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Cholesterol Lowering Drugs

, MD and , MD, PhD.

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Last Update: August 10, 2016.

ABSTRACT

There are currently six different classes of drugs available for lowering cholesterol levels. There are currently seven HMG-CoA reductase inhibitors (statins) approved for lowering cholesterol levels and they are the first line drugs for treating lipid disorders and can lower LDL cholesterol levels by as much as 60%. Statins also are effective in reducing triglyceride levels in patients with hypertriglyceridemia. Statins lower LDL levels by inhibiting HMG-CoA reductase activity leading to decreases in hepatic cholesterol content resulting in an up-regulation of hepatic LDL receptors, which increases the clearance of LDL. The major side effects are muscle complications and an increased risk of diabetes. The different statins have varying drug interactions. Ezetimibe lowers LDL cholesterol levels by approximately 20% by inhibiting cholesterol absorption by the intestines leading to the decreased delivery of cholesterol to the liver, a decrease in hepatic cholesterol content, and an up-regulation of hepatic LDL receptors. Ezetimibe is very useful as add on therapy when statin therapy is not sufficient or in statin intolerant patients. Ezetimibe has few side effects. Bile acid sequestrants lower LDL cholesterol by10-30% by decreasing the absorption of bile acids in the intestine which decreases the bile acid pool consequently stimulating the synthesis of bile acids from cholesterol leading to a decrease in hepatic cholesterol content and an up-regulation of hepatic LDL receptors. Bile acid sequestrants can be difficult to use as they decrease the absorption of multiple drugs, increase triglyceride levels, and cause constipation and other GI side effects. They do improve glycemic control in patients with diabetes which is an additional benefit. PCSK9 monoclonal antibodies lower LDL cholesterol by 50-60% by binding PCSK9, which decreases the degradation of LDL receptors. PCSK9 inhibitors also decrease Lp(a) levels. PCSK9 inhibitors are very useful when maximally tolerated statin therapy does not reduce LDL sufficiently and in statin intolerant patients. PCSK9 inhibitors have very few side effects. Mipomersen and lomitapide are approved for lowering LDL levels in patients with Homozygous Familiar Hypercholesterolemia. Mipomersen is a second generation apolipoprotein anti-sense oligonucleotide that decreases apolipoprotein B synthesis resulting in a reduction in the formation and synthesis of VLDL. Lomitapide inhibits microsomal triglyceride transfer protein decreasing the formation of chylomicrons in the intestine and VLDL in the liver. Both mipomersen and lomitapide have the potential to cause liver toxicity and therefore they were approved with a risk evaluation and mitigation strategy (REMS) to reduce risk. For complete coverage of all related aeas of Endocrinology, please visit our on-line FREE web-text, WWW.ENDOTEXT.ORG.

INTRODUCTION

This chapter will discuss the currently available drugs for lowering cholesterol levels, especially LDL cholesterol: statins, ezetimibe, bile acid sequestrants, PCSK9 inhibitors, lomitapide, and mipomersen. We will not discuss the effect of lifestyle changes on LDL cholesterol as this is addressed in detail in chapter 23 [1]. Additionally, we will not discuss the effect of food additives, such as phytosterols, on LDL cholesterol as these are also discussed in chapter 23 [1]. Finally, we will not discuss guidelines for determining who to treat, how aggressively to treat, or targets of treatment as these issues are discussed in detail in chapter 4 [2].

STATINS

Introduction

In the 1970s Dr. Akira Endo, working at Sankyo, discovered that compounds isolated from fungi inhibited the activity of HMG-CoA reductase, a key enzyme in the synthesis of cholesterol [3]. Further studies at Merck led to the development of the first HMG-CoA reductase inhibitor, lovastatin, approved in 1987 for the treatment of hypercholesterolemia [4]. There are currently seven HMG-CoA reductase inhibitors (statins) approved in the United States for lowering cholesterol levels. Three statins are derived from fungi (lovastatin, simvastatin, and pravastatin) and four statins are synthesized (atorvastatin, rosuvastatin, fluvastatin, and pitavastatin). Most of these statins are now generic drugs and therefore they are relatively inexpensive. Which particular statin one elects to use may depend on the degree of cholesterol lowering needed and the potential of drug-drug interactions. Statins are the first line drugs for treating lipid disorders and therefore one of the most widely utilized class of drugs. Statins have revolutionized the field of preventive cardiology and making an important contribution to the reduction in atherosclerotic cardiovascular events.

Effect on Statins on Lipid and Lipoprotein Levels

The major effect of statins is lowering LDL cholesterol levels. The effect of the various statins at different doses on LDL cholesterol levels is shown in Table 1. As can be seen in Table 1 different statins have varying abilities to lower LDL with maximal reductions of approximately 60% seen with rosuvastatin 40mg. Doubling the dose of a statin results in an approximate 6% further decrease in LDL levels. The percent reduction in LDL cholesterol levels is similar in patients with high and low starting LDL levels but the absolute decrease is greater if the starting LDL is high. Because of this profound ability of statins to lower LDL cholesterol levels, treatment with these drugs as monotherapy is often sufficient to lower LDL cholesterol below target levels.

Table 1Approximate effect of different doses of statins on LDL cholesterol levels

% LDL ReductionSimvastatin
(Zocor)
Atorvastatin
(Lipitor)
Lovastatin
(Mevacor)
Pravastatin
(Pravachol)
Fluvastatin
(Lescol)
Rosuvastatin
(Crestor)
Pitavastatin
(Livalo)
2710mg-20mg20mg40mg--
3420mg10mg40mg40mg80mg-1mg
4140mg20mg80mg80mg--2mg
4880mg40mg---10mg4mg
54-80mg---20mg-
60-----40mg-

Data modified from package inserts

As would be predicted from the effect of statins on LDL cholesterol levels, statins are also very effective in lowering non-HDL cholesterol levels (LDL cholesterol is the major contributor to non-HDL cholesterol levels) [5, 6]. In addition statins also lower plasma triglyceride levels [7, 8]. The ability of statins to lower triglyceride levels correlates with the reduction in LDL cholesterol [8]. Statins that are most efficacious in lowering LDL cholesterol are also most efficacious in lowering plasma triglyceride and VLDL cholesterol levels. Notably the percent reduction in plasma triglyceride levels is dependent on the baseline triglyceride levels [8]. For example in patients with normal triglyceride levels (<150mg/dl), simvastatin 80mg per day lowered plasma triglyceride levels by 11%. In contrast, if plasma triglyceride levels were elevated (> 250mg/dl), simvastatin 80mg per day lowered triglyceride levels by 40% [8]. In patients with both elevated LDL cholesterol and triglyceride levels statin therapy can be very effective in improving the lipid profile and are therefore the first line class of drugs to treat patients with mixed hyperlipidemia unless the triglyceride levels are markedly elevated (>500-1000mg/dl). As expected, given the ability of statins to lower LDL cholesterol and triglyceride/VLDL levels, statin therapy is very effective in lowering apolipoprotein B levels [5, 6].

Of note despite the ability of statins to lower LDL cholesterol, non-HDL cholesterol, and apolipoprotein B levels, statins do not lower Lp(a) levels [9]. Finally statins modestly increase HDL cholesterol levels [7, 10, 11]. In most studies HDL cholesterol levels increase between 5-10% with statin therapy. Interestingly, while low dose atorvastatin increases HDL levels similar to other statins at high doses the effect of atorvastatin is blunted with either very modest increases or no change observed [10].

Non-Lipid Effects of Statins

In addition to effects on lipid metabolism statins also have pleiotropic effects that may not be directly related to alterations in lipid metabolism [12]. For example, statins are anti-inflammatory and consistently decrease CRP levels [13]. Other pleiotropic effects of statins include anti-proliferative effects, antioxidant properties, anti-thrombosis, improving endothelial dysfunction, and attenuating vascular remodeling [12]. Whether these pleiotropic effects contribute to the beneficial effects of statins in preventing cardiovascular disease is uncertain and much of the beneficial effect of statins on cardiovascular disease can be attributed to reductions in lipid levels.

Mechanism Accounting for the Statin Induced Lipid Effects

Statins are competitive inhibitors of HMG-CoA reductase, which leads to a decrease in cholesterol synthesis in the liver. This inhibition of hepatic cholesterol synthesis results in a decrease in cholesterol in the endoplasmic reticulum resulting in the movement of sterol regulatory element binding proteins (SREBPs) from the endoplasmic reticulum to the golgi where they are cleaved by proteases into active transcription factors [14]. The SREBPs then translocate to the nucleus where they increase the expression of a number of genes including HMG-CoA reductase and, most importantly, the LDL receptor [14]. The increased expression of HMG-CoA reductase restores hepatic cholesterol synthesis towards normal while the increased expression of the LDL receptor results in an increase in the number of LDL receptors on the plasma membrane of hepatocytes leading to the accelerated clearance of apolipoprotein B and E containing lipoproteins (LDL and VLDL) (Figure 1) [14]. The increased clearance of LDL and VLDL accounts for the reduction in plasma LDL and triglyceride levels. In patients with a total absence of LDL receptors (Homozygous Familiar Hypercholesterolemia) statin therapy is not very effective in lowering LDL cholesterol levels.

Figure 1: Mechanism for the Decrease in LDL Levels

etx-lipid-ch24-fif1

In addition to lowering LDL and VLDL levels by accelerating the clearance of lipoproteins some studies have also shown that statins reduce the production and secretion of VLDL particles by the liver [15]. This could contribute to the decrease in triglyceride levels. The mechanism by which statins increase HDL cholesterol levels is not clear.

Pharmacokinetics and Drug Interactions

Statins have different pharmacokinetic properties which can explain clinically important differences in safety and drug interactions [16-18]. Most statins are lipophilic except for pravastatin and rosuvastatin, which are hydrophilic. Lipophilic statins can enter cells more easily but the clinical significance of this difference is not clear. Most of the clearance of statins is via the liver and GI tract [16-18]. Renal clearance of statins in general is low with atorvastatin having a very low renal clearance making this particular drug the statin of choice in patients with significant renal disease. The half-life of statins varies greatly with lovastatin, pravastatin, simvastatin, and fluvastatin having a short half-life (1-3 hours) while atorvastatin, rosuvastatin, and pitavastatin having a long half-life [16-18]. In patients intolerant of statins the use of a long acting statin every other day or 2 times per week has been employed. Additionally, while all statins are most effective when administered in the evening when HMG-CoA reductase activity is maximal the long acting statins are preferred in patients that desire to take their statin in the morning.

A key difference between statins is their pathway of metabolism. Simvastatin, lovastatin, and atorvastatin are metabolized by the CYP3A4 enzymes and drugs that affect the CYP3A4 pathway can alter the metabolism of these statins [16-19]. Fluvastatin is metabolized mainly by CYP2C9 with a small contribution by CYP2C8 [16-19]. Pitavastatin and rosuvastatin are minimally metabolized by the CYP2C9 pathway [16-19]. Pravastatin is not metabolized at all via the CYP enzyme system [16-18].

Drugs that inhibit CYP3A4 can impede the metabolism of simvastatin, lovastatin, and to a smaller extent atorvastatin resulting in high serum levels of these drugs [16-19]. These higher levels are associated with adverse effects particularly muscle toxicity. Drugs that inhibit CYP3A4 include intraconazole, ketoconazole, erythromycin, clarithromycin, HIV protease inhibitors (amprenavir, darunavir, fosamprenavir, indinavir, nelfinavir, ritonavir, and saquinavir), amiodarone, diltiazem, verapamil, and cyclosporine [16-19]. It should be noted that grapefruit juice contains compounds that inhibit CYP3A4 and the consumption of grapefruit juice can significantly increase statin blood levels [20]. The inhibition of CYP3A4 by grapefruit juice is dose dependent and increases with the concentration and volume of grapefruit juice ingested. One glass of grapefruit juice everyday can influence the metabolism of statins that are metabolized by the CYP3A4 pathway [20]. If a patient requires treatment with a drug that inhibits CYP3A4 the clinician has a number of options to avoid potential drug interactions. One could use a statin that is not metabolized via the CYP3A4 system such as pravastatin or rousuvastatin, one could use an alternative drug to the CYP3A4 inhibitor (for example instead of using erythromycin use azithromycin), or one could temporary suspend for a short period of time the use of the statin that is metabolized by the CYP3A4 pathway (this is particularly useful when a short course of treatment with an antifungal or antibiotic is required). Drugs that inhibit CYP2C9 do not seem to increase the toxicity of fluvastatin, pitavastatin, or rosuvastatin probably because metabolism via the CYP2C9 pathway is not a dominant pathway.

Most statins are transported into the liver and other tissues by organic anion transporting polypeptides, particularly OATP1B1 [16-19]. Drugs, such as clarithromycin, ritonavir, indinavir, saquinavir, and cyclosporine that inhibit OATP1B1 can increase serum statin levels thereby increasing the risk of statin muscle toxicity [16-19]. Fluvastatin is the statin that is least affected by OATP1B1 inhibitors. In fact fluvastatin 40mg per day has been studied in patients receiving renal transplants concomitantly treated with cyclosporine and over a five year study period the risk of myopathy or rhabdomyolysis was not increased in the fluvastatin treated patients compared to those treated with placebo [21].

Gemfibrozil inhibits the glucuronidation of statins, which accounts for a significant portion of the metabolism of most statins [19]. This can lead to the reduced clearance of statins and elevated blood levels increasing the risk of muscle toxicity [19]. The only statin whose metabolism is not altered by gemfibrozil is fluvastatin [19]. Notably, fenofibrate, another fibrate that has very similar effects on lipid and lipoprotein levels as gemfibrozil, does not inhibit statin glucuronidation [19]. Therefore in patients on statin therapy who also need treatment with a fibrate one should use fenofibrate and not gemfibrozil in combination with statin therapy. Studies have shown that fenofibrate combined with statins does not increase toxicity [22].

There are other drug interactions with statins whose mechanisms are unknown. For example, the lopinavir/ritonavir combination used to treat HIV increases rosuvastatin levels by 2-5 fold and atazanavir/ritonavir increases rosuvastatin levels by 2-6 fold [23-27]. Similarly, the tipranavir/ritonavir combination increases rosuvastatin levels 2 fold and atorvastatin levels 8 fold [26]. When HIV patients are on these drugs other statins should be used to lower LDL cholesterol levels.

Thus despite the excellent safety record of statins, careful attention must be paid to the potential drug-drug interactions.

Effect of Statin Therapy on Clinical Outcomes

A large number of studies using a variety of statins in diverse patient populations have shown that statin therapy reduces atherosclerotic cardiovascular disease. The Cholesterol Treatment Trialists have published meta-analyses derived from individual subject data. Their first publication included data from 14 trials with over 90,000 subjects [28]. There was a 12% reduction in all-cause mortality in the statin treated subjects, which was mainly due to a 19% reduction in coronary heart disease deaths. Non-vascular causes of death were similar in the statin and placebo groups indicating that statin therapy and lowering LDL did not increase the risk of death from other causes such as cancer, respiratory disease, etc. Of particular note there was a 23% decrease in major coronary events per 1 mmol/L (39mg/dl) reduction in LDL cholesterol. Decreases in other vascular outcomes including non-fatal MI, coronary heart disease death, vascular surgery and stroke were also reduced by 20-25% per 1 mmol/L (39mg/dl) reduction in LDL cholesterol. Additionally, analysis of these studies demonstrated that the greater the reduction in absolute LDL cholesterol levels the greater the decrease in cardiovascular events. For example, while a 40mg/dl decrease in LDL cholesterol will reduce coronary events by approximately 20%, an 80mg/dl decrease in LDL cholesterol will reduce events by approximately 40%. These results support aggressive lipid lowering with statin therapy.

Of note the decrease in the number of events begins to be seen in the first year of therapy indicating that the ability of statins to reduce events occurs quickly and increases over time. The ability of statins to reduce cardiovascular events was seen in a wide diversity of patients including those with and without a history of prior cardiovascular disease, patients over age 65 and younger than age 65, males and females, and patients with and without a history of diabetes or hypertension. Additionally, the beneficial effects of statins were seen regardless of the baseline lipid levels. Subjects with elevated or low LDL, HDL, or triglyceride levels all had similar decreases in the relative risk of cardiovascular events.

A subsequent publication by the Cholesterol Treatment Trialists has focused on five studies with over 39,000 subjects that have compared usual vs. intensive statin therapy [29]. It was noted that there was a 0.51mmol/L (20mg/dl) further reduction in LDL cholesterol in the intensively treated subjects. This further decrease in LDL resulted in a15% reduction in cardiovascular events. The strong numerical relationship between decreases in LDL cholesterol levels and the reduction in cardiovascular events provides evidence indicating that much of the beneficial effect of statins is accounted for by lipid lowering.

In addition, the authors added 7 additional trials to their original comparison of statin treatment vs. placebo for a total of 21 trials with over 129,000 subjects. In this larger cohort a 1mmol/L (39mg/dl) decrease in LDL was associated with a 21% reduction in major cardiovascular events. As seen previously the benefits of statin therapy were seen in a wide variety of subjects including patients older than age 75, obese patients, cigarette smokers, patients with decreased renal function, and patients with low and high HDL levels. Additionally, a reduction of cardiovascular events with statin therapy was seen regardless of baseline LDL levels.

