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Guidelines for the Management of High Blood Cholesterol

, MD and , MD.

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Last Update: November 30, 2019.


The cholesterol hypothesis holds that high blood cholesterol is a major risk factor for atherosclerosis cardiovascular disease (ASCVD) and lowering cholesterol levels will reduce risk for ASCVD. This hypothesis is based on epidemiological evidence that both within and between populations higher cholesterol levels raise the risk for ASCVD; and conversely, randomized clinical trials (RCTs) show that lowering cholesterol levels will reduce risk. Cholesterol in the circulation is embedded in lipoproteins. The major atherogenic lipoproteins are low density lipoproteins (LDL) and very low-density lipoproteins (VLDL). Together they constitute non-high-density lipoproteins (non-HDL). Clinically these lipoproteins are identified by their cholesterol (C) content, i.e. LDL-C, VLDL-C, and non-HDL-C. Atherogenic lipoproteins can be reduced by both lifestyle intervention and cholesterol-lowering drugs. The efficacy of lifestyle intervention is best demonstrated in epidemiological studies, whereas efficacy of drugs is revealed through RCTs. Currently available cholesterol-lowering drugs are statins, ezetimibe, bile acid sequestrants, proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, niacin, fibrates, and n-3 fatty acids (e.g., icosapent ethyl). The latter three generally are reserved for patients with hypertriglyceridemia; here they can be combined with statins that together lower non-HDL-C. Highest priority to cholesterol-lowering therapy goes to patients with established ASCVD (secondary prevention). RCTs in such patients show that “lower is better” for cholesterol reduction. The greatest risk reductions are attained by reducing LDL-C concentrations by at least 50% with a high intensity statin; and if necessary, to achieve LDL-C < 70 mg/dL, combining a statin with ezetimibe or PCSK9 inhibitor. For primary prevention, a decision to initiate statin therapy is made on multiple factors (i.e., presence of diabetes or severe hypercholesterolemia, estimated 10-year risk for ASCVD, presence of risk enhancing factors (e.g., metabolic syndrome and chronic kidney disease); and if in doubt, detection of subclinical atherosclerosis (e.g., coronary artery calcium [CAC]). A reasonable goal for primary prevention using moderate-intensity statin therapy is an LDL-C in the range of 70-99 mg/dL. Both population epidemiology and genetic epidemiology show that low serum cholesterol throughout life will minimize lifetime risk of ASCVD. For this reason, cholesterol-lowering intervention, preferably through lifestyle change, should be carried out as early as possible. If cholesterol concentrations are very high in younger adults, it sometimes may be judicious to introduce a cholesterol-lowering drug. For complete coverage of all related areas of Endocrinology, please visit our on-line FREE web-text, WWW.ENDOTEXT.ORG.


Atherosclerotic cardiovascular disease (ASCVD) remains the foremost cause of death among chronic diseases. Its prevalence is increasing in many countries. This increase results from aging of the population and combined with atherogenic lifestyles. Even so, mortality from ASCVD has been declining in most developed countries. This decline comes from improvements in preventive measures and better clinical intervention. One of the most important advances in the cardiovascular field resulted from risk factors for ASCVD. Risk factors directly or indirectly promote atherosclerosis, or they otherwise predispose to vascular events. The major risk factors are cigarette smoking, dyslipidemia, hypertension, hyperglycemia, and advancing age. Dyslipidemia consists of elevations of atherogenic lipoproteins (LDL and VLDL) and low levels of HDL. Advancing age counts as a risk factor because it reflects the impact of all risk factors over the lifespan. Several other factors, called risk enhancing factors, associate with higher risk for ASCVD (1). Lifestyle factors (e.g., overnutrition and physical inactivity) contribute importantly to both major and enhancing risk factors. Hereditary factors undoubtedly contribute to the identifiable risk factors; but genetic influences likely affect ASCVD risk through other ways not understood.


The first evidence for a connection between serum cholesterol levels and atherosclerosis came from laboratory animals. Feeding cholesterol to various animal species raises serum cholesterol and causes deposition of cholesterol in the arterial wall. The latter recapitulates early stages of human atherosclerosis. Subsequently, in humans, severe hereditary hypercholesterolemia was observed to cause premature atherosclerosis and ASCVD. Later, population surveys uncovered a positive association between serum cholesterol levels and ASCVD (2, 3). Finally, clinical trials with cholesterol-lowering agents documented that lowering of serum cholesterol levels reduces the risk for ASCVD (4). These findings have convinced most investigators that the cholesterol hypothesis is proven. Moreover, the relationship between cholesterol levels and ASCVD risk is bidirectional; raising cholesterol levels increases risk, whereas reducing levels decreases risk (Figure 1).

Figure 1. . The Cholesterol Hypothesis.

Figure 1.

The Cholesterol Hypothesis. Between the years 1955 and 1985, many epidemiologic studies showed a positive relation between cholesterol levels and atherosclerotic cardiovascular disease (ASCVD) events. Over the next 30 years, a host of randomized controlled clinical trials has demonstrated that lowering cholesterol levels will reduce risk for ASCVD. This bidirectional relationship between cholesterol levels and ASCVD provides ample support for the cholesterol hypothesis.

Epidemiological Evidence

A relationship between cholesterol levels and ASCVD risk is observed in both developing and developed countries (2; 3). Populations with the lowest cholesterol levels have the lowest rates of ASCVD. Within populations, individuals with the lowest serum cholesterol carry the least risk. In other words, “the lower, the better” for cholesterol levels holds, both between populations and for individuals within populations.

