C-Reactive Protein

Much interest has centered on CRP, a general measure of inflammation that is produced in the liver in response to interleukin-6. This inflammatory marker is one of the “risk-enhancing factors” and is useful in assessment of patients at borderline or intermediate risk (5%–20% 10-year risk) according to traditional risk factors. hs-CRP level < 1 mg/L is considered low risk, and > 3 mg/L is high risk, with an approximate doubling of the relative risk compared with the low-risk category. Elevated CRP is associated with obesity and the metabolic syndrome, and levels can be reduced through weight loss, increased physical activity, and smoking cessation. The Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) trial (see later), which studied apparently healthy persons at increased ASCVD risk because of age, elevated hs-CRP (> 2 mg/L), and one additional ASCVD risk factor, demonstrated the utility of hs-CRP in identifying individuals at increased risk despite having low to normal levels of LDL-C. Patients in this trial who attained LDL-C levels < 50 mg/dL with rosuvastatin 20 mg daily had greater reductions in cardiovascular morbidity and mortality than the rest of the cohort.

Primary Prevention

Assessment of global CVD risk is a fundamental step in primary prevention. In general, patients without known CHD have a much lower baseline risk of CVD events than patients with known CVD, and their potential absolute risk reduction with treatment for hypercholesterolemia will usually be smaller than for patients with established CVD. Hence, the decision of whether to initiate LDL-C treatment relies heavily on determination of global CVD risk. Based on the 2018 AHA/ACC cholesterol guidelines and 10-year ASCVD risk as estimated by the Pooled Cohort Equation, adults 40–75 years of age in primary prevention can be classified as low risk (10-year risk of ASCVD < 5%), borderline risk (5% to < 7.5%), intermediate risk (7.5% to < 20%), and high risk (≥ 20%). The 2019 ESC/EAS dyslipidemia guidelines, on the other hand, divide patients into low risk (calculated SCORE < 1%), moderate risk (calculated SCORE ≥ 1% but < 5%), high risk (calculated SCORE ≥ 5% but < 10%), or very high risk (calculated SCORE ≥ 10%). Individuals with markedly elevated single risk factors such as familial dyslipidemias (LDL-C > 190 mg/dL or total cholesterol > 310 mg/dL), severe hypertension (blood pressure ≥ 180/110 mmHg), or moderate chronic kidney disease (CKD) with estimated glomerular filtration rate < 60 mL/min/1.73 m ² are classified as high risk irrespective of SCORE in the ESC/EAS guidelines. Individuals with very high risk are treated similar to secondary prevention. Lifestyle interventions (dietary modification, smoking cessation, and physical activity) are first-line treatment and may achieve meaningful cholesterol reduction in many patients. Clinical trials of statins in the past decade have demonstrated safety and clinical event reduction across a spectrum of cardiovascular risk, even in populations with low baseline risk such as the Japanese. The current 2018 AHA/ACC guidelines recommend statin therapy along with lifestyle intervention for intermediate- to high-risk individuals; the absolute risk for developing CVD in the next 10 years determines the aggressiveness of lipid-lowering therapy. For individuals with intermediate risk, moderate-intensity statin to reduce LDL-C by 30%–49% is recommended, whereas for high risk, high-intensity statin to reduce LDL-C by ≥ 50% is recommended. The 2019 ESC/EAS dyslipidemia guidelines recommend consideration of lipid-lowering therapy in addition to lifestyle interventions in individuals at moderate risk if LDL-C remains > 100 mg/dL and in those at low risk if LDL-C remains > 116 mg/dL. In patients at high risk, statin therapy along with lifestyle intervention is recommended to achieve LDL-C reduction of ≥ 50% from baseline and goal LDL-C goal of < 70 mg/dL (Class IIa). The Heart Outcomes Prevention Evaluation–3 (HOPE-3) trial showed that ASCVD risk reduction in a large diverse population with intermediate risk outweighs the observable risk of treatment. Furthermore, individuals in the high-risk category or with risk-enhancing factors as seen in the JUPITER trial benefit from maximal statin therapy to achieve greater reductions in LDL-C level and ASCVD events. Still debated, however, are the fiscal and ethical issues related to the cost effectiveness of lipid drug therapy in lower-risk primary prevention.

Secondary Prevention

The 2018 AHA/ACC guidelines support aggressive lipid-lowering therapies for patients with established CHD or other ASCVD (including peripheral vascular disease, stroke, and aortic aneurysm) and recommend an LDL-C threshold of 70 mg/dL (1.8 mmol/L) to consider further LDL-C–lowering therapy, with the addition of ezetimibe or, in very-high-risk ASCVD patients, a PCSK9 inhibitor. Very high risk ASCVD was defined as either a history of multiple major ASCVD events or one major ASCVD event and multiple high-risk conditions (age >= 65 years, history of familial hypercholesterolemia, history of CABG or primary cutaneous intervention outside of the major ASCVD event, DM, HTN, CKD (eGFR 15–59 mL/min/1.73 m ² ), current tobacco smoking, persistently elevated LDL-C >=100 mg/dL despite maximally tolerated statin and ezetimibe or history of congestive HF.

In contrast, the 2019 ESC/EAS dyslipidemia guidelines adopted a broader definition of individuals at very high risk to include anyone with documented ASCVD, either clinically or on imaging. This group includes all of those identified in the 2018 AHA/ACC guideline as secondary prevention but additionally patients with diabetes mellitus and end organ damage, moderate to severe CKD (estimated glomerular filtration rate < 30 mL/min/1.73 m ² ) even in the absence of ASCVD, familial hypercholesterolemia with ASCVD or with another major risk factor, or a calculated SCORE of ≥ 10% (roughly equivalent to a 30% risk of 10-year ASCVD events according to the Pooled Cohort Equation). Furthermore, unlike the “threshold” of 70 mg/dL set by the AHA/ACC guidelines for considering the addition of a nonstatin lipid-modifying agent in very-high-risk patients, the ESC/EAS guidelines recommend a more aggressive approach: ≥ 50% reduction in LDL-C with an absolute “goal” of < 55 mg/dL (Class IIa), with first ezetimibe and then PCSK9 inhibitors in all patients with ASCVD, even without a recent ASCVD event. This goal is based on LDL-C levels achieved in large-scale trials of PCSK9 inhibitors. For patients with ASCVD who have a second vascular event within 2 years, a more aggressive LDL-C goal of < 40 mg/dL may be considered.

While maximally tolerated high-intensity statin remains the cornerstone of lipid lowering, more recent trials such as the Improved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT), Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk (FOURIER), and Evaluation of Cardiovascular Outcomes after an Acute Coronary Syndrome During Treatment with Alirocumab (ODYSSEY Outcomes) now provide convincing evidence of clinical benefit with the addition of ezetimibe or PCSK9 inhibitors to statin to reduce LDL-C levels further. Although drug-induced LDL-C reduction remains an essential component of cardiovascular risk factor management, total risk can also be reduced through blood pressure control, dietary changes, increased exercise, weight loss, smoking cessation, and treatment of diabetes.

