Manual of Cardiovascular Medicine

I.Introduction. Cardiovascular disease (CVD) is the leading cause of morbidity and mortality in the industrialized world. It is estimated that 30% of all deaths worldwide can be ascribed to cardiovascular causes, and this number is expected to rise further as the incidence of CVD in the developing world increases as a result of lifestyle changes.

A.Morbidity and mortality. CVD is the number one killer in the United States, accounting for 36% of all deaths. CVD is responsible for one death every 40 seconds and claims more lives each year than all forms of cancer combined. One of every seven deaths in the United States is caused by coronary heart disease (CHD). There are 15.5 million Americans with a history of myocardial infarction (MI) or angina pectoris. As many as 660,000 Americans have a new MI each year, and 326,200 are victims of sudden cardiac death. The average age at first MI is 65.1 years for men and 70.2 years for women. According to the Centers for Disease Control and Prevention, elimination of all forms of CVD would raise the overall life expectancy by 7 years.

B.Economic consequences of CVD. The economic burden of CVD and stroke in the United States was estimated to be $316.6 billion in 2011 to 2012 and is projected to increase to $918 billion by 2030. In 2010, CVD was the leading cause of hospitalization, contributing to >5.8 million patient discharges and 4.4 million emergency department visits.

TABLE 42.1 Goals for Secondary Prevention among Patients with Known Vascular Disease
Risk Factor	Goal
Hypertension (mm Hg)	140/90
Dyslipidemia (mg/dL)	LDL < 100 (<70 in very high-risk patients) [or non-HDL <100 for very high-risk patients] as recommended by European Society and Canadian Societies of Cardiology, National Lipid Association and International Atherosclerosis Society No goal per the ACC/AHA 2013 guidelines. High-intensity statin therapy is recommended Triglycerides < 100
Physical activity	30 min, three or four times per week
Body mass index	≤24.9 kg/m²
Diabetes mellitus	Near-normal blood sugar (HbA1c < 6.5%)
Smoking	Complete cessation

HbA1c, hemoglobin A1c; HDL, high-density lipoprotein; LDL, low-density lipoprotein.

C.Prevention of coronary artery disease (CAD). Table 42.1 shows important targets for secondary prevention among patients with known coronary or noncoronary vascular disease. The goals for primary prevention are similar, but the cost-effectiveness of medical intervention is not so favorable in all populations. The consequences of modest population-wide risk reduction (e.g., reduction in fat intake [currently 33% of total calories] and cholesterol levels) and lifesaving technologies (e.g., surgery, angioplasty, and coronary care units) have reduced the death rate and possibly contributed to reduced morbidity, but the burden of CVD remains a major challenge.

II.Hyperlipidemia. Dyslipidemia is an important correctable predictive factor for CAD. There is a strong, independent, continuous, and graded relation between total cholesterol (TC) or low-density lipoprotein cholesterol (LDL-C) level and risk of CAD events. This relation has been clearly demonstrated in men and women in all age groups. More than one-half of US adults (105 million) have TC levels >200 mg/dL, and of these, 37 million have values >240 mg/dL. In general, a 1% increase in LDL-C level leads to a 2% to 3% increase in risk of CAD.

A.Physiology

1.Lipoproteins are large molecular compounds that are essential to the transport of cholesterol and triglycerides within the blood. They contain a lipid core composed of triglycerides and cholesterol esters surrounded by phospholipids and specialized proteins known as apolipoproteins. The five major families of lipoproteins are chylomicrons and chylomicron remnants, very low density lipoproteins (VLDLs), intermediate-density lipoproteins, low-density lipoproteins (LDL), and high-density lipoproteins (HDLs).

2.Apolipoproteins are necessary for the structure and enzymatic processes of lipids. Apolipoprotein A1 (apo A1) is a major component of HDL, and apolipoprotein B (apo B) is the main apolipoprotein for the remaining non-HDL lipoproteins.

B.Lipid-lowering trials. Aggressive lipid-lowering drug treatment of persons at various risk levels reduces CAD morbidity and mortality rates and increases overall survival. Although the association between hyperlipidemia and CAD was established much earlier, the demonstration of a relationship between reduction in serum lipid levels and a reduction in all-cause mortality had to await the development of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, or “statins.” Multiple randomized trials have provided overwhelming evidence of the benefit of statins in both primary and secondary prevention of cardiovascular events.

1.Primary prevention trials

a.The West of Scotland Coronary Prevention Study (WOSCOPS) (1995) demonstrated that treatment of men at relatively high risk with profoundly elevated cholesterol levels significantly reduced the risk of heart attack and death from heart disease. The double-blind study randomized 6,600 healthy men with a baseline mean LDL-C level of 193 mg/dL to pravastatin (40 mg/d) or to placebo, for an average of 5 years, and demonstrated a 31% relative reduction in the incidence of nonfatal MI or CAD death. Follow-up of this population published in 2007 showed that the statin group continued to experience lower rates of cardiovascular death after a further 10 years, even though only one-third continued to take statins during the additional follow-up period.

b.The Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS) (1998) demonstrated benefit among patients with more typical risk profiles, including lower cholesterol values, than among those in the WOSCOPS. AFCAPS/TexCAPS patients had a baseline mean TC level of 220 mg/dL and LDL of 150 mg/dL. The study randomized 6,600 patients to lovastatin 20 to 40 mg daily or placebo and demonstrated a 36% relative risk reduction (RRR) for first acute major coronary events in the lovastatin group.

c.The Heart Protection Study (HPS) (2002) randomized 20,536 subjects with a mean LDL of 131 mg/dL in a 2 × 2 factorial design to daily simvastatin (40 mg) or placebo and to antioxidants or placebo (the antioxidant arm did not show any benefit or harm). The study focused on patients who were deemed high risk for CVD but not thought to merit treatment with statins based on the prevalent clinical practice at that time. Increased risk was defined as presence of or history of CAD, cerebrovascular disease, peripheral arterial disease, diabetes mellitus, or treated hypertension. Simvastatin therapy was associated with a 13% reduction in all-cause mortality, including an 18% reduction in coronary death rate. The beneficial impact of statin therapy was seen with respect to all cardiovascular end points, with significant reductions in risk of nonfatal MI, incidence of first stroke, and coronary and noncoronary revascularization. Treating patients with LDL levels <100 mg/dL was also associated with a beneficial reduction in vascular events. The benefit was maintained in patients receiving other cardioprotective medications, such as angiotensin-converting enzyme inhibitors, β-blockers, and aspirin. Although not strictly a primary prevention trial, the HPS provided evidence to support treatment of risk as endorsed by the National Cholesterol Education Program (NCEP) guidelines. However, the HPS results refuted the threshold LDL level (as proposed by NCEP III at that time) below which statins were not previously indicated.

d.Pravastatin in Elderly Individuals at Risk of Vascular Disease (2002) randomized 5,804 patients between the ages of 70 and 82 years with mean LDL of 147 mg/dL to placebo or pravastatin. These patients had preexisting coronary, cerebral, or peripheral vascular disease or had a history of smoking, hypertension, or diabetes. The study demonstrated a 15% reduction in the composite of coronary death, nonfatal MI, and stroke over a period of 3 years. The study demonstrated the efficacy of primary and secondary prevention in the elderly.

