#90844: Hyperlipidemias and Atherosclerotic Cardiovascular Disease

Dietary lipids provide 30% to 40% of calories in Western diets. With the exception of the essential fatty acids (e.g., linoleic, linolenic), most lipids can also be synthesized by humans. Triglycerides, specifically, account for more than 95% of dietary lipid intake. Cholesterol from animal sources and small amounts of plant sterols comprise the majority of dietary lipid intake. Free fatty acids, phospholipids, and fat-soluble vitamins account for the remaining lipids from dietary sources [46,50,53].

Dietary fat is digested by enzymes produced in the mouth, stomach, and pancreas. The small intestine is the main site of lipid transformation and absorption. In the small intestine, triglycerides are hydrolyzed by gastric and pancreatic lipases, phospholipids are transformed by phospholipase A2 into lysophospholipids and fatty acids, and cholesterol is hydrolyzed by bile salts and pancreatic hydrolase (also known as cholesterol esterase).

Studies have established that cholesterol absorption in the small intestine is regulated by selective transporters, such as the Niemann-Pick C1 like 1 (NPC1L1). Selective inhibition of NPC1L1 prevents intestinal absorption of dietary cholesterol, a mechanism targeted by ezetimibe, a lipid-lowering drug. In the enterocyte, free cholesterol is esterified to cholesteryl esters by the enzyme acyl-CoA cholesterol acyltransferase isoform 2 (ACAT2) and incorporated into chylomicrons [54].

In a separate pathway, after enzymatic hydrolysis, free fatty acids and monoacylglycerides are transported to the intestinal cells in bile-salt micelles. Micelles deliver the lipid molecules to the enterocyte, and bile salts remain in the lumen, where they are subsequently re-used to form new micelles.

Intracellularly, lipid molecules are re-assembled and packaged in chylomicrons. These are large lipoproteins (75–1,200 nm in diameter) rich in triglycerides and cholesterol but poor in protein content. Chylomicrons are released by exocytosis into the extracellular space, enter the lymphatics, and ultimately reach the bloodstream. Circulating chylomicrons are transformed by lipoprotein lipase, an enzyme expressed in endothelial cells of the capillaries in muscle and adipose tissue, and deliver triglycerides to the muscle (for energy) and adipose tissue (for storage). Chylomicron remnants deliver the cholesterol and the remaining triglycerides to the liver, where cholesterol is used in the synthesis of bile salts and triglycerides and free fatty acids are used in the production of energy by β-oxidation and synthesis of new molecules of cholesterol. The synthesis of cholesterol in hepatocytes is known as the endogenous pathway.

It is relevant to mention that unesterified cholesterol can also be transported back into the intestinal tract by selective transporters, such as the ATP-binding cassette transporters ABCG5 and ABCG8 [55]. A new generation of lipid-lowering drugs that stimulate the ATP-binding cassette transporter is being investigated [56].

The hepatic pathway is the major source of cholesterol in the body. It is well-established that daily cholesterol synthesis in the liver has a circadian pattern, with lowest levels in the day (30% to 35%) and highest levels at night (65% to 70%). This diurnal rhythm in cholesterol synthesis is regulated by HMG-CoA activity [240]. Selective inhibitors of HMG-CoA reductase, such as statins, effectively prevent the synthesis of cholesterol and are powerful hypolipidemic drugs [31,57].

Newly formed cholesterol molecules can either be transiently stored in the hepatocytes or further transformed either into bile salts, steroids, or "packaged" in lipoproteins. These lipoproteins, which carry cholesterol and triglycerides from the liver into the circulation, are known as very-low density lipoproteins (VLDL) and have a very high content in triglycerides and cholesterol. VLDLs comprise 15% to 20% of the total blood cholesterol and most of the circulating triglycerides [31,52].

In the liver, cholesterol is also eliminated by biliary secretion in the form of bile acids. Bile acids, which are highly soluble in water, are released by the hepatocytes into the biliary canaliculi and then transported to the gallbladder, where they are stored in bile and later released into the lumen of the small intestine. Most bile acid molecules (>95%) are not excreted in the feces, but rather are reabsorbed in the ileum, enter the portal circulation, and are then extracted with high first-pass efficiency by hepatocytes. This process of recycling bile acids between liver and intestine is known as enterohepatic circulation. In fact, recycled cholesterol from bile acids is a major source of cholesterol and represents 75% of the total cholesterol that goes through the intestine; dietary cholesterol, even in patients with rich diets, accounts only for up to 25%.

Prior to discussing the properties of the various lipoproteins, it is important to review the most pertinent information related to plasma lipid profiles. In fasting individuals, total cholesterol in plasma is carried primarily in VLDL, LDL, and HDL. Accordingly, total cholesterol is equal to the sum of VLDL, HDL, and LDL.

Clinical laboratories measure total cholesterol, HDL, and triglycerides. Most triglycerides are found in VLDL, which has five times as much triglyceride by weight as cholesterol. Therefore, the amount of cholesterol in VLDL can be calculated as triglycerides (mg/dL) divided by 5 or triglycerides (mmol/dL) divided by 2.2.

For more than 50 years, most clinical laboratories have calculated the value of LDL cholesterol indirectly, according to the Friedewald equation [59,60]:

Or, if the International System of Units is used, total LDL may be calculated as:

A modified Friedewald equation is also used and has been suggested to have a higher level of accuracy in calculating LDL values [61,62]. This equation is:

It is known that in hypertriglyceridemia, LDL calculated using the Friedewald equation can be unreliable, particularly at levels <70 mg/dL. The increased prevalence of high triglyceride states (e.g., diabetes, obesity) and the use of novel lipid lowering medications (e.g., proprotein convertase subtilisin/kexin type 9 [PCSK9] inhibitors) have provided an impetus for finding improved methods for estimating LDL.

Direct LDL assays are not standardized and can be even less accurate than the Friedewald equation. In one study of seven direct methods for measuring LDL, total assessment errors ranged from 13.3% to 13.5% across assays in healthy individuals and from -26.6% to 31.9% in individuals with known ASCVD or dyslipidemias. The National Cholesterol Education Program has a target total error goal of ≤13%, meaning that all seven direct assays failed standard accuracy goals [63,64].

