grundy et al., 2019). Contrary to the 2014 ACC/AHA cholesterol cholesterol) are located on the surface. Except for apo(a), the lipid-binding guidelines (Stone et al., 2014), these updated guidelines recommend cho- regions of all apoproteins contain amphipathic helices that interact with lesterol percent reduction targets in certain high-risk groups for the pri- the polar, hydrophilic lipids (such as surface phospholipids) and with the mary prevention of cardiovascular disease. This change signaled a shift to aqueous plasma environment in which the lipoproteins circulate. Differ- previous approaches used for cholesterol management, like those high- ences in the non–lipid-binding regions determine the functional specific- lighted in the 2004 Adult Treatment Panel III guidelines (Grundy et al., ities of the apolipoproteins. 2004; NCEP, 2002). However, fixed-dose statin recommendations, like Figure 37–1 summarizes the pathways involved in the uptake and those emphasized in the 2014 ACC/AHA guideline, remained in place in transport of dietary fat and cholesterol from the intestines to adipose tis- the 2018 AHA/ACC cholesterol guidelines, particularly when managing sue, peripheral tissues, and the liver. Figure 37–2 shows the reverse cho- secondary prevention of cardiovascular disease and patients with diabe- lesterol pathway that transports cholesterol from peripheral tissues back tes mellitus. With these changes, the most recent guidelines appear to to the liver for excretion in the bile. These pathways involve the lipopro- merge recommendations and varying schools of thought on cholesterol tein structures described in the next sections. management from previously published guidelines (Table 37–1). Since its release, part of the 2018 AHA/ACC cholesterol guidelines have been updated and published separately as the 2019 ACC/AHA Guideline on Chylomicrons the Primary Prevention of Cardiovascular Disease (Arnett et al., 2019). Intestinal cholesterol absorption is mediated by the Niemann-Pick C1– However, only updates on aspirin use and more specific recommenda- like 1 protein, which appears to be the target of ezetimibe, a cholesterol tions on nonpharmacological aspects of ASCVD prevention were added. absorption inhibitor. After their uptake by epithelial cells in the small intestines, dietary lipids and endogenous lipids are transferred to the endoplasmic reticulum where newly synthesized apo B-48 is available to Plasma Lipoprotein Metabolism form chylomicrons. Apo B-48, synthesized only by intestinal epithelial Lipoproteins are macromolecular assemblies that contain lipids and pro- cells, is unique to chylomicrons and functions primarily as a structural teins. The lipid constituents include free and esterified cholesterol, triglyc- component of chylomicrons. erides, and phospholipids. Lipoproteins are generally spherical particles, Chylomicrons are synthesized from the fatty acids of dietary triglyc- with a shell composed of free cholesterol and phospholipid, with fatty erides and cholesterol absorbed by epithelial cells in the small intestine. acids oriented toward the core of the particle. The protein components, Chylomicrons are the largest and lowest-density plasma lipoproteins. In https://ebooksmedicine.net/  730 Abbreviations adipose tissue, skeletal and cardiac muscle, and breast tissue of lactat- ing women. The resulting free fatty acids are taken up and used by the adjacent tissues. The interaction of chylomicrons and LPL requires apo ABC: ATP-binding cassette C-II as a cofactor. ACAT-2: type 2 isozyme of acyl coenzyme A:cholesterol acyltransferase Chylomicron Remnants ACC: American College of Cardiology LPL-mediated removal of much of the dietary triglycerides generates the ACL: ATP-citrate lyase chylomicron remnants, which contain all of the dietary cholesterol. Chy- ACTH: adrenocorticotropic hormone lomicron remnants detach from the capillary surface and are removed ADA: American Diabetes Association from the circulation by the liver within minutes (see Figure 37–1). First, AHA: American Heart Association the remnants are sequestered by the interaction of apo E with heparan ALT: alanine aminotransferase sulfate proteoglycans on the surface of hepatocytes and are processed ANGPTL3: angiopoietin-like protein 3 by the hepatic lipase (HL), further reducing the remnant triglyceride apo(a): apolipoprotein (a) content. Next, apo E mediates remnant uptake by interacting with the ASCVD: atherosclerotic cardiovascular disease hepatic low-density lipoprotein (LDL) receptor or the LDL receptor– CETP: cholesteryl ester transfer protein related protein (LRP). CHD: coronary heart disease During the initial hydrolysis of chylomicron triglycerides by LPL, apo CYPs: cytochrome P450s A-I and phospholipids are shed from the surface of chylomicrons and DHA: docosahexaenoic acid remain in the plasma. This is one mechanism by which nascent (precur- sor) HDL is generated (see Figure 37–2). Chylomicron remnants are not CHAPTER 37 DRUG THERAPY FOR DYSLIPIDEMIAS EL: endothelial lipase EPA: eicosapentaenoic acid precursors of LDL, but the dietary cholesterol delivered to the liver by ER: extended release remnants increases plasma low-density lipoprotein cholesterol (LDL-C) FH: familial hypercholesterolemia levels. Increased liver cholesterol suppresses steroid receptor element GI: gastrointestinal binding protein–regulated expression of proprotein convertase subtilisin/ GWAS: genome-wide association