e.The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (2002) randomized 10,355 hypertensive patients with one other coronary risk factor and a baseline mean LDL-C level of 148 mg/dL to pravastatin 20 to 40 mg/d or usual care. The study did not demonstrate a mortality difference in the two arms after a follow-up period of 4.8 years. This lack of observable difference in outcome might have resulted from the relatively modest LDL reduction (17% with pravastatin vs. 8% in usual care) or the fact that 26% of the patients in the “usual care” group were taking a statin at the end of the trial.

f.The Anglo-Scandinavian Cardiac Outcomes Trial—Lipid-Lowering Arm (2003) randomized 10,305 patients with hypertension and at least three other cardiovascular risk factors and a baseline mean LDL-C level of 133 mg/dL to atorvastatin 10 mg/d or placebo. The study was stopped prematurely after a median follow-up of 3.3 years by the safety monitoring committee because of a significantly higher incidence of the primary end point (nonfatal MI or fatal CHD) in the placebo group. The study demonstrated a 36% RRR for the primary end point in the atorvastatin group compared with the placebo group. Further analysis demonstrated that the benefit of statin therapy started after only 1 year of treatment. There was also a significant reduction (RRR of 27%) in the incidence of fatal and nonfatal stroke in the atorvastatin group. This study, like the HPS, provided further evidence of the benefit of statins in patients at high risk for CVD without regard for baseline TC or LDL levels.

g.The Collaborative Atorvastatin Diabetes Study (CARDS) (2004) randomized 2,838 diabetic patients with one additional cardiovascular risk factor, no history of CVD, and an average baseline LDL-C of only 117 mg/dL to atorvastatin 10 mg/d or placebo. This study was also terminated prematurely owing to an excess incidence of the primary end point (a composite of acute coronary events, coronary revascularization, or stroke) in the placebo group after a median follow-up of 3.9 years. Overall, the atorvastatin group had an RRR of 37% for the primary end point and 27% for all-cause mortality. The importance of this trial was its demonstration of the clinical benefit of statin use in diabetic patients regardless of baseline LDL-C level, making a compelling case for statin use in all diabetic patients with at least one additional cardiovascular risk factor. According to the NHANES III data, 82% of diabetic patients in the United States would meet the entry criteria for the CARDS trial.

h.The Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) (2005) trial focused on the prevention of CHD in patients with type 2 diabetes using fenofibrates. The study randomized patients with type 2 diabetes diagnosed after 35 years of age with no clear indication for cholesterol-lowering therapy at baseline to fenofibrate (200 mg/d) or placebo. The study failed to show a difference in the primary composite end point of CHD or nonfatal MI between the two groups at 5-year follow-up. However, several secondary end points were lower in the fenofibrate group including nonfatal MI and coronary revascularization.

i.Japan EPA Lipid Intervention Study (2007). The goal of this trial was to evaluate treatment with the fish oil supplement eicosapentaenoic acid (EPA) in addition to statin therapy compared with statin therapy alone among patients with hypercholesterolemia (baseline LDL 187 mg/dL and median triglycerides 151 mg/dL). The study randomized patients in an open-label manner to treatment with EPA (1,800 mg/d) in addition to statin therapy (pravastatin 10 mg/d) or simvastatin (5 mg/d) or to statin therapy alone. At a mean follow-up of 4.6 years, there was a significant reduction in the primary end point of major adverse cardiovascular events in the EPA plus statin group (2.8% vs. 3.5%). This was driven primarily by a significant reduction in rates of unstable angina and a trend toward lower rates of nonfatal MI and revascularization. No difference was seen in sudden cardiac death or fatal MI.

j.The Justification for the Use of Statins in Primary Prevention: An Intervention Trial Evaluating Rosuvastatin (2008) focused on patients with normal LDL-C levels but increased levels of high-sensitivity C-reactive protein (CRP). This was the first clinical trial to demonstrate that statin therapy may benefit patients with low-to-normal LDL levels and no known CVD. The study randomized 17,802 healthy subjects with an LDL-C <130 mg/dL and a CRP ≥2.0 mg/L to daily rosuvastatin of 20 mg or placebo. The trial was stopped early for a mortality benefit after a median follow-up of 1.9 years. The study demonstrated that after 1 year of therapy, there were lower levels of LDL-C (55 vs. 110 mg/dL) and lower levels of CRP (2.2 vs. 3.5 mg/L) in the rosuvastatin-treated group. There was also a lower incidence of the primary end point of nonfatal MI, nonfatal stroke, hospitalization for unstable angina, arterial revascularization procedure, or confirmed death from cardiovascular cause (0.77 vs. 1.36 events per 100 person-life years) as well as the risk of all-cause mortality (1.00 vs. 1.25 deaths per 100 person-life years) in the rosuvastatin-treated group.

k.The Action to Control Cardiovascular Risk in Diabetes Lipid Trial (ACCORD Lipid) (2010) was designed to evaluate whether the addition of fenofibrate to statin therapy among patients with type 2 diabetes (baseline LDL 100 mg/dL and median triglycerides 164 mg/dL) would be effective in preventing cardiovascular events. The study randomized half of the patients within the initial ACCORD trial with type 2 diabetes and treated with a statin medication to fenofibrate (160 mg daily) or placebo. Although a significant reduction in median triglyceride level (164 to 122 mg/dL) was seen with the addition of fenofibrate to statin therapy, there was no reduction in the primary end point (first occurrence of cardiovascular death, nonfatal MI, or nonfatal stroke) when compared with statin therapy alone. In a subgroup analysis, a trend toward benefit of fenofibrate was shown in the group of patients with diabetes that had a significant dyslipidemia (low HDL and high triglycerides). Additional subgroup analysis showed a trend toward harm in women (but not men) in the fenofibrate group that warrants further investigation in future studies.

2.Secondary prevention trials

a.The Scandinavian Simvastatin Survival Study (4S) (1994) was the first secondary prevention trial to demonstrate a clear reduction in total mortality. Simvastatin reduced total mortality among patients with CAD by 30%, largely because of a 42% reduction in deaths from CAD. The 4S treated 4,444 men and women with CAD and mean baseline LDL of 188 mg/dL, with a range of 130 to 266 mg/dL.

b.The randomized, controlled Cholesterol and Recurrent Events Trial (1996) was designed to evaluate the effects of treatment with pravastatin on 4,159 persons who had experienced acute MI 3 to 20 months before randomization and had moderately elevated TC levels (mean 209 mg/dL) and LDL levels (mean 139 mg/dL). The benefits of pravastatin therapy in preventing recurrent coronary events were similar in the subset analysis of age, sex, ejection fraction, hypertension, diabetes mellitus, and smoking.

c.The Long-Term Intervention with Pravastatin in Ischemic Disease Study (LIPID) (1998) was the first to examine the use of a statin for patients with a history of unstable angina. The LIPID study provided new data on noncoronary mortality (i.e., stroke) and on other groups, such as women and patients with diabetes, who previously had been underrepresented in clinical trials. LIPID demonstrated improved CAD outcomes among all patients, including those with unstable angina.