A more recent meta-analysis by the Cholesterol Treatment Trialists examined the effect of statins in 27 trials that included 46,675 women and 127,474 men [30]. They found that statin therapy was similarly effective in reducing cardiovascular events in both men and women. Thus there is an overwhelming database of randomized clinical outcome trials showing the benefits of statin therapy in reducing cardiovascular disease, which, coupled with their excellent safety profile, has resulted in statins becoming a very widely used class of drugs and first line therapy for the prevention of cardiovascular disease.

Effect of Statins Therapy on Clinical Outcomes in Specific Patient Groups

Primary Prevention:

While there is no doubt that individuals with pre-existing cardiovascular disease require statin therapy, the use of statins for primary prevention was initially debated. There are now a large number of statin primary prevention studies. The Cholesterol Treatment Trialists reported that statin therapy was very effective in reducing cardiovascular events in subjects without a history of vascular disease and the magnitude of risk reduction was similar to subjects with a history of cardiovascular events [29]. Additionally, vascular deaths were reduced by statin treatment even in subjects without a history of vascular disease. As expected, non-vascular deaths were not altered in these subjects without a history of pre-existing vascular disease. Additionally, the Cholesterol Treatment Trialists compared the benefits of statin therapy based on baseline risk of developing cardiovascular disease (<5%, ≥5% to <10%, ≥10% to <20%, ≥20% to <30%, ≥30%) [31]. The proportional reduction in major vascular events was at least as big in the two lowest risk categories as in the higher risk categories indicating that subjects at low risk benefit from statin therapy. Similar to the Cholesterol Treatment Trialists analysis, a Cochrane review published in 2013 on the effect of statins in primary prevention patients reached the following conclusion: “Reductions in all-cause mortality, major vascular events, and revascularisations were found with no excess adverse events among people without evidence of CVD treated with statins” [32]. Recently, an additional study has been completed that focused on intermediate risk patients without cardiovascular disease. In this trial 12,705 men and women who had at least one risk factor for cardiovascular disease were randomized to 10mg rosuvastatin vs. placebo [33]. Rosuvastatin treatment resulted in a 27% reduction in LDL cholesterol levels and a 24% decrease in cardiovascular events providing additional evidence that statin treatment can reduce events in primary prevention patients. It is therefore clear that statins are effective in safely reducing events in primary prevention patients.

The key issue is “which primary prevention patients should be treated” and this is still controversial. It should be noted that the higher the baseline risk the greater the absolute reduction in events with statin therapy. For example, in a high risk patient with a 20% risk of developing a vascular event, a 25% risk reduction will result in a 15% risk of an event (absolute decrease of 5%). In contrast in a low risk patient with a 4% risk of developing a vascular event, a 25% risk reduction will result in a 3% risk (absolute decrease of only 1%). Thus, the absolute benefit of statin therapy over the short term will depend on the risk of developing cardiovascular disease.

Additionally, based on the Cholesterol Treatment Trialists results the reduction in cardiovascular events is dependent on the absolute decrease in LDL cholesterol levels. Thus the effect of statin treatment will be influenced by baseline LDL levels. For example a 50% decrease in LDL is 80mg/dl if the starting LDL is 160mg/dl and only 40mg/dl if the starting LDL is 80mg/dl. Based on studies showing that a decrease in LDL of 1 mmol/L (40mg/dl) reduces cardiovascular events by ~20% the relative benefit of statin therapy will be greater in the patient with the starting LDL of 160mg/dl (40% decrease in events) than in the patient with the starting LDL of 80mg/dl (20% decrease in events). Thus, decisions on treatment need to factor in both relative risk and baseline LDL levels.

Elderly:

The Cholesterol Treatment Trialists reported that cardiovascular events were reduced by 22% in subjects age 65 years or younger, 22% in subjects 66 to 75 years old, and 16% for those older than 76 years for every 1mmol/L (39mg/dl) decrease in LDL cholesterol [29]. The Prosper Study was specifically designed to determine the effect of pravastatin 40mg per day in patients 70-82 years of age with either evidence of vascular disease or risk factors for vascular disease [34]. Pravastatin therapy reduced LDL cholesterol levels by 27% and after 3.2 years decreased the risk of coronary heart disease events by 19%. Thus, the data clearly indicate that statin induced reductions in LDL cholesterol will decrease cardiovascular events in the elderly. Unfortunately studies on the very old (>85 year) are not available.

Women:

As noted above a recent meta-analysis by the Cholesterol Treatment Trialists examined the effect of statins in 27 trials that included 46,675 women and 127,474 men [30]. They found that statin therapy was similarly effective in reducing cardiovascular events in both men and women.

Asians:

Pharmacokinetic data have shown that the serum levels of statins are higher in Asians than in Caucasians [35]. Moreover, Asians achieve similar LDL lowering at lower statin doses than Caucasians [35]. Therefore the statin dose used should be lower in Asians. For example the starting dose of rosuvastatin is 5mg in Asians as compared to 10mg in Caucasians. Additionally, the maximum recommended dose of statin is lower in Japan vs. the United States (Table 2).

Table 2Maximum Statin Dose in Japan and United States

StatinJapanUnited States
Atorvastatin4080
Fluvastatin6080
Pravastatin2080
Rosuvastatin2040
Simvastatin2040

Diabetes:

Statin trials, including both primary and secondary prevention trials, have consistently shown the beneficial effect of statins on cardiovascular disease in patients with diabetes [36]. The Cholesterol Treatment Trialists analyzed data from 18,686 subjects with diabetes (mostly type 2 diabetes) from 14 randomized trials [37]. In the statin treated group there was a 9% decrease in all-cause mortality, a 13% decrease in vascular mortality, and a 21% decrease in major vascular events per 1mmol/L (39mg/dl) reduction in LDL cholesterol. The beneficial effect of statin therapy was seen in both primary and secondary prevention patients. The effect of statin treatment on cardiovascular events in patients with diabetes was similar to that seen in non-diabetic subjects. It should be noted that while the data for patients with type 2 diabetes is robust, the number of patients with type 1 diabetes in these trials is relatively small and the results less definitive. Also of note is that information on young patients with diabetes (< age 40) is very limited. Thus, these studies indicate that statins are beneficial in reducing cardiovascular disease in patients with diabetes.

Renal Disease:

The Cholesterol Treatment Trialists examined the effect of renal function on statin effectiveness. They reported that the relative risk reduction for cardiovascular events was similar if the eGFR was < 60ml/min as compared to > 90 or 60-90 [29]. Similarly, a recent meta-analysis of 57 studies with >143,000 participants with renal disease not on dialysis reported a 31 % reduction in major cardiovascular events in statin treated subjects compared to placebo groups [38]. Thus, in patients with renal disease not on dialysis, treatment with statins is beneficial and should be utilized in this population at high risk for vascular disease.

In contrast to the above results, studies examining the role of statins in dialysis patients have not found a benefit from statin therapy. The Deutsche Diabetes Dialyse Studie (4D) randomized 1255 type 2 diabetic subjects on hemodialysis to either 20 mg atorvastatin or placebo [39]. The LDL-cholesterol reduction was similar to that seen in non-dialysis patients but there was no significant reduction in cardiovascular death, nonfatal myocardial infarction, or stroke in the atorvastatin treated compared to the placebo group. Similarly, A Study to Evaluate the Use of Rosuvastatin in Subjects on Regular Hemodialysis (AURORA) randomized 2776 subjects on hemodialysis to rosuvastatin 10 mg or placebo [40]. Again, the LDL-cholesterol lowering in dialysis patients was similar to that seen in other studies but there was no significant effect on the primary endpoint of cardiovascular death, nonfatal myocardial infarction, or stroke. A meta-analysis of 25 studies involving 8289 dialysis patients found no benefit of statin therapy on major cardiovascular events, cardiovascular mortality, all-cause mortality or myocardial infarction, despite efficacious lipid lowering. The reason for the failure of statins in patients on maintenance dialysis is unclear but could be due to a number of factors including the possibility that the marked severity of atherosclerosis in end stage renal disease may limit reversal, that different mechanisms of atherosclerosis progression occurs in dialysis patients (for example an increased role for inflammation, oxidation, or thrombosis), or that cardiovascular events in this patient population may not be due to atherosclerosis. We would recommend continuing statin therapy in patients on dialysis who have been previously treated with statins but not initiating therapy in the rare statin naïve patient beginning dialysis.

Statins are primarily metabolized in the liver and therefore the need to adjust the statin dose is not usually needed in patients with renal disease until the eGFR is < 30ml/min. The effect of renal dysfunction on statin clearance varies from statin to statin [41]. For some statins such as atorvastatin, there is no need to adjust the dose in renal disease because there is limited renal clearance [41]. However, for other statins it is recommended to adjust the dose in patients when the eGFR is < 30ml/min. In patients with an eGFR < 30ml/min the maximum dose of rosuvastatin is 10mg, simvastatin 40mg, pitavastatin 2mg, pravastatin 20mg, lovastatin 20mg, and fluvastatin 40mg per day [41].

Congestive Heart Failure:

In the Corona study 5011 patients with systolic heart failure were randomly assigned to receive 10 mg of rosuvastatin or placebo per day [42]. While rosuvastatin treatment reduced LDL cholesterol levels by 45% compared to placebo, rosuvastatin did not decrease death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke. Why statin treatment was not beneficial in this patient population with congestive heart failure is unknown.

Liver Disease:

Many patients with liver disease, particularly those with nonalcoholic fatty liver disease (NAFLD), are at high risk for cardiovascular disease and therefore require statin therapy [43]. There have been concerns that these patients would not tolerate statin therapy and that statin therapy would worsen their underlying liver disease. Fortunately, there are now studies of statin therapy in patients with abnormal liver function tests and underlying liver disease at baseline [43-45]. With a variety of statins studies have demonstrated no significant worsening of liver disease and in fact several studies have suggested improvement in liver function tests with statin therapy [45]. This is true for patients with hepatitis C, NAFLD/NASH, and primary biliary cirrhosis. Additionally, in the GREACE trial, statin treatment reduced cardiovascular events in patients with moderately abnormal liver function tests (transaminases < 3x the upper limit of normal) [46]. Thus, in patients with mild liver disease without elevations in bilirubin or abnormalities in synthetic function, statins are safe and reduce the risk of cardiovascular disease.

Statin Side Effects

Diabetes:

After many years of statin use it was recognized that statins increase the risk of developing diabetes. In a meta-analysis of 13 trials with over 90,000 subjects, there was a 9% increase in the incidence of diabetes during follow-up among subjects receiving statin therapy [47]. All statins appear to increase the risk of developing diabetes. In comparisons of intensive vs. moderate statin therapy, Preiss et al observed that patients treated with intensive statin therapy had a 12% greater risk of developing diabetes compared to subjects treated with moderate dose statin therapy [48]. Older subjects, obese subjects, and subjects with high glucose levels were at a higher risk of developing diabetes while on statin therapy [36]. Thus, statins may be unmasking and accelerating the development of diabetes that would have occurred naturally in these subjects at some point in time. In patients without risk factors for developing diabetes, treatment with statins does not appear to increase the risk of developing diabetes. In patients with diabetes, an analysis of 9 studies with over 9,000 patients with diabetes reported that the patients randomized to statin therapy had a 0.12% higher A1c than the placebo group indicating that statin therapy is associated with only a very small increase in A1c levels in patients with diabetes that is unlikely to be clinically significant [49]. Individual studies, such as CARDS and the Heart Protection Study, have also shown only a very modest effect of statins on A1c levels in patients with diabetes [50, 51].

The mechanism by which statins increase the risk of developing diabetes is unknown. A recent study has demonstrated that a polymorphism in the gene for HMG-CoA reductase that results in a decrease in HMG-CoA reductase activity and a small decrease in LDL levels is also associated with an increase in body weight and plasma glucose and insulin levels [52]. This observation suggests that the inhibition of HMG-CoA reductase per se may be leading to the statin induced increased risk of diabetes. In balancing the benefits and risks of statin therapy it is important to recognize that an increase in plasma glucose levels is a surrogate marker for an increased risk of developing micro and macrovascular disease (i.e. an increase in plasma glucose per se is not an event but rather increases the risk of future events). In contrast, statin therapy is preventing actual clinical events that cause morbidity and mortality. Furthermore, it may take many years for an elevated blood glucose to induce diabetic complications while the reduction in cardiovascular events with statin therapy occurs relatively quickly. Patients on statin therapy should be periodically screened for the development of diabetes with measurement of fasting glucose levels or A1c levels.

Cancer:

Analysis of 14 trials with over 90,000 subjects by the Cholesterol Clinical Trialists did not demonstrate an increased risk of cancer or any specific cancer with statin therapy [28]. An update with an analysis of 27 trials with over 174,000 participants also did not observe an increase in cancer incidence or death [30]. Additionally, no differences in cancer rates were observed with any particular statin.

Cognitive Dysfunction:

Several randomized clinical trials have examined the effect of statin therapy on cognitive function and have not indicated any increased risk [53-55]. The Prosper Trial was designed to determine whether statin therapy will reduce cardiovascular disease in older subjects (age 70-82) [34]. In this trial cognitive function was assessed repeatedly and no difference in cognitive decline was found in subjects treated with pravastatin compared to placebo [34, 56]. In the Heart Protection Study over 20,000 patients were randomized to simvastatin 40mg or placebo and again no significant differences in cognitive function was observed between the statin vs. placebo group [57]. Additionally, a Cochrane review examined the effect of statin therapy in patients with established dementia and identified 4 studies with 1154 participants [58]. In this analysis no benefit or harm of statin therapy on cognitive function could be demonstrated in this high risk group of patients. Thus, while the FDA has mandated warnings regarding statin induced cognitive dysfunction randomized clinical trials do not indicate a significant association.

Liver Disease:

It was in initially thought that statins induced liver dysfunction and it was recommended that liver function tests be routinely obtained while patients were taking statins. However, studies have now shown that the risk of liver function test abnormalities in patients taking statins is very small [44]. For example, in a survey of 35 randomized studies involving > 74,000 subjects, elevations in transaminases were seen in 1.4% of statin treated subjects and 1.1% of controls [59]. Similarly, in a meta-analysis of > 49,000 patients from 13 placebo controlled studies, the incidence of transaminase elevations greater than three times the upper limit of normal was 1.14% in the statin group and 1.05% in the placebo group [60]. Moreover, even when the transaminase levels are elevated, repeat testing often demonstrates a return towards normal levels [61]. The increases in transaminase levels with statin therapy are dose related with high doses of statins leading to more frequent elevations [62]. At this time, routine monitoring of liver function tests in patients taking statins is no longer recommended. However, obtaining baseline liver function tests prior to starting statin therapy is indicated [44]. If liver function tests are obtained during statin treatment, one should not be overly concerned with modestly elevated transaminase levels (less than 3x the upper limit of normal) [44]. If the transaminase is greater than 3x the upper limit of normal the test should be repeated and if it remains > 3x the upper limit of normal, statin therapy should be stopped and the patient evaluated [44].

A more clinically important issue is whether statins lead to an increased risk of liver failure. Studies have suggested that the incidence of liver failure in patients taking statins is very similar to the rate observed in the general population (approx. 1 case per 1 million patient years) [63, 64]. Thus statin therapy causing serious liver injury is a very rare event.

Muscle:

The most common side effect of statin therapy is muscle symptoms. These can range from life threatening rhabdomyolysis to myalgias (Table 3) [65].

Table 3

Spectrum of Statin Induced Muscle Disorders (Adapted from J. Clinical Lipidology 8:S58-71, 2014)

Myalgia- aches, soreness, stiffness, tenderness, cramps with normal CK levels
Myopathy- muscle weakness with or without increased CK
Myositis- muscle inflammation
Myonecrosis- mild (CK >3x ULN); moderate (CK> 10x ULN); severe (CK> 50x ULN)
Rhabdomyolysis- myonecrosis with myoglobinuria or acute renal failure

Many patients will discontinue the use of statins due to muscle symptoms. Risk factors associated with an increased incidence of statin associated muscle symptoms are listed in Table 4 [66, 67].

Table 4Risk factors for Statin Myopathy

Medications that alter statin metabolism
Older age
Female
Hypothyroidism
Excess alcohol
Vitamin D deficiency
History of muscle disorders
Renal disease
Liver disease
Personal or family history of statin intolerance
Low BMI
Polymorphism in SLCO1B1 gene
High dose statin
Drug-drug interactions

In most randomized clinical trials, the incidence of myalgia was similar in the statin and placebo groups (see table 5) [68]. For example, in the AFCAPS/TexCAPS trial in the 3,301 subjects treated with 20-40mg lovastatin, 2,053 reported musculoskeletal symptoms [69]. However, in the 3,301 subjects in the placebo group 1,971 also reported musculoskeletal symptoms. Similarly, in the Jupiter trial, where 18,902 subjects were randomized to rosuvastatin 20mg per day or placebo 16% of the subjects treated with rosuvastatin had muscle symptoms [70]. However, in the placebo group muscle symptoms occurred in 15.4% of subjects.

