Atherosclerotic cardiovascular disease (ASCVD) is the leading cause of death in developing countries and accounts for 25.7% of all deaths in the United States and 45% of deaths in Europe [1,2]. According to the World Health Organization (WHO), 17.9 million people die each year from cardiovascular disease, an estimated 32% of all deaths worldwide [3]. It has been estimated that by 2030, ASCVD will account for approximately 23 million annual deaths worldwide, an increase of more than 5 million from current estimates [3].

American Heart Association data from 2015 to 2018 show unfavorable lipid measures of LDL cholesterol >130 mg/dL were present in 27.8% of adults 20 years of age and older, and total blood cholesterol concentrations >240 mg/dL (6.2 mmol/L) were present in 11.5% of adults [234]. Both lipid parameters are associated with excess risk of cardiovascular morbidity and mortality [15].

Atherosclerosis results from a chronic inflammatory process that targets medium- and large-sized arteries. This process begins in childhood and progresses slowly with age. However, the condition is rapidly accelerated by a variety of genetic and environmental factors, and hyperlipidemia is a major risk factor in the pathogenesis and progression of atherosclerosis [12,14,26,27].

An elevated concentration of LDL is a major cause of atherosclerosis and increased ASCVD [14,17,18,19,20,21,22]. The causative role of hyperlipidemia has been supported by the finding that decreasing the plasma levels of LDL and triglycerides has a beneficial effect on primary and secondary prevention of ASCVD by reversing, to some extent, the underlying pathology of atherosclerosis [23].

Atherosclerotic vascular disease develops in three progressive stages: fatty streak formation, plaque formation, and plaque disruption [12,27,28,29,30,31].

As discussed, hyperlipidemia has been established as a main risk factor in the development of atherosclerosis and ASCVD. Together with obesity, hypertension, diabetes, smoking, and physical inactivity, hyperlipidemia is a known modifiable risk factor of ASCVD. Additionally, several biomarkers, including C-reactive protein (CRP), hyperhomocysteinemia, and lipoprotein(a), are also considered modifiable risk factors of ASCVD. Modifiable risk factors play a major role in the pathogenesis of ASCVD because they activate the endothelium and stimulate the release of proinflammatory mediators and cell surface adhesion molecules. Because modifiable risk factors account for up to 90% of population-attributable cardiac risk, regulation of these factors has a beneficial effect on the primary and secondary prevention of ASCVD [11,12].

Numerous clinical studies have also revealed that high levels of lipoprotein(a) are associated with significant increases in ASCVD [12,27,31,46,47,48]. Lipoprotein(a) is a subtype of LDL that includes apoprotein A (Apo A) in its structure. The role of lipoprotein(a) in atherogenesis relates to a variety of mechanisms including inhibition of fibrinolysis by preventing the transformation of plasminogen to plasmin, enhanced capacity to traverse the arterial endothelium, and low affinity for the LDL-receptor mediated clearance from circulation [47]. High lipoprotein(a) concentrations (greater than 30 mg/dL) in patients with an elevated total cholesterol:HDL ratio (greater than 5.5) or other major risk factors indicates the need for a more aggressive therapy to further lower LDL [23,49].

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).

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].

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].

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].

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].

At the early stages, primary hyperlipidemias are asymptomatic. However, as the disease progresses, a constellation of signs and symptoms develop, such as eruptive xanthomas (located on the trunk, back, buttocks, elbows, knees, hands, and feet), severe hypertriglyceridemia (greater than 2,000 mg/dL), lipemic plasma (i.e., plasma develops a creamy supernatant when incubated overnight), and lipemia retinalis (i.e., creamy white-colored blood vessels in the fundus) often associated with premature CHD or peripheral vascular disease [46,100,103].

Polygenic hypercholesterolemia, also known as nonfamilial hypercholesterolemia, is the most common form of hyperlipidemia, with a prevalence of more than 25% in the American population [106]. Polygenic hypercholesterolemia is a typical example of the combination of multiple genetic deficiencies that result in decreased activity of the LDL receptor and reduction of LDL clearance. This underlying genetic susceptibility, not yet completely understood, becomes apparent with dietary intake of saturated fats, obesity, and sedentary lifestyle. Twenty percent of polygenic hypercholesterolemia patients have a family history of CHD. Patients present with mild-to-high increases in total cholesterol (250–350 mg/dL or 6.5–9.0 mmol/L) and LDL (130–250 mg/dL or 3.33–6.45 mmol/L). A combination of lifestyle changes (e.g., reduction in saturated fat) and lipid-lowering drugs (e.g., statins, bile acid sequestrants, ezetimibe, niacin) effectively control the condition [31,107].