d.The Veterans Affairs High-Density Lipoprotein Intervention Trial (VA-HIT) (1999) was a multicenter study that randomized patients with known CHD and low HDL-C (≤40 mg/dL) and LDL-C (≤140 mg/dL) levels to gemfibrozil (1,200 mg/d) or placebo with a mean follow-up of 5.1 years. The study showed that gemfibrozil therapy was associated with a significant 22% reduction in the combined incidence of nonfatal MI and CHD death. This was the first lipid intervention trial to show that raising HDL-C concentrations in patients with CHD and low HDL-C and LDL-C levels will reduce the incidence of major coronary events.

e.Myocardial Ischemia Reduction with Acute Cholesterol–Lowering Trial (2001). This trial demonstrated cardiovascular benefits with initiation of early statin therapy following acute coronary syndrome (ACS). The trial randomized 3,086 adults with unstable angina or non–Q-wave MI to high-dose atorvastatin (80 mg/d) or placebo between 24 and 96 hours after hospital admission. There was a reduction in the primary end point of nonfatal infarction, cardiac arrest with resuscitation, or recurrent symptomatic ischemia requiring hospitalization in the atorvastatin group (14.8% vs. 17.4%, RRR of 16%). The benefit was driven primarily by a 26% reduction in recurrent symptomatic ischemia. The trial did not show a mortality benefit (death, MI, or need for revascularization).

f.Pravastatin or Atorvastatin Evaluation and Infection Therapy–TIMI 22 (PROVE-IT–TIMI-22) (2004). This trial was designed to determine whether intensive lipid-lowering therapy in patients with ACS reduced major coronary events and mortality more than “standard” lipid lowering. A total of 4,162 patients who had been hospitalized for ACS within the preceding 10 days were randomized to atorvastatin 80 mg/d or pravastatin 40 mg/d. After 2 years of follow-up, the composite end point (all-cause mortality, MI, unstable angina, coronary revascularization, and stroke) was significantly reduced by 16% with atorvastatin compared with pravastatin. High-dose atorvastatin was well tolerated, with no cases of rhabdomyolysis. Of note, the LDL-C level attained on atorvastatin 80 mg/d was 33 mg/dL lower than on pravastatin with a mean of 62 mg/dL. These results suggested that the use of intensive lipid-lowering therapy to achieve very low LDL-C levels was of benefit in a group of patients at high risk for recurrent coronary events.

g.A to Z trial: phase Z (2004)—early intensive vs. a delayed conservative simvastatin strategy in patients with acute coronary syndromes (2004). This trial studied whether early initiation of high-dose statin therapy would lead to a reduction in long-term cardiac events compared with a more conservative, delayed low-dose statin strategy in high-risk patients with ACS. The trial enrolled a total of 4,497 patients with a recent ACS, TC level ≤250 mg/dL and median LDL level 111 mg/dL, and at least one additional risk factor who were randomized to either intensive statin therapy strategy (simvastatin 40 mg for 1 month, followed by 80 mg through 2 years) or a conservative strategy (placebo for 4 months followed by simvastatin 20 mg through 2 years). Although the study showed an early and sustained reduction in LDL in the aggressive strategy arm, it did not show a significant reduction in the primary composite end point of cardiovascular events (cardiovascular death, MI, readmission for ACS, and CVA) or death from any cause compared with a more conservative strategy. There were also more patients who developed creatine kinase (CK) concentrations more than 10 times the upper limit of normal in the aggressive strategy arm (9 vs. 1) and three patients who developed rhabdomyolysis while on simvastatin 80 mg.

h.The Treating to New Targets (TNT) (2005) trial sought to demonstrate the benefit of intensive lipid-lowering therapy in patients with stable coronary disease. The trial randomized 10,001 patients with clinically evident CHD and baseline LDL-C levels <130 mg/dL to atorvastatin 80 mg/d or atorvastatin 10 mg/d. After 4.9 years of follow-up, the group receiving atorvastatin 80 mg/d had a 22% RRR in the primary composite end point of death from CHD, nonfatal MI, resuscitation after cardiac arrest, or fatal or nonfatal stroke compared with the group receiving atorvastatin 10 mg/d. High-dose atorvastatin was remarkably safe, with a 1.2% incidence in elevation of alanine aminotransferase (ALT)/aspartate aminotransferase (AST) more than three times the upper limit of normal, compared with a 0.2% incidence in the atorvastatin 10 mg group. Rates of myalgias and rhabdomyolysis were similar between the two groups. This study provided compelling evidence that the use of intensive statin therapy to reduce LDL-C to levels below 100 mg/dL had marked clinical benefit in patients with stable CHD.

i.The Incremental Decrease in End Points through Aggressive Lipid Lowering (2005) trial randomized 8,888 patients with a prior history of acute MI and baseline LDL level of 122 mg/dL to atorvastatin 80 mg/d or simvastatin 20 mg/d. After 4.8 years of follow-up, there was a nonsignificant difference in the risk of the composite end point of coronary death, acute MI, or cardiac arrest. However, if either stroke or revascularization was added to the primary end point, the results favored the atorvastatin group, and the associated hazard ratios were similar to the results of PROVE-IT and TNT. Despite the published negative result of this trial, it provided complementary evidence for the benefit of intensive LDL lowering in patients at high risk for coronary events.

j.The Improved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT) (2015) was a study that compared the effect of adding ezetimibe versus placebo to simvastatin in patients with a recent ACS. The study randomized 18,144 patients who had been hospitalized for ACS within the preceding 10 days and had LDL cholesterol levels of 50 to 100 mg/dL if they were receiving lipid-lowering therapy or 50 to 125 mg/dL if they were not to either ezetimibe (10 mg) and simvastatin (40 mg) versus placebo and simvastatin (40 mg). Over median follow-up of 6 years, the median LDL level was 53.7 mg/dL in the ezetimibe–simvastatin group versus 69.5 in the simvastatin monotherapy group. There was 6.4% RRR and 2% absolute risk reduction in the primary end point of cardiovascular death, nonfatal MI, unstable angina requiring rehospitalization, coronary revascularization (≥30 days after randomization), or nonfatal stroke in the ezetimibe–simvastatin group. There were no increased side effects in the ezetimibe–simvastatin group. This trial was the first trial to highlight that more intensive LDL reduction with non-statin medications (ezetimibe) can reduce the risk of recurrent CVD in a secondary prevention population.

k.The Atherothrombosis Intervention in Metabolic syndrome with low HDL/high triglycerides: Impact on Global Health outcomes (2011) was a study that compared treatment of extended-release niacin versus placebo among statin-treated patients with established heart and vascular disease and baseline LDL 71 mg/dL and HDL 35 mg/dL. The study randomized 3,414 patients with optimally treated LDL-C and low HDL-C with established vascular disease (documented by coronary angiography or by prior MI, or carotid angiography or prior ischemic stroke, or peripheral arterial disease) to extended-release niacin (1,500 to 2,000 mg/d) or placebo. There was no significant difference in the primary composite outcome of CHD death, nonfatal MI, ischemic stroke, hospitalization for ACS, or symptom-driven coronary/cerebral revascularization (16.4% in the extended-release niacin group vs. 16.2% in the placebo group). The study was terminated 18 months early after it was evident that the addition of extended-release niacin would not be beneficial. Furthermore, there was a small (numerical) excess in ischemic strokes and hospitalizations for ACS.