Table 5: Muscle Disorders in Randomized Controlled Statin Trials

Myalgia % Myopathyb % Rhabdomyolysisc %

TrialDrugDoseSaPaSPSP
4SSimva20-403.73.20.05000
WOSCOPSPrava403.53.70000
HPSSimva40NRNR0.070.020.040.01
PROSPERPrava401.21.10000
CARDSAtorva104.04.80000
ASPENAtorva103.01.6000.080.08
SPARCLAtorva805.56.00.30.30.10.1
JUPITERRosuva207.96.90.10.10.010

a- S= statin, P= placebo; b- muscle pain of weakness with CK > 10x ULN; c- myopathy with CK > 40x ULN and/or renal impairment; d- HPS asked about muscle symptoms at each visit

While the results of the randomized trials suggest that muscle symptoms are not induced by statin therapy, in typical clinical settings a significant percentage of patients are unable to tolerate statins due to muscle symptoms (in many studies as high as 5-25% of patients) [71-73]. Recently there was a randomized trial that explored the issue of myopathy with statin therapy in great detail [74]. In this trial the effect of atorvastatin 80mg a day vs. placebo for 6 months on creatine kinase (CK), exercise capacity, and muscle strength was studied in 420 healthy, statin-naive subjects. Atorvastatin treatment led to a modest increase in CK levels (20.8U/L) with no change observed in the placebo group. None of the subjects had an elevation of CK > 10x the upper limits of normal. There were no changes in muscle strength or exercise capacity with atorvastatin treatment. However, myalgia was reported in 19 subjects (9.4%) in the atorvastatin group compared to 10 subjects (4.6%) in the placebo group (p=0.05). In this study “myalgia” was considered to be present if all of the following occurred: (1) subjects reported new or increased muscle pain, cramps, or aching not associated with ex­ercise; (2) symptoms persisted for at least 2 weeks; (3) symptoms resolved within 2 weeks of stopping the study drug; and (4) symp­toms reoccurred within 4 weeks of restarting the study medication. Notably these myalgias were not associated with elevated CK levels. In the atorvastatin group the myalgias tended to occur soon after therapy (average 35 days) whereas in the placebo group myalgias occur later (average 61 days). In the atorvastatin group the symptoms were predominantly localized to the legs and included aches, cramps, and fatigue, whereas in the placebo group they were more diverse including whole body fatigue, foot cramps, worsening of pain in previous injuries, and groin pain. A number of conclusions can be reached from this study. First, statin treatment does in fact increase the incidence of myalgias. Second, a substantial number of patients treated with placebo will also develop myalgias. Third, clinically differentiating statin induced myalgias from placebo induced myalgias is difficult, as there are no specific symptoms, signs, or biomarkers that clearly distinguish between the two. It should be recognized that the patient population typically treated with statins (patients 50-80 years of age) often have muscle symptoms in the absence of statin therapy and it is therefore difficult to be certain that the muscle symptoms described by the patient are actually due to statin therapy.

In a very small study in the Annals of Internal Medicine eight patients with “statin related myalgia” were re-challenged with statin or placebo and there were no statistically significant differences in the recurrence of myalgias on the statin or placebo [75]. This approach has been expanded upon in two larger studies. In 120 patients with “statin induced myalgia” patients were randomized in a double blinded crossover trial to either simvastatin 20mg per day or placebo and the occurrence of muscle symptoms was determined [76]. Only 36% of these patients were confirmed to actually have statin induced myalgia (presence of symptoms on simvastatin without symptoms on placebo). In a similar study, Nissen and colleagues studied 491 patients with “statin induced myalgia” treating with either atorvastatin 20mg per day or placebo in a double-blind crossover trial [77]. In this trial 42.6% of patients were confirmed to have statin induced muscle symptoms. Thus while statin induced myalgias are a real entity, in the clinic it is difficult to be certain whether the muscle symptoms are actually due to true statin intolerance or to other factors. The approach to treating these patients will be discussed later in this chapter (Treatment of Stain Intolerant Patients). While some patients will not tolerate statin therapy due to myalgias, this side effect does not appear to result in serious morbidity or long term consequences.

Fortunately the more serious muscle related side effects of statin therapy are rare (table 5). In a meta-analysis of 21 statin vs. placebo trials there was an excess risk of rhabdomyolysis of 1.6 patients per 100,000 patient years or a standardized rate of 0.016/patient years [61]. Other studies report a rate of rhabdomyolysis between 0.03- 0.16 per 1,000 patient years [78]. Similarly, the risk of statin induced myositis (muscle symptoms with an increase in CK 10 times the upper limits of normal) is also very low (table 5). In an analysis of 21 randomized trials myositis occurred in only 5 patients per 100,000 person years or 0.05/1000 patient years [61]. The higher the dose of statin used the greater the risk of myositis and rhabdomyolysis. In a comparison of five trials that compared high dose statin vs. low dose statin there was an excess risk of rhabdomyolysis of 4 per 10,000 people treated [29]. The likely basis for an increased risk of myositis or rhabdomyolysis is elevated statin blood levels, which are more likely to occur with high doses of statins. In the development of statins, manufacturers have studied higher doses that are not approved for clinical use. For example, simvastatin and pravastatin at 160mg per day were studied but discontinued due to an increased incidence of muscle side effects [79, 80]. Recently the use of simvastatin 80mg per day, a previously approved dose, was restricted due to an increased risk of muscle side effects. Similarly, pitavastatin at doses greater than 4mg per day was investigated, but development was abandoned when an increased risk of rhabdomyolysis was observed. Along similar lines, in many of the patients that develop rhabdomyolysis, the etiology can be linked to the use of other drugs that alter statin metabolism thereby increasing statin blood levels [67]. For example, prior to drug interactions being recognized the use of cyclosporine, gemfibrozil, HIV protease inhibitors, and erythromycin in conjunction with certain statins was linked with the development of rhabdomyolysis [67]. Finally, common variants in SLCO1B1, which encodes the organic anion-transporting polypeptide OATP1B1, are strongly associated with an increased risk of statin-induced myopathy [81]. OATP1B1 facilitates the transport of statins into the liver and certain polymorphisms are associated with an increased risk of developing statin induced muscle disorders, due to a the decreased transport of statins into the liver resulting in increased blood levels [82]. The exact mechanism by which elevated blood levels induce muscle toxicity remains to be elucidated.

Recently it has been recognized that a very small number of patients taking statins develop a progressive autoimmune necrotizing myopathy, which is characterized by progressive symmetric proximal muscle weakness, elevated CK levels (typically >10x the ULN), and antibodies against HMG-CoA reductase [83]. It is estimated that this occurs in 2 or 3 per 100,000 patients treated with a statin [83]. This myopathy may begin soon after initiating statin therapy or develop after a patient has been on statins for many years [83]. Muscle biopsy reveals necrotizing myopathy without severe inflammation [83]. In contrast to the typical muscle disorders induced by statin therapy, the autoimmune myopathy progresses despite discontinuing therapy. Spontaneous improvement is not typical and most patients will need to be treated with immunosuppressive therapy (glucocorticoids plus methotrexate, azathioprine, or mycophenolate mofetil) [83].

From the above certain conclusions can be reached. First, the risk of serious muscle disorders due to statin therapy is very small, particularly if one is aware of the potential drug interactions that increase the risk. Second, the muscle toxicity is usually linked to elevated statin blood levels and the higher the dose of the statin the more likely the chance of developing toxicity. Third, myalgias in patients taking statins are very common and can be due to statin treatment. However, in the individual patient, it is very difficult to know if the myalgia is actually secondary to statin therapy and in many patients the myalgias are not due to the statin therapy. Fourth, the muscle symptoms that occur in association with statin treatment are a major reason why patients discontinue statin use and therefore better diagnostic algorithms and treatments are required to allow patients to better comply with these highly effective treatments to reduce cardiovascular disease.

Contraindications

Statins are contraindicated in pregnant women or lactating women. In women of child bearing age birth control should be discussed and statins should be discontinued prior to conception. In addition, liver function tests should be obtained prior to initiating statin treatment and moderate to severe liver disease is a contraindication to statin therapy [44].

Summary

An enormous data base has been accumulated which demonstrates that statins are very effective at reducing the risk of cardiovascular disease and that statins have an excellent safety profile. The risk benefit ratio of treating patients with statins is very favorable and has resulted in this class of drugs being widely utilized to lower serum lipid levels and to reduce the risk of cardiovascular disease and death.

EZETIMBE

Introduction

Ezetimibe (Zetia) inhibits the absorption of cholesterol by the intestine thereby resulting in modest decreases in LDL cholesterol levels [84]. Ezetimibe is primarily used in combination with statin therapy when statin treatment alone does not lower LDL levels sufficiently. It may also be used as monotherapy to lower LDL cholesterol levels in patients with statin intolerance. Finally, it is the drug of choice in patients with the rare genetic disorder sitosterolemia (discussed in detail in chapter 9) [85].

Effect of Ezetimibe on Lipid and Lipoprotein Levels

Pandor and colleagues have published a meta-analysis of ezetimibe monotherapy that included 8 studies with 2,722 patients [86]. They reported that ezetimibe decreased LDL cholesterol levels by 18.6%, decreased triglyceride levels by 8.1%, and increased HDL cholesterol levels by 3% compared to placebo. In a pooled analysis by Morrone and colleagues of 27 studies with 11, 714 subjects treated with ezetimibe in combination with statin therapy similar results were observed [87]. Specifically, LDL cholesterol levels were decreased by 15.1%, non-HDL cholesterol levels by 13.5%, triglycerides by 4.7%, apolipoprotein B levels by 10.8%, and HDL cholesterol levels were increased by 1.6%. The combination of a high dose potent statin plus ezetimibe can lower LDL cholesterol levels by 70% [88]. The effect of ezetimibe on lipid parameters occurs quickly and can be seen after 2 weeks of treatment. In patients with Heterozygous Familial Hypercholesterolemia who have marked elevations in LDL cholesterol levels, the addition of ezetimibe to statin therapy resulted in similar changes with a further 16.5% decrease in LDL cholesterol levels [89]. Thus in comparison with statins, ezetimibe treatment produces modest decreases in LDL cholesterol levels (15-20%). In addition to these changes in lipid parameters, ezetimibe in combination with a statin decreased hs-CRP by 10-19% compared to statin monotherapy [90, 91]. However, ezetimibe alone does not decrease hs-CRP levels [91].

Mechanisms Accounting for the Ezetimibe Induced Lipid Effects

NPC1L1 (Niemann-Pick C1-like 1 protein) is highly expressed in the intestine with the greatest expression in the proximal jejunum, which is the major site of intestinal cholesterol absorption [92, 93]. Knock out animals deficient in NPC1L1 have been shown to have a decrease in intestinal cholesterol absorption [92]. Ezetimibe binds to NPC1L1 and inhibits cholesterol absorption [84, 92, 93]. In animals lacking NPC1L1, ezetimibe has no effect on intestinal cholesterol absorption, demonstrating that ezetimibe’s effect on cholesterol absorption is mediated via NPC1L1 [84, 93]. Thus, a major site of action of ezetimibe is to block the absorption of cholesterol by the intestine [84, 93]. Cholesterol in the intestinal lumen is derived from both dietary cholesterol (approximately 25%) and biliary cholesterol (approximately 75%); thus the majority is derived from the bile [93]. As a consequence, even in patients that have very little cholesterol in their diet ezetimibe will decrease cholesterol absorption. While ezetimibe is very effective in blocking intestinal cholesterol absorption it does not interfere with the absorption of triglycerides, fatty acids, bile acids, or fat soluble vitamins including vitamin D and K.

When intestinal cholesterol absorption is decreased the chylomicrons formed by the intestine contain less cholesterol and thus the delivery of cholesterol from the intestine to the liver is diminished [94]. This results in a decrease in the cholesterol content of the liver, leading to the activation of SREBPs, which enhance the expression of LDL receptors resulting in an increase in LDL receptors on the plasma membrane of hepatocytes (Figure 1) [94]. Thus, similar to statins the major mechanism of action of ezetimibe is to decrease the levels of cholesterol in the liver resulting in an increase in the number of LDL receptors leading to the increased clearance of circulating LDL [94]. In addition, the decreased cholesterol delivery to the liver may also decrease the formation and secretion of VLDL [94].

In addition to NPC1L1 expression in the intestine this protein is also expressed in the liver where it mediates the transport of cholesterol from the bile back into the liver [95]. The inhibition of NPC1L1 in the liver will result in the increased secretion of cholesterol in bile and thereby could also contribute to a decrease in the cholesterol content of the liver and an increase in LDL receptor expression and a decrease in VLDL production.

Pharmacokinetics and Drug Interactions

Following absorption by intestinal cells ezetimibe is rapidly glucuronidated. The glucuronidated ezetimibe is then secreted into the portal circulation and rapidly taken up by the liver where it is secreted into the bile and transported back to the intestine [84]. This enterohepatic circulation repeatedly returns the ezetimibe to its site of action (note glucuronidated ezetimibe is a very effective inhibitor of NPC1L1) [84]. Additionally, this enterohepatic circulation accounts for the long duration of action of ezetimibe and limits peripheral tissue exposure [84]. Ezetimibe is not significantly excreted by the kidneys and thus the dose does not need to be adjusted in patients with renal disease.

Ezetimibe is not metabolized by the P450 system and does not have many drug interactions [84]. It should be noted that cyclosporine does increase ezetimibe levels.

Effect of Ezetimibe Therapy on Clinical Outcomes

There have been a limited number of ezetimibe clinical outcome trials. Two have studied the effect of ezetimibe in combination with a statin vs. placebo making it virtually impossible to determine if ezetimibe per se has beneficial effects. However, one study has compared ezetimibe plus a statin vs. a statin alone.

The SEAS Trial was a randomized trial of 1873 patients with mild-to-moderate, asymptomatic aortic stenosis [96]. The patients received either simvastatin 40mg per day in combination with ezetimibe 10mg per day vs. placebo daily. The primary outcome was a composite of major cardiovascular events, including death from cardiovascular causes, aortic-valve replacement, non-fatal myocardial infarction, hospitalization for unstable angina pectoris, heart failure, coronary-artery bypass grafting, percutaneous coronary intervention, and non-hemorrhagic stroke. Secondary outcomes were events related to aortic-valve stenosis and ischemic cardiovascular events. Simvastatin plus ezetimibe lowered LDL cholesterol levels by 61% compared to placebo. There were no significant differences in the primary outcome between the treated vs. placebo groups. Similarly, the need for aortic valve replacement was also not different between the treated and placebo groups. However, fewer patients had ischemic cardiovascular events in the simvastatin plus ezetimibe treated group than in the placebo group (hazard ratio, 0.78; 95% CI, 0.63 to 0.97; P=0.02), which was primarily accounted for by a decrease in the number of patients who underwent coronary-artery bypass grafting. The design of this study does not allow for one to determine if the beneficial effect on ischemic cardiovascular events typically produced by statin therapy was enhanced by the addition of ezetimibe.

The SHARP Trial was a randomized trial of 9270 patients with chronic kidney disease (3023 on dialysis and 6247 not on dialysis) with no known history of myocardial infarction or coronary revascularization [97]. Patients were randomly assigned to simvastatin 20 mg plus ezetimibe 10 mg daily vs. placebo. The primary outcome was first major atherosclerotic event (non-fatal myocardial infarction or coronary death, non-hemorrhagic stroke, or any arterial revascularization procedure). Treatment with simvastatin plus ezetimibe resulted in a decrease in LDL cholesterol of 0·85 mmol/L (~34mg/dl). This decrease in LDL cholesterol was associated with a 17% reduction in major atherosclerotic events. In patients on hemodialysis there was a 5% decrease in cardiovascular events that was not statistically significant. Unfortunately similar to the SEAS Trial, it is impossible to tell whether the addition of ezetimibe improved outcomes above and beyond what would occur with statin treatment alone.

The IMPROVE-IT Trial tested whether the addition of ezetimibe to statin therapy will provide an additional beneficial effect in patients with the acute coronary syndrome [98]. The IMPROVE-IT Trial was a large trial with over 18,000 patients randomized to simvastatin 40mg per day vs. simvastatin 40mg per day + ezetimibe 10mg per day. On treatment LDL cholesterol levels were 70mg/dl in the statin alone group vs. 54mg/dl in the statin + ezetimibe group. There was a small but significant 6.4% decrease in major cardiovascular events (Cardiovascular death, MI, documented unstable angina requiring rehospitalization, coronary revascularization, or stroke) in the statin + ezetimibe group (HR 0.936 CI (0.887, 0.988) p=0.016). Cardiovascular death, non-fatal MI, or non-fatal stroke were reduced by 10% (HR 0.90 CI (0.84, 0.97) p=0.003). The results of this study have a number of important implications. First, it demonstrates that combination therapy may have benefits above and beyond statin therapy alone. Second, it provides further support for the hypothesis that lowering LDL per se will reduce cardiovascular events. Third, it suggests that lowering LDL levels into the 50s will have benefits above and beyond lowering LDL levels to the 70mg/dl range. These results have implications for determining goals of therapy and provide support for combination therapy.