Pre-Statin Clinical Trial Evidence

Another line of evidence supporting the cholesterol hypothesis comes from randomized controlled trials (RCTs) of cholesterol-lowering therapies. Several earlier RCTs tested efficacy by reducing cholesterol through diet, bile acid sequestrants, or ileal exclusion operation (Table 1) (3). When taken individually, results from some of the smaller trials were not definitive; but meta-analysis, which combines data from all RCTs, demonstrated significant risk reduction due to cholesterol lowering. In addition, before the discovery of statins, several secondary-prevention RCTs were performed with various cholesterol-lowering drugs. Although some of these trials showed significant risk reduction, others gave equivocal results. But when taken together, meta-analysis demonstrated ASCVD risk reduction from cholesterol reduction (5).

Table 1.

Summary of Pre-Statin Clinical Trials of Cholesterol-Lowering Therapy

InterventionNo. trialsNo. treatedPerson-yearsMean cholesterol reduction (%)CHD incidence (% change)CHD Mortality

This table is derived from National Cholesterol Education Program Adult Treatment Panel III (3)

Statins and Clinical Trial Evidence

Statins were discovered in the 1970s by Endo of Japan (6). These drugs lower cholesterol by inhibiting cholesterol synthesis in the liver. They block HMG CoA reductase, a key enzyme in cholesterol synthesis. This inhibition enhances the liver’s synthesis LDL receptors. The latter, discovered by Brown and Goldstein (7), remove LDL and VLDL from the bloodstream, which lower serum cholesterol. Statin have proven to be highly efficacious with few side effects. The development of statins as a cholesterol-lowering drug has been actively pursued by the pharmaceutical industry. Several statins have been approved for use in clinical practice by the FDA. Over the past three decades, a series of RCTs have been carried out that documents the efficacy and safety of statin therapy. In these RCTs, statin therapy has been shown to significantly reduce morbidity and mortality from ASCVD. Although individual RCTs produced significant results, the strongest evidence of benefit comes from meta-analysis. i.e., by combining data from all the trials (4).

Meta-analysis has shown that for every mmol/L (39 mg/dl) reduction in LDL-C with statin therapy there is an approximate 22% reduction in ASCVD events (8, 4, 9, 10, 11). Another report (12) showed that an almost identical relationship holds when several different kinds of LDL-lowering therapy were analyzed together. This response appears to be consistent throughout all levels of LDL-C. Individual statins vary in their intensity of cholesterol-lowering therapy at a given dose (1) (Table 2). For example, per mg per day, rosuvastatin is twice as efficacious as atorvastatin, which in turn is twice as efficacious as simvastatin. Statins are best classified according to percentage reductions in LDL-C. As shown in Table 2, moderate- intensity statins reduce LDL-C by 30-49%, whereas high-intensity statins reduce LDL-C by > 50%. On average, a 35% LDL-C reduction by moderate-intensity statin reduces risk by approximately one third, whereas high-intensity statins lower risk by about one-half. But, in fact, absolute reductions vary depending on baseline levels of LDL-C. For example, for a baseline LDL-C of 200 mg/dL, a 50% reduction in LDL-C equates to a 100 mg/dL (2.6 mmol/L) decline; this translates into a 59% reduction in 10-year risk for ASCVD events. In contrast, in a patient with a baseline LDL-C a 100 mg per dL, a 50% reduction in LDL-C equates to a 50 mg/dL (1.3 mmol/L) decline, which will reduce ASCVD risk by about 30%. Thus, at lower and lower levels of LDL-C, progressive reductions of LDL-C produce diminishing benefit from cholesterol-lowering therapy. This modifies the aphorism "lower is better". Whereas the statement is true, it must be kept in mind that there are diminishing benefits from intensifying cholesterol-lowering therapy when LDL-C levels are already low.

Table 2.

Categories of Intensities of Statins

20-25% ↓ LDL-C
30-49%↓ LDL-C
High Intensity
>50%↓ LDL-C
Lovastatin10-20 mg40-80 mg
Pravastatin10-20 mg40-80 mg
Simvastatin10 mg20-40 mg
Fluvastatin20-40 mg80 mg
Pitavastatin1-4 mg
Atorvastatin5 mg10-20 mg40-80 mg
Rosuvastatin5-10 mg20-40 mg

Non-Statin Cholesterol-Lowering Drugs

Beyond statins, other agents are currently available or loom on the horizon (Table 3). Bile acid sequestrants inhibit intestinal absorption of bile acids, which likewise raises hepatic LDL receptors. They are moderately efficacious for reducing LDL-C concentrations. A large RCT showed that bile acid sequestrants significantly reduce risk for CHD in patients with baseline elevations in LDL-C (13). Theoretically, bile acid sequestrants could enhance risk reduction in patients with ASCVD are treated with moderate-intensity statins.

Ezetimibe blocks cholesterol absorption in the intestine and also raises LDL receptor activity. It moderately lowers LDL-C (15-25%). The combination of statin + ezetimibe is additive for LDL-C lowering (14). A recent clinical trial (15) tested demonstrated that adding ezetimibe to moderate intensity statins in very high-risk patients with ASCVD is beneficial showing that combination therapy reduced risk more than a statin alone (15). In this trial, the higher the risk, the greater was risk reduction (16).

Niacin and fibrates, which are primarily triglyceride-lowering drugs, have been used for many years. They modestly reduce cholesterol levels as well. Their effects on ASCVD risk vary. Niacin used alone appears to attenuate risk, but when used in combination with high-intensity statin, any incremental benefit is minimal (17). Like niacin, fibrates moderately reduce risk for CHD when used alone in patients with hypertriglyceridemia; risk reduction is less in those who do not have elevated triglycerides (18). When fibrates are used in combination with statins, risk for severe myopathy is greater than for statins alone. Fenofibrate is the preferred fibrate in combination with statins because it carries the lowest risk of myopathy (19).