Secondary hyperlipidemias can also be associated with a number of drug-induced conditions such as estrogen therapy (increased triglycerides and increased total cholesterol), atypical antipsychotics (increased triglycerides), corticosteroids (increased total cholesterol), selective α-blockers without intrinsic sympathetic activity or α-antagonism (increased total cholesterol and decreased HDL), and thiazides (modest increase in total cholesterol and LDL) [67,114].

In summary, secondary hyperlipidemias with elevated triglycerides are the primary lipid abnormality in patients with obesity, diabetes, alcohol abuse, hormone replacement therapy, and atypical antipsychotic therapy. Secondary hyperlipidemias with elevated cholesterol are the main dyslipidemia in patients with chronic renal failure, hypothyroidism, and typical β-blocker use (e.g., propranolol, atenolol).

Management of existing hyperlipidemia is a cornerstone in the prevention and management of ASCVD. In large randomized controlled trials, LDL lowering has been consistently shown to reduce the risk of ASCVD. However, in clinical practice, absolute responses in LDL levels to statin therapy depend on baseline LDL levels and the intensity of lipid-lowering therapy. Furthermore, it is important to bear in mind that as cardiovascular risk increases, so does the absolute benefit of therapeutic interventions proven to lower LDL cholesterol levels; both the absolute risk and the magnitude of LDL cholesterol level reduction achieved are important [235]. A given dose of statins produces a similar percentage reduction in LDL levels across a broad range of baseline levels; therefore, percentage reduction is a more reliable indicator of statin efficacy. The 2018 AHA/ACC guideline uses percentage reduction to estimate the efficacy of statin therapy, with the primary goal being a ≥50% reduction in LDL levels [24].

Modifiable lifestyle factors for cardiovascular disease risk reduction include diet, weight reduction, physical activity (exercise), and smoking cessation [24,236]. The 2018 AHA/ACC guideline on management of blood cholesterol and 2019 guideline on primary prevention of cardiovascular disease concur on the recommendations for good nutrition, diet, and exercise [24,236]. All adults should consume a healthy diet that [236]:

It is important to adapt the dietary pattern to the patient's calorie requirements, personal and cultural food preferences, and nutrition therapy for other medical conditions, including diabetes. For adults with obesity, counseling and caloric restriction are recommended for achieving and maintaining weight reduction [236]. A successful dietary approach to lipid lowering requires instruction by a dietitian or other knowledgeable healthcare professional.

Instructions to patients should not be presented as a list of "foods to avoid" but rather should provide dietary alternatives and teach the patients how to make appropriate dietary choices and control portions. A balanced diet, particularly in the modality known as the Mediterranean diet, is associated with a significant reduction in cardiovascular events and mortality [116,117,118]. The Mediterranean diet is characterized by meals predominately consisting of vegetables/fruits, lean protein, and healthy fats (e.g., olive oil) and the moderate consumption of wine. Plans such as those offered by the USDA's Dietary Guidelines for Americans, the AHA Diet and Lifestyle Recommendations, and the DASH Eating Plan can also help the patient achieve recommended lifestyle changes [119,120,121].

Physical activity stimulates the activity of lipoprotein lipase in adults as well as in children, lowers triglycerides and VLDL, and promotes cardiovascular fitness and weight loss [31,122]. Adults should engage in 150 minutes per week of accumulated moderate-intensity or 75 minutes per week of vigorous-intensity aerobic physical activity to reduce ASCVD risk [236]. An example of moderate exercise is brisk walking; examples of vigorous exercise are swimming, biking, and playing tennis. Combining moderate and vigorous physical activity allows for a proportionate reduction in time allotted to exercise each week.

Although dietary changes should always be included in the treatment of hyperlipidemias, the length of time given to lifestyle changes prior to initiation of pharmacotherapy remains controversial. In patients with low cardiovascular risk, it has been proposed that the efficacy of dietary and other lifestyle changes can be assessed in two to three visits over a two- to three-month period. Drug therapy is recommended only in select patients with moderately-high LDL (≥160 mg/dL) or patients with very-high LDL (190 mg/dL). High-intensity or maximal statin therapy plus ezetimibe and/or a PCKS9 inhibitor is recommended for the patient at very-high risk (i.e., history of multiple major ASCVD events) [24].

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.

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].

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).

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].

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].

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).

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].

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].

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.