Side Effects

Ezetimibe has not demonstrated significant side effects. In monotherapy trials, the effect on liver function tests was similar to placebo. In a meta-analysis by Toth et al. of 27 randomized trials in > 20,000 participants evaluating statin plus ezetimibe vs. statin alone the incidence of liver function test abnormalities was slightly greater in the combination therapy group (statin alone- 0.35% vs. statin plus ezetimibe 0.56%) [99]. In contrast, Luo and colleagues in a meta-analysis of 20 randomized with > 14,000 subjects did not observe a difference in liver function tests in the ezetimibe plus statin vs. statin alone group [100]. With regards to muscle side effects, a meta-analysis of seven randomized trials by Kashani and colleagues found that monotherapy with ezetimibe or ezetimibe in combination with a statin did not increase the risk of myositis compared to placebo or monotherapy with a statin [101]. Similarly, Luo et al also did not observe that combination therapy with ezetimibe and a statin increased the risk of myositis [100]. In a meta-analysis by Savarese et al. of 7 randomized long term studies including SEAS, SHARP, and IMPROVE-IT, the incidence of cancer was similar in patients treated with ezetimibe vs. patients not treated with ezetimibe [102]. This confirms a previous study that also did not demonstrate an increased cancer risk in the three largest ezetimibe trials [103].

Thus, over many years of use ezetimibe has been shown to be a very safe drug without major side effects.

Contraindications

Ezetimibe is contraindicated in patients with active liver disease. The use of ezetimibe during pregnancy and lactation has not been studied.

Summary

Ezetimibe has a modest ability to lower LDL cholesterol levels and can be a very useful adjunct to statin therapy. When added to statin therapy it will lower the LDL cholesterol by an additional 15-20% which is equivalent to three titrations of the statin dose (for example adding ezetimibe is equivalent to increasing atorvastatin from 10mg to 80mg per day). Additionally, the combination of a high dose of a potent statin (rosuvastatin 40mg per day) with ezetimibe was able to lower the LDL by approximately 70%, which will allow many patients to reach their LDL goal [91]. In patients intolerant of statins who either cannot take a statin or can only take low doses of a statin, ezetimibe is extremely useful in further lowering LDL cholesterol. The ease of taking ezetimibe and the lack of serious side effects make it an obvious second choice drug after statins to lower LDL.

BILE ACID SEQUESTRANTS

Introduction

There are three bile acid sequestrants approved for use in the United States. The first bile acid sequestrant, cholestyramine (Questran), was developed in the 1950s and was the second drug available to lower cholesterol levels (niacin was the first drug). Colestipol (Colestid) was developed in the 1970s and is very similar to cholestyramine. In 2000, Colesevelam was approved. Colesevelam has enhanced binding and affinity for bile acids compared to cholestyramine and colestipol and therefore can be given in much lower doses reducing some side effects [104]. Because these drugs work by binding bile acids they are most effective when taken with meals.

Effect of Bile Acid Sequestrants on Lipid and Lipoprotein Levels

The major effect of bile acid sequestrants is to lower LDL cholesterol levels in a dose dependent fashion. Depending upon the specific drug and dose the decrease in LDL ranges from approximately 5 to 30% [104-106]. The effect of monotherapy with bile acid sequestrants on LDL levels observed in various studies is shown in table 6.

Table 6Effect of bile acid sequestrants on LDL cholesterol

DrugLDL lowering
Cholestyramine 4g/day7% decrease
Cholestyramine 24g/day28% decrease
Colestipol 4g/day12% decrease
Colestipol 16g/day24% decrease
Colesevelam 3.8g/day15% decrease
Colesevelam 4.3g/day18% decrease

Bile acid sequestrants are typically used in combination with statins and the addition of bile acid sequestrants to statin therapy will result in a further 10% to 25% decrease in LDL cholesterol levels [104-106]. Combination therapy can result in a 60% reduction in LDL levels when high doses of potent statins are combined with high doses of bile acid sequestrants. Bile acid sequestrants will also further lower LDL cholesterol levels by as much as 18% when added to statins and ezetimibe [107]. This is particularly useful in patients with Heterozygous Familial Hypercholesterolemia who can have very high LDL levels at baseline. Additionally, in patients who are statin intolerant, the combination of a bile acid sequestrant and ezetimibe resulted in an additional 10-20% decrease in LDL cholesterol compared to either drug alone [108, 109]. Thus both in monotherapy and in combination with other drugs that lower LDL levels, bile acid sequestrants are very effective in lowering LDL levels

Bile acid sequestrants have a very modest effect on HDL levels, typically resulting in a 3-9% increase [104-106]. The effect of bile acid sequestrants on triglyceride levels varies [104-106]. In patients with normal triglyceride levels, bile acid sequestrants increase triglyceride levels by a small amount. However, as baseline triglyceride levels increase, the effect of bile acid sequestrants on plasma triglyceride levels becomes greater, and can result in substantial increases in triglyceride levels. In patients with triglycerides > 400mg/dl the use of bile acid sequestrants is contraindicated.

Non-Lipid Effects of Bile Acid Sequestrants

Bile acid sequestrants have been shown to reduce fasting glucose and hemoglobin A1c levels [110]. Colesevelam has been most intensively studied and in a number of different studies colesevelam has decreased A1c levels by approximately 0.5-1.0% in patients also treated with a variety of glucose lowering drugs including metformin, sulfonylureas, and insulin. The Food and Drug Administration (FDA) has approved colesevelam for improving glycemic control in patients with type 2 diabetes.

Bile acid sequestrants decrease CRP. For example, Devaraj et al have shown that colesevelam decreases hs-CRP by 18% compared to placebo [111]. In combination with a statin, colesevelam reduced hs-CRP levels by 23% compared to statin alone [112].

Mechanisms Accounting for Bile Acid Sequestrants Induced Lipid Effects

Bile acid sequestrants bind bile acids in the intestine, preventing their reabsorption in the terminal ileum leading to the increased fecal excretion of bile acids [113]. This decrease in bile acid reabsorption reduces the size of the bile acid pool, which stimulates the conversion of cholesterol into bile acids in the liver [113]. This increase in bile acid synthesis decreases hepatic cholesterol levels leading to the activation of SREBPs that up-regulate the expression of the enzymes required for the synthesis of cholesterol and the expression of LDL receptors [113]. The increase in hepatic LDL receptors results in the increased clearance of LDL from the circulation leading to a decrease in serum LDL levels (Figure 1). Thus similar to statins and ezetimibe, bile acids lower plasma LDL cholesterol levels by decreasing hepatic cholesterol levels, which stimulates LDL receptor production and thereby accelerates the clearance of LDL from the blood.

The key regulator of bile acid synthesis is FXR (farnesoid X receptor), a nuclear hormone receptor that forms a heterodimer with RXR to regulate gene transcription [114, 115]. Bile acids down-regulate cholesterol 7α hydroxylase, the first enzyme in the bile acid synthetic pathway by several FXR mediated mechanisms. In the ileum, bile acids via FXR stimulate the production of FGF19, which is secreted into the portal vein and inhibits cholesterol 7α hydroxylase expression in the liver [114]. Additionally, in the liver, bile acids activate FXR leading to the increased expression of SHP (small heterodimer partner), which inhibits the transcription of cholesterol 7α hydroxylase [115]. Thus, a decrease in bile acids will lead to the decreased activation of FXR in the liver and intestines and thereby result in an increase in cholesterol 7α hydroxylase expression and the increased conversion of cholesterol to bile acids resulting in a decrease in hepatic cholesterol content.

Decreased activation of FXR can also explain the adverse effects of bile acid sequestrants on triglyceride levels [116, 117]. Activation of FXR increases the expression of apolipoprotein C-II, apolipoprotein A-V, and the VLDL receptor, proteins that decrease plasma triglyceride levels while decreasing the expression of apolipoprotein C-III, a protein that is associated with increases in plasma triglycerides [116, 117]. Thus, activation of FXR would be expected to decrease triglyceride levels as increases in apolipoprotein C-II, apolipoprotein A-V, and the VLDL receptor and decreases in apolipoprotein C-III would reduce plasma triglyceride levels. With bile acid sequestrants the activation of FXR would be reduced and decreases in the expression of apolipoprotein C-II, apolipoprotein A-V, and the VLDL receptor and increased expression of apolipoprotein C-III would increase plasma triglyceride levels.

The mechanism by which treatment with bile acid sequestrants improves glycemic control is unclear.

Pharmacokinetics and Drug Interactions

Bile acid sequestrants are not absorbed and not altered by digestive enzymes and thus their primary effects are localized to the intestine [104-106]. It should be noted that bile acid sequestrants can indirectly have systemic effects by decreasing the reabsorption of bile acids and thereby reducing the exposure of cells to bile acids, which are biologically active compounds.

Unfortunately, in the intestine bile acid sequestrants can impede the absorption of many other drugs [104-106]. This is particularly true for cholestyramine and colestipol which are used in large quantities (maximum doses- cholestyramine 24 grams per day; colestipol 30 grams per day). In contrast, colesevelam, which requires a much lower quantity of drug because of its high affinity and binding capacity for bile salts, has less of an effect on the absorption of other drugs (recommended dose of colesevelam 3.75 grams/day). Of particular note colesevelam does not interfere with absorption of statins, fenofibrate, or ezetimbe. A list of some of the drugs whose absorption is affected by cholestyramine or colestipol is shown in table 7 and a list of drugs whose absorption is affected by colesevelam is shown in table 8.

Table 7Some of the Drugs Affected by Cholestyramine/Colestipol

StatinsEzetimibeGemfibrozilFenofibrate
ThiazidesFurosemideSpironolactoneDigoxin
WarfarinL-thyroxineCorticosteroidsVitamin K
CyclosporineRaloxifineNSAIDsSulfonylureas
AspirinBeta blockersTricyclic

Table 8Some of the Drugs Affected by Colesevelam

L-thyroxineCyclosporineGlimepirideGlipizide
GlyburidePhenytoinOlmesartanWarfarin
Oral contraceptives

It is currently recommended that medications should be taken either 4 hours before or 4 hours after taking bile acid sequestrants. This is particularly important with drugs that have a narrow toxic/therapeutic window, such as thyroid hormone, digoxin, or warfarin. It can be very difficult for many patients, particularly those on multiple medications, to take bile acid sequestrants given the need to separate pill ingestion.

Cholestyramine and colestipol may also interfere with the absorption of fat soluble vitamins. Taking a multivitamin 4 hours before or after these drugs can reduce the likelihood of a vitamin deficiency.

Effect of Bile Acid Sequestrants on Clinical Outcomes

The Lipid Research Clinics Coronary Primary Prevention Trial (LRC-CPPT) of cholestyramine vs. placebo was the first large drug study to explore the effect of specifically lowering LDL cholesterol on cardiovascular outcomes [118]. LRC-CPPT was a multicenter, randomized, double-blind study in 3,806 asymptomatic middle-aged men with primary hypercholesterolemia. The treatment group received cholestyramine 24 grams per day and the control group received a placebo for an average of 7.4 years. In the cholestyramine group total and LDL cholesterol was decreased by 8.5% and 12.6% as compared to the placebo group. In the cholestyramine group there was a 19% reduction in risk (p < 0.05) of the primary end point accounted for by a 24% reduction in definite CHD death and a 19% reduction in nonfatal myocardial infarction. In addition, the incidence rates for new positive exercise tests, angina, and coronary bypass surgery were reduced by 25%, 20%, and 21%, respectively, in the cholestyramine group. The reduction in events correlated with the decrease in LDL cholesterol levels [119]. Of note, compliance with cholestyramine 24 grams per day was limited with many patients taking much less than the prescribed doses. These results indicate that lowering LDL cholesterol with bile acid sequestrant monotherapy will reduce cardiovascular disease.

In addition to the LRC-CPPT clinical outcome study, two studies have examined the effect of cholestyramine monotherapy on angiographic changes in the coronary arteries. The National Heart, Lung, and Blood Institute Type II Coronary Intervention Study and the St Thomas Atherosclerosis Regression Study reported that cholestyramine decreased the progression of atherosclerosis [120, 121]. There are a number of studies that have employed bile acid sequestrants in combination with other drugs and have shown a reduction in the progression of atherosclerosis or an increase in the regression of atherosclerosis but given the use of multiple drugs it is difficult to attribute the beneficial effects to the bile acid sequestrants [122-124]. Unfortunately there are no clinical outcome studies comparing statins alone vs. statins plus bile acid sequestrants.

Side Effects

Bile acid sequestrants do not have major systemic side effects as they are not absorbed and remain in the intestinal tract. However, they do cause gastrointestinal (GI) side effects [104-106]. Constipation is a very common side effect and can be severe. In addition, patients will often complain of bloating, abdominal discomfort, and aggravation of hemorrhoids. Because of GI distress, a significant number of patients will discontinue therapy with bile acid sequestrants. These GI side effects are much more common with cholestyramine and colestipol compared to colesevelam, which is much better tolerated. One can reduce or ameliorate these GI side effects by increasing hydration, adding fiber to the diet (psyllium), and using stool softeners. Notably, bile acid sequestrants do not cause liver or muscle problems.

One should also be aware that bile acid sequestrants can be difficult for many patients to take. Colestipol and colesevelam pills are large and can be difficult for some patients to swallow. Additionally, patients need to take a large number of these pills (colesevelam- 6 pills per day; colestipol- as many as 16 pills per day). The granular forms of cholestyramine and colestipol do not dissolve and are ingested as a suspension in liquid. Many patients find mixing with water leads to an unpalatable mixture that is difficult to take. Sometimes mixing with fruit juice, apple sauce, mash potatoes, etc. make the mixture more palatable. The suspension form of colesevelam with either 1.875 or 3.75 grams is preferred by many patients.

Contraindications

Bile acid sequestrants usually should be avoided in patients with pre-existing GI disorders. Bile acid sequestrants are contraindicated in patients with recent or repeated intestinal obstruction and patients with plasma triglyceride levels > 400mg/dl. In contradistinction from other lipid lowering drugs, bile acid sequestrants are not contraindicated during pregnancy or lactation (category B) [125]. In women of child bearing age who are planning to become pregnant bile acid sequestrants can be a good choice to lower LDL levels.

Summary

Bile acid sequestrants are useful secondary drugs for the treatment of elevated LDL cholesterol levels. They are typically used in combination with statin therapy as a second line drug or as an addition to statin plus ezetimibe therapy as a third line drug. In statin intolerant patients the combination of ezetimibe and a bile acid sequestrant is frequently employed. Bile acid sequestrants can be difficult drugs for patients to take due to GI side effects, difficulty taking the medication, and the need to avoid taking these drugs with other medications. To improve compliance with these drugs the clinician needs to spend time educating the patient on how to take these drugs and how to avoid side effects.

PCSK9 INHIBITORS

Introduction

In 2015 two monoclonal antibodies that inhibit PCSK9 (proprotein convertase subtilisin kexin type 9) were approved for the lowering of LDL cholesterol levels. Alirocumab (Praluent) is produced by Regeneron/Sanofi and evolocumab (Repatha) is produced by Amgen [126, 127]. Alirocumab is administered as either 75mg or 150mg subcutaneously every 2 weeks while evolocumab is administered as either 70mg subcutaneously every 2 weeks or 420mg subcutaneously once a month. Other monoclonal antibodies that inhibit PCSK9 are under development so it is likely that in the future there will be several monoclonal antibodies available for clinical use [126, 127].

Effect of PCSK inhibitors on Lipid and Lipoprotein Levels

There are a large number of studies that have examined the effect of PCSK9 inhibitors on lipid and lipoprotein levels. A meta-analysis of 24 studies comprising 10,159 patients reported a reduction in LDL cholesterol levels of approximately 50% and in an increase in HDL of 5-8% [128]. Notably, in 12 RCTs with 6,566 patients, Lp(a) levels were reduced by 25-30% [128]. It should be recognized that most LDL cholesterol lowering drugs (statins, ezetimibe, and bile acid sequestrants) do not lower Lp(a) levels. PCSK9 inhibitors have not been shown to decrease hs-CRP levels [129].

Monotherapy:

Both alirocumab and evolocumab have been studied as monotherapy vs. ezetimibe. In the Mendel-2 study patients were randomly assigned to evolocumab, placebo, or ezetimibe [130]. In the evolocumab group, LDL cholesterol levels decreased by 57% while in the ezetimibe group LDL cholesterol levels decreased by 18% compared to placebo. Additionally, non-HDL cholesterol was decreased by 49%, apolipoprotein B by 47%, triglycerides by 5.3% (NS), and Lp(a) by 18.5% while HDL levels increased by 5.5% in the evolocumab treated subjects. In a study of alirocumab vs. exetimibe LDL cholesterol levels were reduced by 47% in the alirocumab group and 16% in the ezetimibe group [131]. In addition alirocumab decreased non-HDL cholesterol by 41%, apolipoprotein B by 37%, triglycerides by 12%, and Lp(a) by 17% and increased HDL by 6%. Thus PCSK9 monoclonal antibodies are very effective in lowering pro-atherogenic lipoproteins when used in monotherapy and have a more robust effect than ezetimibe.