N-3 fatty acids also lower serum triglyceride. In one notable RCT, treatment of high-risk, hypertriglyceridemic patients with statin + 2 g of the N-3 fatty acid icosapent ethyl twice daily, compared to placebo, significantly reduced the risk of ischemic events, including cardiovascular death (20). The mechanism for this beneficial effect is unknown. If the results of this trial can be duplicated in similar RCTs, the combination of statin + icosapent ethyl could become attractive for high-risk, hypertriglyceridemic patients.

Other LDL-lowering drugs include microsomal triglyceride transfer protein (MTP) inhibitors (21) and RNA antisense drugs that block hepatic synthesis of apolipoprotein B (22). Both of these drugs inhibit secretion of atherogenic lipoproteins into the circulation. At present their use is restricted to patients with severe hypercholesterolemia. Another class of drugs inhibits cholesterol ester transfer protein (CETP); these agents lower LDL-C levels as well as raising HDL-C (23; 24). RCTs show their benefit is small, if any, so the pharmaceutical industry shows little interest in further development. Finally, a new class of drugs inhibits a circulating protein called proprotein convertase subtilisin/kexin type 9 (PCSK9); the PCSK9 protein promotes degradation of LDL receptors and raises LDL-C levels. Inhibition of PCSK9 markedly lowers LDL-C concentrations (25). Recent reports indicate that PCSK9 inhibitors reduce risk in ASCVD patients at very high risk when combined with statins (26, 27). However, absolute risk reductions are limited because LDL-C levels usually are already low in patients who are treated with high-intensity statins. PCSK9 inhibitors, however, could be useful for patients who are statin intolerant or those with very high baseline LDL-C, such as familial hypercholesterolemia.

Table 3.

Non-Statin Cholesterol Lowering Drugs

Drug ClassMechanism of ActionEffects on Plasma LipidsLDL-C loweringSide effects
Bile acid sequestrantsImpairs reabsorption of bile acids
Raise LDL receptor activity
Reduces LDL
Raises VLDL
Minimal effect on HDL
15-25%, depending on doseConstipation
GI distress
Increases TG
EzetimibeImpairs absorption of cholesterol
Raises LDL receptor activity
Reduces LDL
Reduces VLDL
Minimal effect on HDL
NiacinReduces hepatic secretion of VLDLReduces VLDL
Reduces LDL
Raises HDL
5-20%Flushing, rash, raise plasma glucose, hepatic dysfunction, others
FibratesReduces secretion of VLDL
Enhances degradation of VLDL
Reduces VLDL
(lowers TG 25-35%)
Small effect on LDL
Raises HDL
5-15%Myopathy (in combination with statins)
Uncommonly various others
MTP inhibitorsReduces hepatic secretion of VLDLReduces VLDL and LDL50+%Fatty liver
(RNA antisense)
Reduces hepatic secretion of VLDLReduces VLDL and LDL50+%Fatty liver
CETP inhibitorsBlocks transfer of cholesterol from HDL to VLDL&LDLRaises HDL
Lowers LDL
20-30%Not approved by the FDA for clinical use
PCSK9 inhibitorsBlocks effects of PCSK9 to destroy LDL receptorsLowers LDL45-60%Recommended only for ASCVD patients at very high risk for future cardiovascular events


National Cholesterol Education Program (NCEP)

The most influential guidelines for cholesterol management in the United States have been those developed by the NECP. This program was sponsored by the National Heart, Lung and Blood Institute and included many health-related organizations in the United States (28). Between 1987 and 2004, three major Adult Treatment Panel (ATP) reports (3; 30; 31) and one update were published (31) (Table 4).

Table 4.

National Cholesterol Education Program’s Adult Treatment Panel (ATP) Reports

ThrustPrimary preventionSecondary preventionHigh-risk primary preventionVery high risk
DrugsBile acid resins Nicotinic acid FibratesSame as ATP +StatinsSame as ATP IISame as ATP III
LDL-C goal
Low risk <190 Moderate risk <160 High risk < 130Low risk <160 Moderate risk <130 High risk =100Low risk <160 Moderate risk <130 Moderately high risk <130 High risk < 100Low risk <160 Moderate risk <130 Moderately high risk <130 High risk < 100 Very high risk < 70

ATP reports identified LDL-C as the major target of cholesterol-lowering therapy. The intensity of LDL-lowering therapy was based on aggregate knowledge from multiple sources in the cholesterol field. Priority was given the clinical trial evidence when available. ATP I (1987) emphasized lifestyle therapy for primary prevention. Use of cholesterol-lowering drugs was down-played in ATP I. ATP II (1993) placed more emphasis on secondary prevention; this was because a large meta-analysis of RCTs using cholesterol-lowering drugs confirmed CHD risk reduction. ATP III (2001) added more emphasis on high-risk primary prevention. At each successive ATP report, the intensity of LDL lowering therapy was increased.

The NCEP put highest priority for cholesterol management for patients with clinical forms of atherosclerotic disease. The latter included CHD, clinical carotid artery disease, peripheral arterial disease, and abdominal aortic aneurysm. ASCVD is the inclusive term for these conditions. The 10-year risk for future cardiovascular events in patients with established ASCVD is usually > 20%. In ATP III, the presence of ASCVD of any type warranted an LDL-C goal of < 100 mg/dL. For high-risk patients with hypertriglyceridemia, a non-HDL-C goal of < 130 mg/dL was recommended.

