**2. Pharmacological therapies**

#### **2.1. Statins**

Statins have been shown to be beneficial in hypercholesterolemia for both primary and secondary prevention of CV events (see **Figure 1**) [41]. Their main mechanism of action involves competitive inhibition of an enzyme, 3-Hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, a rate-limiting step in cholesterol synthesis (see **Figure 2**) [42, 43]. This prevents substrate from binding to the enzymatic active site resulting in a decrease in intrahepatic cholesterol synthesis [44]. The decrease in intrahepatic cholesterol leads to an increase in LDL receptors, and consequently an increase in LDL reuptake [45]. Other mechanisms described include alteration of hepatic Apolipoprotein B (Apo-B) secretion leading to a reduction in very low-density lipoprotein (VLDL) through decreased secretion and increased clearance. This consequently also contributes to the reduction in plasma TG [46]. Statins' effect on HDL has been attributed to their impact on hepatic microRNA33 (miR33) and consequent macrophage ATP-binding cassette transporter (ABCA)1-mediated efflux [47]. These additional mechanisms are thought to translate into clinical benefit through varied pathways including reversal of endothelial dysfunction, atheroma stabilization, and decreased thrombogenicity [48].

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

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

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].

Statins have been shown to be beneficial in hypercholesterolemia for both primary and secondary prevention of CV events (see **Figure 1**) [41]. Their main mechanism of action involves competitive inhibition of an enzyme, 3-Hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, a rate-limiting step in cholesterol synthesis (see **Figure 2**) [42, 43]. This prevents substrate from binding to the enzymatic active site resulting in a decrease in intrahepatic cholesterol synthesis [44]. The decrease in intrahepatic cholesterol leads to an increase in LDL receptors, and consequently an increase in LDL reuptake [45]. Other mechanisms described include alteration of hepatic Apolipoprotein B (Apo-B) secretion leading to a reduction in very low-density lipoprotein (VLDL) through decreased secretion and increased clearance. This consequently also contributes to the reduction in plasma TG [46]. Statins' effect on HDL has been attributed to their impact on hepatic microRNA33 (miR33) and consequent macrophage ATP-binding cassette transporter (ABCA)1-mediated efflux [47]. These additional mechanisms are thought to translate into clinical benefit through varied pathways including reversal of endothelial dysfunction, atheroma stabilization, and decreased thrombogenicity

ASCVD calculator such as diabetes duration and type [37].

82 Cholesterol Lowering Therapies and Drugs

**2. Pharmacological therapies**

**2.1. Statins**

[48].

found to be more cost-effective when compared with ≥10% threshold [38].

**Figure 1.** LDL, statins, and cardiovascular events. Reduction in cardiovascular event rates by lower low-density lipoprotein using statins in secondary prevention trials. *Abbreviations*: 4S, Scandinavian Simvastatin Survival Study; CARE, Cholesterol and Recurrent Events Trial; HPS, Heart Protection Study; LIPID, Long-term Intervention with Pravastatin in Ischemic Disease.

**Figure 2.** Mechanisms of HMG-CoA reductase inhibitors. Statins inhibit hepatic HMG-CoA reductase resulting in decreased downstream cholesterol production.

Statins are considered the most potent agents for lowering LDL cholesterol, and do so up to 63% [49]. They do have a predominant effect on small LDL particles leading to a shift in the LDL subfractions toward less atherogenic LDL [50]. Rosuvastatin has been shown to increase HDL by about 10%, appearing to be the most effective statins on HDL modification [51]. Regarding lowering TG, atorvastatin and rosuvastatin appear to be the most potent of the statins, with a dose-dependent decrease in TG of up to 33% [51].

Statins as a drug category demonstrate varying cholesterol-lowering potencies (see **Table 2**) [51–53]. Low-potency statins include simvastatin, lovastatin, pravastatin, and fluvastatin [51]. High-potency statins include atorvastatin and rosuvastatin [51]. Statins combined with a cholesterol absorption inhibitor (such as ezetimibe) or bile acid sequestrant show an additive cholesterol-lowering effect [54, 55].