In Combination with Statins:

In the Odyssey Combo I study, patients on maximally tolerated statin therapy were randomized to alirocumab or placebo [132]. Similar to monotherapy results, when alirocumab was added to statin therapy there was a further decrease in LDL cholesterol levels by 46%, non-HDL cholesterol by 38%, apolipoprotein B by 36%, and Lp(a) by 15% with an increase in HDL of 7% and no change in triglyceride levels. In the Odyssey Combo II study, patients on maximally tolerated statin therapy were randomized to alirocumab vs. ezetimibe [133]. Alirocumab reduced LDL levels by 51% while ezetimibe reduced LDL by 21%, demonstrating that even when added to statin therapy, alirocumab has a significantly greater ability to reduce LDL cholesterol levels than ezetimibe. In Odyssey Combo II, non-HDL cholesterol levels were decreased by 42%, apolipoprotein B by 41%, triglycerides by 13%, and Lp(a) by 28% while HDL increased by 9% in the alirocumab treated group. In the Laplace-2 study, evolocumab was added to various statins used at different doses [134]. It didn’t make any difference which statin was being used (atorvastatin, rosuvastatin, or simvastatin) or what dose (atorvastatin 10mg or 80mg; rosuvastatin 5mg or 40mg); the addition of evolocumab resulted in an approximately 60% further decrease in LDL cholesterol levels beyond statin alone. Additionally, the Laplace-2 trial also showed that evolocumab was much more potent than ezetimibe when added to statin therapy (evolocumab resulted in an approximately 60% decrease in LDL vs. while ezetimibe resulted in an approximately 20-25% reduction).

In Combination with a Statin and Ezetimibe:

When evolocumab was added to patients receiving atorvastatin 80mg and ezetimibe 10mg there was 48% further reduction in LDL cholesterol levels indicating that even in patients on very aggressive lipid lowering therapy the addition of a PCSK9 inhibitor can still result in a marked reduction in LDL [135]. In addition to decreasing LDL there was also a 41% decrease in non-HDL cholesterol, a 38% decrease in apolipoprotein B, and a 19% decrease in Lp(a) when evolocumab was added to statin plus ezetimibe therapy.

Patients with Heterozygous Familial Hypercholesterolemia:

Both alirocumab and evolocumab have been tested in patients with Heterozygous Familial Hypercholesterolemia [136, 137]. In the Rutherford-2 trial, evolocumab lowered LDL cholesterol by 60%, non-HDL cholesterol by 56%, apolipoprotein B by 49%, Lp(a) by 31%, and triglycerides by 22% while increasing HDL by 8% [136]. In the Odyssey FH I and FH II studies, alirocumab lowered LDL cholesterol by approximately 55%, non-HDL cholesterol by ~50%, apolipoprotein B by ~43%, Lp(a) by ~19% and triglycerides by ~14% while increasing HDL by ~7% [137]. Thus, in these difficult to treat patients PCSK9 monoclonal antibodies were still very effective at lowering pro-atherogenic lipoproteins.

Patients with Homozygous Familial Hypercholesterolemia:

Evolocumab resulted in a 31% decrease in LDL levels compared to placebo in patients with Homozygous Familial Hypercholesterolemia [138]. The response to therapy appears to be dependent on the underlying genetic cause. Patients with mutations in the LDL receptor leading to the expression of defective receptors respond to therapy whereas patients with mutations leading to negative receptors have a poor response [138, 139]. Given the mechanism by which PCSK9 inhibitors lower LDL cholesterol levels it is not surprising that patients that do not have any functional LDL receptors will not respond to therapy (see section on Mechanism of Lipid Lowering)

Statin Intolerant Patients:

A number of studies have examined the effect of PCSK9 monoclonal antibodies in statin intolerant patients (myalgias) and compared the response to ezetimibe treatment [77, 140, 141]. As expected treatment with a PCSK9 inhibitor was more effective in lowering LDL cholesterol levels than ezetimibe. Importantly, muscle symptoms were less frequent in the pCSK9 treated patients than those treated with ezetimibe, indicating that PCSK9 monoclonal antibodies will be an effective treatment choice in statin intolerant patients with myalgias.

Patients with Diabetes:

A meta-analysis of three trials with 413 patients with type 2 diabetes found that in patients with type 2 diabetes evolocumab caused a 60% decrease in LDL cholesterol compared to placebo and a 39% decrease in LDL compared to ezetimibe treatment [142]. In addition, in patients with type 2 diabetes, evolocumab decreased non-HDL cholesterol 55% vs. placebo and 34% vs. ezetimibe) and Lp(a) (31% vs. placebo and 26% vs. ezetimibe). These beneficial effects were not affected by glycemic control, insulin use, renal function, and cardiovascular disease status. Thus, PCSK9 inhibitors are effective therapy in patients with type 2 diabetes and the beneficial effects on pro-atherogenic lipoproteins is similar to what is observed in non-diabetic patients.

Patients with Hypertriglyceridemia:

There are no studies that have examined the effect of PCSK9 monoclonal antibodies in patients with marked elevations in triglyceride levels (>400mg/dl).

Mechanism Accounting for the PCSK9 Inhibitor Induced Lipid Effects

The linkage of PCSK9 with lipoprotein metabolism was first identified by Abifadel and colleagues in 2003, when they demonstrated that certain mutations in PCSK9 could result in the phenotypic appearance of Familiar Hypercholesterolemia [143]. Subsequent studies demonstrated that gain of function mutations in PCSK9 are an uncommon cause of Familiar Hypercholesterolemia [126, 127, 144]. In 2005 it was shown that loss of function mutations in PCSK9 resulted in lower LDL cholesterol levels and this decrease in LDL cholesterol levels is associated with a reduction in the risk of cardiovascular events [145, 146].

The main route of clearance of clearance of plasma LDL is via LDL receptors in the liver [147]. When the LDL particle binds to the LDL receptor the LDL particle- LDL receptor complex is taken into the liver by endocytosis [147]. The LDL particle and the LDL receptor then disassociate and the LDL lipoprotein particle is delivered to lysosomes where it is degraded and the LDL receptor returns to the plasma membrane (Figure 2) [147]. After endocytosis LDL receptors recirculate back to the plasma membrane over 100 times.

PCSK9 is predominantly expressed in the liver and secreted into the circulation. Once extracellular, PCSK9 can bind to the LDL receptor and alter the metabolism of the LDL receptor [148, 149]. Instead of the LDL receptor recycling to the plasma membrane the LDL receptor bound to PCSK9 remains associated with the LDL particle and is delivered to the lysosomes where it is also degraded (Figure 2) [148, 149]. This results in a decrease in the number of plasma membrane LDL receptors resulting in the decreased clearance of circulating LDL leading to elevations in plasma LDL cholesterol levels.

The PCSK9 monoclonal antibodies bind PCSK9 preventing the PCSK9 from interacting with LDL receptors and thereby preventing PCSK9 from inducing LDL receptor degradation [148, 149]. The decreased LDL receptor degradation results in an increase in hepatic LDL receptors on the plasma membrane leading to decreases in plasma LDL cholesterol levels. Thus, similar to statins, ezetimibe, and bile acid sequestrants, PCSK9 inhibitors are reducing plasma LDL levels by up-regulating hepatic LDL receptors. The difference is that PCSK9 inhibitors are decreasing the degradation of LDL receptors while statins, ezetimibe, and bile acid sequestrants stimulate the production of LDL receptors.

etx-lipid-ch24-fig2

The expression of PCSK9 is stimulated by SREBP-2 [148, 149]. Statins and other drugs that lower hepatic cholesterol levels lead to the activation of SREBP-2 and thereby increase plasma PCSK9 levels [148, 149]. Inhibition of PCSK9 with monoclonal antibodies is more effective in lowering plasma LDL cholesterol levels in patients on statin therapy due to the higher levels of plasma PCSK9 in these individuals.

The mechanism by which PCSK9 inhibitors reduce Lp(a) levels is unclear. It has recently been postulated that increasing hepatic LDL receptor levels in the setting of marked reductions in circulating LDL levels will result in the clearance of Lp(a) by liver LDL receptors [150]. Whether this entirely explains the decrease in Lp(a) is unclear given that in patients with Homozygous Familiar Hypercholesterolemia the absolute LDL cholesterol levels are not profoundly reduced but Lp(a) levels still decrease.

Pharmacokinetics and Drug Interactions

PCSK9 monoclonal antibodies are eliminated primarily by cellular endocytosis, phagocytosis, and target-mediated clearance. They are not metabolized or cleared by the liver or kidneys and therefore there is no need to adjust the dose in patients with either liver or kidney disease. There are no interactions with the cytochrome P450 system or transport proteins and thus the risk of drug-drug interactions is minimal. Currently there are no reported drug-drug interactions with PCSK9 monoclonal antibodies.

Effect of PCSK9 Inhibitors on Clinical Outcomes

There are four large outcome trials with > 70,000 patients that are expected to be completed in 2017/2018 (Table 9) [126, 127]. There are two studies that provide preliminary data addressing cardiovascular outcomes. In the Osler study, 4465 patients who had completed phase 2 or 3 studies with evolocumab .were randomly assigned in to receive either evolocumab plus standard therapy or standard therapy alone [151]. Patients were followed for a median of 11.1 months. Evolocumab treatment reduced LDL cholesterol levels by 61% and the rate of cardiovascular events at 1 year was reduced from 2.18% in the standard-therapy group to 0.95% in the evolocumab group (hazard ratio 0.47; P=0.003). In the Odyssey long term trial, 2341 patients on statin therapy and at high risk for cardiovascular events who had LDL cholesterol levels > 70 mg/dl despite therapy were randomly assigned to receive alirocumab or placebo [152]. LDL cholesterol levels were decreased by 62% and the rate of major adverse cardiovascular events at 78 weeks was decreased with alirocumab compared to placebo (1.7% vs. 3.3%; hazard ratio, 0.52; P=0.02). These two trials provide preliminary data supporting that lowering LDL cholesterol levels with PCSK9 inhibitors will have beneficial effects on cardiovascular outcomes.

Table 9PCSK9 Outcome Trials

NumberDrugPatient Population
ODYSSEY18,000AlirocumabPost-acute coronary syndrome
FOURIER27,500EvolocumabStable cardiovascular disease
SPIRE-117,000BococizumabHigh risk patients; LDL 70-100
SPIRE-29,000BococizumabHigh risk patients; LDL > 100

Side Effects

The major side effect of PCSK9 monoclonal antibodies has been injection site reactions including erythema, itching, swelling, pain, and tenderness. Allergic reactions have been reported and as with any protein there is potential immunogenicity. In general side effects have been minimal, which is not surprising, as monoclonal antibodies do not typically have off target side effects. Since PCSK9 does not appear to have important functions other than regulating LDL receptor degradation, it is not surprising that inhibiting PCSK9 function has not resulted in major side effects. One must recognize that these PCSK9 monoclonal antibodies have only been in use for a relatively short time in a small number of patients and it of course possible that unexpected side effects will be revealed with longer use in a larger number of subjects. The large cardiovascular outcome studies described above should provide further insights into potential side effects (Table 9).

An issue of concern is whether lowering LDL to very low levels has the potential to cause toxicity. In a number of the PCSK9 studies a significant number of patients have had LDL cholesterol levels < 25mg/dl. For example, in the Odyssey long term study 37% of patients on alirocumab had two consecutive LDL cholesterol levels below 25mg/dl and in the Osler long term study in patients treated with evolocumab 13% had values below 25mg/dl [152, 153]. In these short term PCSK9 studies, toxicity from very low LDL cholesterol levels has not been observed. Additionally, in patients with Familial Hypobetalipoproteinemia LDL levels can be very low and these patients do not have any major disorders [85]. Similarly, there are rare individuals who are homozygous for loss of function mutations in the PCSK9 gene and they also do not appear to have major medical issues [127]. Finally, in a number of statin trials there have been patients with very low LDL cholesterol levels and an increased risk of side effects has not been consistently observed in those patients [154-156]. Thus, with the limited data available there does not appear to be a major risk of markedly lowering LDL cholesterol levels. However, the large outcome studies that are in progress will shed further light on this important issue.

Contraindications

Other than a history of a hypersensitivity to these drugs there are currently no contraindications.

Summary

PCSK9 monoclonal antibodies robustly reduce LDL cholesterol levels when used as monotherapy or when used in combination with statins. In distinction to most other cholesterol lowering drugs the PCSK9 inhibitors also decrease Lp(a) levels. The side effect profile appears to be very favorable and there are no drug-drug interactions. Crucial studies are underway to determine whether PCSK9 inhibitors will reduce cardiovascular events and whether significant side effects will occur.

LOMITAPIDE

Introduction

Lomitapide (Juxtapid), a selective microsomal triglyceride transfer protein inhibitor, was approved in December 2012 for lowering LDL cholesterol levels in adults with Homozygous Familial Hypercholesterolemia [157-159]. As will be discussed below it lowers LDL cholesterol levels by an LDL receptor independent mechanism.

Effect on Lomitapide on Lipid and Lipoprotein Levels

The effect of lomitapide on lipid and lipoprotein levels has been studied in patients with Homozygous Familial Hypercholesterolemia. The pivotal study was a 78 week single arm open label study in 29 patients receiving treatment for Homozygous Familial Hypercholesterolemia [160]. Lomitapide was initiated at 5mg per day and was up-titrated to 60mg per day based on tolerability and liver function tests. On an intention to treat basis, LDL was decreased by 40% and apolipoprotein B by 39%. In patients who were taking lomitapide, LDL levels were reduced by 50%. In addition to decreasing LDL cholesterol levels, non-HDL cholesterol levels were decreased by 50%, Lp(a) by 15%, and triglycerides by 45%. Interestingly HDL and apolipoprotein A-I levels were decreased by 12% and 14% respectively in this study.

The effect of lomitapide has also been studied in patients without Homozygous Familial Hypercholesterolemia. A study by Samaha and colleagues compared the effect of ezetimibe and lomitapide in patients with elevated cholesterol levels [161]. Patients were treated with ezetimibe alone, lomitapide alone, or the combination of ezetimibe and lomitapide. Ezetimibe monotherapy led to a 20–22% decrease in LDL cholesterol levels, lomitapide monotherapy led to a dose dependent decrease in LDL-cholesterol levels (19% at 5.0 mg, 26% at 7.5 mg and 30% at 10 mg). Combined therapy produced a larger dose-dependent decrease in LDL cholesterol levels (35%, 38% and 46%, respectively). Additionally, lomitapide decreased triglycerides by 10%, non-HDL cholesterol by 27%, apolipoprotein B by 24%, and Lp(a) by 17%.

The above studies demonstrate that lomitapide decreases LDL cholesterol, non-HDL cholesterol, triglycerides, and Lp(a) levels.

Mechanism Accounting for the Lomitapide Induced Lipid Effects

Lomitapide is a selective inhibitor of microsomal triglyceride transfer protein (MTP) [157-159]. MTP is located in the endoplasmic reticulum of hepatocytes and enterocytes where it plays a key role in transferring triglycerides onto newly synthesized apolipoprotein B leading to the formation of VLDL and chylomicrons [162]. Loss of function mutations in both alleles of MTP results in abetalipoproteinemia, which is characterized by the virtual absence of apolipoprotein B, VLDL, and LDL in the plasma due to the failure of the liver to produce VLDL [85]. Lomitapide by inhibiting MTP activity reduces the secretion of chylomicrons by the intestine and VLDL by the liver leading to a decrease in LDL, apolipoprotein B, triglycerides, non-HDL cholesterol, and Lp(a) [157-159].

Pharmacokinetics and Drug Interactions

Lomitapide is extensively metabolized in the liver by the CYP3A4 pathway [157, 158]. Therefore lomitapide is contraindicated in patients on strong CYP3A4 inhibitors and lower doses should be used in patients on weak inhibitors. Of particular note, in patients on atorvastatin the maximal dose of lomitapide is 30mg per day and lomitapide should not be used in patients taking more than 20mg of simvastatin [157, 158]. Lomitapide can increase warfarin levels and therefore close monitoring is required. Finally, given the risk of liver abnormalities (see side effect section) the avoidance of alcohol or a reduction in alcohol intake is prudent.

Effect of Lomitapide on Clinical Outcomes

There are no clinical outcome trials but it is presumed that lowering LDL cholesterol levels in patients with Homozygous Familial Hypercholesterolemia will reduce cardiovascular events.