Several prior equations have attempted to improve upon the Friedewald equation, but most used the same fixed ratio between triglycerides and VLDL. In a study of more than 1.3 million fasting and nonfasting patients, Martin and colleagues derived and validated a novel equation that replaced the fixed ratio with one of 180 adaptable ratios based on the patient's individual non-HDL and triglyceride values. The overall accuracy of the Martin/Hopkins approach compared with direct measurement was 92% for HDL and 85% for triglycerides. LDL estimation accuracy with the Martin/Hopkins equation was 94%, compared with 77% with the Friedewald method [65]. The 2018 AHA/ACC guideline acknowledges the importance of accurate LDL estimation and recommends measuring LDL either directly or with an alternative method (e.g., the Martin/Hopkins equation) [24,63].

In adults who are 20 years of age or older and not on lipid-lowering therapy, the ACC/AHA assert measurement of either a fasting or a nonfasting plasma lipid profile is effective in estimating ASCVD risk and documenting baseline LDL. If an individual has ingested an extremely high-fat meal in the preceding eight hours, it may be prudent to assess lipids on another day after counseling the patient to avoid such meals.

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Level of Evidence: Expert Opinion/Consensus Statement

The ratio of total cholesterol (TC) to HDL (TC:HDL) and the ratio of LDL to HDL (LDL:HDL) are clinically relevant predictors of coronary heart disease (CHD) risk. The lower the ratio value, the better the predicted outcome [66,67,68,69]. The Apo B:Apo A-I lipoprotein ratio has also been used as a predictor for CHD. However, comparative studies have concluded that Apo B:Apo A-I ratio for prediction of CHD "does not provide incremental value for CHD risk prediction over established traditional lipid ratios" [66]. However, the ratio may be useful for evaluating the severity of CHD [70]. A cross-sectional study enrolled 792 patients with angiographically defined CHD following hospital admission. The patients were placed into three groups based on the degree of angiographic atherosclerosis or the number of stenotic coronary branches. Demographic and biochemical data were collected, and lipoprotein ratios were calculated. According to the results, the ratios of LDL:HDL and Apo B:Apo A-I increased with increasing degree of angiographic atherosclerosis, and the ratios of triglyceride:HDL, TC:HDL, LDL:HDL and Apo B:Apo A-I increased with the number of stenotic coronary branches. The ratios of TC:HDL, LDL:HDL, and Apo B:Apo A-I were positively associated with both the degree of atherosclerosis and the number of stenotic vessels, and the ratio of triglyceride:HDL was positively associated with the number of stenotic vessels. The Apo B:Apo A-I ratio was also shown to be a direct mediator between the risk factors of age, BMI, HDL, LDL, and severity of CHD [70].

Chylomicrons are large lipoproteins 75–1,200 nm in diameter that are very rich in lipids (98% content), mainly triglycerides (83%) and cholesterol (8%), and have the lowest protein content (2%) of all lipoproteins. Chylomicrons are only synthesized in the intestine and are produced in large amounts during fat ingestion [53]. In normolipidemic individuals they are present in the plasma for 3 to 6 hours after fat ingestion and are absent after 10 to 12 hours fasting [14].

Chylomicrons secreted by intestinal cells are known as "incomplete" chylomicrons because they only express Apo B-48. After entering the lymph and later reaching the bloodstream, chylomicrons interact with circulating HDL, from which they receive Apo C-II and Apo E and then referred to as "complete" chylomicrons. In the capillaries of muscle and adipose tissue, chylomicrons are transformed by the enzyme lipoprotein lipase, a process that requires Apo C-II as a cofactor. As a result of this process, 90% of the triglycerides are hydrolyzed to free fatty acids and glycerol that will be used either as a source of energy in the muscle or stored in the adipose tissue. Individual chylomicrons have a short half-life of 15 to 20 minutes [71]. After interaction with lipoprotein lipase, these cholesterol-rich chylomicron remnants deliver cholesterol and triglycerides to the liver. This process of endocytosis is mediated by a protein, the LDL receptor, expressed on the surface of hepatocytes and requires Apo E and Apo B as cofactors [72].

The concentration of chylomicrons can only be lowered by reducing dietary fat consumption or by drugs that inhibit the intestinal absorption of cholesterol. However, drugs specifically targeting the step of chylomicron secretion have not yet been developed [14]. Although rare, individuals with a genetic deficiency that results in low lipoprotein lipase activity may present with abnormally high concentrations of circulating triglycerides (1,000–5,000 mg/dL) [31].

VLDLs are smaller than chylomicrons (80 nm in diameter) and have a very high triglyceride and cholesterol content—five times as much triglycerides by weight as cholesterol. As noted, VLDL makes up 15% to 20% of the total blood cholesterol and most of the circulating triglycerides [73].

In the muscle and adipose tissue capillaries, lipoprotein lipase interacts with circulating VLDL, from which it removes triglycerides in a process that requires Apo C-II as a cofactor, as described for chylomicrons. VLDL also expresses Apo E and Apo B-100. Apo B-100 plays a fundamental role in the regulation of circulating cholesterol.

From a metabolic viewpoint, both chylomicrons and VLDL deliver triglycerides to muscle and adipose tissue [30]. However, whereas chylomicrons are an integral part of the exogenous pathway and carry dietary lipids, VLDL transport triglycerides and cholesterol synthesized in the liver as a part of the endogenous pathway. From a clinical perspective, it is particularly relevant to point out that the hepatic synthesis of VLDL is increased when the concentration of free fatty acids in the liver is increased (e.g., in high-fat diets) as well as when adipose tissue releases high amounts of free fatty acids in the circulation (e.g., as a result of obesity or diabetes) [46]. Genetic deficiencies that result in either total (abetalipoproteinemia) or partial liver failure to produce Apo B-100 (familial hypobetalipoproteinemia) inhibit the release of VLDL by hepatocytes and result in fatty liver [74].

IDLs, also known as VLDL remnants, are created when VLDL is depleted in triglycerides as a result of the hydrolysis by the enzyme lipoprotein lipase. IDLs have a short half-life (less than 30 minutes) and undergo liver absorption by selective uptake mainly by binding to the LDL receptor, with Apo B-100 and Apo E as required cofactors. Genetic variants of Apo E are responsible for low binding to the LDL receptor, which results in high concentrations of circulating VLDL and IDL, a condition clinically known as type III hyperlipoproteinemia [14,75].