Total Cholesterol and Low-Density Lipoprotein Cholesterol

Optimal total blood cholesterol levels are < 150 mg/dL (3.9 mmol/L), but it bears reemphasizing that cholesterol level is only part of the patient’s absolute global risk. Furthermore, LDL-C, not total cholesterol, is the real target of therapy. Both the 2018 AHA/ACC guidelines and 2019 ESC/EAS guidelines emphasize lowering LDL-C as the primary target of therapy.

Every reduction in LDL-C of 40 mg/dL (1 mmol/L) is accompanied by a 22% reduction in vascular events. There is now an overall consensus that “lower LDL is better.” In a large meta-analysis, the Cholesterol Treatment Trialists’ (CTT) Collaboration suggested that lower LDL-C levels with more-intensive statin therapy resulted in greater reductions in cardiovascular events and proposed that aggressive reduction of LDL-C by 2–3 mmol/L (about 80–120 mg/dL) would reduce risk by about 40%–50%. Similarly, the Pravastatin or Atorvastatin Evaluation or Infection Therapy (PROVE IT) trial showed that in patients with recent acute coronary syndrome (ACS), LDL-C levels of 62 mg/dL (1.60 mmol/L) led to convincingly better clinical outcomes than levels of 95 mg/dL (2.46 mmol/L). In primary prevention, the JUPITER study also supported this theory: a subgroup of patients achieving LDL-C levels < 50 mg/dL had a 65% reduction in cardiovascular events compared with placebo, whereas risk reduction was 44% in the study overall. In a study involving patients with stable coronary disease and much lower values of hs-CRP, high-dose atorvastatin reduced atheroma volume at an LDL-C of 79 mg/dL. In another study, an LDL-C value of approximately 75 mg/dL (2 mmol/L) marked the point at which progression and regression of the atheroma volume were in balance.

There had been debate in the past about whether there is a lower limit of LDL-C beyond which no further benefit occurs; this argument is now largely settled with the recent trials. In IMPROVE-IT, mean LDL-C level of 54 mg/dL led to convincingly better clinical outcomes than mean LDL-C level of 70 mg/dL. Furthermore, LDL-C reduction even to very low levels (< 30 mg/dL) appeared to be safe; these patients, in fact, had the lowest event rates. Similarly, in the FOURIER trial (discussed later), the absolute event rate of cardiovascular death, myocardial infarction (MI), or stroke was lowest in patients achieving LDL-C level < 20 mg/dL compared with the group with LDL-C > 100 mg/dL (5.7% versus 7.8%; hazard ratio [HR] 0.69; 95% confidence interval [CI] 0.56–0.85; P < 0.0001). From a safety perspective, there were no differences in drug discontinuation rates or serious adverse events regardless of the achieved LDL-C at 4 weeks. Of the 1839 subjects who achieved ultralow LDL-C levels (< 15 mg/dL), cardiovascular events further declined without any major safety concerns. However, it is important to note these data are limited to only 2.2 years of follow-up. An open-label extension study (FOURIER-OLE; NCT02867813) is currently ongoing in the United States and Europe to determine safety over a 5-year follow-up period.

Based on these substantial data, the 2018 AHA/ACC Guideline on the Management of Blood Cholesterol reintroduced thresholds for LDL-C in secondary prevention. An LDL-C threshold of ≥ 70 mg/dL is recommended for consideration of combination therapy to lower LDL-C further in patients with ASCVD.

High-Density Lipoprotein Cholesterol

High-density lipoprotein (HDL) is postulated to aid in clearing cholesterol from the foam cells that develop in diseased arteries, either by returning cholesteryl esters directly to the liver through scavenger receptor class B type I (SR-BI) or through transfer to the apoB-containing lipoproteins in exchange for triglycerides (reverse cholesterol transport mediated by cholesteryl ester transfer protein). HDL is also hypothesized to exert antiinflammatory and antioxidant effects.

Low HDL-C level is an independent risk factor that is strongly associated with risk for CHD. Many observational studies have shown an inverse relationship between HDL-C levels and incident cardiovascular events. In the Cholesterol and Recurrent Events (CARE) study, every 10 mg/dL decrease in HDL-C led to a 10% increase in risk. HDL-C ≥ 60 mg/dL (1.6 mmol/L) is a negative (protective) risk factor, although it remains to be proven that raising HDL-C is cardioprotective. Low HDL-C is often associated with other lipid abnormalities such as high triglycerides, but there is insufficient evidence to support treating these lipid components separately. The Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglycerides: Impact on Global Health Outcomes (AIM-HIGH) study, which investigated the effect of raising HDL-C with niacin, did not show cardiovascular benefit in CHD patients who were already treated with a statin to a baseline mean LDL-C of 71 mg/dL. Furthermore, genetic studies do not show that genetic variants that can raise HDL-C lower cardiovascular events. Although American and European guidelines do not propose a target value for HDL-C, they do recommend raising low HDL-C when possible by lifestyle modification (exercise, modest alcohol intake, weight loss, smoking cessation).

A low HDL-C level is often part of atherogenic dyslipidemia , with the other two components being elevated triglycerides and small, dense LDL particles. Atherogenic dyslipidemia is a risk factor in its own right and is commonly found in patients with the metabolic syndrome, type 2 diabetes, and premature CHD. Lifestyle modification, combined with omega-3 fatty acids or fibrates, are the recommended treatments for patients with atherogenic dyslipidemia.

Triglycerides

Although triglyceride levels are commonly high in patients with CHD, the specific role of hypertriglyceridemia in atherogenesis remains controversial because it often occurs in conjunction with obesity, hypertension, and diabetes mellitus. Epidemiologically, an elevated triglyceride level can be an independent risk factor, even with adjustment for HDL-C, and in PROVE IT, triglyceride < 150 mg/dL (1.6 mmol/L) was associated with reduced cardiovascular risk even after major reduction of LDL-C. AHA defines normal triglycerides as fasting level < 150 mg/dL and optimal as < 100 mg/dL. The 2018 AHA/ACC guidelines define two categories of elevated triglycerides: moderate hypertriglyceridemia (fasting or nonfasting triglycerides 150–499 mg/dL [1.6–5.6 mmol/L]) and severe hypertriglyceridemia (fasting triglycerides ≥ 500 mg/dL [≥ 5.6 mmol/L]) ( Fig. 6.3 ). The guidelines recommend treatment with intensive dietary and lifestyle therapy for patients with moderate hypertriglyceridemia prior to initiating medications to lower triglyceride levels. A severely elevated triglyceride level (> 500 mg/dL [2.3 mmol/L]) may be viewed with special concern for risk of pancreatitis and should be treated with therapy shown to lower triglycerides most reliably, i.e., fibrates or omega-3 fatty acids. The Reduction of Cardiovascular Events with Icosapent Ethyl–Intervention Trial (REDUCE-IT; discussed later), which was published after the AHA/ACC guidelines and hence was not included in the guidelines, showed favorable reduction in cardiovascular events, including cardiovascular mortality, in patients with established ASCVD or diabetes and moderately elevated triglyceride levels treated with icosapent ethyl. The 2019 ESC/EAS guidelines, which came out afterwards, however, did recommend the addition of omega-3 fatty acids (icosapent ethyl 4 g/day) to statins in high-risk patients with triglyceride of 135–499 mg/dL) despite statin treatment (Class IIa). Similar recommendations are endorsed by both the National Lipid Association (NLA) and American Diabetes Association (ADA) (see below).