For primary prevention, ATP III identified four levels of risk for increasing intensity of LDL-C lowering. Different LDL-C goals were set for different levels of risk (Table 4). Risk for CHD was calculated using Framingham risk scoring. Framingham risk factors included cigarette smoking, hypertension, elevated total cholesterol, low HDL-C, and advancing age. A 10-year risk > 20% for CHD was called high risk. Moderately high risk was defined as a 10-year risk of 10-19%; at this level of risk, cholesterol-lowering drugs were considered to be cost-effective. A 10-year risk of < 10% was divided into moderate risk and low risk depending on the presence or absence of major risk factors. Moderate risk corresponds to a 10-year risk for CHD of approximately 5-9%. Generally speaking, cholesterol-lowering drugs were not recommended for low- to- moderate risk individuals except when LDL-C levels are high.

In 2004, ATP III underwent an update and set an optional LDL-C goal of < 70 mg/dL for patients deemed to be at very high risk for future CHD events. This option included CHD plus other atherosclerotic conditions and/or multiple major risk factors. This progression of treatment intensity was made possible by the results of several clinical trials with statin therapy.

Transfer of NHLBI Guidelines to American Heart Association (AHA) and the American College of Cardiology (ACC)

In 2013, NHLBI made the decision to remove treatment guidelines from its agenda. This was done even though it had almost finished writing prevention guidelines. These included guidelines for high blood cholesterol, high blood pressure, obesity, and nutrition. Late in this process, the guideline process was transferred to the (American Heart Association) AHA and American College of Cardiology (ACC). Then in 2013 the NHLBI guidelines for high blood cholesterol were modified to fit the criteria for guideline development required by AHA/ACC. The 2013 cholesterol guidelines (32) adhered closely to the Institute of Medicine (National Academy of Medicine) recommendations for evidence-based guidelines (33). These recommendations advocated priority to randomized controlled trials (RCTs) as the foundation of evidence-based medicine. The NHLBI cholesterol committee carried out an extensive review of the literature and limited recommendations largely to RCTs. Most acceptable RCTs had utilized statin therapy in middle-aged persons. Therefore, the 2013 report committee did not include detailed recommendations for younger or older adults. Recommendations were largely limited to the age range 40-75 years. High-intensity statin therapy was recommended for patients with established ASCVD. For primary prevention, risk was stratified by use of a pool cohort equation (PCE), which are derived from five large population studies in the United States (34). The PCE was an extension of the Framingham Heart Study risk equations. 10-year risk for ASCVD was based on the following risk factors: age, gender, cigarette smoking, blood pressure, total cholesterol, HDL cholesterol, and presence or absence of diabetes. Although the PCE was validated in another large study (35), it has been criticized by some investigators as being imprecise for many individuals or specific groups (36, 37, 38, 39, 40).

For primary prevention, an effort was made to determine what level 10-year risk is associated with efficacy of reduction of ASCVD from statin RCTs. It was determined that statins are effective for risk reduction when 10-year risk for ASCVD is > 7.5%. Most primary prevention trials employed moderate intensity statins, so these were recommended for most patients; but in one RCT (41), a high-intensity statin appeared to produce greater risk reduction than found with moderate-intensity statins. So high-intensity statins were considered a favorable option in patients at higher 10-year risk. It was recognized that these recommendations may not be optimal for all patients; therefore, consideration should be given to any extenuating circumstances that could modify the translation of RCTs directly into clinical care. A clinician patient risk discussion thus was advocated for all patients to consider the pros and cons of statin therapy.


2018 cholesterol guidelines were revised by AHA/ACC in collaboration with multiple other societies concerned with preventive medicine (1). These guidelines extended those published in 2013. They expanded recommendations to include children, adolescents, young adults (20-39 years), and older patients (> 75 years). Although RCTs may be lacking in these categories, epidemiology and clinical studies indicate that high blood cholesterol is an important risk factor for future ASCVD in these age ranges. From the evidence acquired over many years related to the cholesterol hypothesis, it is reasonable to craft recommendations based on the totality of the evidence. In the following, 2018 guidelines will be highlighted in relation to general areas of cholesterol management as identified by all the previous national and international guidelines. These newer guidelines proposed a top-10 list of recommendations to highlight the key points. These key points will be examined.

Lifestyle Intervention

1. In all individuals, emphasize heart-healthy lifestyle across the life-course.

There is widespread agreement in the cardiovascular field that lifestyle factors contribute to the risk for ASCVD. These factors include cigarette smoking, sedentary life habits, obesity, and an unhealthy eating pattern. The ACC/AHA strongly recommends that a healthy lifestyle be adopted throughout life. These recommendations are strongly supported by 2018 cholesterol guidelines. They are the foundation for cardiovascular prevention and should receive appropriate attention in clinical practice (42).

Secondary Prevention

2. In patients with clinical ASCVD, reduce LDL-C with high-intensity statins or maximally tolerated statins to decrease ASCVD risk. The goal of therapy is to reduce LDL-C by > 50%. If necessary to achieve this goal, consider adding ezetimibe to moderate intensity statin therapy.

The strongest evidence for efficacy of statin therapy is meta-analysis of RTCs carried out in patients with established ASCVD. As previously mentioned, the best fit line comparing percent ASCVD versus LDL-C in secondary prevention studies demonstrates that for every mmol/L reduction in LDL-C the risk for ASCVD is decreased by approximately 22% (9). High intensity statins typically reduce LDL-C by 50% or more; this percentage reduction occurs regardless of baseline levels of LDL-C. This explains why the guidelines set a goal for LDL-C secondary prevention to be a > 50% reduction in levels. There are two options to achieve such reductions. RCTs give priority to use of high-intensity statins. But second, if high-intensity statins are not tolerated, similar LDL-C lowering can be attained by combining a moderate-intensity statin with ezetimibe (15). An approach to lowering LDL-C in patients with ASCVD is shown in Figure 2.