LDLs play a central role in atherogenesis and are often called "bad cholesterol." The discovery of the LDL receptor by Goldstein and Brown and their work elucidating its role in cholesterol homeostasis is one of the most important advances in cardiovascular research. Their studies have been a major contribution to the understanding of the mechanisms underlying hyperlipidemias [72]. The proatherogenic role of LDL on the release of pro-inflammatory cytokines (e.g., IL-1, TNF-α) and adhesion molecules (e.g., LAM, ICAM-1) is well established.

LDLs are the product of VLDL and IDL metabolism by lipoprotein lipase. LDL is the most cholesterol-rich of all lipoproteins, and even in healthy individuals, LDLs carry two-thirds of the circulating cholesterol [14]. LDL has a half-life of 1.5 to 2 days, which accounts for a plasma concentration higher than VLDL and IDL [14,46,53,57].

There are several subtypes, also known as subfractions, of LDL, and it has been proposed that smaller, denser LDL particles are more atherogenic than larger and less dense LDL. However, research suggests that the use of clinically available LDL subfractions to estimate the risk of ASCVD is premature [76,77,78].

Plasma clearance of LDL is primarily mediated by the LDL receptor expressed on the cell surface. Although LDL receptors are expressed in various cell types, approximately 75% of all LDL receptors are expressed in hepatocytes [79]. The uptake of LDL in hepatocytes is mediated by the interaction between the LDL receptor and Apo B-100 (the only apoprotein expressed in LDL), which acts as a ligand at the LDL receptor. This selective and highly effective mechanism accounts for the extraction of approximately 75% of all LDL from plasma [80]. Hepatic LDL receptors are downregulated by the high delivery of cholesterol by chylomicrons or dietary saturated fat and upregulated by decreased cholesterol and saturated fat intake [46,81].

The crucial role of LDL in atherogenesis results from it being oxidized in the arterial subendothelium. Oxidized LDL has a high affinity for the scavenger receptor expressed in macrophages undergoing endocytosis, which leads to intracellular accumulation and the transformation of lipid-rich macrophages into foam cells.

Genetic mutations of either the LDL receptor or Apo B-100 alter the effectiveness of the binding and increase the plasma concentration of LDL. Familial hypercholesterolemia and familial defective Apo B-100 are examples of clinical conditions that result from these genetic mutations [82,83]. Homozygotes for familial hypercholesterolemia inherit two mutant LDL receptor genes and present with a 6- to 10-fold elevation in plasma LDL from birth. These patients suffer from advanced CHD starting in early childhood [72,84].

The expression of LDL receptors in the liver is also regulated by the intracellular enzyme HMG-CoA reductase. Inhibition of HMG-CoA reductase, for example by the administration of statins, not only results in direct inhibition of the intracellular synthesis of cholesterol but indirectly increases the expression of LDL receptors and therefore promotes the LDL-receptor-mediated removal of circulating cholesterol.

The LDL receptor is also relevant from a clinical perspective because both thyroid hormones and estrogens stimulate its expression in the liver [80,85]. Consequently, deficiencies of these hormones decrease the availability of LDL receptors and result in increased concentrations of circulating LDL and increased risk of ASCVD [14,80].

The subtype of lipoprotein(a) is associated with increased risk for ASCVD [12,27,31,46,47]. Lipoprotein(a) has a similar lipid composition to more typical LDL but has a higher protein content [86]. The atherogenic role of lipoprotein(a) relates to its unique molecular properties and results in the inhibition of fibrinolysis, enhanced capacity to traverse the arterial endothelium, and low affinity for the LDL-receptor-mediated clearance from circulation [47]. Lipoprotein(a) also exhibits platelet activating and pro-inflammatory properties that further contribute to atherogenesis [87]. Patients with high levels of lipoprotein(a) (greater than 30 mg/dL) and an elevated total cholesterol:HDL ratio (>5.5) or other major risk factors require a more aggressive therapy to lower LDL [23,49]. Lowering circulating LDL remains the primary goal in the treatment and prevention of atherosclerosis and ASCVD [15,22,24].

HDLs are the smallest (5–12 nm in diameter) but the densest lipoproteins (33% protein content). HDL removes cholesterol from the periphery and transports it to the liver [53]. HDLs are a heterogeneous population classified based on size, density, and apoprotein content. The two most important subclasses of HDL express either Apo A-I alone or both Apo A-I and A-II, but the clinical relevance of the various subtypes is unknown [88].

HDL concentration in the plasma is inversely related to the risk of ASCVD, and for this reason HDL is also known as "good cholesterol." The role played by HDL in the transport of cholesterol from the periphery to the liver, known as reverse cholesterol transport, and subsequent excretion in bile is a very well-understood mechanism through which HDL protects against atherosclerosis [88,89].

Two main factors are involved in cholesterol removal from the periphery. First, a cell membrane protein (ABCA1) promotes the efflux of cholesterol from cell membranes; second, ABCA1 interacts with Apo A-I from HDL and captures cholesterol. Cholesterol, in the form of cholesteryl esters, is subsequently transferred to LDL, which will carry it to the liver. In the liver, hepatic extraction requires binding to the LDL receptor. Genetic mutations that cause loss of function of ABCA1 result in extremely low levels of HDL and cholesterol accumulation in the liver, spleen, tonsils, and central and peripheral nervous systems. This results in early-life coronary and peripheral artery disease, a condition known as Tangier disease or familial alpha-lipoprotein deficiency [90,91].

In vitro and in vivo studies have revealed that HDL has anti-inflammatory and antioxidant properties and inhibits atherogenesis. It has been suggested that high levels of HDL have a protective effect on the development of atherosclerosis and ASCVD [88,92].

However, authors of a systematic review of clinical studies concluded that "simply increasing the amount of circulating HDL does not necessarily confer cardiovascular benefits" and that reduction of LDL should remain "the primary goal for lipid-modifying interventions" [93]. Other researchers concluded that raising endogenous HDL levels in humans to reduce the development of atherosclerosis "has yet to be established conclusively" [88]. Together, these studies further support the recommendation that lowering LDL should remain the target goal for patients with hyperlipidemia and/or at risk for ASCVD-related conditions [22,24].