*Abbreviations*: NNT, number needed to treat; WOSCOPS, West of Scotland Coronary Prevention Study; AFCAPS/ TEXCAPS, Air Force/Texas Coronary Atherosclerosis Prevention Study; ALLHAT-LLT, Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial; CARDS, Collaborative Atorvastatin Diabetes Study; MEGA, Management of Elevated Cholesterol in the Primary Prevention Group of Adult Japanese; JUPITER, Justification for the Use of statins in Prevention: an Intervention Trial Evaluating Rosuvastatin; 4S, Scandinavian Simvastatin Survival Study; CARE, Cholesterol and Recurrent Events trial; LIPID, Long-Term Intervention with Pravastatin in Ischemic Disease study;. HPS, Heart Protection Study; PROSPER, Prospective Study of Pravastatin in the Elderly at Risk; PROVE-IT, Pravastatin or Atorvastatin Evaluation and Infection Therapy; TNT, Treating to New Targets; IDEAL, Incremental Decrease in End Points through Aggressive Lipid Lowering.

**Table 2.** Potencies of different statins.

Numerous clinical trials have shown a trend toward improved CV outcomes, but not all have demonstrated statistical significance [56]. Statins have been shown to be effective in primary prevention of CHD (see **Table 3**) 21, 25–28, 32, 41, 57–63]. This was demonstrated in the Heart Protection Study [25], CARDS trial [26], and MEGA trial [27], where statins led to a significant reduction in MACE. Statins have also been shown to be effective in the secondary prevention of CHD as well (see **Table 3**). This benefit was evident in the Scandinavian Simvastatin Survival study (4S) [28], Lipid trial [29], and MIRACLE [30], where statin use resulted in a significant reduction in MACE. In a meta-analysis, which included 17,617 patients randomized to statins from the Cholesterol and Recurrent Events (CARE), Long-term Intervention with Pravastatin in Ischemic Disease (LIPID), and 4S trials, there was a significant reduction in MACE and allcause mortality, but no effect on noncardiovascular mortality [31]. In addition, high-dose statin therapy was shown to have a significant reduction in MACE when compared to lower-dose therapy, as seen in the Treating to New Target (TNT) trial [41] and PROVE IT-TIMI 22 trial [32].


**Table 3.** Primary and secondary prevention statin trials.

Statins are considered the most potent agents for lowering LDL cholesterol, and do so up to 63% [49]. They do have a predominant effect on small LDL particles leading to a shift in the LDL subfractions toward less atherogenic LDL [50]. Rosuvastatin has been shown to increase HDL by about 10%, appearing to be the most effective statins on HDL modification [51]. Regarding lowering TG, atorvastatin and rosuvastatin appear to be the most potent of the

Statins as a drug category demonstrate varying cholesterol-lowering potencies (see **Table 2**) [51–53]. Low-potency statins include simvastatin, lovastatin, pravastatin, and fluvastatin [51]. High-potency statins include atorvastatin and rosuvastatin [51]. Statins combined with a cholesterol absorption inhibitor (such as ezetimibe) or bile acid sequestrant show an additive

**Statin TC (%) LDL (%) HDL (%) TG (%) Dose range (mg)**

*Abbreviations*: NNT, number needed to treat; WOSCOPS, West of Scotland Coronary Prevention Study; AFCAPS/ TEXCAPS, Air Force/Texas Coronary Atherosclerosis Prevention Study; ALLHAT-LLT, Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial; CARDS, Collaborative Atorvastatin Diabetes Study; MEGA, Management of Elevated Cholesterol in the Primary Prevention Group of Adult Japanese; JUPITER, Justification for the Use of statins in Prevention: an Intervention Trial Evaluating Rosuvastatin; 4S, Scandinavian Simvastatin Survival Study; CARE, Cholesterol and Recurrent Events trial; LIPID, Long-Term Intervention with Pravastatin in Ischemic Disease study;. HPS, Heart Protection Study; PROSPER, Prospective Study of Pravastatin in the Elderly at Risk; PROVE-IT, Pravastatin or Atorvastatin Evaluation and Infection Therapy; TNT, Treating to New Targets; IDEAL,