Side Effects

As expected from its mechanism of action lomitapide causes side effects in the GI tract and liver. In the GI tract diarrhea, nausea, vomiting, and dyspepsia occur very commonly [157-159]. In the pivotal study in patients with Homozygous Familial Hypercholesterolemia, 90% of the patients developed GI symptoms during drug titration[160]. GI side effects are potentiated by high fat meals and it is therefore recommended that dietary fat be limited. Approximately 10% of patients will discontinue lomitapide mostly from diarrhea. Lomitapide also reduces the absorption of fat soluble vitamins and therefore patients need to take vitamin supplements [157, 158]. Additionally, it may also block the absorption of essential fatty acids and it is therefore recommended that supplements of essential fatty acids also be provided (at least 200 mg linoleic acid, 210 mg alpha-linolenic acid (ALA), 110 mg eicosapentaenoic acid (EPA), and 80 mg docosahexaenoic acid (DHA) [157, 158].

Blocking the formation of VLDL in the liver can lead to fatty liver with elevated liver enzymes [157-159]. Approximately 30% of patients will develop increased transaminase levels but in the small number of patients studied this has not resulted in liver failure. After stopping the drug the transaminases have returned to normal. Whether long term treatment with lomitapide will lead to an increase in liver disease is unknown. There is a single case of a patient with lipoprotein lipase deficiency who was treated for 13 years with lomitapide who developed steatohepatitis and fibrosis [163].

Because of the high potential risk of serious complications the FDA has mandated several measures to ensure that patients are closely followed and monitored for liver toxicity ((Risk Evaluation and Mitigation Strategy (REMS) Program) [157, 158]. ALT, AST, alkaline phosphatase, and total bilirubin should be measured before initiating treatment. During the first year, liver function tests should be measured prior to each increase in dose or monthly, whichever occurs first. After the first year, liver function tests should be measured at least every 3 months and before any increase in dose.

Contraindications

Lomitapide should not be used during pregnancy and in patients with moderate or severe liver disease. In addition, it should not be used in patients on strong CYP3A4 inhibitors.

Summary

Lomitapide is approved only for the treatment of lipid disorders in patients with Homozygous Familiar Hypercholesterolemia. The frequent GI side effects and the potential risk of serious liver disease greatly limit the use of this drug and it should be reserved for the small number of patients in which more benign therapies are not sufficient in lowering LDL cholesterol into a reasonable range. It is used as an adjunct to other lipid lowering therapies in patients with Homozygous Familiar Hypercholesterolemia.

MIPOMERSEN

Introduction

Mipomersen (Kynamro) is a second generation apolipoprotein B antisense oligonucleotide that was approved in January 2013 for the treatment of patients older than 12 years with Homozygous Familiar Hypercholesterolemia [158, 159, 164]. It is administered as a 200mg subcutaneous injection once a week [158, 159, 164]. As will be discussed below, it lowers LDL cholesterol levels by an LDL receptor independent mechanism.

Effect on Mipomersen on Lipid and Lipoprotein Levels

In the pivotal trial, 51 patients with Homozygote Familial Hypercholesterolemia on treatment were randomized to additional treatment with mipomersen (n= 34) or placebo (n=17) and followed for 26 weeks [165]. Mipomersen lowered LDL cholesterol levels by 21% and apolipoprotein B levels by 24% compared to placebo. In addition, non-HDL cholesterol was decreased by 21.6%, triglycerides by 17%, and Lp(a) by 23% while HDL and apolipoprotein A-I were increased by 11.2% and 3.9% respectively.

Mipomersen has also been studied in patients with Heterozygous Familial Hypercholesterolemia. In a double-blind, placebo-controlled, randomized trial patients on maximally tolerated statin therapy were treated weekly with subcutaneous mipomersen 200 mg or placebo for 26 weeks [166]. LDL cholesterol levels decreased by 33% in the mipomersen group compared to placebo. Additionally, mipomersen significantly reduced apolipoprotein B by 26%, triglycerides by 14%, and Lp(a) by 21% compared to placebo with no significant changes in HDL cholesterol levels. In an extension follow-up study the beneficial effects of mipomersen were maintained for at least 2 years [167].

In a meta-analysis of 8 randomized studies with 462 subjects with either non-specified hypercholesterolemia or Heterozygous Familial Hypercholesterolemia, Panta and colleagues reported that mipomersen decreased LDL cholesterol levels by 32% compared to placebo [168]. Additionally, non-HDL cholesterol was decreased by 31%, apolipoprotein B by 33%, triglycerides by 36%, and Lp(a) by 26% with no effect on HDL levels.

Mechanism Accounting for the Mipomersen Induced Lipid Effects

Apolipoprotein B 100 is the main structural protein of VLDL and LDL and is required for the formation of VLDL and LDL [147]. Familiar Hypobetalipoproteinemia is a genetic disorder due to a mutation of one apolipoprotein B allele that is characterized by very low concentrations of LDL and apolipoprotein B due to the decreased production of lipoproteins by the liver [85]. Mipomersin, an apolipoprotein B antisense oligonucleotide, mimics Familiar Hypobetalipoproteinemia by inhibiting apolipoprotein B 100 production in the liver by pairing with apolipoprotein B mRNA preventing its translation [158, 159, 164]. This decrease in apolipoprotein B synthesis results in a decrease in hepatic VLDL production leading to a decrease in LDL levels.

Pharmacokinetics and Drug Interactions

No significant drug interactions have been reported. Given the risk of liver abnormalities (see side effect section) the avoidance of alcohol or a reduction in alcohol intake would be prudent.

Effect of Mipomersen on Clinical Outcomes

There are no clinical outcome trials but it is presumed that lowering LDL cholesterol levels in patients with Homozygous Familial Hypercholesterolemia will reduce cardiovascular events.

Side Effects

The most common side effect is injection site reactions, which occur in 75-98% of patients and typically consist of one or more of the following: erythema, pain, tenderness, pruritus and local swelling [158, 159, 164]. Additional, influenza like symptoms, which typically occur within 2 days after an injection, occur in 30-50% of patients and include one or more of the following: influenza-like illness, pyrexia, chills, myalgia, arthralgia, malaise or fatigue which result in a substantial percentage of patients discontinuing therapy [158, 159, 164].

A major safety concern is liver toxicity [158, 159, 164]. By inhibiting VLDL formation and secretion the risk of fatty liver is increased. Fatty liver has been observed in 5-20% of patients treated with mipomersen [158, 159, 164]. In 10-15% treated with mipomersen increases in transaminases occur [158, 159, 164]. Additionally, liver biopsies from 7 patients after a minimum of 6 months of mipomersen therapy have demonstrated the presence of fatty liver although there was no inflammation despite elevations in liver enzymes [169]. Fortunately when treatment is discontinued liver function tests and fatty liver return to normal.

Because of the high potential risk of serious complications the FDA has mandated several measures to ensure that patients are closely followed and monitored for liver toxicity (Risk Evaluation and Mitigation Strategy (REMS) Program) [158, 159, 164]. Liver function should be measured prior to initiating therapy and monthly during the first year and every 3 months after the first year.

Contraindications

Mipomersen is contraindicated in patients in patients with liver disease or severe renal disease. Mipomersen is not recommended for use during pregnancy or lactation. In animal studies mipomersen has not resulted in fetal abnormalities.

Summary

Mipomersen is approved only for the treatment of lipid disorders in patients with Homozygous Familiar Hypercholesterolemia. The potential risk of serious liver disease greatly limits the use of this drug and therefore it should be reserved for the small number of patients in which more benign therapies are not sufficient in lowering LDL cholesterol into a reasonable range. It is used as an adjunct to other lipid lowering therapies in patients with Homozygous Familiar Hypercholesterolemia.

APPROACH TO TREATING PATIENTS WITH HYPERCHOLESTEROLEMIA

Introduction

The issues of deciding who to treat, how aggressive to treat, and the goals of therapy are discussed in detail in Chapter 4 and therefore will not be addressed in this chapter [2]. Additionally, the role of life style changes to lower LDL cholesterol is discussed in great depth in chapter 23 and therefore will also not be addressed here [1]. Rather we will focus on how to use the drugs discussed in this chapter to treat various categories of patients. The factors to consider when deciding which drugs are appropriate to use for lowering plasma LDL cholesterol levels are; the efficacy in lowering LDL cholesterol levels, the effect on other lipid and lipoprotein levels, the ability to reduce cardiovascular events, the side effects of drug therapy, the ease of complying with the drug regimen, and the cost of the drugs. The approximate monthly cost of various cholesterol lowering drugs is shown in table 10.

Table 10Monthly Cost of Cholesterol Lowering Drugs

Simvastatin 40mg per day$3.69*
Pravastatin 40mg per day$9.03*
Atorvastatin 10mg per day$10.26
Atorvastatin 80mg per day$19.50*
Rosuvastatin 40mg per day$260.83*
Pitavastatin 4mg per day$232.65*
Ezetimibe 10mg per day$272.41*
Colesevelam 3.75g packet (1 per day)$643.36*
Colesevelam 625mg (6 per day)$641.52*
Colestipol 1g (10 per day)$367.12*
Alirocumab twice a monthApprox. $1166
Evolocumab twice a monthApprox. $1166
Lomitapide (dose varies)Approx. $20,000
Mipomersen 200mg q 2weeksApprox. $14,000-15,000

*Costco prices May 18, 2016

Isolated Hypercholesterolemia

In patients with isolated hypercholesterolemia (LDL cholesterol < 190mg/dl), initial drug therapy should be a generic statin such as atorvastatin. The dose should be chosen based on the percent reduction in LDL required to lower the LDL level to below the target goal. As discussed earlier, the side effects of statin therapy increase with higher doses so one should not routinely use high doses, but instead should choose a dose balancing the benefits and risks. Generic statins are inexpensive drugs and are very effective in both lowering LDL cholesterol levels and reducing cardiovascular events. Additionally, they have an excellent safety profile. If the initial statin dose does not lower LCL cholesterol to goal, one can then increase the dose. If the maximal statin dose does not lower LDL cholesterol sufficiently adding ezetimibe is a reasonable next step. Ezetimibe is easy to take, has few side effects, will modestly lower LDL cholesterol, and has been shown in combination with statins to further reduce cardiovascular events. High dose statin and ezetimibe will lower LDL cholesterol by as much as 70%, which will lower LDL to goal in the vast majority of patients who do not have a genetic basis for their elevated LDL levels. If the combination of statin plus ezetimibe does not lower the LDL to goal one can add a third drug. If the LDL is close to goal one could add a bile acid sequestrant such as colesevelam. If the LDL is not very close to goal one could instead use a statin plus a PCSK9 inhibitor, which together will result in marked reductions in LDL cholesterol levels. If the patient has diabetes with a moderately elevated A1c level using a bile acid sequestrant such as colesevelam instead of ezetimibe or in combination with ezetimibe could improve both glycemic control and further lower LDL levels.

Mixed Hyperlipidemia

In patients with mixed hyperlipidemia (elevated LDL cholesterol and triglyceride levels) Initial drug therapy should also be a generic statin unless triglyceride levels are greater than 500-1000mg/dl. In addition to lowering LDL cholesterol levels, statins are also very effective in lowering triglyceride levels particularly when the triglycerides are elevated. If LDL is not lowered sufficiently ezetimibe is a reasonable next step. Bile acid sequestrants are not appropriate drugs in patients with hypertriglyceridemia. The great uncertainty is what to do when the LDL levels are at goal but the triglycerides and non-HDL cholesterol are still elevated. Should one add a fibrate, niacin, or fish oil to lower triglycerides and non-HDL cholesterol levels? At this time it is uncertain as there are no randomized outcome studies demonstrating benefit of adding triglyceride lowering drugs to statins and therefore experts have diverse opinions. Hopefully, future studies will clarify the appropriate approach.

Heterozygous Familial Hypercholesterolemia

In patients with Heterozygous Familial Hypercholesterolemia or other disorders with very elevated LDL cholesterol levels (>190mg/dl), high doses of a potent statin such as atorvastatin or rosuvastatin are the first step to lower LDL cholesterol levels. In many patients this will not be sufficient. If the LDL cholesterol levels are close to goal then adding ezetimibe is a reasonable next step. However, if the LDL cholesterol still needs to be markedly reduced a PCSK9 inhibitor may be a better choice as these drugs can markedly lower LDL cholesterol levels.

Statin Intolerantance

Statin intolerance is almost always due to myalgias but on occasion can be due other issues, such as increased liver or muscle enzymes, cognitive dysfunction, or other neurological disorders. The percentage of patients who are “statin intolerant” varies greatly but in clinical practice a significant number of patients have difficulty taking statins.

As discussed earlier it can be difficult to determine if the muscle symptoms that occur when a patient is taking a statin are actually due to the statin or are unrelated to statin use. The first step in a “statin intolerant patient” is to take a careful history of the nature and location of the muscle symptoms and the timing of onset in relation to statin use to determine whether the presentation fits the typical picture for statin induced myalgias. The characteristic findings with a statin induced myalgia are shown in table 11 and findings that are not typical for statin induced myalgia are shown in table 12.

Table 11Characteristic Findings with Statin Induced Myalgia

Symmetric
Proximal muscles
Muscle pain, tenderness, weakness, cramps
Symptom onset < 4 weeks
Improves within 2-4 weeks of stopping statin
Same symptoms occur with re-challenge within 4 weeks

Table 12Symptoms Atypical in Statin Induced Myalgia

Unilateral
Asymmetric
Small muscles
Joint or tendon pain
Shooting pain, muscle twitching or tingling
Symptom onset > 12 weeks
No improvement after discontinuing statin

One should also check a CK level but this is almost always in the normal range. If the CK is not elevated and the symptoms do not suggest a statin induced myalgia one can often reassure the patient and continue statin therapy. This is often successful and studies have shown that many patients that stop taking statins due to “statin induced myalgia” can be successfully treated with a statin. If the CK is elevated it should be repeated after instructing the patient to avoid exercise for 48 hours. Also the CK levels should be compared to CK levels prior to starting therapy. If the CK remains elevated (3x upper limit of normal) the statin should be discontinued. Similarly if the CK is normal but the symptoms are suggestive of a statin induced myalgia the statin should also be discontinued. The next step is to determine if one can identify reversible factors that could be increasing statin toxicity (hypothyroidism, vitamin D deficiency, drug interactions). If none are identified the next step after the myalgias have resolved is to try a low dose of a different statin that is metabolized by a different pathway (for example instead of atorvastatin, which is metabolized by the CYP3A4 pathway, rosuvastatin, which has a different pathway of metabolism). Because statin side effects are dose related, a low dose of a statin may often be tolerated. One can also try several different statins as sometimes a patient may tolerate one statin and not others. In some instances using a long acting statin (rosuvastatin or atorvastatin) 1-3 times per week can work (we usually start with once per week and then slowly increase frequency as tolerated). In these circumstances (low doses or 1-3 times per week) the reduction in LDL cholesterol may not be sufficient but one can use combination therapy with other drugs such as ezetimibe, bile acid sequestrants, or PCSK9 inhibitors to achieve LDL target goals.

Many providers have combined Coenzyme Q10 with statins to prevent statin induced myalgias. However, randomized trials with Coenzyme Q10 supplementation have not consistently shown benefit. A recent trial, which carefully screened patients to make sure they actually had statin induced myalgias, failed to show a benefit from Coenzyme Q10 supplementation. It has also been recommended that vitamin D supplementation be used to prevent statin induced myalgias but there are no randomized trials demonstrating benefit.

If after trying various approaches a patient still has myalgias and is unable to tolerate statin therapy one needs to utilize other approaches to lower LDL levels. Similarly, if there are other reasons why a patient cannot take a statin, such as developing muscle pathology, one will also need to utilize other approaches to lower LDL levels. These patients can be treated with ezetimibe, bile acid sequestrants, or PCSK 9 inhibitors either as monotherapy or in combination to achieve LDL goals.

There are patients who will refuse statins and other drug therapy because they do not believe in taking pharmaceuticals but will take natural products. In these patients we have employed red yeast rice, which decreases LDL cholesterol because it contains a form of lovastatin. It is effective but one should recognize that the quality control is not similar to the standards of pharmaceutical products and that there can be batch to batch variations. Furthermore there is a risk of drug-drug interactions if used with inhibitors of CYP3A4. However, in this particular patient population, who refuses to take statins or other drugs, this can be a reasonable alternative. If a patient just refuses statins (usually based on a belief that statins are toxic) we will employ other cholesterol lowering drugs.

CONCLUSIONS

With currently available drugs to lower LDL cholesterol levels we are now able to markedly reduce LDL cholesterol levels and achieve our LDL goals in the vast majority of patients and thereby reduce the risk of cardiovascular disease. Patients with Homozygous Familial Hypercholesterolemia and some patients with Heterozygous Familial Hypercholesterolemia still present major clinical challenges and it can be very difficult in these patients to achieve LDL goals.