Management of hypertriglyceridemia: 2018 AHA/ACC cholesterol guidelines.

For ASCVD prevention, treatment of elevated triglycerides includes lifestyle modification, controlling secondary dyslipidemias, and, if needed, drug therapy. Patients with severe hypertriglyceridemia are also at risk for pancreatitis and should be treated accordingly. ASCVD , Atherosclerotic cardiovascular disease; CLD , chronic liver disease; CKD , chronic kidney disease; DM , diabetes mellitus; MetS , metabolic syndrome; TG , triglycerides.

(Data from Grundy SM, Stone NJ, Bailey AL, et al. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the management of blood cholesterol: A report of the American College of Cardiology/American Heart Association task force on clinical practice guidelines. J Am Coll Cardiol 2019;73:e285–e350.)

Other Lipoproteins and Lipoprotein Carriers

The combination of cholesterol in LDL and very-low-density lipoprotein (VLDL) is known as non-HDL-C and is a strong predictor of cardiovascular risk, especially in patients with elevated triglycerides or diabetes. Elevated triglycerides result from accumulation of VLDL and other triglyceride-rich lipoproteins, which are highly atherogenic. In such cases, non-HDL-C provides a more accurate measure of the cholesterol content of all atherogenic lipoproteins than LDL-C alone. The 2018 AHA/ACC guidelines support a non-HDL-C threshold of 100 mg/dL (2.6 mmol/L), along with LDL-C, to guide therapy and enhance identification of those at increased ASCVD risk, especially in very-high-risk patients with ASCVD.

Similarly, measurement of apoB may be valuable in patients with moderately elevated triglycerides, as it may be a more accurate indicator of atherogenic potential in these individuals. ApoB level ≥ 130 mg/dL, especially in patients with elevated triglycerides, denotes a high lifetime risk and is a risk-enhancing factor (see Table 6.1 ) in the 2018 AHA/ACC guidelines.

Lp(a), which is structurally similar to LDL with the addition of apo(a) covalently linked to apoB, may also be useful in risk assessment. The 2018 AHA/ACC guidelines define Lp(a) ≥ 50 mg/dL as a risk-enhancing factor and consider family history of premature ASCVD a relative indication for measurement of Lp(a) level. The 2019 ESC/EAS dyslipidemia guidelines recommend Lp(a) measurement in all adults at least once to identify individuals with very high inherited Lp(a) levels > 180 mg/dL, whose lifetime ASCVD risk may be equivalent to individuals with heterozygous familial hypercholesterolemia.

Metabolic Syndrome

Metabolic syndrome is a cluster of risk factors ( Fig. 6.4 ) that greatly enhances the risk for coronary morbidity and mortality at any level of LDL-C. The underlying pathology of the metabolic syndrome appears to be linked to obesity and insulin resistance, and its prevalence increases with age and with presence of type 2 diabetes mellitus. The 2018 AHA/ACC cholesterol guidelines incorporate metabolic syndrome in the risk-enhancing factors (see Table 6.1 ), which influence initiation or up-titration of lipid-lowering therapy in primary prevention. First-line therapy for metabolic syndrome is weight control and increased physical activity. LDL-C and non-HDL-C should be controlled; achieving a significant increase in HDL-C, although desirable, has not proven to be clinically useful.

Metabolic syndrome.

Metabolic syndrome is a constellation of risk factors, including central obesity, insulin resistance, hypertriglyceridemia, low HDL-C, and hypertension, that increases risk for ASCVD and diabetes. In the 2018 AHA/ACC cholesterol guidelines, metabolic syndrome is diagnosed by ≥ three of the risk factors shown. ASCVD , Atherosclerotic cardiovascular disease; HDL-C, high-density lipoprotein cholesterol.

(Data from Grundy SM, Stone NJ, Bailey AL, et al. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the management of blood cholesterol: A report of the American College of Cardiology/American Heart Association task force on clinical practice guidelines. J Am Coll Cardiol 2019;73:e285–e350.)

Secondary Dyslipidemias

Diabetes mellitus, hypothyroidism, nephrotic syndrome, and alcoholism should be remedied if possible. Among drugs causing adverse lipid changes are β-blockers and diuretics ( Table 6.2 ), progestogens, and oral retinoids. Nonetheless, cardiac drugs known to be protective should not be withheld on the basis of their lipid effects alone, especially in postinfarct patients when there is clear indication for the expected overall benefit.

Diabetic Patients

Patients with diabetes constitute a high-risk group and warrant aggressive risk reduction. Risk for MI is increased almost fivefold in diabetic women aged 35–54 years and more than twofold in diabetic men aged 35–54 years, compared with age-matched women and men, respectively, without diabetes. In line with this, type 2 diabetes is regarded as a risk category in its own right in the 2018 AHA/ACC cholesterol guidelines, and in the 2019 ESC/EAS guidelines, type 2 diabetes is considered a high-risk category, irrespective of calculated SCORE. Both guidelines recommend initiation of statin therapy along with lifestyle modification in these patients. In recent years, growing awareness of the overlapping pathophysiologic characteristics of CHD and type 2 diabetes has led to increased coordination between cardiologists and endocrinologists in addressing the joint risk. Patients with type 2 diabetes may have a preponderance of smaller, denser, more atherogenic LDL particles, even though the LDL-C level may be relatively normal.

Meta-analysis of 14 randomized trials with a follow-up of at least 2 years indicated that lipid-lowering drug treatment significantly reduced cardiovascular risk in both diabetic and nondiabetic patients. The Collaborative Atorvastatin Diabetes Study (CARDS), a multicenter, randomized primary-prevention trial in patients with type 2 diabetes and at least one other risk factor who were treated with atorvastatin, 10 mg/day, or placebo, was stopped early because of a favorable clinical benefit of statin therapy. Taken together with a large subgroup analysis from the Heart Protection Study (HPS) and Anglo-Scandinavian Cardiac Outcomes Trial–Lipid-Lowering Arm (ASCOT-LLA), there are strong arguments for considering statin therapy, in addition to lifestyle modification and blood pressure control, in all patients with type 2 diabetes. A meta-analysis of all four double-blinded primary-prevention randomized controlled trials with large cohorts with diabetes found that use of moderate-intensity statin therapy in a total of 10,187 participants was associated with a risk reduction of 25%, with no apparent difference in benefit between type 1 and type 2 diabetes mellitus.