Numerous clinical trials have shown a trend toward improved CV outcomes, but not all have demonstrated statistical significance [56]. Statins have been shown to be effective in primary prevention of CHD (see **Table 3**) 21, 25–28, 32, 41, 57–63]. This was demonstrated in the Heart Protection Study [25], CARDS trial [26], and MEGA trial [27], where statins led to a significant reduction in MACE. Statins have also been shown to be effective in the secondary prevention of CHD as well (see **Table 3**). This benefit was evident in the Scandinavian Simvastatin Survival study (4S) [28], Lipid trial [29], and MIRACLE [30], where statin use resulted in a significant reduction in MACE. In a meta-analysis, which included 17,617 patients randomized to statins from the Cholesterol and Recurrent Events (CARE), Long-term Intervention with Pravastatin in Ischemic Disease (LIPID), and 4S trials, there was a significant reduction in MACE and allcause mortality, but no effect on noncardiovascular mortality [31]. In addition, high-dose statin

Atorvastatin ↓ 27–39 ↓ 37–51 ↑ 2–6 ↓ 20–28 10–80 Rosuvastatin ↓ 33–40 ↓ 46–55 ↑ 8–10 ↓ 20–26 10–40 Simvastatin ↓ 20–28 ↓ 28–39 ↑ 5–6 ↓ 12–15 10–40 Pravastatin ↓ 15–22 ↓ 20–30 ↑ 3–6 ↓ 8–13 10–40 Fluvastatin ↓ 13–19 ↓ 17–23 ↑ 1–3 ↓ 5–13 20–80 Pitavastatin ↓ 22–31 ↓ 31–44 ↑ 1–4 ↓ 13–22 1–4

Incremental Decrease in End Points through Aggressive Lipid Lowering.

statins, with a dose-dependent decrease in TG of up to 33% [51].

cholesterol-lowering effect [54, 55].

84 Cholesterol Lowering Therapies and Drugs

**Table 2.** Potencies of different statins.

The most important side effects associated with statins are hepatic injury and myopathy [64, 65]. The risk of liver injury with the use of statins appears to be dose dependent and is most likely to occur in the first 3 months. This risk was demonstrated in a meta-analysis of 35 randomized trials that showed an excess risk of 4.2 cases per 1000 patients associated with statin use [66]. Multiple mechanisms of liver injury have been demonstrated with statins including hepatocellular and cholestatic [67]. Among the different statins, the risk of liver injury appears to be similar, except with fluvastatin that has a higher risk [68]. Numerous studies have found no significant difference in elevated aminotransferases when statins were compared to placebo [25, 28, 57]. It was for this reason that the Food and Drug Administration (FDA) revised the recommendation for liver function testing with regard to statin therapy in 2012 [69]. In the setting of rising aminotransferases three times the upper limit of normal, it is recommended to lower the statin dose or change medication.

Statin muscle injury remains the most concerning side effect, despite severe myopathy occurring in only 0.1–0.5% of patients [70, 71]. The degree of injury ranges from myalgia, myopathy, myositis, myonecrosis, to rhabdomyolysis [65]. Rhabdomyolysis, the most severe of the statin myopathy spectrum, was largely seen when statins were used with gemfibrozil or cyclosporine [72, 73]. This is thought to be related to the decrease in mevalonic acid associated with HMG-CoA reductase inhibition. Other mechanisms attributed to muscle injury include statins' effects on coenzyme Q10, also called ubiquinone, which is involved in muscle energy production [74]. Different statins possess varying risk to cause muscle injury, with fluvastatin exhibiting the lowest risk and simvastatin exhibiting a higher risk of muscle injury, especially at 80 mg/day dose, as shown in the SEARCH trial that was the basis of the FDA restriction of this dose of simvastatin [64, 70, 75]. The major predisposing factor for statininduced myopathy injury includes hypothyroidism, obstructive liver disease, and renal failure; these contribute to both hypercholesterolemia and myopathy. Thus, it is important to test for thyroid-stimulating hormone (TSH) levels prior to starting statins [76].