REFERENCES

  1. Enkhmaa, B., et al., Lifestyle Changes: Effect of Diet, Exercise, Functional Food, and Obesity Treatment, on Lipids and Lipoproteins, in Endotext, L.J. De Groot, et al., Editors. 2015: South Dartmouth (MA).
  2. Grundy, S., Risk Assessment and Guidelines for the Management of High Blood Cholesterol, in Endotext, L.J. De Groot, et al., Editors. 2015: South Dartmouth (MA).
  3. Endo, A., A gift from nature: the birth of the statins. Nat Med, 2008. 14(10): p. 1050-2.
  4. Alberts, A.W., Discovery, biochemistry and biology of lovastatin. Am J Cardiol, 1988. 62(15): p. 10J-15J.
  5. Ballantyne, C.M., et al., Correlation of non-high-density lipoprotein cholesterol with apolipoprotein B: effect of 5 hydroxymethylglutaryl coenzyme A reductase inhibitors on non-high-density lipoprotein cholesterol levels. Am J Cardiol, 2001. 88(3): p. 265-9.
  6. Jones, P.H., et al., Effects of rosuvastatin versus atorvastatin, simvastatin, and pravastatin on non-high-density lipoprotein cholesterol, apolipoproteins, and lipid ratios in patients with hypercholesterolemia: additional results from the STELLAR trial. Clin Ther, 2004. 26(9): p. 1388-99.
  7. Jones, P.H., et al., Comparison of the efficacy and safety of rosuvastatin versus atorvastatin, simvastatin, and pravastatin across doses (STELLAR* Trial). Am J Cardiol, 2003. 92(2): p. 152-60.
  8. Stein, E.A., M. Lane, and P. Laskarzewski, Comparison of statins in hypertriglyceridemia. Am J Cardiol, 1998. 81(4A): p. 66B-69B.
  9. Bos, S., R. Yayha, and J.E. van Lennep, Latest developments in the treatment of lipoprotein (a). Curr Opin Lipidol, 2014. 25(6): p. 452-60.
  10. Adams, S.P., M. Tsang, and J.M. Wright, Lipid-lowering efficacy of atorvastatin. Cochrane Database Syst Rev, 2015. 3: p. CD008226.
  11. Adams, S.P., S.S. Sekhon, and J.M. Wright, Lipid-lowering efficacy of rosuvastatin. Cochrane Database Syst Rev, 2014. 11: p. CD010254.
  12. Liao, J.K., Clinical implications for statin pleiotropy. Curr Opin Lipidol, 2005. 16(6): p. 624-9.
  13. Joshi, P.H. and T.A. Jacobson, Therapeutic options to further lower C-reactive protein for patients on statin treatment. Curr Atheroscler Rep, 2010. 12(1): p. 34-42.
  14. Goldstein, J.L. and M.S. Brown, A century of cholesterol and coronaries: from plaques to genes to statins. Cell, 2015. 161(1): p. 161-72.
  15. Huff, M.W. and J.R. Burnett, 3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors and hepatic apolipoprotein B secretion. Curr Opin Lipidol, 1997. 8(3): p. 138-45.
  16. Causevic-Ramosevac, A. and S. Semiz, Drug interactions with statins. Acta Pharm, 2013. 63(3): p. 277-93.
  17. Hu, M. and B. Tomlinson, Evaluation of the pharmacokinetics and drug interactions of the two recently developed statins, rosuvastatin and pitavastatin. Expert Opin Drug Metab Toxicol, 2014. 10(1): p. 51-65.
  18. Sirtori, C.R., The pharmacology of statins. Pharmacol Res, 2014. 88: p. 3-11.
  19. Kellick, K.A., et al., A clinician's guide to statin drug-drug interactions. J Clin Lipidol, 2014. 8(3 Suppl): p. S30-46.
  20. Lee, J.W., J.K. Morris, and N.J. Wald, Grapefruit Juice and Statins. Am J Med, 2016. 129(1): p. 26-9.
  21. Holdaas, H., et al., Effect of fluvastatin on cardiac outcomes in renal transplant recipients: a multicentre, randomised, placebo-controlled trial. Lancet, 2003. 361(9374): p. 2024-31.
  22. Group, A.S., et al., Effects of combination lipid therapy in type 2 diabetes mellitus. N Engl J Med, 2010. 362(17): p. 1563-74.
  23. Busti, A.J., et al., Effects of atazanavir/ritonavir or fosamprenavir/ritonavir on the pharmacokinetics of rosuvastatin. J Cardiovasc Pharmacol, 2008. 51(6): p. 605-10.
  24. Gervasoni, C., et al., Potential association between rosuvastatin use and high atazanavir trough concentrations in ritonavir-treated HIV-infected patients. Antivir Ther, 2015. 20(4): p. 449-51.
  25. Kiser, J.J., et al., Drug/Drug interaction between lopinavir/ritonavir and rosuvastatin in healthy volunteers. J Acquir Immune Defic Syndr, 2008. 47(5): p. 570-8.
  26. Pham, P.A., et al., Differential effects of tipranavir plus ritonavir on atorvastatin or rosuvastatin pharmacokinetics in healthy volunteers. Antimicrob Agents Chemother, 2009. 53(10): p. 4385-92.
  27. van der Lee, M., et al., Pharmacokinetics and pharmacodynamics of combined use of lopinavir/ritonavir and rosuvastatin in HIV-infected patients. Antivir Ther, 2007. 12(7): p. 1127-32.
  28. Baigent, C., et al., Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins. Lancet, 2005. 366(9493): p. 1267-78.
  29. Cholesterol Treatment Trialists, C., et al., Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials. Lancet, 2010. 376(9753): p. 1670-81.
  30. Cholesterol Treatment Trialists, C., et al., Efficacy and safety of LDL-lowering therapy among men and women: meta-analysis of individual data from 174,000 participants in 27 randomised trials. Lancet, 2015. 385(9976): p. 1397-405.
  31. Cholesterol Treatment Trialists, C., et al., The effects of lowering LDL cholesterol with statin therapy in people at low risk of vascular disease: meta-analysis of individual data from 27 randomised trials. Lancet, 2012. 380(9841): p. 581-90.
  32. Taylor, F., et al., Statins for the primary prevention of cardiovascular disease. Cochrane Database Syst Rev, 2013. 1: p. CD004816.
  33. Yusuf, S., et al., Cholesterol Lowering in Intermediate-Risk Persons without Cardiovascular Disease. N Engl J Med, 2016.
  34. Shepherd, J., et al., Pravastatin in elderly individuals at risk of vascular disease (PROSPER): a randomised controlled trial. Lancet, 2002. 360(9346): p. 1623-30.
  35. Liao, J.K., Safety and efficacy of statins in Asians. Am J Cardiol, 2007. 99(3): p. 410-4.
  36. Feingold, K.R. and C. Grunfeld, Diabetes and Dyslipidemia, in Endotext, L.J. De Groot, et al., Editors. 2015: South Dartmouth (MA).
  37. Cholesterol Treatment Trialists, C., et al., Efficacy of cholesterol-lowering therapy in 18,686 people with diabetes in 14 randomised trials of statins: a meta-analysis. Lancet, 2008. 371(9607): p. 117-25.
  38. Su, X., et al., Effect of Statins on Kidney Disease Outcomes: A Systematic Review and Meta-analysis. Am J Kidney Dis, 2016.
  39. Wanner, C., et al., Atorvastatin in patients with type 2 diabetes mellitus undergoing hemodialysis. N Engl J Med, 2005. 353(3): p. 238-48.
  40. Fellstrom, B.C., et al., Rosuvastatin and cardiovascular events in patients undergoing hemodialysis. N Engl J Med, 2009. 360(14): p. 1395-407.
  41. Tannock, L., Dyslipidemia in Chronic Kidney Disease, in Endotext, L.J. De Groot, et al., Editors. 2000: South Dartmouth (MA).
  42. Kjekshus, J., et al., Rosuvastatin in older patients with systolic heart failure. N Engl J Med, 2007. 357(22): p. 2248-61.
  43. Corey, K.E. and D.E. Cohen, Lipid and Lipoprotein Metabolism in Liver Disease, in Endotext, L.J. De Groot, et al., Editors. 2000: South Dartmouth (MA).
  44. Bays, H., et al., An assessment by the Statin Liver Safety Task Force: 2014 update. J Clin Lipidol, 2014. 8(3 Suppl): p. S47-57.
  45. Herrick, C., S. Bahrainy, and E.A. Gill, Statins and the Liver. Endocrinol Metab Clin North Am, 2016. 45(1): p. 117-28.
  46. Athyros, V.G., et al., Safety and efficacy of long-term statin treatment for cardiovascular events in patients with coronary heart disease and abnormal liver tests in the Greek Atorvastatin and Coronary Heart Disease Evaluation (GREACE) Study: a post-hoc analysis. Lancet, 2010. 376(9756): p. 1916-22.
  47. Sattar, N., et al., Statins and risk of incident diabetes: a collaborative meta-analysis of randomised statin trials. Lancet, 2010. 375(9716): p. 735-42.
  48. Preiss, D., et al., Risk of incident diabetes with intensive-dose compared with moderate-dose statin therapy: a meta-analysis. JAMA, 2011. 305(24): p. 2556-64.
  49. Erqou, S., C.C. Lee, and A.I. Adler, Statins and glycaemic control in individuals with diabetes: a systematic review and meta-analysis. Diabetologia, 2014. 57(12): p. 2444-52.
  50. Colhoun, H.M., et al., Primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS): multicentre randomised placebo-controlled trial. Lancet, 2004. 364(9435): p. 685-96.
  51. Collins, R., et al., MRC/BHF Heart Protection Study of cholesterol-lowering with simvastatin in 5963 people with diabetes: a randomised placebo-controlled trial. Lancet, 2003. 361(9374): p. 2005-16.
  52. Swerdlow, D.I., et al., HMG-coenzyme A reductase inhibition, type 2 diabetes, and bodyweight: evidence from genetic analysis and randomised trials. Lancet, 2015. 385(9965): p. 351-61.
  53. Rojas-Fernandez, C., Z. Hudani, and V. Bittner, Statins and cognitive side effects: what cardiologists need to know. Cardiol Clin, 2015. 33(2): p. 245-56.
  54. Rojas-Fernandez, C.H., et al., An assessment by the Statin Cognitive Safety Task Force: 2014 update. J Clin Lipidol, 2014. 8(3 Suppl): p. S5-16.
  55. Richardson, K., et al., Statins and cognitive function: a systematic review. Ann Intern Med, 2013. 159(10): p. 688-97.
  56. Trompet, S., et al., Pravastatin and cognitive function in the elderly. Results of the PROSPER study. J Neurol, 2010. 257(1): p. 85-90.
  57. Collins, R., et al., Effects of cholesterol-lowering with simvastatin on stroke and other major vascular events in 20536 people with cerebrovascular disease or other high-risk conditions. Lancet, 2004. 363(9411): p. 757-67.
  58. McGuinness, B., et al., Statins for the treatment of dementia. Cochrane Database Syst Rev, 2014. 7: p. CD007514.
  59. Kashani, A., et al., Risks associated with statin therapy: a systematic overview of randomized clinical trials. Circulation, 2006. 114(25): p. 2788-97.
  60. de Denus, S., et al., Statins and liver toxicity: a meta-analysis. Pharmacotherapy, 2004. 24(5): p. 584-91.
  61. Law, M. and A.R. Rudnicka, Statin safety: a systematic review. Am J Cardiol, 2006. 97(8A): p. 52C-60C.
  62. Alsheikh-Ali, A.A., et al., Effect of the magnitude of lipid lowering on risk of elevated liver enzymes, rhabdomyolysis, and cancer: insights from large randomized statin trials. J Am Coll Cardiol, 2007. 50(5): p. 409-18.
  63. Russo, M.W., M. Scobey, and H.L. Bonkovsky, Drug-induced liver injury associated with statins. Semin Liver Dis, 2009. 29(4): p. 412-22.
  64. Tolman, K.G., Defining patient risks from expanded preventive therapies. Am J Cardiol, 2000. 85(12A): p. 15E-9E.
  65. Rosenson, R.S., et al., An assessment by the Statin Muscle Safety Task Force: 2014 update. J Clin Lipidol, 2014. 8(3 Suppl): p. S58-71.
  66. Stroes, E.S., et al., Statin-associated muscle symptoms: impact on statin therapy-European Atherosclerosis Society Consensus Panel Statement on Assessment, Aetiology and Management. Eur Heart J, 2015. 36(17): p. 1012-22.
  67. Thompson, P.D., P. Clarkson, and R.H. Karas, Statin-associated myopathy. JAMA, 2003. 289(13): p. 1681-90.
  68. Newman, C.B. and J.A. Tobert, Statin intolerance: reconciling clinical trials and clinical experience. JAMA, 2015. 313(10): p. 1011-2.
  69. Downs, J.R., et al., Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TEXCAPS): additional perspectives on tolerability of long-term treatment with lovastatin. Am J Cardiol, 2001. 87(9): p. 1074-9.
  70. Ridker, P.M., et al., Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med, 2008. 359(21): p. 2195-207.
  71. Bruckert, E., et al., Mild to moderate muscular symptoms with high-dosage statin therapy in hyperlipidemic patients--the PRIMO study. Cardiovasc Drugs Ther, 2005. 19(6): p. 403-14.
  72. Buettner, C., et al., Prevalence of musculoskeletal pain and statin use. J Gen Intern Med, 2008. 23(8): p. 1182-6.
  73. Cohen, J.D., et al., Understanding Statin Use in America and Gaps in Patient Education (USAGE): an internet-based survey of 10,138 current and former statin users. J Clin Lipidol, 2012. 6(3): p. 208-15.
  74. Parker, B.A., et al., Effect of statins on skeletal muscle function. Circulation, 2013. 127(1): p. 96-103.
  75. Joy, T.R., et al., N-of-1 (single-patient) trials for statin-related myalgia. Ann Intern Med, 2014. 160(5): p. 301-10.
  76. Taylor, B.A., et al., A randomized trial of coenzyme Q10 in patients with confirmed statin myopathy. Atherosclerosis, 2015. 238(2): p. 329-35.
  77. Nissen, S.E., et al., Efficacy and Tolerability of Evolocumab vs Ezetimibe in Patients With Muscle-Related Statin Intolerance: The GAUSS-3 Randomized Clinical Trial. JAMA, 2016. 315(15): p. 1580-90.
  78. Cziraky, M.J., et al., Risk of hospitalized rhabdomyolysis associated with lipid-lowering drugs in a real-world clinical setting. J Clin Lipidol, 2013. 7(2): p. 102-8.
  79. Davidson, M.H., et al., The efficacy and six-week tolerability of simvastatin 80 and 160 mg/day. Am J Cardiol, 1997. 79(1): p. 38-42.
  80. Rosenson, R.S. and H.E. Bays, Results of two clinical trials on the safety and efficacy of pravastatin 80 and 160 mg per day. Am J Cardiol, 2003. 91(7): p. 878-81.
  81. Group, S.C., et al., SLCO1B1 variants and statin-induced myopathy--a genomewide study. N Engl J Med, 2008. 359(8): p. 789-99.
  82. Hopewell, J.C., C. Reith, and J. Armitage, Pharmacogenomics of statin therapy: any new insights in efficacy or safety? Curr Opin Lipidol, 2014. 25(6): p. 438-45.
  83. Mammen, A.L., Statin-Associated Autoimmune Myopathy. N Engl J Med, 2016. 374(7): p. 664-9.
  84. Bruckert, E., P. Giral, and P. Tellier, Perspectives in cholesterol-lowering therapy: the role of ezetimibe, a new selective inhibitor of intestinal cholesterol absorption. Circulation, 2003. 107(25): p. 3124-8.
  85. Shapiro, M.D., Rare Genetic Disorders Altering Lipoproteins, in Endotext, L.J. De Groot, et al., Editors. 2000: South Dartmouth (MA).
  86. Pandor, A., et al., Ezetimibe monotherapy for cholesterol lowering in 2,722 people: systematic review and meta-analysis of randomized controlled trials. J Intern Med, 2009. 265(5): p. 568-80.
  87. Morrone, D., et al., Lipid-altering efficacy of ezetimibe plus statin and statin monotherapy and identification of factors associated with treatment response: a pooled analysis of over 21,000 subjects from 27 clinical trials. Atherosclerosis, 2012. 223(2): p. 251-61.
  88. Ballantyne, C.M., et al., Efficacy and safety of rosuvastatin 40 mg alone or in combination with ezetimibe in patients at high risk of cardiovascular disease (results from the EXPLORER study). Am J Cardiol, 2007. 99(5): p. 673-80.
  89. Kastelein, J.J., et al., Simvastatin with or without ezetimibe in familial hypercholesterolemia. N Engl J Med, 2008. 358(14): p. 1431-43.
  90. Sager, P.T., et al., Effects of ezetimibe coadministered with simvastatin on C-reactive protein in a large cohort of hypercholesterolemic patients. Atherosclerosis, 2005. 179(2): p. 361-7.
  91. Ballantyne, C.M., et al., Effect of ezetimibe coadministered with atorvastatin in 628 patients with primary hypercholesterolemia: a prospective, randomized, double-blind trial. Circulation, 2003. 107(19): p. 2409-15.