Mechanism of Action and Clinical Pharmacology

Under certain circumstances, the ACC/AHA assert that nonstatin medications (i.e., ezetimibe, bile acid sequestrants, and PCSK9 inhibitors) may be useful in combination with statin therapy.

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Level of Evidence: Expert Opinion/Consensus Statement

Bile acid-binding resins, also known as bile acid sequestrants, are cationic polymers that bind to the negatively charged bile acids in the lumen of the intestine. The bile-acid complex cannot be absorbed by the intestinal mucosa and is subsequently eliminated in the feces [129]. Bile acids are the source of 75% of cholesterol in the intestine, and inhibition of their reabsorption effectively disrupts chylomicron formation and decreases the availability of cholesterol and triglycerides in the liver.

These events upregulate 7α-hydroxylase, also known as cytochrome P450 7A1 (CYP7A1), the enzyme responsible for the synthesis of bile acid in the liver. This increases the conversion of cholesterol to bile acid synthesis in hepatocytes. Consequently, the intracellular recruitment of cholesterol to bile acid synthesis both depletes its intracellular storage and upregulates the expression of LDL receptors to remove circulating cholesterol. Ultimately, the therapeutic benefit of these drugs is to lower circulating LDL by 10% to 24% [30].

The LDL-lowering benefit of bile acid-binding resins is offset in the long term by the upregulation of cholesterol and triglyceride synthesis and a possible increase in VLDL synthesis. Accordingly, these drugs should be used cautiously in patients with hypertriglyceridemia.

Bile acid-binding resins lower the incidence of coronary events in middle-aged men by about 20%, with no significant effect on total mortality [67]. Overall, bile acid-binding resins have a solid safety record, have been shown to lower LDL by 10% to 24%, and help reduce the risk of CHD [30,31,130,131]. Colesevelam, the newest drug in this class, lowers glycated hemoglobin and fasting plasma glucose and is approved as add-on therapy for glycemic control in select patients with type 2 diabetes [109,132].

Adverse Effects

Bile acid-binding resins have very low potential to cause systemic adverse effects because they are not absorbed systemically. However, some patients may report gastrointestinal symptoms, including constipation (10%), dyspepsia, and bloating (1% to 8%) [109,133].

Drug Interactions

The bile acid-binding resins cholestyramine, colestipol, and to a lesser extent colesevelam inhibit intestinal absorption of a variety of lipophilic drugs. This includes fat-soluble vitamins (A, D, E, and K), corticosteroids, estrogens, progestins, thyroid and thyroxine preparations, and negatively charged (i.e., acidic) compounds such as warfarin, nonsteroidal anti-inflammatory drugs (NSAIDs), acetaminophen, valproic acid, folic acid, furosemide and thiazide diuretics, digitalis glycosides, tetracyclines, propranolol, and the oral antidiabetic drugs glipizide, troglitazone, and glyburide. These drug interactions increase intestinal elimination of the drug-resin complexes, resulting in decreased absorption, drug bioavailability, and therapeutic efficacy.

Mechanism of Action and Clinical Pharmacology

Cholesterol absorption inhibitors block the intestinal absorption of cholesterol of dietary and biliary origin as well as plant sterols. Plant sterols (also known as phytosterols) and ezetimibe block the absorption of cholesterol in the intestine through two different mechanisms of action. Phytosterols are more hydrophobic than cholesterol and displace the latter from micelles, promoting its intestinal elimination. The absorption of sterols and cholesterol across cells of the intestinal lumen requires the participation of the molecular transporter NPC1L1. Sterol binding to the NPC1L1 transporter further inhibits cholesterol absorption. Sterols are available from plant sources, dietary fiber supplements, and plant sterol-enriched margarines. If absorbed in the intestine, sterols' action against cholesterol is compromised.

Ezetimibe selectively targets and inhibits the transporter NPC1L1, preventing the uptake of cholesterol and phytosterol across the intestinal lumen. Inhibition of cholesterol absorption increases the expression of hepatic LDL receptors and enhances clearance of LDL from the circulation. Ezetimibe is indicated as adjunctive therapy to diet for the reduction of total cholesterol, LDL, and Apo B in patients with primary (heterozygous familial and nonfamilial) hyperlipidemia [109,133]. It lowers LDL by 15% to 20% and causes minimal increases in HDL, but its beneficial effect on prevention of CHD remains unclear. This agent is synergistic with statins and, if taken in conjunction, can lower LDL by up to 25% in addition to the results obtained by statins alone [109,134]. Ezetimibe is available in a combination formulation with the statin simvastatin under the brand name Vytorin. A second combination formulation combining ezetimibe with the statin atorvastatin, brand name Liptruzet, received FDA approval in 2013. However, Liptruzet was recalled in 2014 for packaging issues and discontinued in 2016 [109,133,135,136].

Ezetimibe reduces cholesterol absorption by approximately 50%. However, quite unlike the bile acid-binding resins, it does not prevent the absorption of triglycerides or fat-soluble vitamins, and the effects of ezetimibe in the prevention of CHD have not yet been clearly established [30,46,67,137,138].

Adverse Effects

Upper respiratory tract infection (4%), sinusitis (3%), diarrhea (4%), arthralgia (3%), and pain in an extremity (4%) are the most commonly reported adverse events associated with these medications [109].

Drug Interactions

Ezetimibe interacts with cyclosporine, cholestyramine, and fibrates. The combination of ezetimibe with a statin is contraindicated in patients with active liver disease or unexplained persistent elevations in serum transaminases, as well as in pregnant and nursing women [109,133].

Fibrates, also known as fibric acid derivatives, are agonists at the PPAR-α. These nuclear receptors are expressed primarily in hepatocytes and muscle cells, and their stimulation by fibrates results in activation of specific genes and subsequent changes in lipid metabolism. The lipid-lowering properties of fibrates result from multiple mechanisms of action, namely activation of lipoprotein lipase, which lowers triglycerides and VLDL; inhibition of Apo C-III synthesis in the liver, preventing the inhibitory action of Apo C-III on lipoprotein lipase activity; and stimulation of Apo A-I and Apo A-II expression, which increases HDL levels [139].