Figure 2.

Figure 2.

Secondary Prevention in Patients with Clinical ASCVD (1)

3. In very high-risk patients with ASCVD, first use a maximally tolerated statin + ezetimibe to achieve an LDL-C goal of < 70 mg/dL (<1.8 mmol/L). If this goal is not achieved, consider adding a PCSK9 inhibitor.

2018 guidelines defined very high risk of future ASCVD events as a history of multiple ASCVD events or one major event plus multiple high-risk conditions (Table 5). This definition is based in large part on subgroup analysis of the IMPROVE-IT trial (15,16).

Table 5.

Very High Risk of Future ASCVD Events (1)

Major ASCVD Events
Recent ACS (within the past 12 mo)
History of MI (other than recent acute coronary syndrome event listed above)
History of ischemic stroke
Symptomatic peripheral arterial disease (history of claudication with ABI <0.85, or previous revascularization or amputation)
High Risk Conditions
Age ≥65 y
Heterozygous familial hypercholesterolemia
History of prior coronary artery bypass surgery or percutaneous coronary intervention outside of the major ASCVD event(s)
Diabetes mellitus
CKD (eGFR 15-59 mL/min/1.73 m2)
Current smoking
Persistently elevated LDL-C (LDL-C ≥100 mg/dL [≥2.6 mmol/L]) despite maximally tolerated statin therapy and ezetimibe
History of congestive heart failure

ABI indicates ankle-brachial index; CKD indicates chronic kidney disease

Recent RCTs have demonstrated that addition of non-statins to statin therapy can enhance risk reduction. These RCTs (and their add-on drugs) were IMPROVE-IT (ezetimibe) (15), FOURIER (evolocumab) (26), and ODYSSEY OUTCOMES (alirocumab) (27). All RCTs were carried out in patients at very high-risk. For IMPROVE-IT, addition of ezetimibe to statin therapy produced an additional 6% reduction in ASCVD events. In this trial, baseline LDL-C on moderate-intensity statin alone averaged about 60 mg/dL; in spite of this low level, further LDL lowering with addition of ezetimibe enhanced risk reduction. RCTs with the two PCSK9 inhibitors (evolocumab and alirocumab) restricted recruitment to patients having LDL-C > 70 mg/dL on maximally tolerated statin+ ezetimibe. In these RCTs, duration of therapy was only about 3 years. A marked additional LDL lowering was achieved. In both trials, risk for ASCVD events was reduced by 15%.

2018 guidelines allow consideration of PCSK9 inhibitor as an add-on drug if patients are at very high risk for future ASCVD events and have an LDL-C > 70 mg/dL during treatment with maximally tolerated statin plus ezetimibe (Figure 3). This latter threshold LDL-C was chosen because it was a recruitment criteria for PCSK9 inhibitor therapy in reported RTCs (26, 26)

An important question about use of PCSK9 inhibitors is whether they are cost-effective When they first became available, they were marketed at a very high cost, which was widely considered to be excessive. More recently, the cost of these drugs has declined considerably. A recent analysis of cost-effectiveness has shown that at current prices in very high-risk patients PCSK9 inhibitors can be cost-effective (43). Another analysis (44) of approximately 1 million patients with ASCVD in the Veterans Affairs system indicate that approximately 10% of patients will be classified as very high risk and having LDL-C > 70 mg/dL while taking maximal statin therapy plus ezetimibe. These later patients are potential candidates for PCSK9 inhibitors.

Figure 3.

Figure 3.

Secondary Prevention in Patients with Very High-Risk ASCVD (1)

Primary Prevention

4. In patients with severe primary hypercholesterolemia (LDL-C ≥190 mg/dL (≥4.9 mmol/L)), without concomitant ASCVD, begin high-intensity statin therapy (or moderate intensity statin + ezetimibe) to achieve in LDL-C goal of < 100 mg/dL; if this goal is not achieved, consider adding PCSK9 inhibitor in selected patients at higher risk. Measurement of 10-year risk for ASCVD is not necessary.

Patients with severe hypercholesterolemia are known to be at relatively high risk for developing ASCVD (45). In view of massive evidence that elevated LDL-C promotes atherosclerosis and predisposes to ASCVD, it stands to reason that such patients deserve intensive treatment with LDL-lowering drugs. RCTs with cholesterol-lowering drugs demonstrate benefit of statin therapy in patients with severe hypercholesterolemia (46, 47). It is not necessary to calculate 10-year risk in such patients. Moreover, patients who have extreme elevations of LDL-C (e.g., heterozygous familial hypercholesterolemia) may be candidates for PCSK9 inhibitors if LDL-C cannot be lowered sufficiently with maximal statin therapy plus ezetimibe.

5. In patients with diabetes mellitus aged 40 to 75 years with an LDL-C ≥70 mg/dL (≥1.8 mmol/L), without concomitant ASCVD, begin moderate-intensity statin therapy. For older patients (> 50 years), consider using high-intensity statin (or moderate intensity statin plus ezetimibe) to achieve a reduction in LDL-C of > 50%. Measurement of 10-year risk for ASCVD is not necessary.

Middle-aged patients with diabetes have an elevated lifetime risk for ASCVD. The trajectory of risk is steeper in patients with diabetes than in those without. For this reason, estimation of 10-year risk for ASCVD with PCE is not a reliable indicator of lifetime risk. Meta-analysis of RCTs in middle-aged patients with diabetes treated with moderate intensity statins therapy shows significant risk reduction (11). Hence, most middle-aged patients with diabetes deserve statin therapy. It is not necessary to measure 10-year risk before initiation of statin therapy in these patients. With progression of age and accumulation of, multiple risk factors, increasing the intensity of statin therapy or adding ezetimibe seems prudent (Tables 6 and 7).