Recent trials have provided evidence for the role of nonstatin lipid-lowering therapy in combination with statin to reduce cardiovascular risk among patients with diabetes. In IMPROVE-IT, which evaluated the addition of ezetimibe to statin therapy in patients with recent ACS (27% of whom had diabetes), individuals with diabetes had significantly greater relative and absolute benefit on cardiovascular outcomes than those without diabetes. Subanalysis of the diabetic subgroup in the FOURIER trial showed that median LDL-C levels were reduced to a similar degree with evolocumab relative to placebo (57% in those with diabetes mellitus versus 60% in those without diabetes mellitus). In the ODYSSEY OUTCOMES trial, a similar subgroup analysis compared patients with diabetes (n = 5444; 29%), prediabetes (n = 8246; 43%), and normoglycemia (n = 5234; 28%). Over a median follow-up of 2.8 years, treatment with alirocumab resulted in twice the absolute reduction in cardiovascular events among patients with diabetes as in those without diabetes given higher baseline risk. Similarly, in REDUCE-IT, 30% of subjects enrolled had diabetes and at least one other traditional risk factor, along with elevated triglycerides, and had significant reduction in risk of ischemic events, including cardiovascular death, with icosapent ethyl compared to placebo. Based on this study, the American Diabetes Association updated its comprehensive evidence-based recommendations to endorse the use of icosapent ethyl in patient with diabetes already on statin with elevated triglyceride level (134–499 mg/dL). Similar endorsements were made by the NLA and 2019 ESC/EAS guidelines.

Older Adults

Although the relation between cholesterol and CHD weakens with age, physicians should continue to consider lipids as a modifiable risk factor in older adults. The absolute risk for clinical CHD in older adults is much higher because age is a powerful risk factor and because blood pressure, another risk factor, often increases with age. Furthermore, consider the cumulative effect of lifetime exposure to a coronary risk factor on an older adult patient. While the Prospective Study of Pravastatin in the Elderly at Risk (PROSPER) found coronary but not overall mortality benefit with statin treatment in older adults (see section on pravastatin), this trial may have been too short (3 years) to show major decreases in cerebrovascular disease. In a recent meta-analysis of JUPITER and HOPE-3, benefits on ASCVD reduction with rosuvastatin were similar among those ≥ 70 years of age versus < 70 years of age, with relative risk reduction for nonfatal MI, nonfatal stroke, or cardiovascular death of about 26% and no difference in adverse events between the two age groups. Furthermore, those ≥ 70 years of age had much higher event rates, which along with the comparable relative risk reductions, would mean that larger absolute risk reductions can be achieved with statin treatment and hence a smaller number needed to treat (NNT) to prevent an event in older compared with younger patients. Other meta-analyses similarly support primary prevention for adults in their 70s. The Study Assessing Goals in the Elderly (SAGE) confirmed the safety and benefit of intensive treatment with atorvastatin, 80 mg/day, in older adult patients with stable coronary syndromes, but failed to demonstrate the superiority of intensive versus moderate treatment in reducing the primary endpoint of total ischemia duration from baseline to 1 year. However, data on older subsets (≥ 80 years of age) remain sparse. Furthermore, older adults may be more susceptible to statin-related risk, owing to increasing frailty, multiple comorbidities, cognitive impairment, polypharmacy, and altered pharmacodynamics in older adults. The 2018 AHA/ACC guidelines therefore recommend judicious use of statin therapy in higher-risk older adults and support clinical judgment and thorough risk and benefit discussion between patient and clinician prior to initiating statin. The 2019 ESC/EAS dyslipidemia guidelines recommend initiation of statin in older adults > 75 years old with high risk or above, and suggest that statin be started at a low dose and titrated upwards to achieve LDL-C treatment goals. In individuals whose cumulative risk outweighs benefit or with limited lifespan, the guidelines recommend not initiating therapy and, in individuals already taking statin, deprescription.

Women

Women have a lower baseline risk for CHD than men at all ages except perhaps beyond 80 years. Risk lags by about 10–15 years, perhaps because of a slower rate of increase in LDL-C, higher levels of HDL-C, or ill-understood protective genetic factors in the heart itself. It is not simply a question of being pre- or postmenopausal. In large statin trials such as HPS, women had relative risk reduction comparable to that in men. In the Management of Elevated Cholesterol in the Primary Prevention Group of Adult Japanese (MEGA) trial of low-dose pravastatin (10–20 mg daily) in low-risk Japanese patients, 69% of whom were women, women had marginally less CHD risk reduction than men, possibly because of their lower initial risk. The JUPITER trial, which enrolled 6801 women (38% of the study population), showed that women had similar risk reduction as men, primarily because of reductions in risk for revascularization and unstable angina. A meta-analysis conducted by the JUPITER investigators found that statins reduced cardiovascular events in women in primary prevention trials by one-third.

The 2018 AHA/ACC guidelines address certain conditions specific to women that may augment their baseline risk for CVD and may help clinical decision-making regarding lifestyle intervention and lipid-lowering therapy. These conditions include pregnancy-related complications (hypertensive disorders during pregnancy, preeclampsia, gestational diabetes mellitus, delivering a preterm or low-birth weight infant) and premature menopause, all of which have been shown to increase future risk of CVD and portend increased cardiovascular morbidity and mortality.

Pregnant Women

As a group, lipid-lowering drugs are either completely or relatively contraindicated during pregnancy because of the essential role of cholesterol in fetal development. Bile acid sequestrants may be safest, whereas statins should not be used (see “Contraindications and Pregnancy Warning” in the later section on statins).

Lifestyle and Risk Factor Reduction

Nondrug dietary therapy is fundamental to the management of all primary hyperlipidemias and frequently suffices as basic therapy when coupled with weight reduction, exercise, ideal (low) alcohol intake, and treatment of other risk factors such as smoking, hypertension, or diabetes. Regular exercise may also increase insulin sensitivity and lessen the risk of type 2 diabetes. If lifestyle recommendations, including diet, were rigorously followed, CHD would be dramatically reduced in those younger than age 70. However, high-intensity lifestyle modification is required to prevent progression or even to achieve regression of CHD.

Statins: 3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase Inhibitors

Statins are well established as the first drugs of choice in primary and secondary prevention of CHD because of their favorable clinical outcomes, predictable effects on LDL-C, and relatively few side effects across multiple large clinical trials. Available statins include lovastatin, pravastatin, simvastatin, fluvastatin, atorvastatin, rosuvastatin, and pitavastatin. All the statins decrease hepatic cholesterol synthesis by inhibiting 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase. They are highly effective in reducing total cholesterol and LDL-C, they usually increase HDL-C, and long-term safety and efficacy is well established. Many are now available in generic form. The landmark Scandinavian Simvastatin Survival Study (4S) showed that simvastatin used in secondary prevention achieved a reduction in total mortality and in coronary events. This was soon followed by a successful primary-prevention study with pravastatin in high-risk men (CARE). Successful primary prevention of common events has been found in patients with LDL-C values near the U.S. national average. An interesting concept is that lipid-lowering drugs may act in ways beyond regression of the atheromatous plaque, for example, by improving endothelial function, stabilizing platelets, reducing fibrinogen (strongly correlated with triglyceride levels), or inhibiting the inflammatory response associated with atherogenesis.

Cholesterol Absorption Inhibitors: Ezetimibe (Zetia, Vytorin, Nexlizet)

Although statins remain the mainstay for treatment of hypercholesterolemia and secondary prevention of ASCVD, recent data suggest that ezetimibe may serve as a valuable addition to the armamentarium of lipid-lowering drugs. Cholesterol absorption inhibitors selectively interrupt intestinal absorption of cholesterol and phytosterols. Ezetimibe acts at the brush border of the small intestine and inhibits the absorption of cholesterol, leading to decreased delivery of intestinal cholesterol to the liver, which reduces hepatic cholesterol and increases cholesterol clearance from the blood. This mechanism is complementary to that of statins. Ezetimibe has a half-life of 22 hours and is not metabolized by the CYP system.