The removal of triglycerides from chylomicrons alters the size and composition of LDL from small, dense particles (which are thought to be more atherogenic due to their susceptibility to oxidation) to large, buoyant, and less atherogenic particles that have a greater affinity for LDL receptors and are rapidly cleared from the plasma. The fibrates fenofibrate, gemfibrozil, and bezafibrate decrease triglyceride levels by 20% to 50%, increase HDL 10% to 20%, and lower LDL by about 5% to 15%, although the latter result is quite variable [109].

Fibrates are indicated in the treatment of hypertriglyceridemias and dysbetalipoproteinemia and in individuals with moderately elevated triglyceride levels (150–400 mg/dL or 1.7–4.5 mmol/L), a sign often associated with metabolic syndrome. Fibrates are also indicated in the prevention of pancreatitis in patients with severely high triglyceride levels (greater than 1,000 mg/dL or 11.3 mmol/L) [109].

Fibrates are one of the most prescribed lipid-lowering drugs, second only to statins, and it is clinically relevant that they have been shown to reduce fatal and non-fatal ASCVD by about 20%, although their effect on LDL, as mentioned previously, is limited and variable.

Fibrates are usually well tolerated. Gastrointestinal side effects such as diarrhea, nausea, dyspepsia, and abdominal pain, are reported by 5% of patients. Even less common adverse effects include skin rash, myalgias, headache, and impotence [109].

Myositis occurs in up to 5% of patients taking a fibrate who are also being treated with statins. When combined with statins, fenofibrate is the preferred drug because it has less risk of rhabdomyolysis compared with gemfibrozil [140].

Fibrates potentiate the effects of oral anticoagulants (e.g., warfarin), as they compete for their binding sites to albumin. Fibrates also increase cholesterol excretion into the bile, leading to a risk of cholelithiasis. In patients with suspected cholelithiasis, diagnostic studies should be conducted; if gallstones are found, fibrate therapy should be discontinued [109].

HMG-CoA reductase inhibitors, usually known as statins, are the most effective and the most prescribed class of lipid-lowering drugs. Statins selectively inhibit HMG-CoA reductase, the enzyme responsible for the conversion of HMG-CoA to mevalonate, the rate-limiting step in cholesterol synthesis in the liver [109]. Inhibition of HMG-CoA reductase leads to increased expression of the hepatic LDL receptor and increased clearance of LDL from the circulation [235]. Statins are the primary pharmacotherapeutic agents used to lower LDL cholesterol levels.

The first statin to be tested and approved for clinical use, lovastatin, was isolated from the mold Aspergillus terreus, and pravastatin and simvastatin are chemically modified derivatives of the original molecule. Atorvastatin, fluvastatin, and rosuvastatin are synthetic compounds with distinct molecular structures. Lovastatin, pravastatin, and simvastatin are inactive prodrugs that require hydroxylation in the liver into their active forms. Although all statins are clinically very effective, rosuvastatin, atorvastatin, and simvastatin have the highest drug efficacy in this class (Table 5).

The selective inhibition of hepatic HMG-CoA reductase initiates a cascade of events that results in decreased synthesis of cholesterol; decreased liver release of VLDL; and activation of the transcription factor SREBP2, which upregulates the LDL receptor and consequently increases the clearance of plasma LDL. As 60% to 70% of serum cholesterol is synthesized in the liver by HMG-CoA reductase, inhibition of this enzyme drastically lowers circulating LDL [142].

In addition to the lipid-lowering actions of statins, studies suggest that the drugs are also implicated in a number of additional actions known as pleiotropic effects. This includes modulation of endothelial function, decrease in vascular inflammation, neuroprotection, and immunomodulation by inhibition of major histocompatibility complex II expression, which is upregulated in patients with myocarditis, multiple sclerosis, and rheumatoid arthritis [143,144,145]. Statins have been linked to a reduction in the risk of developing Alzheimer disease independent of the drugs' lipophilicity [145,146].

As stated, the percentage reduction in LDL levels is used to estimate the efficacy of statin therapy, with the primary goal being a ≥50% reduction [24]. In clinical practice, absolute responses in LDL levels to statin therapy depend on baseline levels and the intensity (i.e., low, moderate, or high) of lipid-lowering therapy [24].

In addition to efficacy, therapeutic goals, and patient preferences, the clinical choice of a statin also considers cost and drug safety. Lovastatin, simvastatin, and pravastatin have all been shown to be safe in clinical trials involving thousands of subjects for five or more years. This should be particularly taken into account when treating younger patients.

The combination of statins with other lipid-lowering drugs further improves the lipid-lowering outcome. The combination of simvastatin with ezetimibe lowers LDL by an additional 18% to 20% compared with simvastatin alone [147]. Administration of a statin with a bile acid-binding resin (e.g., cholestyramine, colestipol) produces 20% to 30% greater reductions in LDL than statins alone [148,149].

Statins are well absorbed through the gastrointestinal system and are metabolized in the liver by cytochrome P450. Metabolites are eliminated through the bile and excreted in the feces and, to a much lesser extent, by the kidneys. These drugs should not be used in patients with active liver disease and should be used cautiously at lower doses in patients with kidney disease [109].

Statins are effective in the prevention of ASCVD [67,150,151]. In a 2009 review and meta-analysis, these drugs are referred to as "the most important advance in stroke prevention since the introduction of aspirin and antihypertensive treatments" [152]. Analysis of the risk-benefit ratio of statins after one year of treatment reveals that an estimated 1,587 cases of fatal and non-fatal cases of ASCVD were prevented against 3.4 cases of rhabdomyolysis [140,153,154]. Randomized controlled trials across differing risk categories of patients have shown that statins confer significant relative risk reductions in cardiovascular events and all-cause mortality [235].

Dizziness (7%), diarrhea (4.5%), nausea/vomiting (3%), and abdominal cramps (3%) are among the most frequently reported adverse effects. Statins are contraindicated during pregnancy and lactation [128].

Statins are associated with hepatotoxicity and elevated transaminases in 1% to 2% of patients [128]. However, in 2014, the FDA concluded that the rate of liver injury associated with statin use is rare enough that routine liver enzyme screening while using statins is not needed. It is recommended that liver enzyme tests be performed before statin use begins and then only if there are symptoms of liver damage, including extreme fatigue, loss of appetite, right upper abdominal discomfort, dark urine, or jaundice [155,156].

