**1. Introduction**

Atherosclerotic cardiovascular disease (CVD) affects more than 15 million Americans and is considered the leading cause of death in the United States (US) in both men and women (REF). Dyslipidemia is a major risk factor for atherosclerotic CVD [1]. We review current standard treatment of abnormal cholesterol levels and discuss future directions. Lipid-altering therapies favorably impact the lipid profile by lowering total cholesterol, low-density lipoprotein (LDL), and triglycerides (TGs), while beneficially increasing high-density lipoprotein (HDL; see **Table**

© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

**1**) [2–4]. In addition, lipid-altering therapies cause a desirable shift toward less atherogenic cholesterol subparticles [5]. The benefit of lipid therapy has been borne out in studies evaluating their effects on coronary atherosclerosis regression (by angiography) and incidence of major adverse cardiovascular events (MACEs) [6–10]. The lipoprotein transport system mediates the movement of cholesterol and TG in plasma, in addition to numerous other important physiologic functions. These include transport of dietary fat absorbed in the intestines to the liver, transport of modified cholesterol to peripheral tissues for cell membrane and steroid hormone synthesis, and transport of free fatty acids that may be used for fuel [11]. Lipoproteins are typically classified by their size and density. The main lipoprotein carriers of cholesterol to peripheral tissues are LDL particles. They are internalized by LDL receptors, where they are then hydrolyzed. This is an important pathway in controlling plasma cholesterol levels, as evidenced in those with loss-of-function mutations of LDL receptors leading to an inherited hyperlipidemia [12]. Importantly, LDL particles vary in size. Those with fewer cholesteryl esters and more TGs are smaller, denser, and thus more atherogenic [11].


*Abbreviations*: LDL, low-density lipoprotein cholesterol; HDL, high-density lipoprotein; TC, total cholesterol; TG, triglycerides.

**Table 1.** Potencies of various lipid lowering agents.

Increased concentrations of LDL have been shown in epidemiological studies to be associated with an increased risk of MACE. This was demonstrated in The Lipid Research Clinics Prevalence Study, where after 10 years of follow-up in patients with known coronary heart disease (CHD), a higher death rate was evident in those with higher levels of plasma total cholesterol and LDL [13]. In addition, those with inherited hyperlipidemia have early atherothrombosis [14]. Reducing LDL cholesterol is strongly linked to reductions in MACE, especially when using statins [10]. One-third of all middle-aged or older adults in the general population of the US and United Kingdom (UK) have an indication for statin therapy [15]. Notably decreased LDL and raising HDL levels have been associated with regression of atherosclerosis as evident in the Regression Growth Evaluation Statin Study (REGRESS) trial and several other trials [6–9].

Until recently, it was strongly recommended to treat to specific LDL targets [16]. These targets were based on post hoc analyses demonstrating greater reductions in MACE with LDL levels below certain levels. However, subsequent head-to-head statin trials compared different agents at different doses. These studies did not investigate the effects of different LDL target levels [17]. For such reasons, the most recent US guidelines advocate for using high-intensity statins for patients at high risk of cardiovascular events. By contrast, guidelines in Europe and Canada have maintained their recommendation on using LDL targets [18].

Statins are well known for pleotropic effects independent of cholesterol lowering, mainly antiinflammatory properties [19]. In many statin trials, subjects with the largest reduction in highsensitivity C-reactive protein (hsCRP) have decreased primary end points [20, 21]. In two statin trials, lower hsCRP and LDL levels were associated with a decrease in atheroma progression as assessed by serial intravascular ultrasound observation [22, 23]. Moreover, in the Justification for the Use of Statins in Prevention (JUPITER) trial, a decrease in MACE and all-cause mortality was seen in asymptomatic subjects with baseline elevated hsCRP levels and already low LDL level, which contemporary risk calculators would exclude from therapy. Notably, elevated LDL cholesterol is associated with MACE without the need for overt evidence of inflammation [24] .

#### **1.1. Cardiovascular risk stratification: Who to treat?**

**1**) [2–4]. In addition, lipid-altering therapies cause a desirable shift toward less atherogenic cholesterol subparticles [5]. The benefit of lipid therapy has been borne out in studies evaluating their effects on coronary atherosclerosis regression (by angiography) and incidence of major adverse cardiovascular events (MACEs) [6–10]. The lipoprotein transport system mediates the movement of cholesterol and TG in plasma, in addition to numerous other important physiologic functions. These include transport of dietary fat absorbed in the intestines to the liver, transport of modified cholesterol to peripheral tissues for cell membrane and steroid hormone synthesis, and transport of free fatty acids that may be used for fuel [11]. Lipoproteins are typically classified by their size and density. The main lipoprotein carriers of cholesterol to peripheral tissues are LDL particles. They are internalized by LDL receptors, where they are then hydrolyzed. This is an important pathway in controlling plasma cholesterol levels, as evidenced in those with loss-of-function mutations of LDL receptors leading to an inherited hyperlipidemia [12]. Importantly, LDL particles vary in size. Those with fewer

cholesteryl esters and more TGs are smaller, denser, and thus more atherogenic [11].