l.The Heart Protection Study 2–Treatment of HDL to Reduce the Incidence of Vascular Events (HPS2-THRIVE) was a trial to assess the effects of adding extended-release niacin (2 g) in combination with laropiprant (40 mg) to effective statin-based LDL cholesterol–lowering treatment in 25,673 high-risk patients with prior vascular disease (baseline LDL 63 mg/dL and HDL 44 mg/dL). Laropiprant is an antagonist of the prostaglandin D2 receptor DP₁ that has been shown to improve adherence to niacin therapy by reducing flushing in up to two-thirds of patients. The niacin–lopiprant group had a lower LDL by 10 mg/dL and a higher HDL by 6 mg/dL; however, there were no significant differences in the incidence of major adverse vascular events between the treatment group and placebo. There was an increased incidence of worsening of diabetes control in the treatment group. This trial provided evidence that increasing HDL levels did not necessarily improve cardiovascular outcomes which was also later found in cholesterylester transfer protein (CETP) inhibitor trials.

m.CETP inhibitor trials: CETP is responsible for transfer of cholesterylesters from HDL to LDL and VLDL, thus leading to increased HDL levels and reduced LDL levels if inhibited. Several preclinical studies have shown a significant ability of this class of drugs to increase HDL levels by >50% and reduce LDL levels by >20% and there was tremendous excitement about its potential. However, randomized trials examining clinical outcomes showed either no effect or possibly harm of CETP inhibitors when added to a statin therapy background. In ILLUMINATE, torcetrapib was associated with an increased risk of cardiovascular events by 25% and mortality risk by 50% despite reducing LDL by 25% and increasing HDL by 72% thought to be due to an off target effect of increasing blood pressure. The DAL-OUTCOMES study (15,871 patients) and ACCELERATE study (12,000) were terminated because of lack of efficacy. These trials highlight the importance of approving new drugs based on large trials examining clinical outcomes rather than approving them based on their effect on surrogate markers. CETP inhibitors had consistent positive effects on LDL and HDL, yet showed harm or no effect on cardiovascular clinical outcomes. More recently, the HPS3/TIMI55-REVEAL trial (30,449 patients) showed that adding anacetrapib to high-intensity statin therapy (HIST) in patients with CVD resulted in a lower rate of coronary events but there was no effect on death. Many experts argue that the observed benefit in this trial was mainly related to the magnitude of LDL lowering. Given the inconsistent evidence for clinical benefit from this class of drugs, the exact role of CETP inhibitors in clinical practice needs to be better defined in future studies.

n.Proprotein Convertase Subtilisin/Kexin type 9 inhibitors: Proprotein convertase subtilisin/kexin type 9 (PCSK-9) is a protease that promotes the binding and degradation of LDL receptors intracellularly. As such, inhibition of PCSK-9 leads to increased LDL receptors on the cell membrane and therefore, increased uptake of LDL leading to a reduction in LDL serum levels. It only took a decade since genetic variants increasing PCSK-9 expression were identified and shown to be associated with life-long lower levels of LDL and cardiovascular events to development of monoclonal antibodies that inhibit PCSK-9. Phase II and III clinical trials have shown a promising effect of PCSK-9 inhibitors. In the OSLER and ODYSSEY LONG TERM trials, evolocumab and alirocumab, respectively, showed ~60% reduction in LDL levels on a background of statin therapy in high-risk cardiovascular patients. Furthermore, they were associated with ~50% reduction in cardiovascular events, although these trials were not designed as outcome trials and the event rate was low over a short period of follow-up. Based on these preliminary promising results, the US Food and Drug Administration (FDA) approved the use of evolocumab and alirocumab for treatment of patients with clinical atherosclerotic cardiovascular events and familial hypercholesterolemia as adjuncts to maximally tolerated statin therapy if greater reductions in LDL levels are required. The short-term results of some of the large clinical outcome trials are as follows. The FOURIER trial (27,564 patients) randomized patients with CVD on HIST to evolocumab vs. placebo. Evolocumab resulted in 60% reduction in LDL levels (median posttreatment LDL was 30 mg/dL) and was associated with a 15% decrease in CV events at 2 years. However, the annual cost of PCSK-9 inhibitors is very high at this time and there has been significant debate regarding their cost-effectiveness in clinical practice given the small absolute clinical benefit (NNT over 2 years is 74) and high cost to benefit ratio. Gathering more data will be necessary to determine the optimal cost for these drugs in comparison to the suggested benefit.

3.Meta-analyses

a.CTT Collaborators (2005). A large meta-analysis of 90,056 individuals from 14 randomized trials of statin drugs, this analysis demonstrated an impressive 12% reduction in all-cause mortality for each 1 mmol/L (39 mg/dL) reduction in LDL. There was a 19% reduction in coronary mortality and 21% reduction in MI, coronary revascularization, and stroke. Statin use showed benefit within the first year of use, but was greater in subsequent years. Statins were also remarkably safe, with no increase in cancer seen and a 5-year excess risk of rhabdomyolysis of 0.1%.

b.Cannon—Intensive Statin Therapy (2006). A meta-analysis of 27,548 patients from four trials that investigated intensive versus standard lipid-lowering therapy found a significant 16% odds ratio reduction in coronary death or MI in the group that received intensive therapy. There was a nonsignificant trend toward decreased cardiovascular mortality.

c.Boekholdt—Very low levels of atherogenic lipoproteins from statin trials (J Am Coll Cardiol, 2014). This meta-analysis of 38,153 patients from eight statin trials showed that there was significant interindividual variability in response to statins with more than 40% of patients on HIST not reaching LDL <70 mg/dL. Those who achieved very low levels of LDL <50 mg/dL had a lower risk of cardiovascular events than those who achieved moderately low levels.

C.Management of lipids. Despite overwhelming evidence supporting the treatment of dyslipidemia, a large number of patients remain untreated. The NCEP Adult Treatment Panel III has released guidelines for the treatment of hyperlipidemia in adults and these were based on LDL treatment targets. However, the ACC/AHA released new guidelines in 2013 that abandoned the use of treatment targets to guide therapy and instead recommended statin therapy to certain patient populations. This has been a source of extensive debate lately particularly in the setting of recent studies showing benefit of non-statin medications such as ezetemibe or PCSK-9 inhibitors. It is worth mentioning that the European Society of Cardiology, Canadian Society of Cardiology, National Lipid Association, and the International Atherosclerosis Society continue to recommend LDL and non-HDL treatment targets but here we will focus on the ACC/AHA guidelines.

1.The new ACC/AHA 2013 cholesterol treatment guidelines:

a.TC, LDL-C, and HDL-C levels. All adults 20 years or older and without a history of CAD or other atherosclerotic disease should have a fasting lipid panel (i.e., TC, LDL-C, HDL-C, and triglyceride levels) every 5 years. If a nonfasting lipid panel is obtained and the TC level is 200 mg/dL or the HDL-C is <40 mg/dL, a follow-up fasting lipid panel is recommended

b.Heart healthy lifestyle habits are the foundation of atherosclerotic cardiovascular disease (ASCVD) prevention. In patients not taking statins, recalculate the estimated 10-year ASCVD risk using the new 2013 calculator every 4 to 6 years in patients aged 40 to 75 years without clinical ASCVD or diabetes and with LDL 70 to 189 mg/dL.

c.HIST is defined as that which lowers LDL levels by ≥50% whereas moderate intensity therapy lowers it by 30% to less than 50%.

d.Patient groups who are candidates for statin therapy:

(1)Patients with clinical ASCVD: Patients should receive HIST unless they are >75 years old or cannot tolerate HIST in case of which moderate intensity statin is recommended.