The FDA has also noted a small increase in the risk for type 2 diabetes while taking statins. It is noted that there may be a need to assess blood sugar levels after beginning statin use, especially in those with other risk factors [156].

The incidence of myopathy, characterized by muscle pain, weakness, and grossly elevated creatine kinase levels (>10 times the upper limit of normal), with the use of a statin alone is reported in 0.1% to 0.2% of patients [128]. Yet, studies have indicated that the occurrence of statin-induced myopathy may be much higher than originally reported, as high as 10% to 15% of patients treated with statins [140,157].

A deficiency in coenzyme Q10 (CoQ10), a product of the HMG-CoA reductase pathway selectively inhibited by statins, has been proposed as a possible mechanism of statin-related myotoxicity. Although CoQ10 serum levels are below normal in patients taking statins, there is no direct correlation between myotoxicity and CoQ10 levels in muscle cells. Furthermore, studies of supplementation with CoQ10 to prevent myopathy in patients taking statins have not found conclusive evidence of effectiveness [140,158,159,160]. Alternatively, other studies have shown that the inhibition of HMG-CoA reductase by statins inhibits mitochondrial function, increases intracellular calcium, and activates apoptosis (i.e., programmed cell death) [161]. This latter mechanism is being further investigated and may play a crucial role in the development of lipid-lowering drugs with an even higher safety profile [140].

The occurrence of rhabdomyolysis, defined as skeletal muscle necrosis with release of potentially toxic muscle cell components into the general circulation, has been rarely reported. Possible complications of rhabdomyolysis include myoglobinuric acute renal failure, disseminated intravascular coagulation, hyperkalemia, and cardiac arrest.

The risk of myopathy or rhabdomyolysis increases with higher statin plasma levels, which can be the result of higher doses, decreased hepatic clearance, or drug interactions [109,156,162].

The AHA/ACC recommend that a clinician-patient risk discussion be conducted prior to the initiation of statin therapy to review and weigh the risk reduction benefit against the potential for adverse effects, drug-drug interactions, and safety. Patients with statin-associated muscle symptoms should be evaluated for nonstatin causes and predisposing factors. When a statin is indicated, identify predisposing factors for statin-associated side effects (e.g., new-onset diabetes mellitus, muscle symptoms) prior to initiating statin therapy (Table 6) [24].

Statins have pharmacokinetic interactions with drugs that inhibit their metabolism and increase their bioavailability, such as CYP3A4 inhibitors (e.g., azole antifungals, erythromycin, protease inhibitors, amiodarone, grapefruit) and CYP2C9 inhibitors (e.g., NSAIDs, phenytoin, warfarin), as well as drugs that potentiate statins' therapeutic and adverse effects (e.g., fibrates, niacin). These interactions increase statin toxicity [67,128,163]. Interaction between statins and fibrates, particularly with gemfibrozil, increases the risk of rhabdomyolysis. For this reason, fenofibrate is preferred when the two classes are combined [140].

The more LDL is reduced on statin therapy, the greater will be subsequent risk reduction. Therefore, the ACC/AHA recommend patients with clinical ASCVD be treated with a maximally tolerated statin to lower LDL levels by ≥50%.

(https://www.ahajournals.org/doi/pdf/10.1161/CIR.0000000000000677 Last Accessed: July 25, 2022)

Level of Evidence: I (Strong)

Statins, the most potent lipid-lowering drugs, are indicated in a variety of clinical conditions and are effective in the prevention of ASCVD and stroke. They lower LDL in a dose-dependent manner by 20% to 55% and are accepted as the drug of choice in the treatment of elevated LDL. They are also effective in the treatment of hypertriglyceridemias when levels are greater than 250 mg/dL, although fibrates remain the drug of choice for hypertriglyceridemias. When elevation of HDL is required, niacin remains the drug of choice, although co-administration of statins and niacin may be considered in patients who also have an elevated LDL. Co-administration of statins and niacin, fibrates, or ezetimibe increases the lipid-lowering benefit but also increases the risk for adverse effects. Furthermore, randomized controlled trials do not support the use of fibrates and niacin as add-on drugs to statin therapy. However, if a fibrate is necessary in a patient being treated with a statin, it is safer to use fenofibrate than gemfibrozil due to lower risk of severe myopathy [24]. These patients should be carefully monitored.

In patients taking statins who develop myopathy and creatine kinase levels 10 or more times higher than normal, immediate discontinuation of the drug is recommended. Dietary therapy and lifestyle changes should be implemented and other lipid-lowering drugs, such as niacin, fibrates, and bile-acid sequestrants, should be considered. The National Lipid Association Muscle Expert Panel guidelines recommend considering the re-introduction of low doses of statins in conjunction with ezetimibe in cases in which the lipid-lowering benefit of statins outweighs the risk of myopathy [140,164].

Niacin, also known as nicotinic acid or vitamin B3, is a water-soluble vitamin that at physiologic levels is a substrate for nicotinamide adenine dinucleotide (NAD) and NAD phosphate (NADP), important cofactors in intermediary metabolism. Niacin is available in normal- or extended-release formulation as well as in conjunction with lovastatin (as Advicor).

The lipid-lowering and vasodilatory effects of niacin are not related to its vitamin properties. The discovery that the vasodilatory properties of niacin result from its binding to a G protein-coupled receptor (GPR109A) expressed in blood vessels has allowed for better understanding of the mechanisms underlying its metabolic and vascular effects [165]. In addition, further evidence suggests that the lipid-lowering effects result from niacin binding to another G protein-coupled receptor on adipocytes that inhibits lipoprotein lipase and prevents triglyceride release from chylomicrons. The vasodilatory effect of niacin, on the other hand, involves the release of vasodilatory prostaglandins D2 and E2 [30].

It is relevant to emphasize that niacinamide, a nicotinic acid derivative usually preferred as a vitamin supplement, has neither lipid-lowering nor vasodilatory properties [30,166]. The lipid-lowering effects of niacin require a dose of 1,500–3,000 mg/day, whereas the recommended vitamin dose is 50 mg/day.