Table 6.

Diabetes Specific Risk Enhancers That Are Independent of Other Risk Factors in Diabetes (1)

Long duration (≥10 years for type 2 diabetes mellitusS4.3-20 or ≥20 years for type 1 diabetes mellitus
Albuminuria ≥30 mcg of albumin/mg creatinine
eGFR <60 mL/min/1.73 m2
ABI <0.9

ABI indicates ankle-brachial index

6. Initiation of primary prevention should begin with a clinician-patient risk discussion.

This discussion is necessary to put a patient’s total risk status and perspective. The risk discussion should always begin with a review of the critical importance of lifestyle intervention. This is true for all age groups. Beyond the issue of lifestyle, the discussion can further consider the potential benefit of a cholesterol-lowering drug, especially statin therapy. When the latter may be beneficial, the provider should next review major risk factors and estimated 10-year risk for ASCVD derived from the PCE risk calculator (48; https://www.acc.org/guidelines/hubs/blood-cholesterol). Estimation of lifetime risk is also useful. All major risk factors (e.g., cigarette smoking, elevated blood pressure, LDL-C, hemoglobin A1C [if indicated], should be discussed. In patients 40-75 years, the 10-year risk estimate is most useful. In these patients, four categories of 10-year risk for ASCVD are recognized: low risk (<5%); borderline risk (5-7.4%); intermediate risk (7.5-19.9%), and high risk (> 20%). Estimates of lifetime risk for patients 20-39 years also are available (https://www.acc.org/guidelines/hubs/blood-cholesterol or https://qrisk.org/lifetime/index.php). Three other components of the risk discussion are: risk enhancing factors (see #8), possible measurement of coronary artery calcium (CAC) (see #9), and a review of extenuating life circumstances (issues of cost and safety considerations, as well as patient motivation and preferences). The decision to initiate statin therapy should be shared between clinician and patient. All of these factors deserve a full discussion in view of the fact that statin therapy represents a lifetime commitment to taking a cholesterol-lowering drug.

7. In adults 40 to 75 years of age without diabetes and LDL-C ≥70 mg/dL (≥1.8 mmol/L), RTC's show that moderate intensity statin therapy is efficacious when 10-year risk for developing ASCVD is > 7.5%. Therefore, initiating statin therapy should be considered in the risk discussion.

A 10-year risk > 7.5% does not mandate statin therapy but indicates that moderate-intensity statins can reduce risk by 30-40% with a minimum of side effects (49). This fact alone can justify moderate intensity statin therapy, but only if other considerations noted above (#6) are taken into account in the risk discussion. An approach to lipid lowering in primary prevention patients is shown in figure 4.

Figure 4.

Figure 4.

Approach to Primary Prevention in Patients without LDL-C >190mg/dl or Diabetes (1)

8. Determine presence of risk-enhancing factors in adults 40 to 75 years of age to inform the decision regarding initiation of statin therapy.

If risk assessment based on PCE is equivocal or ambiguous, the presence of risk enhancing factors in patients at intermediate risk (10-year risk 7.5 to 19.9%), can tip the balance in favor of statin therapy. Risk enhancing factors are shown in Table 7.

Table 7.

ASCVD Risk Enhancers (1)

Family history of premature ASCVD
Persistently elevated LDL > 160mg/dl (>4.1mmol/L
Chronic kidney disease
Metabolic syndrome
History of preeclampsia
History of premature menopause
Inflammatory disease (especially rheumatoid arthritis, psoriasis, HIV)
Ethnicity (e.g., South Asian ancestry)
Persistently elevated triglycerides > 175mg/dl (>2.0mmol/L)
Hs-CRP > 2mg/L
Lp(a) > 50mg/dl or >125nmol/L
Apo B > 130mg/dl
Ankle-brachial index (ABI) < 0.9


CAC measurements are a safe and inexpensive method to assess severity of coronary atherosclerosis. CAC scores generally reflect lifetime exposure to coronary risk factors. Recent studies (50) show that CAC accumulation is a strong predictor of probability of ASCVD events. A CAC core of zero generally is accompanied by few if any ASCVD events over the subsequent decade. A CAC score of 1-100 Agatston units is associated with relatively low rates of ASCVD, both in middle-aged and older patients. In contrast, a CAC >100 Agatston units carries a risk well into the statin-benefit zone. Data such as these led to the following recommendation of 2018 guidelines for patients at intermediate risk by PCE.


If CAC is zero, treatment with statin therapy may be withheld or delayed, except in cigarette smokers, those with diabetes mellitus, and those with a strong family history of premature ASCVD


A CAC score of 1 to 99 Agatston units favors statin therapy in intermediate-risk patients ≥55 years of age, whereas benefit in 40-54 years is marginal.


A CAC score ≥100 Agatston units (or ≥75th percentile), strongly favors statin therapy, unless otherwise countermanded by clinician–patient risk discussion.


10. Assess adherence and percentage response to LDL-C lowering medications and/or lifestyle changes with repeat lipid measurement 4 to 12 weeks after statin initiation or dose adjustment and every 3-12 months as needed.