(2)Patients with LDL ≥190 mg/dL: HIST is recommended unless patients cannot tolerate it.

(3)Patients with type 1 or 2 diabetes mellitus, age 40 to 75 and with LDL 70 to 189 mg/dL: Moderate intensity statin is recommended unless the 10-year estimated ASCVD risk by the pooled cohort equation is ≥7.5% in case of which HIST is recommended.

(4)Patients without diabetes mellitus or ASCVD, age 40 to 75, with LDL 70 to 189 mg/dL and an estimated 10-year ASCVD risk of ≥7.5%: Moderate- to high-intensity statin is recommended.

e.ASCVD prevention using statins may be less clear in other patient groups: In selected individuals, use other factors to determine eligibility for statin therapy such as the presence of additional factors influencing ASCVD risk (e.g., family history of premature CAD), drug–drug interactions, and patient preference for initiating statin therapy.

f.In selected individuals who do not meet criteria for statin therapy per the new guidelines, further risk stratification with other tools such as coronary artery calcium, high-sensitivity C-reactive protein levels, lifetime risk of ASCVD, or ankle-brachial index may be of value in certain situations.

g.Use of the new Pooled Cohort Equations is recommended to estimate 10-year ASCVD risk in both white and black men and women who do not have clinical ASCVD. This equation replaces the Framingham Risk Score. There has been some criticism that the new equation overestimates the number of patients that may benefit from statin therapy leading to more widespread use of statins.

h.Despite the well-proven concept that lower LDL is associated with lower ASCVD risk, the guidelines did not recommend using non-statin medications to reduce LDL beyond maximally tolerated statin therapy because of the lack of outcome data at that time. However, recent data from the IMPROVE-IT trial examining adding ezetemibe to simvastatin in addition to PCSK-9 inhibitor trials have shown there may be incremental value to using these medications to lower LDL further after using maximally tolerated statin therapy.

2.Types of therapy

a.Therapeutic Lifestyle Changes (TLCs) encompass increased physical activity, ideal weight maintenance, and a diet that includes a reduced intake of saturated fat (<10% of total calories), reduced intake of added sugars (<10% of total calories), <2,300 mg of sodium per day, and cholesterol (<200 mg/d). Other TLCs are listed in Table 42.2. Intake of trans-fatty acids should be kept to a minimum. For most patients, it is essential to reduce saturated fat intake over total fat intake; for patients with metabolic syndrome, a fat intake of 30% to 35% may be optimal for reducing lipid and nonlipid risk factors. High-carbohydrate diets may worsen the lipid abnormalities in these patients. Dietary carbohydrates should be derived predominantly from foods rich in complex carbohydrates, such as whole grains, fruits, and vegetables. Daily intake of 5 to 10 g of viscous fiber reduces LDL levels by approximately 5% and the use of plant stanols and sterols (2 to 3 g/d) by another 6% to 15%. TLCs can achieve an almost 30% reduction in LDL-C level in highly motivated individuals and should form the cornerstone of all preventive activity. Benefits of LDL-C lowering may be evident within 6 to 12 months, although the individual response to a cholesterol-lowering diet depends on many factors. Some of the response is genetically determined, and increased body mass index is associated with less response to dietary change. LDL-C should be measured 6 weeks after initiating optimal diet, and if the goals are not met, intensification of TLCs and use of plant sterols or stanols should be considered. Referral to a dietitian for education and dietary counseling is often invaluable at this stage. If, after 3 months of TLCs, adequate control is not achieved, drug therapy should be considered.

TABLE 42.2 Components of Therapeutic Lifestyle
Component	Recommendation	Approximate LDL Reduction
Diet
Saturated fat	<7% of total calories	8%–10%
Dietary cholesterol	<200 mg/d	3%–5%
Polyunsaturated fat	Up to 10% of total calories
Monounsaturated fat	Up to 20% of total calories
Total fat	25%–35% of total calories
Carbohydrate	50%–60% of total calories
Dietary fiber	20–30 g/d
Total protein	15% of total calories
Therapeutic Options for LDL Lowering
Plant stanols/sterols	2 g/d	6%–15%
Increased viscous soluble fiber	5–10 g/d (consumption of 10–25 g/d may have added benefit)	3%–5%
Physical activity	Enough moderate activity to expend at least 200 kcal/d

LDL, low-density lipoprotein.

b.Pharmacotherapy. The high efficacy of statins in lowering LDL-C level and their demonstrated mortality benefits make them the agents of first choice for treatment of most forms of hyperlipidemia. Table 42.3 summarizes the most commonly used agents affecting lipoprotein metabolism.

TABLE 42.3 Drugs Affecting Lipoprotein Metabolism

Drug Class

Agents and Daily Doses

Lipid/Lipoprotein Effects

Side Effects

Contraindications

HMG-CoA reductase inhibitors (statins)

Lovastatin (20–80 mg)

Pravastatin (20–40 mg)

Simvastatin (20–80 mg)

Fluvastatin (20–80 mg)

Atorvastatin (10–80 mg)

Rosuvastatin (10–40 mg)

LDL-C ↓ 18%–55%

HDL-C ↑ 5%–15%

TG ↓ 7%–30%

Gastrointestinal distress

Myopathy

Increased liver enzymes

Absolute: Active or chronic liver disease

Relative: Concomitant use of certain drugs^a

Bile acid sequestrants

Cholestyramine (4–16 g)

Colestipol (5–20 g)

Colesevelam (2.6–3.8 g)

LDL-C ↓ 15%–30%

HDL-C ↑ 3%–5%

TG—no change or increase

Gastrointestinal distress

Constipation

Decreased absorption of other drugs

Absolute: Dysbetalipoproteinemia–TG > 400 mg/dL

Relative: TG > 200 mg/dL

Nicotinic acid

Immediate release (crystalline nicotinic acid [1.5–3 g])

Extended release (Niaspan; 1–2 g)

Sustained release (1–2 g)

LDL-C ↓ 5%–25%

HDL-C ↑ 15%–35%

TG ↓ 20%–50%

Flushing

Hyperglycemia

Hyperuricemia (or gout)

Upper GI distress

Hepatotoxicity

Absolute: Chronic liver disease–Severe gout

Relative: Diabetes–Hyperuricemia–Peptic ulcer disease

PCSK-9 inhibitors

Evolocumab (140 mg subQ every 2 wk or 420 mg every month)

Alirocumab (75 mg subQ every 2 wk)

LDL-C ↓ 60%

Flu-like symptoms

Injection site reactions

Diarrhea

Muscle pain or spasm

Contraindications:

Absolute—Patients with serious hypersensitivity to PCSK-9 inhibitors

Fibric acids

Gemfibrozil (600 mg bid) Fenofibrate (200 mg)

Clofibrate (1,000 mg bid)

LDL-C ↓ 5%–20% (may be increased in patients with high TG)

HDL-C ↑ 10%–20%

TG ↓ 20%–50%

Dyspepsia

Gallstones

Myopathy

Absolute: Severe renal disease–Severe hepatic disease

^aCyclosporine, macrolide antibiotics, various antifungal agents, and cytochrome P450 inhibitors (fibrates and niacin should be used with appropriate caution).