**Drug class LDL (%) HDL (%) TG (%)** Bile acid sequestrants ↓ 15–30 ↑ 3–5 No change Cholesterol absorption inhibitors (Ezetimibe) ↓ 17–22 ↑ 2–5 ↓ 4–11 Fibrates ↓ 5–20 ↑ 10–20 ↓ 20–50 Nicotinic acid (niacin) ↓ 5–25 ↑ 15–35 ↓ 20–50 PCSK9 inhibitors ↓ 61–62 ↑ 5–7 ↓ 13–17 HMG-CoA reductase inhibitors (Statins) ↓ 18–55 ↑ 5–15 ↓ 7–30

*Abbreviations*: LDL, low-density lipoprotein cholesterol; HDL, high-density lipoprotein; TC, total cholesterol; TG,

Increased concentrations of LDL have been shown in epidemiological studies to be associated with an increased risk of MACE. This was demonstrated in The Lipid Research Clinics Prevalence Study, where after 10 years of follow-up in patients with known coronary heart disease (CHD), a higher death rate was evident in those with higher levels of plasma total cholesterol and LDL [13]. In addition, those with inherited hyperlipidemia have early atherothrombosis [14]. Reducing LDL cholesterol is strongly linked to reductions in MACE, especially when using statins [10]. One-third of all middle-aged or older adults in the general population of the US and United Kingdom (UK) have an indication for statin therapy [15]. Notably decreased LDL and raising HDL levels have been associated with regression of atherosclerosis as evident in the Regression Growth Evaluation Statin Study (REGRESS) trial

Until recently, it was strongly recommended to treat to specific LDL targets [16]. These targets were based on post hoc analyses demonstrating greater reductions in MACE with LDL levels

triglycerides.

**Table 1.** Potencies of various lipid lowering agents.

80 Cholesterol Lowering Therapies and Drugs

and several other trials [6–9].

In patients with known CVD, treatment with statins has been shown to reduce CV events and all-cause mortality, while other lipid-lowering agents have also been shown to reduce the incidence of CV events in patients not on statins [25–33]. However, in patients without known CVD, cholesterol-lowering agents have only been shown to be beneficial in those at a high risk of CV events. The absolute benefit of treatment is proportional to the underlying absolute CV risk. Therefore, it is important to target patients at a high risk of CV events rather than a specific LDL.

Various CV risk calculators have been used to identify patients at high risk. These calculators are modeled to a particular population; therefore, the choice of which risk calculator to use is important. Below, we will discuss the benefits and pitfalls of using risk calculators to guide decision to treat. The Framingham Risk score is a risk calculator based on a population from the northeastern US (https://www.framinghamheartstudy.org/risk-functions/cardiovasculardisease/10-year-risk.php#). The most current version includes major CV outcomes, stroke, and heart failure. Notably, statins have shown to reduce the incidence of major CV outcomes and stroke, but not heart failure [34]. The American Heart Association/American College of Cardiology (AHA/ACC) Pooled Cohort Equations Cardiovascular risk calculator (ASCVD) is based on a population of non-Hispanic whites and African Americans in the US (http:// tools.acc.org/ASCVD-Risk-Estimator/). Compared to the Framingham risk calculator, it predicts major CV outcomes that are reduced by statins. Limitations of the ASCVD include its dichotomization of diabetes mellitus without considering its duration or type. It also does not take into account family history of premature CV disease, thus underestimating CV risk in those with significant family history of CV events [35].

The Joint British Societies (JBS-3) guidelines calculator is based on a population from the UK (http://www.jbs3risk.com/JBS3Risk.swf). In those with a low 10-year risk of CV events, the JBS-3 recommends using the QRISK® lifetime CV risk calculator [36]. Both the ASCVD and JBS-3 predict both 10-year risk and lifetime risk of CV events. Without the data with long-term effects of statins, there is a limitation to use lifetime risk prediction for using cholesterollowering agents. Therefore, the use of the 10-year risk predictions has been recommended when making such decisions. In patient with diabetes, the UK Prospective Diabetes Study calculator incorporates factors important to those with diabetics that are not found in the ASCVD calculator such as diabetes duration and type [37].

Another factor used when making the decision to treat on a population-based approach is cost-effectiveness. The 2013 AHA/ACC guidelines have recommended the use of a 10-year risk of CV events threshold of 7.5% when deciding to use cholesterol-lowering agents. This was found to be more cost-effective when compared with ≥10% threshold [38].

In older patients, over age 65, the decision to treat is also influenced by the presence of other comorbidities not taken into account in the calculators above. For example, a patient with a concurrent illness with high mortality, such as metastatic pancreatic cancer, is unlikely to benefit from a cholesterol-lowering agent. Thus, clinical trials of cholesterol-lowering agents have typically excluded older patients. However, a healthy elderly patient may potentially benefit from these therapies, and in fact the absolute number to treat is much lower in a healthy elderly population, given the dramatic increase in absolute risk of CV disease in this cohort [39]. A barrier to using cholesterol-lowering agents in the elderly has been the notion that it takes years to see the benefit of cholesterol-lowering agents; however, many studies have shown that they can be beneficial in as early as 6 months, as seen in the 4S trial [40].