A meta-analysis of eight randomized, double-blind, placebo-controlled trials found that ezetimibe significantly reduced LDL-C levels by 18.5% when used as monotherapy. The use of ezetimibe in conjunction with a statin has been shown to be an effective strategy for not only reducing LDL-C levels but also preventing cardiovascular events. Early trials demonstrated that statin and ezetimibe combination therapy reduced LDL-C by 12%–19% more than statin monotherapy. The Plaque Regression With Cholesterol Absorption Inhibitor or Synthesis Inhibitor Evaluated by Intravascular Ultrasound (PRECISE-IVUS) trial in patients with CHD demonstrated greater coronary plaque regression, assessed by serial volumetric intravascular ultrasound, in patients treated with ezetimibe in combination with atorvastatin than in patients treated with atorvastatin monotherapy (78% versus 58%; P = 0.004). However, the Ezetimibe and Simvastatin in Hypercholesterolemia Enhances Atherosclerosis Regression (ENHANCE) study did not find significant reduction of carotid atherosclerosis in patients with familial hypercholesterolemia with combined ezetimibe and simvastatin compared with simvastatin monotherapy, despite greater LDL-C reduction.

The Study of Heart and Renal Protection (SHARP) was the first major trial that assessed cardiovascular outcomes using combination therapy of statin and ezetimibe. In a wide range of patients with CKD, simvastatin 20 mg daily plus ezetimibe 10 mg daily compared to placebo significantly reduced both the LDL-C levels (33-mg/dL [0.85-mmol/L] difference between treatment groups) and the rate of cardiovascular events (11.3% versus 13.4%; rate ratio 0.83; absolute risk reduction 2.1%; NNT 48) at median 5-year follow-up. However, because the study lacked a statin-only comparison arm, it was unclear whether the benefit of adding ezetimibe was independent of the LDL-lowering effects of the statin. Note that this study could equally well argue for lipid lowering with a statin in dialysis patients. The FDA updated the prescribing information for ezetimibe to include data from SHARP. Although the FDA approved the ezetimibe–simvastatin combination for use in CKD as a new indication, ezetimibe without simvastatin was not approved because the relative contributions of simvastatin and ezetimibe were not assessed in the trial.

IMPROVE-IT was the first trial to provide compelling evidence that a nonstatin medication, ezetimibe, resulted in greater reduction in cardiovascular events when added to statin therapy than statin monotherapy in high-risk patients. Patients with known CHD, within 10 days of a recent MI or ACS and with low LDL-C levels (< 125 mg/dL [3.2 mmol/L]), were randomized to ezetimibe therapy in conjunction with simvastatin or to simvastatin monotherapy and followed for a median of 6 years. The combination therapy group had a significantly lower rate of major cardiovascular events (32.7% versus 34.7% in the simvastatin monotherapy group; absolute risk reduction 2.0%; HR 0.936; 95% CI 0.89–0.99; P = 0.016) but no difference in mortality. Adverse effects were similar in the two groups, demonstrating the safety profile of ezetimibe. The application of the findings of IMPROVE-IT are twofold. First, it supports the theory of “lower is better” for LDL-C levels to reduce cardiovascular risk. Second, it demonstrated a significant add-on effect of ezetimibe to statin in terms of both LDL-C reduction and reduction of cardiovascular events.

Subanalysis of IMPROVE-IT demonstrated greater reduction in LDL-C among patients with diabetes within the first year of the trial: 43 mg/dL (1.1 mmol/L) reduction in the simvastatin–ezetimibe arm versus 23 mg/dL (0.6 mmol/L) reduction in the simvastatin monotherapy arm. Addition of ezetimibe also conferred a larger protective cardiovascular benefit in high-risk patients with diabetes. Therefore, combination therapy of statin and ezetimibe may be an effective option for patients with diabetes who are unable to tolerate high-intensity statin or those requiring large LDL-C reductions.

The results of the open-label Ezetimibe Lipid Lowering Trial on Prevention of Atherosclerosis in 75 or Older (EWTOPIA75) showed that in 4000 elderly Japanese patients, without prior history of CHD but with LDL-C level ≥ 140 mg/dL and one or more other cardiovascular risk factors (including diabetes, hypertension, prior cerebral infarction, or peripheral artery disease), patients receiving ezetimibe monotherapy had significantly lower cardiovascular events, including strokes, over a 5-year follow-up than patients not receiving ezetimibe.

Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) Inhibitors (Repatha, Praluent)

PCSK9 inhibitors have been shown to be the most potent LDL-lowering class of drug. The FDA has approved two monoclonal antibodies in this class of drugs for LDL-C reduction and secondary prevention: evolocumab (Repatha) and alirocumab (Praluent).

PCSK9 is a hepatic protease that attaches to and internalizes LDL receptors into lysosomes, promoting LDL receptor degradation. PCSK9 inhibitors bind and inactivate extracellular PCSK9 and prevent its interaction with the LDL receptor, thereby preventing trafficking of LDL receptors to lysosomes and therefore increasing the number of LDL receptors on the surface of liver cells available to clear LDL, which in turn lowers LDL-C levels in the blood. Additionally, PCSK9 inhibitors significantly reduce total cholesterol, apoB, triglycerides, and Lp(a).

Despite widespread use of the statins, a large proportion of high-risk patients are not able to achieve targeted LDL-C levels and have residual risk. Previously, options were limited for patients who develop CVD despite being on maximally tolerated statin therapy, were intolerant to statin therapy, or had severe hypercholesterolemia. The PCSK9 inhibitors evolocumab and alirocumab have been shown in multiple phase III and IV clinical trials to provide consistent and substantial LDL-C reductions of 50%–70% across a broad range of CVD risk, pretreatment LDL-C levels, and background therapy and have been studied as monotherapy (MENDEL-2, ODYSSEY COMBO I ), as an add-on to statin therapy (LAPLACE-2, ODYSSEY CHOICE I ), or in individuals with heterozygous familial hypercholesterolemia (RUTHERFORD-2, ODYSSEY-FH ). The Goal Achievement After Utilizing an Anti-PCSK9 Antibody in Statin Intolerant Subjects 3 (GAUSS-3) randomized clinical trial also demonstrated tolerability of PCSK9 inhibitor therapy in patients with muscle-related statin intolerance. These agents can be used as both adjunctive and alternative therapy for reducing LDL-C and have ushered in a new era of lipid-lowering therapy