GI, gastrointestinal; HDL-C, high-density lipoprotein cholesterol; HMG-CoA, 3-hydroxy-3-methylglutaryl coenzyme A; LDL-C, low-density lipoprotein cholesterol; PCSK-9, proprotein convertase subtilisin/kexin type 9; TG, triglyceride.

(1)HMG-CoA reductase inhibitors. HMG-CoA reductase inhibitors are the first-line therapy in the management of hypercholesterolemia. The category includes seven drugs: lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, pitavastatin, and rosuvastatin.

(a)Effectiveness. When dietary measures are inadequate, HMG-CoA reductase inhibitors effectively lower TC and LDL-C levels in patients with mixed hyperlipidemias (i.e., elevated cholesterol and triglyceride levels). HMG-CoA reductase inhibitors are extremely effective in reducing LDL-C levels in most patients with primary hypercholesterolemia. HMG-CoA reductase inhibitors decrease TC by 15% to 60% and LDL-C by 18% to 55% and increase HDL-C levels by 5% to 15%. Declines in apo B levels commensurate with reductions in LDL have been demonstrated. Statins also reduce triglyceride levels by 7% to 30% but have minimal effects on apo A1, apo A2, and lipoprotein (a) [Lp(a)]. All statin drugs at the starting dose and within one to two dose titrations are well tolerated, efficacious, and reasonably equivalent with respect to safety profiles.

(b)Adverse effects. Statins are remarkably safe drugs, with a low incidence of side effects. However, they are contraindicated in pregnancy.

i.Minor side effects. The most common side effects are mild gastrointestinal disturbances (e.g., nausea, abdominal pain, diarrhea, constipation, and flatulence). Headache, fatigue, pruritus, and myalgias are other minor side effects, but none of these complaints usually warrant discontinuation of therapy.

ii.Liver function test abnormalities. Mild, transient elevations in liver enzymes have been reported with all HMG-CoA reductase inhibitors. Marked elevation of transaminases is rare, but clinicians should avoid or use caution before starting statins in patients with acute or chronic liver disease. In the HPS, only 0.5% of patients had to stop treatment because of elevated ALT levels. Even when taking the highest dose of atorvastatin (80 mg), patients in PROVE-IT and TNT had only a 3.3% and 1.1% incidence, respectively, of transaminase elevation more than three times the upper limit of normal. In general, for each doubling of a statin dose, there is a 0.6% increase in risk of elevation of transaminase levels. Current recommendations state that therapy should be discontinued when greater than threefold elevation occurs. Enzyme levels typically return to normal within 2 weeks. Lower doses of the same medication can be reinstituted or a different statin can be tried. Monitoring of hepatic aminotransferase levels is recommended for those taking HMG-CoA reductase inhibitors, but the frequency of monitoring has been debated. Current package inserts for most statins recommend obtaining a liver panel prior to initiation of statin therapy, prior to dose titration, and when “clinically indicated.” More frequent monitoring is recommended for patients taking the highest dose of a statin. In recent clinical trials, the high-dose statin that appears to have the highest incidence of transaminase elevation is atorvastatin. A panel of hepatologists who examined the potential hepatotoxicity of statins made a recommendation to obtain a liver panel prior to initiating statins as a baseline measurement of hepatic transaminases and bilirubin. If the baseline measurements were within normal limits, the panel recommended follow-up measurement of transaminases only if there was symptomatic or physical evidence of liver disease. An ACC/AHA/NHLBI clinical advisory panel on the safety and use of statins recommends measurement of transaminases at baseline, 12 weeks after starting therapy, and then annually or more frequently if indicated. The most recent ACC guideline do not recommend repeat testing.

iii.Myopathy, a rare but potentially serious side effect of HMG-CoA reductase inhibitors, presents with muscle pain, stiffness, or aching and elevations in serum CK level to more than 10 times the upper limit of normal. CK measurements are not needed unless symptoms occur. Statin-naïve patients should be warned to report symptoms of muscle pain or stiffness immediately if they occur after starting the drug. The risk of myopathy may be increased in the elderly, those with a low body mass index, those with multisystem disease such as chronic renal failure, those in the perioperative period, and those on multiple medications. Simvastatin 80 mg has been associated with a slightly higher incidence of myopathy and rhabdomyolysis compared with other statins, especially when combined with gemfibrozil. This could be due to the decreased rate of plasma clearance of simvastatin in older versus younger patients. Death from statin-induced rhabdomyolysis is exceedingly rare, with an incidence of 1.5 deaths per 10 million prescriptions. Statin-associated myalgias (muscle symptoms without elevations in serum CK) occur with somewhat higher frequency, about 1.4% to 1.5% in published clinical trials but up to 5% to 10% in registries, and can appear at any time during statin therapy, even years after initiation of treatment. Muscle symptoms usually resolve with discontinuation of the statin. There is recent evidence that statin inhibition of mitochondrial coenzyme Q10 may be responsible for statin-induced myalgias, and there are conflicting small studies regarding the benefit of CoQ10 supplementation on statin myalgias.

iv.Drug interactions. When statins are used in combination with certain pharmaceutical agents, such as erythromycin, gemfibrozil, azole antifungals, cimetidine, methotrexate, or cyclosporine, the risks of CK elevation and myositis increase. These drug combinations should be avoided or used judiciously with interval measurements of CK levels and liver function. Pravastatin and fluvastatin are safer in combination with other drugs because these two drugs do not use the cytochrome P450 3A4 microsomal pathways for metabolism. Verapamil and amiodarone are two commonly used cardiovascular agents that inhibit this pathway, and the concurrent use of simvastatin, atorvastatin, or lovastatin may, therefore, predispose to an increased risk of myositis. Recently, the FDA has recommended that simvastatin should not be prescribed at a dose of 80 mg, given the higher rate of myopathy at this dose unless patients have already safely taken this dose for >12 months. Patients requiring this dose to maintain lipid goals should be transferred to another statin drug capable of achieving that goal. Simvastatin dosage in combination with amiodarone, diltiazem, or verapamil should not exceed 10 mg daily and should not exceed 20 mg daily in combination with amlodipine or ranolazine.

(2)Bile acid sequestrants lower LDL-C level by interfering with reabsorption of bile acids in the distal ileum, reducing the amount returned to the liver. They are safe and free of systemic side effects because they are not systemically absorbed; however, gastrointestinal side effects such as constipation are common, and compliance is poor as a result. The average LDL level decrease is approximately 15% to 30%, with a small rise seen in HDL level (3% to 5%). Triglycerides show no change or may rise; therefore, these agents should be avoided in patients with elevated triglycerides. Two small angiographic trials, the NHLBI Type II Coronary Interventional Study and the St. Thomas Atherosclerosis Regression Study, have demonstrated reduced progression of CAD on serial angiograms in men with hypercholesterolemia who were taking cholestyramine. These agents may be of particular benefit in patients with minor elevation in LDL-C, for young patients, for women considering pregnancy, and in combination with a statin in those with very high LDL-C levels. In a pregnant patient, additional supplementation of iron and folate may be necessary because resins used over the long term can interfere with their absorption.