Other notable side effects include proteinuria that has been reported to the Food and Drug Administration with rosuvastatin and simvastatin, but no increased risk of renal failure has been described [77–79]. In addition, there have been several meta-analyses of randomized trials that found a small, yet increased risk of diabetes with high-dose statin therapy when compared to lower-dose statin therapies, possibly related directly to its inhibition of HMG-CoA reductase [80]. However, given that statins have been shown to reduce CV events in diabetics, these studies have suggested that the beneficial effects of statins on CV events outweigh this risk [80, 81].

Despite physicians in practice witnessing the discontinuation of statins due to "intolerance," randomized control trials have failed to validate this finding. The difference between clinical practice and trials may relate to selection bias observed in clinical trials that limit their external validity [66, 82]. Intolerance is largely seen on the basis of muscle pain, leading to discontinuation of therapy. Another cause of intolerance is a rise in aminotransferases, which usually requires statins dose reduction, switch to another statin, or using an alternate drug. In patients, who are unable to tolerate statins, ezetimibe, fenofibrate, cholestyramine, and niacin have been recommended for those with known coronary heart disease (CHD) or at high-risk CV events (10-year risk >20%) [33]. Another option is the recently FDA-approved proprotein convertase subtilisin kexin type 9 (PCSK9) inhibitors.

#### **2.2. PCSK9 inhibitors**

PCSK9 is a serine protease that is mainly secreted by the liver in an inactive form, before undergoing catalytic changes in the endoplasmic reticulum. The mature PCSK9 is then released into the plasma where it has only one substrate, LDL receptors. Once in circulation, it regulates the LDL receptor recycling in the liver, intestines, pancreas, lungs, kidneys, and adipose tissue [83, 84]. PCSK9 binding to LDL receptors causes it to be internalized into endosomal or lysosomal compartments, where they are destroyed. This leads to a decrease in LDL receptors on the surface of the cell. It has therefore been shown that serum PCSK9 levels are inversely proportional to the number of LDL receptors (see **Figure 3**) [85, 86]. Blood levels of PCSK9 are influenced by the diurnal trend in secretion (peak levels at 4 am), gender (higher in females), and fasting states (lower levels) [87, 88]. A mutation in PCSK9 was first described in French families in 2003. It is the third gene implicated in the autosomal dominant familial hypercholesterolemia (FH); the other two genes encode LDL receptor and Apo-B, a component of the LDL particle [89]. It is usually a gain-of-function mutation in PCSK9 that results in a low level of LDL receptors leading to a high level of LDL and consequently increased risk of premature CV disease [90, 91]. On the other hand, loss-of-function PCSK9 mutations result in high level of LDL receptors, and a decrease in LDL and significant reduction in CV events. Of note, the reduction of CV events observed with PCSK9 mutation is higher than that associated with statins. This difference is attributed to the persistently low LDL levels caused by the underlying genetic predisposition. This was demonstrated in the ARIC study, Copenhagen Heart Study, and the Zimbabwe population study [92–94].

(FDA) revised the recommendation for liver function testing with regard to statin therapy in 2012 [69]. In the setting of rising aminotransferases three times the upper limit of normal, it is

Statin muscle injury remains the most concerning side effect, despite severe myopathy occurring in only 0.1–0.5% of patients [70, 71]. The degree of injury ranges from myalgia, myopathy, myositis, myonecrosis, to rhabdomyolysis [65]. Rhabdomyolysis, the most severe of the statin myopathy spectrum, was largely seen when statins were used with gemfibrozil or cyclosporine [72, 73]. This is thought to be related to the decrease in mevalonic acid associated with HMG-CoA reductase inhibition. Other mechanisms attributed to muscle injury include statins' effects on coenzyme Q10, also called ubiquinone, which is involved in muscle energy production [74]. Different statins possess varying risk to cause muscle injury, with fluvastatin exhibiting the lowest risk and simvastatin exhibiting a higher risk of muscle injury, especially at 80 mg/day dose, as shown in the SEARCH trial that was the basis of the FDA restriction of this dose of simvastatin [64, 70, 75]. The major predisposing factor for statininduced myopathy injury includes hypothyroidism, obstructive liver disease, and renal failure; these contribute to both hypercholesterolemia and myopathy. Thus, it is important to

test for thyroid-stimulating hormone (TSH) levels prior to starting statins [76].

