Lipid-Modifying Drugs

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).

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.

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.