  92. Yu, L., The structure and function of Niemann-Pick C1-like 1 protein. Curr Opin Lipidol, 2008. 19(3): p. 263-9.
  93. Turley, S.D. and J.M. Dietschy, Sterol absorption by the small intestine. Curr Opin Lipidol, 2003. 14(3): p. 233-40.
  94. Telford, D.E., et al., The molecular mechanisms underlying the reduction of LDL apoB-100 by ezetimibe plus simvastatin. J Lipid Res, 2007. 48(3): p. 699-708.
  95. Pramfalk, C., Z.Y. Jiang, and P. Parini, Hepatic Niemann-Pick C1-like 1. Curr Opin Lipidol, 2011. 22(3): p. 225-30.
  96. Rossebo, A.B., et al., Intensive lipid lowering with simvastatin and ezetimibe in aortic stenosis. N Engl J Med, 2008. 359(13): p. 1343-56.
  97. Baigent, C., et al., The effects of lowering LDL cholesterol with simvastatin plus ezetimibe in patients with chronic kidney disease (Study of Heart and Renal Protection): a randomised placebo-controlled trial. Lancet, 2011. 377(9784): p. 2181-92.
  98. Cannon, C.P., et al., Ezetimibe Added to Statin Therapy after Acute Coronary Syndromes. N Engl J Med, 2015. 372(25): p. 2387-97.
  99. Toth, P.P., et al., Safety profile of statins alone or combined with ezetimibe: a pooled analysis of 27 studies including over 22,000 patients treated for 6-24 weeks. Int J Clin Pract, 2012. 66(8): p. 800-812.
  100. Luo, L., et al., Safety of coadministration of ezetimibe and statins in patients with hypercholesterolaemia: a meta-analysis. Intern Med J, 2015. 45(5): p. 546-57.
  101. Kashani, A., et al., Review of side-effect profile of combination ezetimibe and statin therapy in randomized clinical trials. Am J Cardiol, 2008. 101(11): p. 1606-13.
  102. Savarese, G., et al., Safety and efficacy of ezetimibe: A meta-analysis. Int J Cardiol, 2015. 201: p. 247-52.
  103. Peto, R., et al., Analyses of cancer data from three ezetimibe trials. N Engl J Med, 2008. 359(13): p. 1357-66.
  104. Aldridge, M.A. and M.K. Ito, Colesevelam hydrochloride: a novel bile acid-binding resin. Ann Pharmacother, 2001. 35(7-8): p. 898-907.
  105. Heel, R.C., et al., Colestipol: a review of its pharmacological properties and therapeutic efficacy in patients with hypercholesterolaemia. Drugs, 1980. 19(3): p. 161-80.
  106. Insull, W., Jr., Clinical utility of bile acid sequestrants in the treatment of dyslipidemia: a scientific review. South Med J, 2006. 99(3): p. 257-73.
  107. Huijgen, R., et al., Colesevelam added to combination therapy with a statin and ezetimibe in patients with familial hypercholesterolemia: a 12-week, multicenter, randomized, double-blind, controlled trial. Clin Ther, 2010. 32(4): p. 615-25.
  108. Zema, M.J., Colesevelam HCl and ezetimibe combination therapy provides effective lipid-lowering in difficult-to-treat patients with hypercholesterolemia. Am J Ther, 2005. 12(4): p. 306-10.
  109. Bays, H., et al., Lipid-lowering effects of colesevelam HCl in combination with ezetimibe. Curr Med Res Opin, 2006. 22(11): p. 2191-200.
  110. Fonseca, V.A., Y. Handelsman, and B. Staels, Colesevelam lowers glucose and lipid levels in type 2 diabetes: the clinical evidence. Diabetes Obes Metab, 2010. 12(5): p. 384-92.
  111. Devaraj, S., B. Autret, and I. Jialal, Effects of colesevelam hydrochloride (WelChol) on biomarkers of inflammation in patients with mild hypercholesterolemia. Am J Cardiol, 2006. 98(5): p. 641-3.
  112. Bays, H.E., et al., Effects of colesevelam hydrochloride on low-density lipoprotein cholesterol and high-sensitivity C-reactive protein when added to statins in patients with hypercholesterolemia. Am J Cardiol, 2006. 97(8): p. 1198-205.
  113. Einarsson, K., et al., Bile acid sequestrants: mechanisms of action on bile acid and cholesterol metabolism. Eur J Clin Pharmacol, 1991. 40 Suppl 1: p. S53-8.
  114. Kliewer, S.A. and D.J. Mangelsdorf, Bile Acids as Hormones: The FXR-FGF15/19 Pathway. Dig Dis, 2015. 33(3): p. 327-31.
  115. Chiang, J.Y., Bile acids: regulation of synthesis. J Lipid Res, 2009. 50(10): p. 1955-66.
  116. Porez, G., et al., Bile acid receptors as targets for the treatment of dyslipidemia and cardiovascular disease. J Lipid Res, 2012. 53(9): p. 1723-37.
  117. Edwards, P.A., H.R. Kast, and A.M. Anisfeld, BAREing it all: the adoption of LXR and FXR and their roles in lipid homeostasis. J Lipid Res, 2002. 43(1): p. 2-12.
  118. The Lipid Research Clinics Coronary Primary Prevention Trial results. I. Reduction in incidence of coronary heart disease. JAMA, 1984. 251(3): p. 351-64.
  119. The Lipid Research Clinics Coronary Primary Prevention Trial results. II. The relationship of reduction in incidence of coronary heart disease to cholesterol lowering. JAMA, 1984. 251(3): p. 365-74.
  120. Levy, R.I., et al., The influence of changes in lipid values induced by cholestyramine and diet on progression of coronary artery disease: results of NHLBI Type II Coronary Intervention Study. Circulation, 1984. 69(2): p. 325-37.
  121. Watts, G.F., et al., Effects on coronary artery disease of lipid-lowering diet, or diet plus cholestyramine, in the St Thomas' Atherosclerosis Regression Study (STARS). Lancet, 1992. 339(8793): p. 563-9.
  122. Blankenhorn, D.H., et al., Beneficial effects of combined colestipol-niacin therapy on coronary atherosclerosis and coronary venous bypass grafts. JAMA, 1987. 257(23): p. 3233-40.
  123. Brown, G., et al., Regression of coronary artery disease as a result of intensive lipid-lowering therapy in men with high levels of apolipoprotein B. N Engl J Med, 1990. 323(19): p. 1289-98.
  124. Kane, J.P., et al., Regression of coronary atherosclerosis during treatment of familial hypercholesterolemia with combined drug regimens. JAMA, 1990. 264(23): p. 3007-12.
  125. Ito, M.K., et al., Management of familial hypercholesterolemias in adult patients: recommendations from the National Lipid Association Expert Panel on Familial Hypercholesterolemia. J Clin Lipidol, 2011. 5(3 Suppl): p. S38-45.
  126. Giugliano, R.P. and M.S. Sabatine, Are PCSK9 Inhibitors the Next Breakthrough in the Cardiovascular Field? J Am Coll Cardiol, 2015. 65(24): p. 2638-51.
  127. McKenney, J.M., Understanding PCSK9 and anti-PCSK9 therapies. J Clin Lipidol, 2015. 9(2): p. 170-86.
  128. Navarese, E.P., et al., Effects of Proprotein Convertase Subtilisin/Kexin Type 9 Antibodies in Adults With Hypercholesterolemia: A Systematic Review and Meta-analysis. Ann Intern Med, 2015. 163(1): p. 40-51.
  129. Sahebkar, A., et al., Effect of monoclonal antibodies to PCSK9 on high-sensitivity C-reactive protein levels: a meta-analysis of 16 randomized controlled treatment arms. Br J Clin Pharmacol, 2016. 81(6): p. 1175-90.
  130. Koren, M.J., et al., Anti-PCSK9 monotherapy for hypercholesterolemia: the MENDEL-2 randomized, controlled phase III clinical trial of evolocumab. J Am Coll Cardiol, 2014. 63(23): p. 2531-40.
  131. Roth, E.M., et al., Monotherapy with the PCSK9 inhibitor alirocumab versus ezetimibe in patients with hypercholesterolemia: results of a 24 week, double-blind, randomized Phase 3 trial. Int J Cardiol, 2014. 176(1): p. 55-61.
  132. Kereiakes, D.J., et al., Efficacy and safety of the proprotein convertase subtilisin/kexin type 9 inhibitor alirocumab among high cardiovascular risk patients on maximally tolerated statin therapy: The ODYSSEY COMBO I study. Am Heart J, 2015. 169(6): p. 906-915 e13.
  133. Cannon, C.P., et al., Efficacy and safety of alirocumab in high cardiovascular risk patients with inadequately controlled hypercholesterolaemia on maximally tolerated doses of statins: the ODYSSEY COMBO II randomized controlled trial. Eur Heart J, 2015. 36(19): p. 1186-94.
  134. Robinson, J.G., et al., Effect of evolocumab or ezetimibe added to moderate- or high-intensity statin therapy on LDL-C lowering in patients with hypercholesterolemia: the LAPLACE-2 randomized clinical trial. JAMA, 2014. 311(18): p. 1870-82.
  135. Blom, D.J., et al., A 52-week placebo-controlled trial of evolocumab in hyperlipidemia. N Engl J Med, 2014. 370(19): p. 1809-19.
  136. Raal, F.J., et al., PCSK9 inhibition with evolocumab (AMG 145) in heterozygous familial hypercholesterolaemia (RUTHERFORD-2): a randomised, double-blind, placebo-controlled trial. Lancet, 2015. 385(9965): p. 331-40.
  137. Kastelein, J.J., et al., ODYSSEY FH I and FH II: 78 week results with alirocumab treatment in 735 patients with heterozygous familial hypercholesterolaemia. Eur Heart J, 2015. 36(43): p. 2996-3003.
  138. Raal, F.J., et al., Inhibition of PCSK9 with evolocumab in homozygous familial hypercholesterolaemia (TESLA Part B): a randomised, double-blind, placebo-controlled trial. Lancet, 2015. 385(9965): p. 341-50.
  139. Stein, E.A., et al., Effect of the proprotein convertase subtilisin/kexin 9 monoclonal antibody, AMG 145, in homozygous familial hypercholesterolemia. Circulation, 2013. 128(19): p. 2113-20.
  140. Stroes, E., et al., Anti-PCSK9 antibody effectively lowers cholesterol in patients with statin intolerance: the GAUSS-2 randomized, placebo-controlled phase 3 clinical trial of evolocumab. J Am Coll Cardiol, 2014. 63(23): p. 2541-8.
  141. Moriarty, P.M., et al., Efficacy and safety of alirocumab vs ezetimibe in statin-intolerant patients, with a statin rechallenge arm: The ODYSSEY ALTERNATIVE randomized trial. J Clin Lipidol, 2015. 9(6): p. 758-69.
  142. Sattar, N., et al., Lipid-lowering efficacy of the PCSK9 inhibitor evolocumab (AMG 145) in patients with type 2 diabetes: a meta-analysis of individual patient data. Lancet Diabetes Endocrinol, 2016. 4(5): p. 403-10.
  143. Abifadel, M., et al., Mutations in PCSK9 cause autosomal dominant hypercholesterolemia. Nat Genet, 2003. 34(2): p. 154-6.
  144. Pendyal, A. and S. Fazio, The Severe Hypercholesterolemia Phenotype: Genes and Beyond, in Endotext, L.J. De Groot, et al., Editors. 2015: South Dartmouth (MA).
  145. Cohen, J., et al., Low LDL cholesterol in individuals of African descent resulting from frequent nonsense mutations in PCSK9. Nat Genet, 2005. 37(2): p. 161-5.
  146. Cohen, J.C., et al., Sequence variations in PCSK9, low LDL, and protection against coronary heart disease. N Engl J Med, 2006. 354(12): p. 1264-72.
  147. Feingold, K.R. and C. Grunfeld, Introduction to Lipids and Lipoproteins, in Endotext, L.J. De Groot, et al., Editors. 2015: South Dartmouth (MA).
  148. Horton, J.D., J.C. Cohen, and H.H. Hobbs, PCSK9: a convertase that coordinates LDL catabolism. J Lipid Res, 2009. 50 Suppl: p. S172-7.
  149. Lambert, G., et al., The PCSK9 decade. J Lipid Res, 2012. 53(12): p. 2515-24.
  150. Raal, F.J., et al., PCSK9 inhibition-mediated reduction in Lp(a) with evolocumab: an analysis of 10 clinical trials and the role of the LDL receptor. J Lipid Res, 2016.
  151. Sabatine, M.S., et al., Efficacy and safety of evolocumab in reducing lipids and cardiovascular events. N Engl J Med, 2015. 372(16): p. 1500-9.
  152. Robinson, J.G., et al., Efficacy and safety of alirocumab in reducing lipids and cardiovascular events. N Engl J Med, 2015. 372(16): p. 1489-99.
  153. Koren, M.J., et al., Efficacy and safety of longer-term administration of evolocumab (AMG 145) in patients with hypercholesterolemia: 52-week results from the Open-Label Study of Long-Term Evaluation Against LDL-C (OSLER) randomized trial. Circulation, 2014. 129(2): p. 234-43.
  154. LaRosa, J.C., et al., Safety and efficacy of Atorvastatin-induced very low-density lipoprotein cholesterol levels in Patients with coronary heart disease (a post hoc analysis of the treating to new targets [TNT] study). Am J Cardiol, 2007. 100(5): p. 747-52.
  155. Wiviott, S.D., et al., Can low-density lipoprotein be too low? The safety and efficacy of achieving very low low-density lipoprotein with intensive statin therapy: a PROVE IT-TIMI 22 substudy. J Am Coll Cardiol, 2005. 46(8): p. 1411-6.
  156. Everett, B.M., et al., Safety profile of subjects treated to very low low-density lipoprotein cholesterol levels (<30 mg/dl) with rosuvastatin 20 mg daily (from JUPITER). Am J Cardiol, 2014. 114(11): p. 1682-9.
  157. Neef, D., H.K. Berthold, and I. Gouni-Berthold, Lomitapide for use in patients with homozygous familial hypercholesterolemia: a narrative review. Expert Rev Clin Pharmacol, 2016. 9(5): p. 655-63.
  158. Gouni-Berthold, I. and H.K. Berthold, Mipomersen and lomitapide: Two new drugs for the treatment of homozygous familial hypercholesterolemia. Atheroscler Suppl, 2015. 18: p. 28-34.
  159. Rader, D.J. and J.J. Kastelein, Lomitapide and mipomersen: two first-in-class drugs for reducing low-density lipoprotein cholesterol in patients with homozygous familial hypercholesterolemia. Circulation, 2014. 129(9): p. 1022-32.
  160. Cuchel, M., et al., Efficacy and safety of a microsomal triglyceride transfer protein inhibitor in patients with homozygous familial hypercholesterolaemia: a single-arm, open-label, phase 3 study. Lancet, 2013. 381(9860): p. 40-6.
  161. Samaha, F.F., et al., Inhibition of microsomal triglyceride transfer protein alone or with ezetimibe in patients with moderate hypercholesterolemia. Nat Clin Pract Cardiovasc Med, 2008. 5(8): p. 497-505.
  162. Hussain, M.M., J. Shi, and P. Dreizen, Microsomal triglyceride transfer protein and its role in apoB-lipoprotein assembly. J Lipid Res, 2003. 44(1): p. 22-32.
  163. Sacks, F.M., M. Stanesa, and R.A. Hegele, Severe hypertriglyceridemia with pancreatitis: thirteen years' treatment with lomitapide. JAMA Intern Med, 2014. 174(3): p. 443-7.
  164. Agarwala, A., P. Jones, and V. Nambi, The role of antisense oligonucleotide therapy in patients with familial hypercholesterolemia: risks, benefits, and management recommendations. Curr Atheroscler Rep, 2015. 17(1): p. 467.
  165. Raal, F.J., et al., Mipomersen, an apolipoprotein B synthesis inhibitor, for lowering of LDL cholesterol concentrations in patients with homozygous familial hypercholesterolaemia: a randomised, double-blind, placebo-controlled trial. Lancet, 2010. 375(9719): p. 998-1006.
  166. Stein, E.A., et al., Apolipoprotein B synthesis inhibition with mipomersen in heterozygous familial hypercholesterolemia: results of a randomized, double-blind, placebo-controlled trial to assess efficacy and safety as add-on therapy in patients with coronary artery disease. Circulation, 2012. 126(19): p. 2283-92.
  167. Santos, R.D., et al., Long-term efficacy and safety of mipomersen in patients with familial hypercholesterolaemia: 2-year interim results of an open-label extension. Eur Heart J, 2015. 36(9): p. 566-75.
  168. Panta, R., K. Dahal, and S. Kunwar, Efficacy and safety of mipomersen in treatment of dyslipidemia: a meta-analysis of randomized controlled trials. J Clin Lipidol, 2015. 9(2): p. 217-25.
  169. Hashemi, N., et al., Liver histology during Mipomersen therapy for severe hypercholesterolemia. J Clin Lipidol, 2014. 8(6): p. 606-11.
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