81].

subtilisin kexin type 9 (PCSK9) inhibitors.

**2.2. PCSK9 inhibitors**

Other notable side effects include proteinuria that has been reported to the Food and Drug Administration with rosuvastatin and simvastatin, but no increased risk of renal failure has been described [77–79]. In addition, there have been several meta-analyses of randomized trials that found a small, yet increased risk of diabetes with high-dose statin therapy when compared to lower-dose statin therapies, possibly related directly to its inhibition of HMG-CoA reductase [80]. However, given that statins have been shown to reduce CV events in diabetics, these studies have suggested that the beneficial effects of statins on CV events outweigh this risk [80,

Despite physicians in practice witnessing the discontinuation of statins due to "intolerance," randomized control trials have failed to validate this finding. The difference between clinical practice and trials may relate to selection bias observed in clinical trials that limit their external validity [66, 82]. Intolerance is largely seen on the basis of muscle pain, leading to discontinuation of therapy. Another cause of intolerance is a rise in aminotransferases, which usually requires statins dose reduction, switch to another statin, or using an alternate drug. In patients, who are unable to tolerate statins, ezetimibe, fenofibrate, cholestyramine, and niacin have been recommended for those with known coronary heart disease (CHD) or at high-risk CV events (10-year risk >20%) [33]. Another option is the recently FDA-approved proprotein convertase

PCSK9 is a serine protease that is mainly secreted by the liver in an inactive form, before undergoing catalytic changes in the endoplasmic reticulum. The mature PCSK9 is then released into the plasma where it has only one substrate, LDL receptors. Once in circulation, it regulates the LDL receptor recycling in the liver, intestines, pancreas, lungs, kidneys, and adipose tissue [83, 84]. PCSK9 binding to LDL receptors causes it to be internalized into

recommended to lower the statin dose or change medication.

86 Cholesterol Lowering Therapies and Drugs

**Figure 3.** Mechanisms of PCSK9 inhibitors. Secreted PCSK9 binds to LDL receptors on the cell surface and forms an endosome that undergoes lysosomal degradation. In the presence of PCSK9 inhibitors, the interaction between PCSK9 and LDL receptors is disrupted, resulting in the recycling of LDL receptors and increased hepatic uptake of LDL from the bloodstream. *Abbreviations*: LDL, low-density lipoprotein cholesterol; PCSK9, proprotein convertase subtilisin kexin 9.

Statins have been described to increase the concentration of PCSK9 inhibitors by 14–47% in a dose- and time-dependent fashion. This is via a decrease in endogenous cholesterol synthesis caused by statin inhibition of HMG-CoA reductase with consequent up-regulation in LDL receptors. It has therefore been demonstrated that a PCSK9 mutation increases the response to statins [95–98]. Neutralizing antibodies to PCSK9 were first described in 2009, and in subsequent studies it was shown to decrease LDL levels by 30% in animal models [99].

Although statins are the most effective cholesterol-lowering agents for preventing CV events, there is a need for additional therapies in those patients who are (1) unable to take statins or (2) already on maximal statin doses with residual CV risk. The National Lipid Association in the US estimates that about 12% of patients discontinue statin therapy, of whom 62% experienced adverse effects [100]. These data signal the need for alternative effective agents, such as PCSK9 inhibitors, to be used with or instead of statins. As monotherapy, PCSK9 inhibitors lower LDL by up to approximately 66% [101]. In conjunction with statins, PCSK9 inhibitors reduce LDL by an additional 60% beyond statins [102]. Examples of monoclonal antibody PCSK9 inhibitors available in the market include evolocumab and alirocumab. Phase I, II, and III clinical trials have shown an additional decrease in LDL levels with the use of PCSK-9 inhibitors (monoclonal antibodies) in combination with statin therapy, as well as a significant decrease in CV events including mortality (hazard ratio (HR): 0.47–0.52) [2, 3]. Other PCSK9 inhibitors include the small interfering RNA (siRNA) molecules that block the synthesis of PCSK9 inhibitors and have been shown to decrease LDL by 40% in a phase I clinical trial when used at the highest dose compared to placebo [103].