studies kexin type 9 (PCSK9), thus reducing LDL receptor–mediated catabolism HDL: high-density lipoprotein of LDL by the liver (see PCSK9 Inhibitors below for additional details). HDL-C: high-density lipoprotein cholesterol concentration HeFH: heterozygous familial hypercholesterolemia Very Low-Density Lipoproteins HIV: human immunodeficiency virus The VLDLs are produced in the liver when triglyceride production is HL: hepatic lipase stimulated by an increased flux of free fatty acids or by increased de novo HMG-CoA: β-hydroxy β-methylglutaryl coenzyme A synthesis of fatty acids by the liver. Apo B-100, apo E, and apo C-I, C-II, HoFH: homozygous familial hypercholesterolemia and C-III are synthesized constitutively by the liver and incorporated into IDL: intermediate-density lipoprotein VLDLs (see Table 37–3). Triglycerides are synthesized in the endoplas- IgG: immunoglobulin G mic reticulum and, along with other lipid constituents, are transferred IR: immediate release by the microsomal triglyceride transfer protein (MTP) to the site in the LCAT: lecithin:cholesterol acyltransferase endoplasmic reticulum where newly synthesized apo B-100 is available LDL: low-density lipoprotein to form nascent (precursor) VLDL. Small amounts of apo E and the C LDL-C: low-density lipoprotein cholesterol concentration apoproteins are incorporated into nascent particles within the liver before LDLR: LDL receptor gene secretion, but most of these apoproteins are acquired from plasma HDL LP(a): lipoprotein (a) after the VLDLs are secreted by the liver. Mutations of MTP that result in LPL: lipoprotein lipase the inability of triglycerides to be transferred to either apo B-100 in the LRP: LDL receptor–related protein liver or apo B-48 in the intestine prevent VLDL and chylomicron produc- MTP: microsomal triglyceride transfer protein tion and cause the genetic disorder abetalipoproteinemia. NAD: nicotinamide adenine dinucleotide Plasma VLDL is catabolized by LPL in the capillary beds in a process NADP: nicotinamide adenine dinucleotide phosphate similar to the lipolytic processing of chylomicrons (see Figure 37–1). NCEP: National Cholesterol Education Program When triglyceride hydrolysis is nearly complete, the VLDL remnants, OTC: over-the-counter usually termed IDLs, are released from the capillary endothelium and PCE: pooled cohort equations reenter the circulation. Apo B-100–containing small VLDLs and IDLs, PCSK9: proprotein convertase subtilisin/kexin type 9 which have a t1/2 of less than 30 min, have two potential fates. About 40% to 60% are cleared from the plasma by the liver via apo B-100– and apo PPAR: peroxisome proliferator–activated receptor E–mediated interaction with LDL receptors and LRP. LPL and HL con- SR: scavenger receptor vert the remainder of the IDLs to LDLs by removal of additional triglyc- VLDL: very low-density lipoprotein erides. The C apoproteins, apo E, and apo A-V redistribute to HDL. Apolipoprotein E plays a major role in the metabolism of triglyceride- rich lipoproteins (chylomicrons, chylomicron remnants, VLDLs, and IDLs). About half of the apo E in the plasma of fasting subjects is associ- normolipidemic individuals, chylomicrons are present in plasma for 3 to ated with triglyceride-rich lipoproteins, and the other half is a constituent 6 h after a fat-containing meal has been ingested. Dietary cholesterol of HDL. is esterified by the acyl coenzyme A:cholesterol acyltransferase type 2 (ACAT-2). ACAT-2 is found in the intestine and in the liver, where cellu- Low-Density Lipoproteins lar free cholesterol is esterified before triglyceride-rich lipoproteins (chy- Virtually all LDL particles in the circulation are derived from VLDL. The lomicrons and very low-density lipoproteins [VLDLs]) are assembled. LDL particles have a t1/2 of 1.5 to 2 days. In subjects without hypertriglyc- Chylomicrons enter the systemic circulation via the thoracic duct. eridemia, two-thirds of plasma cholesterol is found in the LDL. Plasma Chylomicron triglycerides are then metabolized to free fatty acids clearance of LDL is mediated primarily by LDL receptors (apo B-100 by an extracellular lipoprotein lipase (LPL) at the capillary luminal binds LDL to its receptor); a small component is mediated by nonrecep- surface of tissues that synthesize LPL (see Figure 37–1), including tor clearance mechanisms.  731 TABLE 37–1 COMPARISON OF KEY CLINICAL GUIDELINES FOR THE MANAGEMENT OF CHOLESTEROL IN ADULTS ATPIII 2004 ACC/AHA 2014 AHA/ACC 2018 ACC/AHA 2019 Risk assessment 10-year FRS; CHD risk 10-year PCE 10-year or lifetime PCE 10-year or lifetime PCE strategy factors Candidates for Patients above LDL-C Patients in four statin Patients above LDL-C goal Primary prevention in treatment goal benefit groups all patients Recommended Titrated to achieve Moderate-to-high Moderate-to-high intensity (may be titrated Moderate-to-high statin intensity LDL-C goal intensity to achieve a specific LDL-C percent reduction intensity (may be goal) titrated to achieve a specific LDL-C percent reduction goal) Recommendations Risk groups and LDL-C Four statin benefit Risk groups and LDL-C goals: Same recommendations goals: groups: Primary Prevention (ages 40–75 years): as those stated in AHA/ High risk if CHD, risk If ≥21 years old, ACC 2018 under If LDL-C ≥190 mg/dL, high-intensity equivalent, or FRS clinical ASCVD, “Primary Prevention” statin recommended regardless of ≥20% (LDL-C goal high-intensity statin ASCVD risk