Data from two large landmark outcome trials, FOURIER and ODYSSEY OUTCOMES, provided robust proof of the clinical safety and efficacy of evolocumab and alirocumab in reducing ASCVD events when used in combination with a statin compared to statin monotherapy. FOURIER was a large randomized, double-blind, placebo-controlled clinical trial investigating the efficacy and safety of evolocumab when added to high-intensity or moderate-intensity statin therapy in patients with stable clinical ASCVD. Patients were randomized to receive evolocumab or matching placebo as subcutaneous injections for 26 months. The majority of the 27,564 patients (69.3%) were on a high-intensity statin, 30.4% were on moderate-intensity statin, and 5.2% were on ezetimibe. At 48 weeks, evolocumab reduced LDL-C levels by 59% from baseline compared with placebo for a mean absolute reduction of 56 mg/dL. The primary efficacy endpoint (composite of cardiovascular death, MI, stroke, hospitalization for unstable angina, or coronary revascularization) occurred in 9.8% of patients in the evolocumab group and 11.3% of patients in the placebo group, indicating a 15% risk reduction with evolocumab (HR 0.85; 95% CI 0.79–0.92; P < 0.001) and NNT of 74. No effect was observed on hospitalization for unstable angina, cardiovascular death, or all-cause death but there were significant reductions in the risk for nonfatal MI (HR 0.73; 95% CI 0.65–0.82; P < 0.001), nonfatal stroke (HR 0.79; 95% CI 0.66–0.95; P = 0.01), and coronary revascularization (HR 0.78; 95% CI 0.71–0.86; P < 0.001).

ODYSSEY OUTCOMES assessed the efficacy of adding alirocumab to maximally tolerated statins on cardiovascular outcomes in 18,924 patients who had an ACS within a year of enrolling in the trial. At 48 weeks, alirocumab reduced LDL-C levels by 54.7% compared to placebo for an absolute reduction of 48.1 mg/dL. Patients who received alirocumab had significant reduction in major cardiovascular events; the primary composite endpoint (composite of cardiovascular death, MI, stroke, or hospitalization for unstable angina) occurred in 9.5% of patients in the alirocumab group and 11.1% of patients in the placebo group, resulting in a 15% risk reduction (HR 0.85; 95% CI 0.78–0.93; P = 0.0003) and NNT of 62. There were also significant reductions in nonfatal MI (6.6% versus 7.6%; P = 0.006), stroke (1.2% versus 1.6%; P = 0.01), and all-cause death (3.5% versus 4.1%; nominal P = 0.026) but no difference in cardiovascular death. This was the first trial to show mortality benefit with the addition of a nonstatin medication. Whereas alirocumab significantly reduced total deaths, cardiovascular death or noncardiovascular death analyzed separately was not significantly reduced. Patients with nonfatal cardiovascular events were at increased risk for both cardiovascular and noncardiovascular deaths. Because alirocumab reduced total nonfatal cardiovascular events ( P < 0.001), the authors postulated that this may have attenuated the number of cardiovascular and noncardiovascular deaths and thus led to a reduction in total mortality.

Patients with peripheral artery disease are a very-high-risk group and often undertreated. A subanalysis from FOURIER demonstrated that evolocumab reduced both major adverse cardiovascular events and major adverse limb events, defined as acute limb ischemia, major amputation, or urgent peripheral revascularization in patients with history of peripheral artery disease. Furthermore, the subgroup of patients with peripheral artery disease were shown to derive the most benefit from alirocumab therapy, as this subgroup achieved the highest absolute risk reduction in both adverse cardiovascular and adverse limb events. Evolocumab also reduced the risk of major adverse limb events in all patients, regardless of peripheral artery disease diagnosis at baseline, with reduction in lower limb events shown to be directly proportional to achieved LDL-C level, down to an LDL-C level of 10 mg/dL. Thus, PCSK9 inhibitor therapy should be strongly considered to reduce risk for cardiovascular and peripheral artery disease events.

Bempedoic Acid (Nexletol, Nexlizet [US]; Nilemdo, Nustendi [EU])

Bempedoic acid is a recently approved nonstatin therapy designed to inhibit cholesterol biosynthesis primarily in the liver. Bempedoic acid is administered as a prodrug that is converted to its active moiety primarily in the liver and inhibits adenosine triphosphate citrate lyase (ACL), an enzyme two steps upstream from HMG-CoA reductase along the cholesterol biosynthesis pathway, thereby effectively reducing cholesterol synthesis, resulting in LDL receptor upregulation and increased clearance of LDL from the bloodstream. Bempedoic acid can only converted to its active moiety by the enzyme ACSVL1, which is present in hepatocytes but not present in skeletal muscle ; therefore, based on its pharmacological profile, bempedoic acid may have fewer serious muscle adverse effects.

Five randomized, double-blind, placebo-controlled, parallel-group, multicenter phase III clinical trials known as Cholesterol Lowering via Bempedoic Acid, an ACL-inhibiting Regimen (CLEAR) have established safety, tolerability, and LDL-C–lowering efficacy of bempedoic acid in a total 3623 participants. In the largest of these trials, CLEAR Harmony, which studied bempedoic acid only in 2230 patients with ASCVD and/or heterozygous familial hypercholesterolemia on background statin therapy (85% using moderate- to high-intensity statin), bempedoic acid resulted in a significant 16.5% reduction in LDL-C and did not lead to higher incidence of overall adverse events compared to placebo over 52 weeks’ follow-up. In CLEAR Tranquility, in which 269 statin-intolerant patients on stable background therapy and open-label ezetimibe 10 mg were randomized to receive bempedoic acid 180 mg or placebo for 12 weeks, bempedoic acid + ezetimibe resulted in 28.5% greater LDL-C reduction than placebo + ezetimibe. In another phase III clinical trial (not part of the CLEAR program), the safety and efficacy of a fixed-dose combination tablet containing bempedoic acid 180 mg and ezetimibe 10 mg was evaluated in 301 patients with hypercholesterolemia and ASCVD and/or heterozygous familial hypercholesterolemia on background maximally tolerated statin therapy (35% on high-intensity statin, 35% on no statin). Fixed-dose combination therapy lowered LDL-C by 38% compared with placebo at week 12 and had a generally similar safety profile compared with bempedoic acid, ezetimibe, or placebo. . The ongoing CLEAR Outcomes trial (NCT02993406) is a cardiovascular event–driven, multinational, randomized, double-blind, placebo-controlled study in approximately 12,600 patients, with an estimated study duration of 4.75 years.

Omega-3 Fatty Acids (Fish Oils; Lovaza, Vascepa, Epanova)

Omega-3 fatty acids are a major class of polyunsaturated fatty acids. Studies show that omega-3 fatty acids in general decrease blood triglyceride and VLDL levels in hyperlipidemic individuals but may have no effect or may increase LDL-C in patients with very high triglycerides. These effects are most prominently seen with high-dose supplements (> 2 to 44 g/day). Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are two major types of omega-3 fatty acids. EPA and DHA have been shown to reduce inflammation, with production of resolvins and decrease in proinflammatory compounds. A number of other beneficial actions for atherosclerosis prevention have been reported, relating to endothelial function, oxidative stress, foam-cell formation, plaque formation/progression, platelet aggregation, thrombus formation, and plaque rupture. DHA is the major polyunsaturated fatty acid found in the brain and is important for brain development and function.