Regarding their side effects, there were no significant differences in the incidence of adverse drug events between PCSK9 inhibitors (alirocumab, evolocumab) and placebo in the latest phase III trials, except for neurocognitive events, myalgia, injection site reactions, and ophthalmologic events [2, 3]. A major concern with PCSK9 inhibitors revolves around their cost and the very low LDL levels achieved (as low as 18 mg/dL compared to 44 mg/dL with rosuvastatin in the JUPITER study). Potential short- and long-term consequences of very low LDL levels include neurocognitive impairment, hemorrhagic stroke, hemolytic anemia, vitamin, and hormonal deficiencies [21, 104].

#### **2.3. Ezetimibe**

Ezetimibe inhibits the intestinal absorption of dietary and biliary cholesterol without affecting the absorption of fat-soluble vitamins or TG [105]. This possibly occurs by the inhibition of Niemann-Pick C1-like 1 (NPC1L1) protein function that is expressed in the intestines and liver [106]. The benefits of ezetimibe were demonstrated in the IMPROVE-IT trial where the addition of ezetimibe to statin therapy led to a decrease in CV events, excluding all-cause and CV mortality [54]. Ezetimibe is helpful in avoiding high doses of statin and the associated dosedependent statin side effects, especially in patients who do not meet cholesterol targets. It has been well tolerated with the incidence of myopathy and serum transaminase elevations being similar when compared to placebo [54].

#### **2.4. Bile acid sequestrants**

Bile acid sequestrants, such as cholestyramine, colesevelam, and colestipol, lower cholesterol by binding to bile acids in the intestine preventing them from being reabsorbed [107]. The consequent decrease in intrahepatic cholesterol leads to an increase in LDL receptors that bind LDL from plasma with consequent small increase in HDL via increased intestinal synthesis of HDL [108]. They are relatively potent and exhibit a dose-dependent response achieving 10– 25% reduction in LDL, exhibiting a synergistic effect when used with statins or niacin [55, 109, 110].

Major side effects have limited its overall use. Those described include abdominal discomfort with nausea, bloating, cramping, and rise in aminotransferases. Of the bile acid sequestrants, colesevelam is the better-tolerated drug. They also interact with common CV medications (warfarin and digoxin) by binding and inhibiting their absorption. This can be avoided by administering the other medications 1 h before or 4 h after ingestion of bile acid sequestrants [107].

#### **2.5. Fibrates**

receptors. It has therefore been demonstrated that a PCSK9 mutation increases the response to statins [95–98]. Neutralizing antibodies to PCSK9 were first described in 2009, and in subsequent studies it was shown to decrease LDL levels by 30% in animal models [99].

Although statins are the most effective cholesterol-lowering agents for preventing CV events, there is a need for additional therapies in those patients who are (1) unable to take statins or (2) already on maximal statin doses with residual CV risk. The National Lipid Association in the US estimates that about 12% of patients discontinue statin therapy, of whom 62% experienced adverse effects [100]. These data signal the need for alternative effective agents, such as PCSK9 inhibitors, to be used with or instead of statins. As monotherapy, PCSK9 inhibitors lower LDL by up to approximately 66% [101]. In conjunction with statins, PCSK9 inhibitors reduce LDL by an additional 60% beyond statins [102]. Examples of monoclonal antibody PCSK9 inhibitors available in the market include evolocumab and alirocumab. Phase I, II, and III clinical trials have shown an additional decrease in LDL levels with the use of PCSK-9 inhibitors (monoclonal antibodies) in combination with statin therapy, as well as a significant decrease in CV events including mortality (hazard ratio (HR): 0.47–0.52) [2, 3]. Other PCSK9 inhibitors include the small interfering RNA (siRNA) molecules that block the synthesis of PCSK9 inhibitors and have been shown to decrease LDL by 40% in a phase I clinical trial when