Remember that the LDL-C goal for patients with ASCVD or severe hypercholesterolemia is a > 50% reduction in LDL-C. For most such patients, this goal can be achieved by high-intensity statin therapy + ezetimibe. In ASCVD patients at very high risk, the goal is an LDL-C lowering >50% and LDL-C < 70 mg/dL. To achieve these goals, it may be necessary to combine a PCSK9 inhibitor with maximal statin therapy + ezetimibe. For statin therapy in primary prevention, the goal is a lowering of > 35%. This goal can be achieved in most patients with a moderate intensity statin + ezetimibe

2018 guidelines did not set precise on-treatment LDL-C target of therapy, but instead, offer percent reductions as goals of therapy. Baseline levels of LDL-C can be obtained either by chart review or withholding statin therapy for about two weeks. In addition, on-treatment LDL-C can provide useful information about efficacy of treatment (Figure 5). This figure shows expected LDL-C levels for 50% or 35% reductions at different baseline levels of LDL-C. For example, in secondary prevention, an on-treatment LDL-C of <70 mg/dL can be considered adequate treatment regardless of baseline LDL-C. On-treatment levels in the range of 70-100 mg/dL are adequate if baseline-LDL C is known to be in the range of 140- 200 mg/dL; if there is uncertainty about baseline levels, reevaluation of statin adherence and reinforcement of treatment regimen is needed. For optimal treatment, on-treatment levels in this range warrant consideration of adding ezetimibe to maximal statin therapy. If on treatment LDL-C is > 100 mg/dL, the treatment regimen is probably inadequate, and intensification of therapy is needed. For primary prevention, the LDL-C goal is a reduction > 35%, and a similar scheme for evaluating efficacy of therapy can be used.

Figure 5. . Predicted on-treatment LDL-C compared to baseline LDL-C and suggested actions for each category of on-treatment LDL-C in secondary and primary prevention.

Figure 5.

Predicted on-treatment LDL-C compared to baseline LDL-C and suggested actions for each category of on-treatment LDL-C in secondary and primary prevention.

Other Issues

Other age groups

2018 guidelines offered suggestions for management of high blood cholesterol in children, adolescents, young adults (20-39 years), and elderly patients > 75 years. There is no strong RCT evidence to underline cholesterol management in these populations. Instead, treatment suggestions depend largely on epidemiologic data. Lifestyle intervention is a primary method for cholesterol treatment in these age groups. However, under certain circumstances LDL-lowering drugs may be indicated. This is particularly the case for patients with familial hypercholesterolemia or similar forms of very high LDL-C. In young adults, particularly those with other risk factors, in LDL lowering drug therapy (statin or ezetimibe) may be reasonable when LDL-C levels are in the range of 160-189 mg/dL. Older adults having concomitant risk factors are potential candidates for initiation of statins or continuation of existing statin therapy. In all cases, clinical estimation of risk status is critical in a decision to initiate statins.

Statin non-adherence

In spite of proven benefit of statin therapy in high-risk patients, there is a relatively high prevalence of nonadherence to the prescribed drug (51). Some studies suggest that up to 50% of patients discontinue use of prescribed statins over the long run (52, 53, 54, 55). This finding creates a major challenge to the health care system for prevention of ASCVD. Table 8 lists several factors that may contribute to a high prevalence of nonadherence.

Table 8.

Factors Associated with Statin Nonadherence

Healthcare system factors
Cost of statins and accompanying medical care costs
Lack of medical oversight and follow-up (provider therapeutic inertia)
Provider concern for side effects
Patient factors
Uncertainty of benefit
Lack of health consciousness
Lack of motivation
Lack of perceived benefit
Perceived side effects
Nocebo effects
“Brain fog”
Misattributed symptoms or syndromes (arthritis, spondylosis, neuropathy, insomnia, mental confusion and memory loss, fibromyalgia, gastrointestinal symptoms, liver dysfunction, cataract; cancer).

When a decision is made to initiate statin therapy, the presumption is that statins are a lifetime treatment. Their use is similar to other medications, such as antihypertensive drugs, which are expected to be taken for the rest of one’s life. Such treatments imply indefinite participation in the healthcare system. This means regular ongoing visits to a prescribing clinic. Even for those with medical insurance there are usually co-pays both for the visit and for medication, not to mention cost of transportation to and from the clinic. All of these cost-related issues can be an impediment to long-term statin usage. Provider therapeutic inertia (51) can result from lack of provider education, excessive workload, and concerns about statin side effects.

From the patient’s point of view, common issues are lack of understanding of the potential benefits of therapy and lack of health consciousness and motivation. A related problem is expectation of side effects because of preconditioning by information received from the news media, package inserts, Internet, family, and friends. This expectation can discourage individuals from continuation of statin therapy (nocebo effect) (56). The most common symptoms attributed to statin therapy are muscle pain and tenderness (myalgias). A complaint of statin intolerance is registered in about 5-15% of patients. If myalgias attributed to statins are due to actual pathological changes, the character of the changes is yet to be determined. In almost all cases, serum creatine kinase (CK) levels are not increased. There is no evidence for long-term muscle damage. A few reports nonetheless suggest that statins can produce a low-grade myopathy (57); such an effect has not been widely accepted. The literature is replete with case reports of other symptoms attributed to statins (51). In fact, much of the symptomology reported by patients are unrelated to statin treatment but are in fact the symptoms of other conditions. Statin therapy has been given to large numbers of people for many years without evidence of long-term muscle dysfunction.

Still, in rare cases, especially when blood levels of statins are raised, severe myopathy (rhabdomyolysis) can occur. This proves that statins can be myotoxic. Table 9 lists conditions associated with statin-induced severe myopathy (58, 59). In most such cases, severe myopathy is reversible. If the cause can be identified and eliminated, a statin can be cautiously reinstituted. Alternatively, a non-statin LDL-lowering drug (e.g., ezetimibe or PCSK9 inhibitor) can be substituted for the offending statin (60).

Table 9.