Niacin has low cost, a long history of clinical trials, and extensive use as a safe lipid-lowering drug, supported by evidence that it is effective in the prevention of ASCVD [31]. However, it is no longer recommended, except in specific clinical situations, such as a patient with triglyceride levels >500 mg/dL, a patient who is not able to achieve desired response, or a patient with intolerance to other therapies [109]. Although niacin has a mild LDL-lowering action, randomized controlled trials do not support its use as an add-on to statin therapy, and it is not listed as an LDL-lowering drug option in the 2018 AHA/ACC guideline [24]. Niacin has not been shown to reduce ASCVD outcomes beyond that achieved with statin use, and it may be associated with harm [167,168,169].

A 1975 study conducted by Danish scientists showed that the composition of plasma lipids (e.g., cholesterol esters, triglycerides, phospholipids) varied considerably in the Inuit population of Greenland when compared both to the European Danish and to Inuit living in Denmark [170]. Interestingly, epidemiologic studies showed that Inuit living in Greenland following a traditional diet rich in fat had a lower mortality from ASCVD than Inuit living in Denmark who followed a Western diet. This puzzling observation is known as the "Eskimo paradox" [171]. It is now well established that, although individual genetic background plays an important role in the development of ASCVD, the answer is the type of dietary fat consumed. Greenland Inuit consume a traditional diet rich in omega-3 fatty acids from fish and fish-eating mammals (seal and whale) rather than a diet poor in omega-3 sources such as the traditional Western diet [172].

Omega-3 polyunsaturated fatty acids are considered essential fatty acids because humans, as well as other mammals, are unable to synthesize these compounds efficiently. Eicosapentaenoic (EPA) and docosahexaenoic acids (DHA) are omega-3 polyunsaturated fatty acids derived from alpha-linolenic acid (ALA). Although humans are able to transform negligible amounts of ALA into EPA and DHA (<1%), dietary supplementation is the only physiologically relevant source [173]. Omega-3 fatty acids EPA and DHA are abundant in fatty fish, such as salmon, mackerel, sardines, trout, and herring, and other seafood sources, as well as in walnuts and canola, flaxseed, and linseed oils. Vegetable oils such as soybean, corn, sunflower, safflower, and cotton seed oils are good dietary sources of omega-6 fatty acids, which will be discussed in detail later in this course [57,174,175,176].

Although the mechanism of action of omega-3 fatty acids is not yet completely understood, both preclinical and clinical studies provide solid evidence that EPA and DHA both reduce the synthesis and secretion of VLDL and increase triglyceride removal from VLDL and chylomicrons through the upregulation of lipoprotein lipase [177]. The distinct mechanisms of action of omega-3 fatty acids differ from other lipid-lowering drugs, which helps to explain why they have complementary lipid benefits when administered with statins [173]. Omega-3 fatty acids also have well established antiarrhythmic, antihypertensive, anti-atherogenic, and antithrombotic properties [173,178,179,180,181,182,183].

Omega-3 fatty acids are effective in primary and secondary prevention of CHD, reduce the risk of sudden cardiovascular mortality by 45%, and provide a 20% relative risk reduction in overall mortality [175,180,184,185,186,187,188]. EPA and DHA omega-3 fatty acids lower triglycerides by 20% to 50% and were approved by the FDA in 2004 as adjunct to the diet for the treatment of very high triglyceride levels (≥500 mg/dL or 5.65 mmol/L) [189]. The effects on LDL seem to vary among studies from moderate dose-dependent increases to decreases in LDL. A moderate increase in HDL (5% to 10%) is more consistently reported [173,190,191]. As a result, omega-3 fatty acids are used in the treatment of hypertriglyceridemias, either alone or in conjunction with other lipid-lowering drugs.

Omega-3 fatty acids are readily available as dietary supplements in the United States. It is important to note that dietary supplements are not FDA-required to demonstrate safety and efficacy prior to marketing, whereas prescription products are. Dietary supplements generally contain lower levels of EPA and DHA than prescription products, are not approved or intended to treat disease, and may have levels of EPA and DHA that vary widely within and between brands. Supplements should not be substituted for prescription products, as they may also contain unwanted cholesterol or fats or potentially harmful components, including toxins and oxidized fatty acids [192].

Omega-3 fatty acids also are readily available in the United States as prescription medications. One prescription medication is comprised of 900 mg of ethyl esters of omega-3 fatty acids, a combination of EPA (approximately 500 mg) and DHA (approximately 400 mg) [189]. A second available medication consists of 1,000 mg omega-3 in free fatty acid form, which is intended to improve the bioavailability [193]. This drug contains approximately 500–600 mg EPA, 150–250 mg DHA, and 150–350 mg other omega-3 fatty acids. Drug labeling dosage information indicates a dose of 4 g/day, taken as a single 4-g dose (four capsules) or as two 2-g doses (two capsules twice daily) [189]. In one study, a minimum dose of 500 mg per day of combined EPA/DHA was recommended for individuals without underlying overt ASCVD, and 800-1,000 mg/day was recommended for individuals with CHD and heart failure [194]. A 2009 review validated the beneficial effects of EPA/DHA alone or in conjunction with fibrates in the reduction of triglycerides. It also further corroborated the safety profile of omega-3 polyunsaturated fatty acids [195]. In 2019, the FDA approved icosapent ethyl, a prescription omega-3 fatty acid, as an adjunctive therapy (to maximally tolerated statin therapy) to reduce the risk of cardiovascular events in adults with elevated triglyceride levels (≥150 mg/dL), cardiovascular disease and/or diabetes, and at least two additional risk factors [232].

The omega-3 fatty acids EPA and DHA are safe and cost effective and are indicated as an adjunct to diet in patients with hypertriglyceridemias [109,189]. They may be considered for triglyceride levels >1,000 mg/dL and may be used alone or in conjunction with HMG-CoA reductase inhibitors [109]. Omega-3 fatty acids are effective in the prevention of ASCVD. Their effect on cardiovascular morbidity and mortality has not been determined [189].

Omega-3 fatty acids are remarkably well tolerated. Minor gastrointestinal symptoms (e.g., fishy aftertaste, eructation, diarrhea) may be observed in a dose-related manner [189]. Clinical trials have concluded that omega-3 fatty acids do not have adverse effects on plasma glucose levels, bleeding, levels of muscle or liver enzymes, or kidney or nerve function.