(3)Nicotinic acid or niacin. Niacin affects all lipid parameters favorably (i.e., LDL reduction of 5% to 25%, triglyceride reduction of 20% to 50%, and HDL elevation of 15% to 35%). It is one of the only agents that reduces Lp(a) significantly (up to 30%). Unfortunately, compliance is poor because of frequent side effects. Flushing and pruritus, gastrointestinal discomfort, glucose intolerance, and hyperuricemia often accompany the use of niacin. Hepatotoxicity is rare but is more commonly seen with the sustained-release preparation. It is often heralded by a dramatic reduction in lipid levels. There are limited data on long-term therapy with this agent. Niacin may be particularly useful for patients who do not have substantial elevations in their LDL-C levels, and low doses may be used to treat diabetic dyslipidemia. High doses should be avoided in patients with diabetes, and the drug should be avoided in those with a history of gout, peptic ulcer disease, or active hepatic disease. In the HPS2-Thrive trial, niacin and laropiprant on a background statin therapy did not reduce adverse cardiovascular events despite raising HDL concentrations.

(4)Fibrates are effective at lowering triglyceride levels by 20% to 50% and raising HDL levels by 10% to 20%. The mechanism of action involves activation of the nuclear transcription factor peroxisome proliferator–activated receptor α, with resultant increases in hepatic synthesis of apo A1 and A2 (raising HDL) and increase in lipoprotein lipase–mediated lipolysis, thus lowering triglyceride levels. LDL level reduction varies with the agent used and may range from 5% to 20% in patients who are not hypertriglyceridemic. Fenofibrate appears to lower LDL more effectively than gemfibrozil. Although a higher mortality rate was seen in the clofibrate arm of the World Health Organization (WHO) clofibrate study, such a finding was not seen in subsequent studies of gemfibrozil or fenofibrate. These agents have been demonstrated to impart a reduction in risk of CAD events and are of use in patients with elevated triglycerides. The VA-HIT (1999) found a reduction in fatal and nonfatal MI with gemfibrozil use in men with CAD who had low HDL levels (mean 32 mg/dL), but the FIELD trial (2005) did not find a significant reduction in the primary end point of CAD death or MI in diabetic patients. Although fibrates are often used in combination with statin therapy to treat mixed dyslipidemia, there are no studies demonstrating reduction in clinical events with this approach. This combination increases the risk of myopathy. For patients with very high triglyceride levels (>1,000 mg/dL), fibrate therapy reduces the risk of pancreatitis.

(5)Cholesterol absorption inhibitors such as ezetimibe inhibit cholesterol absorption by the enterocyte. Ezetimibe reduces cholesterol absorption from the small bowel by 23% to 50% and reduces serum LDL level by 14% to 20% when used in combination with a statin. Reduction in clinical end points or surrogate end points has not been demonstrated for this group of drugs in all people. The Study of Heart and Renal Protection trial reported that cholesterol lowering with a combination of simvastatin and ezetimibe in patients with chronic kidney disease significantly reduced the risk of major atherosclerotic events by 17%, including significant reductions in the risk of nonhemorrhagic stroke and revascularizations, when compared with placebo. However, the ENHANCE study failed to demonstrate any additional benefit of the use of ezetimibe added to statin over statin alone in slowing progression of carotid intimal thickness in a cohort of patients with familial hyperlipidemia. IMPROVE-IT, a phase III trial comparing ezetimibe/simvastatin versus simvastatin in subjects with stabilized high-risk ACS, showed that the addition of ezetemibe led to lower LDL levels and lower rates of cardiovascular events.

(6)CETP inhibitors such as torcetrapib, dalcetrapib, anacetrapib, and evacetrapib inhibit the process in which triglycerides from VLDL or LDL are exchanged for cholesteryl esters from HDL, resulting in higher HDL levels and reduction of LDL levels. Results from a torcetrapib study in 2004 demonstrated a significant increase in HDL (61%) and a decrease in LDL (17%) when receiving the drug in addition to atorvastatin and a 46% increase in HDL when receiving the drug alone. However, the phase 3 ILLUMINATE trial was terminated in 2006 after an increase of cardiovascular events and mortality was shown to be associated with the drug. As described above, several recent trials have concluded that CETP inhibitors fail to decrease cardiovascular events despite efficient lowering of LDL and raising of HDL levels raising suspicion about whether this class of drugs will continue to be investigated.

(7)Proprotein Convertase Subtilisin/Kexin type 9 inhibitors. PCSK-9 is a protease that promotes the binding and degradation of LDL receptors intracellularly. As such, inhibition of PCSK-9 leads to increased LDL receptors on the cell membrane and therefore, increased uptake of LDL leading to a reduction in LDL serum levels. It only took a decade since genetic variants increasing PCSK-9 expression were identified and shown to be associated with life-long lower levels of LDL and cardiovascular events to development of monoclonal antibodies that inhibit PCSK-9. Phase II and III clinical trials have shown a promising effect of PCSK-9 inhibitors. In the OSLER and ODYSSEY LONG TERM trials, evolocumab and alirocumab, respectively, showed ~60% reduction in LDL levels on a background of statin therapy in high-risk cardiovascular patients. Furthermore, they were associated with ~50% reduction in cardiovascular events, although these trials were not designed as outcome trials and the event rate was low over a short period of follow-up. Based on these preliminary promising results, the FDA approved the use of evolocumab and alirocumab for treatment of patients with clinical atherosclerotic cardiovascular events and familial hypercholesterolemia as adjuncts to maximally tolerated statin therapy if greater reductions in LDL levels are required. There are several large outcome trials currently underway.

(a)Choice of an agent and combination therapy. The use of statin therapy for treatment of hyperlipidemia should be guided by the expected change in LDL-C levels (Table 42.4). Most statins have a log-linear dose–response pattern, with each doubling of dose associated with a further 7% reduction in LDL-C levels. Adverse effects of statins are also dose dependent and rise with the use of higher doses.

TABLE 42.4 Average Reduction in Low-Density Lipoprotein Cholesterol Associated with the Starting Dose of Statin Agents
Agent	Average LDL-C Reduction (%)
Lovastatin (20 mg)	24
Pravastatin (20 mg)	24
Simvastatin (20 mg)	35
Fluvastatin (20 mg)	18
Atorvastatin (10 mg)	37
Rosuvastatin (10 mg)	47

LDL-C, low-density lipoprotein cholesterol.

i.HMG-CoA reductase inhibitors and bile acid resins. In isolated forms of LDL elevation, this combination exhibits highly complementary mechanisms of action. The combination of a statin with a bile acid sequestrant is ideal, owing to the lack of potentiation of side effects. The sequestrant provides little added toxicity, and the LDL-C lowering needed may not necessitate a full sequestrant dosage. Unfortunately, patient compliance with the combination is poor because of the common side effects of resins. Although the combination may reduce LDL level by as much as 70% in some patients, there appears to be a ceiling effect, with no LDL lowering occurring beyond the original level with an increase in dose of either agent.

ii.Combining a statin with niacin is attractive because it can favorably influence all lipid subfractions. The side effects of the combination are increased but not synergistic, and the risk of myopathy may be lower than previously believed. The main serious side effect of the combination is hepatotoxicity, which may be reduced by using extended-release niacin. In small studies using this combination, the risk of hepatotoxicity (i.e., persistent elevation of AST or ALT of more than three times the upper limit of normal) at niacin doses of 2 g/d was about 1%. The HPS2-Thrive showed no benefit in adding niacin + lopiprant to statins.

iii.The combination of a statin plus fibrate is highly effective for treating mixed hyperlipidemias. Although theoretically appealing, no reduction in clinical events has been demonstrated with this approach. The combination is associated with an increased risk of myopathy. Although earlier work suggested a higher incidence, later studies suggest this complication may be seen in approximately 1% of patients with the currently used agents.

iv.The combination of a statin plus ezetimibe has been studied in small trials and has proved to be highly safe and effective at lowering LDL-C levels. Given the small number of patients treated and short follow-up periods, it is suggested that this combination should be reserved for the patients who fail maximal statin doses or are intolerant of statins.

v.The combination of statin and PCSK-9 inhibitors is extremely effective at lowering LDL-C levels by ~60% without many side effects. The FDA has approved this approach for patients with residual hypercholesterolemia and known ASCVD and patients with heterozygous or homozygous familial hypercholesterolemia. The approval was based on trials showing a significant decrease in LDL and a signal toward reduced CV events; however, trials designed to study the impact of this combination on cardiovascular events are still underway.