In the Multi-center, Placebo-controlled, Randomized, Double-blind, 12-Week Study with an Open-label Extension (MARINE) trial, in adult patients with very high fasting triglyceride levels between 500 mg/dL and 2000 mg/dL, patients treated with EPA ethyl ester (icosapent ethyl) 4 g/day for 12 weeks had a statistically significant placebo-adjusted median triglyceride reduction of 33% ( P < 0.0001) and a small reduction in LDL-C levels (5%). In addition, treatment with icosapent ethyl 4 g/day led to statistically significant placebo-adjusted median reductions from baseline in non-HDL-C (18%), total cholesterol (16%), VLDL-C (29%), and apoB (8.5%).

The efficacy of icosapent ethyl was also evaluated in ANCHOR, a phase III placebo-controlled randomized clinical trial in high-risk statin-treated patients (n = 702) with triglyceride levels between 200 mg/dL and 500 mg/dL and with LDL-C levels of 40–100 mg/dL. After 12 weeks, treatment with icosapent ethyl 4 g/day resulted in a significant median placebo-adjusted change from baseline in triglyceride levels of 21.5% ( P < 0.0001).

Historically, clinical trials assessing the role of fish oil supplementation or low-dose prescription omega-3 fatty acids showed variable results without clear benefit in prevention of cardiovascular events. However, both the Japan EPA Lipid Intervention Study (JELIS) and REDUCE-IT provided valuable findings to support clinical benefit of EPA as an add-on to statins in high-risk patients. In JELIS, 18,645 Japanese patients with hypercholesterolemia were randomly assigned to receive either low-intensity statin therapy plus EPA 1.8 g/day or statin therapy alone (there was no placebo group). The risk of major coronary events was significantly reduced by 19% in the group that received EPA plus statin therapy compared with the group that received statin therapy alone. Additional evidence was obtained from REDUCE-IT, which was the first large multinational cardiovascular outcomes study that evaluated the effect of prescription EPA therapy as an add-on to statins. Over 8000 patients with high cardiovascular risk who, despite stable statin therapy, had residual hypertriglyceridemia (fasting triglyceride of at least 135 mg/dL) were randomized to 2 g of icosapent ethyl twice daily (total daily dose, 4 g) or placebo. Patients in the icosapent ethyl group had significantly reduced risk for the primary endpoint of cardiovascular events (cardiovascular death, nonfatal MI, nonfatal stroke, coronary revascularization, or unstable angina), which occurred in 17.2% of the icosapent ethyl group versus 22.0% of the placebo group ( P < 0.001) for an absolute risk reduction of 4.8%. Cardiovascular death was also significantly reduced with icosapent ethyl compared with placebo (4.3% versus 5.2%, respectively; P < 0.001).

Fibrates: Fibric Acid Derivatives

Fibrates are highly effective in reducing triglycerides, but as a rule, none of the fibrates reduce LDL-C as much as do the statins or PCSK9 inhibitors. Unlike statins, which have demonstrated clinical efficacy across a broad range of LDL-C levels, fibrates have primarily shown reductions in cardiovascular events in a subset of patients with high triglycerides (≥ 200 mg/dL [2.2 mmol/L]) and low HDL-C (< 40 mg/dL [1.0 mmol/L]). The primary role of fibrates is to decrease triglyceride level, atherogenic triglyceride-rich lipoproteins, and concentration of small, dense LDL particles. They are therefore suitable for use in atherogenic dyslipidemia. Fibrates are first-line therapy to reduce the risk for pancreatitis in patients with very high levels of plasma triglycerides and may be useful with more modest triglyceride elevations or when the primary dyslipidemia is low HDL-C.

At a molecular level, fibrates are agonists for the nuclear transcription factor peroxisome proliferator–activated receptor–α (PPAR-α), which stimulates the synthesis of the enzymes of fatty acid oxidation, thereby reducing VLDL triglycerides. Although all fibrates belong to the same class of drugs, structural differences between the compounds seem important because of the very different results between large-scale trials of clofibrate (unfavorable) and gemfibrozil (favorable; see below).

Bile Acid Sequestrants: Resins (Questran, Welchol, Colestid)

Bile acid sequestrants— cholestyramine (Questran), colesevelam (Welchol) , and colestipol (Colestid) —bind to bile acids to promote the secretion of bile acids into the intestine, resulting in increased loss of hepatic cholesterol into bile acids and hepatic cellular cholesterol depletion. The latter leads to a compensatory increase in hepatic LDL receptors, increasing the removal of LDL from the circulation and decreasing total cholesterol and LDL-C. There may be a transitory compensatory rise in plasma triglycerides that is usually mild but may require cotherapy or discontinuation of the agent. Colesevelam has an additional FDA indication for glycemic control in the treatment of type 2 diabetes, as combination therapy with metformin, sulfonylureas, or insulin. The major outcome trial conducted with resins was the Lipid Research Clinics Coronary Primary Prevention Trial, in which cholestyramine modestly reduced CHD (primary endpoint: CHD death or nonfatal MI) in hypercholesterolemic patients and improved blood lipid profiles but had no effect on overall mortality. Drug interactions include interference with the absorption of digoxin, warfarin, thyroxine, and thiazides, which need to be taken 1 hour before or 4 hours after the sequestrant. Impaired absorption of vitamin K may lead to bleeding and sensitization to warfarin. Poor palatability is the major problem. Combination therapy is often undertaken, and coadministration with a statin may exploit the complementary mechanisms of action of these two drug classes. Resins may increase triglycerides, so a second agent such as nicotinic acid or a fibrate may be required to lower triglycerides. Resins should be used with caution in patients with hypertriglyceridemia.

Nicotinic Acid (Niacin; Niaspan)

Nicotinic acid was the first hypolipidemic drug shown to reduce overall mortality, in 15-year follow-up from the Coronary Drug Project. The basic effect of nicotinic acid may be decreased mobilization of free fatty acids from adipose tissue, so that there is less substrate for hepatic synthesis of lipoprotein lipid. Consequently, there is less secretion of lipoproteins so that LDL particles, including triglyceride-rich VLDL, are reduced. Nicotinic acid also increases HDL-C and reduces Lp(a).

In the angiographic Familial Atherosclerosis Treatment Study (FATS), men with apoB ≥ 125 mg/dL, CHD, and family history of CVD received either lovastatin (20 mg BID) or nicotinic acid (1 g QID), combined with colestipol (10 g TID). Both regimens were equally effective on blood lipids, and angiographically measured coronary stenosis was lessened, although side effects were worse, with nicotinic acid.

The AIM-HIGH study, an outcomes study examining the effect of adding extended-release niacin to simvastatin in patients with cardiovascular disease, was stopped early because of lack of clinically meaningful efficacy. Niacin failed to demonstrate incremental benefit in cardiovascular event reduction for patients already optimally treated with lipid-lowering therapy to a mean LDL-C of 71 mg/dL at baseline; in addition, an unexplained increase in ischemic stroke was observed in the niacin arm. After 36 months, the difference in HDL-C between treatment groups was only 4 mg/dL; the study may have been underpowered to show benefit of niacin on top of statin therapy.