Contaminants such as methylmercury, polychlorinated biphenyls, and dioxins may be concentrated in certain species of fish, such as shark, swordfish, king mackerel, and golden snapper. The FDA and the Environmental Protection Agency have issued a statement advising women who are or may become pregnant, breastfeeding mothers, and young children to avoid eating some types of fish and to eat fish and shellfish that are lower in mercury [196]. However, the levels of contaminants in omega-3 fatty acids, either as generic supplements or in the ethyl ester formulation, are well below acceptable levels of toxicity due to extensive purification processes. In April 2009, the FDA posted a warning regarding the ethyl ester formulations of omega-3 fatty acids reporting anaphylactic or severe allergic reactions (i.e., rash, hives, itching, difficulty breathing, tightness in the chest, swelling of the mouth, face, lips, or tongue) and hemorrhagic diathesis [197].

Due to their antiplatelet effect, omega-3 fatty acids may increase bleeding time in a dose-dependent manner [109,189]. However, no cases have been reported, even when administered at high doses alone or in combination with anticoagulant medications. In patients receiving anticoagulant medication, it has been recommended that bleeding times be monitored during the first three to six months, the time normally required for omega-3 fatty acids to reach their maximum clinical effect.

Plant sterols and stanols, also known as phytosterols, are bioactive compounds structurally and physiologically similar to cholesterol. Sterols are present naturally in small quantities in many fruits, vegetables, nuts, seeds, cereals, legumes, vegetable oils, and other plant sources, and stanols occur in even smaller quantities in many of the same sources [57,173,174,175,176,198,199].

Omega-6 polyunsaturated fatty acids such as gamma-linoleic acid (GLA) are derived from linoleic acid. Omega-9 polyunsaturated fatty acids, unlike omega-3 and omega-6, are non-essential because they can be synthesized in humans. The most relevant omega-9 fatty acid is oleic acid, which is present in olive oil, and supplementation is not required.

The lipid-lowering properties of omega-6 polyunsaturated fatty acids, and linoleic acid in particular, are related to their ability to alter various steps of the intestinal absorption of cholesterol. Specifically, they downregulate the intestinal expression of the cholesterol transporter NPC1L1, compete with cholesterol for binding to NPC1L1, lower the cholesterol esterification rate by ACAT2, decrease the amount of cholesterol secreted via the chylomicrons, and upregulate the expression of ATP-binding cassette-transporters ABCG5 and ABCG8 in intestinal cells, which may result in an increased excretion of cholesterol by the enterocyte back into the lumen [199].

The beneficial role played by omega-6 polyunsaturated fatty acids in the prevention of CHD results from their transformation into anti-inflammatory and vasodilatory eicosanoids, such as prostacyclin and lipoxin A4. Some studies, however, have recommended dietary reductions in omega-6 intake, based on the potential risk of increased transformation of omega-6 into pro-inflammatory, vasoconstrictive, pro-platelet aggregation eicosanoids, such as prostaglandin E2, thromboxane A2, and leukotriene B4. An advisory of the AHA has concluded that [200]:

Aggregate data from randomized trials, case-control and cohort studies, and long-term animal feeding experiments indicate that the consumption of at least 5% to 10% of energy from omega-6 polyunsaturated fatty acids reduces the risk of CHD relative to lower intakes. The data also suggest that higher intakes appear to be safe and may be even more beneficial (as part of a low-saturated-fat, low-cholesterol diet). In summary, the AHA supports an omega-6 polyunsaturated fatty acid intake of at least 5% to 10% of energy in the context of other AHA lifestyle and dietary recommendations. To reduce omega-6 polyunsaturated fatty acid intakes from their current levels would be more likely to increase than to decrease risk for CHD.

No serious side effects have been reported with omega-6 fatty acids. Some minor gastrointestinal effects may resemble those described for the omega-3 polyunsaturated fatty acids. Plant sterols and stanols lower plasma levels of beta-carotene by 25% and vitamin E by 8% [201].

Bile acid sequestrants and additives and drugs that impair the absorption of fat and soluble nutrients, such as olestra and orlistat, have the potential to significantly impair absorption of omega-3, 6, and 9 polyunsaturated fatty acids.

As noted, in 2020, the FDA approved bempedoic acid for the treatment of Heterozygous familial hypercholesterolemia or established ASCVD [233]. Bempedoic acid is the first in the class of adenosine triphosphate-citrate lyase (ACL) inhibitors. By inhibiting ACL, a hepatic enzyme involved in the synthesis of cholesterol, bempedoic acid decreases the conversion of mitochondrial-derived citrate to cytosolic ACL, creating less substrate for cholesterol and fatty acid synthesis. This ultimately decreases liver cholesterol synthesis and decreases serum LDL-C levels by upregulating LDL receptors [239].

Bempedoic acid is available as monotherapy and in a tablet with ezetimibe as combination therapy. It is an option to modify statin therapy or for patients who cannot tolerate statins. This combination has been demonstrated in clinical trials to lower LDL-C levels by 36% and, when given as monotherapy, bempedoic acid and ezetimibe have been respectively shown to lower LDL-C levels by 15% to 23% and by 13% to 20%, respectively [239]. The usual dose is 180 mg bempedoic acid and, if used, 10 mg ezetimibe once daily.

Potential adverse effects associated with bempedoic acid include leukopenia, thrombocythemia, upper respiratory tract infection, and, most commonly, hyperuricemia and gout. Gout and hyperuricemia are more common at higher doses and related to inhibition of tubular OAT2, which may increase blood uric acid levels [109]. It usually develops within the first four weeks of treatment initiation and persists until cessation of administration.

Rupture or injury of tendon has rarely (<1%) occurred, typically involving the rotator cuff, biceps tendon, or Achilles tendon [109]. Risk factors include age older than 60 years, concomitant use of corticosteroids or fluoroquinolones, kidney failure, and prior tendon disorders.

Bempedoic acid can increase the serum concentration of certain drugs metabolized by the liver, including elagolix, voxilaprevir, and asunaprevir and should be avoided in patients taking these medications [109]. It may also increase the serum levels of the statins simvastatin and lovastatin. If bempedoic acid is coadministered with these agents, the dose should be limited to no more than 20 mg daily for simvastatin or 40 mg daily for lovastatin [109,239].