3.Therapy of specific lipid disorders

a.Very high LDL levels usually result from inherited disorders of lipoprotein metabolism and carry a high risk of premature atherosclerosis with its attendant morbidity and mortality. Hypothyroidism may be associated with markedly elevated LDL levels and should be ruled out in any patient presenting with elevated LDL level. In addition to treating hypothyroidism, most of these patients will need high-dose statin therapy in addition to dietary restrictions. The addition of a bile acid sequestrant with an additional third agent (i.e., niacin) is often warranted to achieve target levels. Ezetimibe is another agent that may prove useful in this group. Therapy should be initiated early, and family members should be screened for hyperlipidemia. Patients with homozygous familial hyperlipidemia are deficient in LDL receptors, and measures that reduce cholesterol absorption (e.g., diet, ileal exclusion, bile acid sequestrants, and ezetimibe) or act by LDL receptor upregulation (e.g., statins) are largely ineffective. These patients may be treated with PCSK-9 inhibitors and LDL apheresis and should be managed in tertiary care centers only. It is important to note that PCSK-9 inhibitors may not work in patients with homozygous familial hypercholesterolemia with mutations that lead to complete absence of production of LDL receptors.

b.Elevated triglyceride levels may be caused by many factors, and more than one cause may be active in a given patient. Minor elevations in triglyceride levels (150 to 299 mg/dL) are usually caused by obesity, sedentary lifestyle, smoking, excess alcohol intake, and high-carbohydrate diets. In other patients, secondary causes such as diabetes, renal failure, Cushing disease, nephrotic syndrome, or medications (e.g., protease inhibitors, corticosteroids, retinoids, β-blockers, and oral estrogens) may be responsible. Genetic causes may be pertinent to others. The therapy for this group of patients involves identification and treatment of secondary causes (if present), change in medications, and lifestyle changes. These patients benefit from total caloric restriction and switching from a very high-carbohydrate diet to a more balanced diet. Very high triglyceride levels (500 mg/dL) usually result from genetic defects of lipoprotein metabolism; in some patients, there is a combination of factors at play. These patients are at risk for acute pancreatitis (especially with triglyceride levels >1,000 mg/dL), and treatment is directed at prevention of this condition. This is achieved with a combination of dietary measures (using very low fat diets [<15% calories from fat] and substituting medium-chain fatty acids in patients with triglyceride levels >1,000 mg/dL), increasing physical activity, maintaining optimal weight, and initiating fibrates or niacin therapy. Fibrates are especially efficacious in this group. Statins are not especially effective agents for triglyceride reduction and should be considered only after the other two agents. Patients with an intermediate rise in triglyceride levels (200 to 499 mg/dL) are a more heterogeneous group, with a wide array of underlying pathogenetic mechanisms at play. This pattern is often a result of an intersection of poor lifestyle, secondary causes, and genetic factors. These patients often have other markers of increased atherogenic risk, such as increased small LDL, low HDL, or elevated VLDL remnants. They need to be treated aggressively to bring the LDL level to the target; statins, with their ability to lower non–HDL-C, are the preferred agents. After the LDL target has been achieved, the secondary goal is non–HDL-C (goal of 30 mg/dL higher than target LDL-C). These patients also need aggressive TLCs. High-dose statins often suffice to achieve the LDL-C and non–HDL-C goals, but for most patients, a second agent becomes necessary. The choices are niacin or fibrates in addition to a statin; these combinations carry an increased risk of hepatotoxicity or myopathy, and careful monitoring for these is essential. Refractory cases may benefit from fish oil supplements (>3 g/d), which, by reducing VLDL production, can lower the serum triglyceride concentration by as much as 50% or more; however, many currently available over-the-counter fish oil supplements contain <50% active ω-3 fatty acids. The commercial preparation Omacor, which has been available for many years in Europe and is now also available in the United States, contains 90% ω-3 fatty acids. The US FDA limited approval for Omacor to the treatment of severe hypertriglyceridemia (≥500 mg/dL) because of concerns that it appears to increase LDL-C levels. Weight loss by obese patients should be encouraged; it is associated with an improvement in the lipid profile and facilitates pharmacologic therapy if still necessary. The STRENGTH trial is currently underway to assess the impact of ω-3 fatty acid treatment on cardiovascular outcomes in patients with elevated triglyceride levels.

c.Low HDL-C levels often accompany minor or modest elevations in triglyceride levels. Low HDL level has been shown in epidemiologic studies to be an independent risk factor of CVD. However, despite a multitude of research on currently available therapies to raise HDL and recent investigation of several newer agents that raise HDL, there has been no conclusive evidence that raising serum HDL-C levels contributes to lower rates of CVD. In patients who have isolated low HDL levels without any elevation in triglyceride levels, the first goal is to identify and modify lifestyle factors (e.g., high-carbohydrate diet, sedentary lifestyle, obesity, and smoking) and medications (e.g., progestational agents and anabolic steroids). The next step encompasses calculation of 10-year risk and treating LDL-C with a statin when appropriate. The AFCAPS/TexCAPS study found a clear benefit for statin therapy in patients with low HDL-C levels.

d.Diabetic dyslipidemia. Patients with diabetes are at an increased risk for cardiovascular events and fare poorly after CAD manifests. Diabetes is associated with an increase in small LDL particles and is often associated with high triglyceride and low HDL levels. As such, it also leads to significant discordance between estimated LDL levels and levels of non-HDL or TC/HDL ratio, which are better predictors of risk in this patient population. Hyperglycemia is an independent risk factor for CAD. Primary prevention is important in this group and was demonstrated to be efficacious in the HPS trial. All diabetic patients (with LDL 70 to 189 mg/dL) should be considered for statin therapy and TLCs. Secondary goals include improved non–HDL-C levels and TC/HDL-C levels and treatment for elevated triglyceride levels. Blood sugar control and insulin therapy often facilitate the former, but fibrates or low-dose niacin may be necessary in some patients. Patients with diabetes also often have coexisting hypertension. Blood pressure control and smoking cessation are essential because both interventions are highly effective at reducing cardiovascular events in this population.

ACKNOWLEDGMENTS: The authors acknowledge the contributions of Drs. James Lai, Hintinder S. Gurm, JoAnne Micale Foody, and Matthew Kaminski to previous editions of this chapter.