Laropiprant was developed in an attempt to reduce the side effects of niacin that led to poor patient compliance but was discontinued. In the Heart Protection Study 2–Treatment of HDL to Reduce the Incidence of Vascular Events (HPS2-THRIVE), a large multicenter, double-blind, controlled clinical trial, 25,673 patients with prior CVD, all on LDL-lowering therapy with simvastatin 40 mg, were randomized to receive either extended-release niacin–laropiprant combination tablets (a total of 2 g of niacin and 40 mg of laropiprant) daily or matching placebo. Over a median follow-up of 4 years, HDL-C levels increased by 6 mg/dL, triglycerides levels decreased by 33 mg/dL, and LDL-C levels decreased by 10 mg/dL in the niacin–laropiprant group. However, no significant difference in the incidence of major vascular events (nonfatal MI, stroke, coronary or noncoronary revascularization, or death from coronary causes) was demonstrated between patients assigned to niacin–laropiprant and those assigned to placebo (13.2% versus 13.6%, respectively, P = 0.29). Lack of efficacy was uniform in all subgroups defined according to different types of vascular disease or diabetes. Patients assigned to niacin–laropiprant were more likely to have disturbances in diabetes control (11.1% versus 7.5%; P < 0.001) and a new diagnosis of diabetes (5.7% versus 4.3%; P < 0.001) than those assigned to placebo. Study drug was discontinued in 25.4% of the niacin–laropiprant group compared with 16.6% of the placebo group ( P < 0.001). Furthermore, the niacin–laropiprant group had a significant excess in serious adverse events associated with the gastrointestinal system (mostly bleeding and ulcerations; 4.8% versus 3.8%; P < 0.001), myopathy (3.7% versus 3.0%; P < 0.001), and skin rash/ulceration (0.7% versus 0.4%; P = 0.003), as well as excess bleeding events (mostly gastrointestinal and intracranial; 2.5% versus 1.9%; P < 0.001) and infections (8.0% versus 6.6%; P < 0.001).

Both AIM-HIGH and HPS2-THRIVE failed to show any incremental clinical benefit from niacin added to standard LDL-lowering therapy and raised doubts about the safety profile of niacin. With widespread acceptance of statin therapy and recent landmark trials supporting the safety and clinical benefit of ezetimibe and PCSK9 inhibitors, the role of niacin as lipid-modifying therapy has become very limited.

Non–LDL-C Therapies in Development

Considerable residual cardiovascular persists despite well-controlled LDL-C levels, and epidemiological and genetic studies have established the role of other lipid parameters, most notably triglycerides, triglyceride-rich lipoproteins (VLDL, chylomicrons, and remnants), and Lp(a), in residual cardiovascular risk, especially among patients on maximal statin therapy. Advances in gene-silencing technology through antisense oligonucleotide inhibition or siRNA provide novel approaches to target lipid parameters, by degrading mRNA transcripts of specific genes to reduce protein production and plasma lipoprotein levels. As discussed previously with inclisiran, the most recently developed agents have been modified to target the liver, allowing much lower doses to be used, for improved safety profiles compared with prior delivery approaches. Pharmacological use of monoclonal antibodies is also being examined for non–LDL-C targets.

Primary Prevention

In primary prevention of CVD, global risk factor assessment and correction are the recommended approach. The atherogenic components of blood lipids, especially LDL-C, are an important part of an overall risk factor profile that includes factors that cannot be changed, such as age, sex, and family history of premature disease, and those that can, such as blood pressure, diet, smoking, exercise, and weight (see Table 6.1 ). The Pooled Cohort Equation should be used to guide treatment and identify individuals for whom aggressive lifestyle modification and statin therapy are indicated. For a heart-healthy diet, a Mediterranean or DASH diet is currently recommended. Risk-enhancing factors (see Table 6.1 ) can help identify individuals at increased risk who may benefit most from initiating or maximizing statin therapy. The ideal blood cholesterol and LDL-C levels appear to be falling lower and lower, based on clinical trial results.

Secondary Prevention

In secondary prevention, strict LDL-C lowering with high-intensity statin therapy, along with lifestyle modification, is an essential part of a comprehensive program of risk-factor modification. The 2018 AHA/ACC guidelines make strong recommendation to use a threshold of LDL-C ≥ 70 mg/dL in patients with established ASCVD for augmenting statin therapy with add-on ezetimibe or (in very-high-risk patients) PCSK9 inhibitor therapy. In individuals already on statin therapy who have residual hypertriglyceridemia, strong evidence supports add-on icosapent ethyl. Strict dietary modification and exercise (minimum of 150 minutes of moderate- or 75 minutes of high-intensity exercise per week) must be emphasized in all patients.

Diabetes

Diabetes is regarded as a risk category in its own right in the 2018 AHA/ACC cholesterol guidelines, as this high-risk group warrants aggressive risk reduction. Guidelines recommend initiation of moderate-intensity statin irrespective of LDL-C levels in patients with diabetes aged 40–75 years.

Statins as Initial Treatment

Statin trials have shown substantial reductions in total and cardiac mortality as well as major adverse cardiovascular events, and statins are recommended for four patient management groups (according to the 2018 AHA/ACC guidelines): 1) secondary prevention for patients with established ASCVD; 2) patients with severe hypercholesterolemia (LDL-C ≥ 190 mg/dL); 3) patients with diabetes; and 4) primary prevention. Statins have few serious side effects or contraindications. In primary prevention, the Pooled Cohort Equation can be used to stratify risk, with 10-year risk < 5% considered low, 5 to < 7.5% borderline, 7.5 to < 20% intermediate, and ≥ 20% high. In intermediate- and high-risk groups, statin therapy is appropriate, with high-intensity statin preferred for the latter group (Class I recommendation). In the borderline-risk group, risk-enhancing factors (see Table 6.1 ) may be considered to guide risk discussion.

Combination Therapy

Combination therapy is now increasingly used to achieve reductions in LDL-C and non-HDL-C. The principle is to combine two different classes of agents with different mechanisms of action, such as a statin and ezetimibe or a statin and a PCSK9 inhibitor. Recent trials have shown overwhelming evidence of efficacious LDL lowering as well as reduction of adverse cardiovascular events with these combined agents. The consensus is that judicious use of combination therapy, when required, is likely to confer more benefit than harm.

Other lipid-regulating agents, which are used less frequently because they lack clinical trial evidence of incremental clinical benefit and increase risk for adverse events, include fibrates, bile acid sequestrants, and niacin. The combination of fibrates and statin increases risk of myopathy and hepatotoxity. Niacin is usually not well tolerated because of multiple side effects including flushing, pruritus, skin rashes, and gastrointestinal issues. Bile acid sequestrants require caution in patients with high triglycerides.

Hypertriglyceridemia

Intensive diet and lifestyle modification remains the cornerstone of therapy for elevated triglycerides, especially in patients with moderate hypertriglyceridemia (triglycerides 150–499 mg/dL [1.7–2.3 mmol/L]). Secondary causes of elevated triglycerides, including obesity, metabolic syndrome, chronic kidney or liver disease, nephrotic syndrome, diabetes, or hypothyroidism, must be evaluated and addressed. Triglyceride levels of more than 1000 mg/dL (11.3 mmol/L) confer increased risk for pancreatitis and require treatment with prescription-strength omega-3 fatty acids or a fibrate (see Fig. 6.4 ).