Regarding their side effects, there were no significant differences in the incidence of adverse drug events between PCSK9 inhibitors (alirocumab, evolocumab) and placebo in the latest phase III trials, except for neurocognitive events, myalgia, injection site reactions, and ophthalmologic events [2, 3]. A major concern with PCSK9 inhibitors revolves around their cost and the very low LDL levels achieved (as low as 18 mg/dL compared to 44 mg/dL with rosuvastatin in the JUPITER study). Potential short- and long-term consequences of very low LDL levels include neurocognitive impairment, hemorrhagic stroke, hemolytic anemia,

Ezetimibe inhibits the intestinal absorption of dietary and biliary cholesterol without affecting the absorption of fat-soluble vitamins or TG [105]. This possibly occurs by the inhibition of Niemann-Pick C1-like 1 (NPC1L1) protein function that is expressed in the intestines and liver [106]. The benefits of ezetimibe were demonstrated in the IMPROVE-IT trial where the addition of ezetimibe to statin therapy led to a decrease in CV events, excluding all-cause and CV mortality [54]. Ezetimibe is helpful in avoiding high doses of statin and the associated dosedependent statin side effects, especially in patients who do not meet cholesterol targets. It has been well tolerated with the incidence of myopathy and serum transaminase elevations being

Bile acid sequestrants, such as cholestyramine, colesevelam, and colestipol, lower cholesterol by binding to bile acids in the intestine preventing them from being reabsorbed [107]. The

used at the highest dose compared to placebo [103].

88 Cholesterol Lowering Therapies and Drugs

vitamin, and hormonal deficiencies [21, 104].

similar when compared to placebo [54].

**2.4. Bile acid sequestrants**

**2.3. Ezetimibe**

Fibrates include gemfibrozil and fenofibrate [111]. The mechanism of action of fibrates is via activation of transcription factor, peroxisome proliferator-activated receptors (PPARs). It decreases TG via reduction in hepatic VLDL secretion, and stimulation of lipoprotein lipase that consequently leads to increased clearance of TG-rich lipoproteins. It also raises HDL by direct stimulation of HDL Apolipoprotein A-I/A-II synthesis and increased transfer of Apo A-I from HDL to VLDL [112].

This class of drugs lowers serum TG by 35–50%, and have also been shown to increase HDL by 5–20% directly proportional to the degree of hypertriglyceridemia [113–115]. Fibrates have not demonstrated any significant effect on cardiovascular outcomes, as seen in the FIELD trial [115], except in those with high TG (>200 mg/dL) or low HDL (<40 mg/dL) and metabolic syndrome, as was seen in the BIP trial [116].

The main side effect associated with fibrates is muscle injury. Muscle injury is often seen in patients who are already on a statin, and is thought to be mediated by fibrate-related inhibition of CYP3A4 with consequent decrease in statin metabolism [117]. Fibrates have also been shown to raise serum creatinine levels, but it remains unknown if there is direct parenchymal or tubular renal injury. Nevertheless, elevated creatinine has been found to be reversible on discontinuation of the medication, as was demonstrated in the FIELD trial [118]. Another noteworthy side effect is pancreatitis, which has been seen in patients with normal TG. However, the absolute risk remains low (number needed to harm over 5 years = 935) [119].

#### **2.6. Nicotinic acid (niacin)**

Nicotinic acid acts by inhibiting the hepatic production of VLDL and consequently decreasing LDL. It also increases HDL by reducing lipid transfer from HDL to VLDL, thus delaying HDL clearance [120]. This class of drugs has positive effects on HDL that occurs at relatively low dosages (1–1.5 g/day result in about 33% increase in HDL). Higher nicotinic acid doses are needed to lower LDL (3 g/day results in about 23% LDL decrease) [121, 122]. This class of drugs is also associated with a significant reduction of MACE in the HATS trial and ARBITER 6- HALTS trial when niacin was added to statin therapy [123, 124]. Contrary to these studies, the AIM-HIGH, ARBITER-2, and HPS2-THRIVE trials found no significant benefit of adding niacin to statin therapy [125–127].

Unfortunately, its use is limited by poor tolerability. The most common side effect is flushing, which occurs in the majority (up to 80%) of patients at standard recommended doses. Other notable side effects include paresthesia, pruritis, and nausea, each of which occurs in 20% of patients at standard doses [120].