Factors Associated with Statin - Induced Rhabdomyolysis

Advanced age (>80 y)
Small body frame and fragility
Female sex
Asian ethnicity
Pre-existing neuromuscular condition
Known history of myopathy or family history of myopathy syndrome
Pre-existing liver disease, kidney disease, hypothyroidism
Certain rare genetic polymorphisms
High-dose statin (?)
Postoperative periods
Excessive alcohol intake
Drug interactions (gemfibrozil, antipsychotics, amiodarone, verapamil, cyclosporine, macrolide antibiotics, azole antifungals, protease inhibitors)

These considerations indicate that statin therapy is a much greater investment in time and effort than commonly recognized. Since statins have the potential to prevent many ASCVD events, they offer great potential in clinical management of patients at risk. Nonetheless, to achieve this benefit, the health care system must be adjusted to the requirements of statin therapy as well as other risk-reducing therapies. Unless these adjustments are made, much of the potential benefit of statin treatment will be lost. It will be necessary to address all the components of healthcare and patient factors to improve long-term adherence of statin therapy.


The most influential of European guidelines for management of cholesterol and dyslipidemia are those developed by the European Society of Cardiology (ESC), the European Atherosclerosis Society (EAS), and representatives from other European organizations (61). A task force appointed by these organizations have recently published an update on dyslipidemia management (62). The recommendations of this report resemble in many ways those of the 2018 AHA/ACC guidelines (1). But notable differences can be identified for specific recommendations. A review of these differences may help to identify gaps in knowledge needed to format best recommendations. In the following, recommendations proposed by AHA/ACC and by ESC/EAS will be compared. These comparisons should illuminate areas of uncertainty where more information is needed for definitive recommendations. At the same time, it is important to emphasize that in many critical areas the two sets of guidelines are in strong agreement. These will be noted first.

Agreement Between AHA/ACC and ESC/EAS Guidelines

There is agreement that elevated LDL is the major atherogenic lipoprotein and that LDL-C is the primary target of treatment. Likewise, both guidelines agree that the intensity of LDL-C lowering therapy should depend on absolute risk to patients. In other words, patients who have highest risk should receive most intensive cholesterol reduction. Both guidelines emphasize therapeutic lifestyle intervention as the foundation of risk reduction, both for elevated cholesterol and for other risk factors. The highest risk patients are those with atherosclerotic disease and are potential candidates for combined drug therapy for cholesterol-lowering. For primary prevention, the intensity of treatment depends on absolute risk as determined by population-based algorithms. For drug therapy, statins are first-line treatment, but in highest risk patients, consideration can be given to adding non-statin drugs (e.g., ezetimibe and PCSK9 inhibitors). Beyond population-based algorithms for primary prevention, measurement of other dyslipidemia markers or other higher risk conditions can be used as risk- enhancing factors to modify intensity of lipid-lowering therapy.

Differences Between AHA/ACC and ESC/EAS Guidelines

Definition of very high risk

This definition is important because it sets the stage for considering combined drug therapy for LDL-C lowering. AHA/ACC defines very high risk as a history of multiple ASCVD events or of one event + multiple high-risk conditions. This limits the definition of very high risk to the highest risk patients among those with ASCVD. In contrast, ESC/EAS allows extension of the definition to highest risk patients in primary prevention, that is, to patients with multiple risk factors and/or subclinical atherosclerosis. Overall, it appears that more patients will be identified as being at very high risk by ESC/EAS guidelines. This could enlarge the usage of PCSK9 inhibitors. AHA/ACC limits the use of PCSK9 inhibitors to patients at highest risk, because of their high cost. One recent study (44) showed that only about 10% of patients with established ASCVD will be eligible for PCSK9 inhibitors by AHA/ACC recommendations.

Table 10.

ESC/EAS Cardiovascular Risk Categories

Very High-Risk
ASCVD, either clinical or unequivocal on imaging
DM with target organ damage or at least three major risk factors or T1DM of long duration (>20 years)
Severe CKD (eGFR <30 mL/min/1.73 m2)
A calculated SCORE >10% for 10-year risk of fatal CVD.
FH with ASCVD or with another major risk factor
High Risk
Markedly elevated single risk factors, in particular Total Cholesterol >8 mmol/L (>310mg/dL), LDL-C >4.9 mmol/L (>190 mg/dL), or BP >180/110 mmHg.
Patients with FH without other major risk factors.
Patients with DM without target organ damage, a with DM duration >_10 years or another additional risk factor.
Moderate CKD (eGFR 30-59 mL/min/1.73 m2).
A calculated SCORE >5% and <10% for 10-year risk of fatal CVD.
Moderate Risk
Young patients (T1DM <35 years; T2DM <50 years) with DM duration <10 years, without other risk factors.
Calculated SCORE >1% and <5% for 10-year risk of fatal CVD.
Low Risk
Calculated SCORE <1% for 10-year risk of fatal CVD

Goals for LDL-C

In 2013, the AHA/ACC eliminated specific numerical goals for LDL-C in both primary and secondary prevention. Recommendations for LDL-C lowering therapy were based exclusively on RCTs of statin therapy. These recommendations have been criticized for lacking a means to evaluate efficacy of statin therapy. In 2018, AHA/ACC identified 2 goals for LDL-C lowering, namely, > 50% LDL-C reduction in secondary prevention and > 35% reduction in primary prevention. These values are based on the expected reductions achieved by high-intensity statins for secondary prevention and by moderate-intensity statins for primary prevention. Again, no numerical targets are identified. The only exception was the recognition of an LDL-C threshold goal of 1.8 mmol/L (70 mg/dL) for consideration of PCSK9 inhibitors in very high-risk patients on maximal statin therapy + ezetimibe.

ESC/EAS supports the 50% reduction of LDL-C in high risk patients but also includes a goal of <1.8 mmol/L (70 mg/dL). This goal applies to all high-risk patients, whether in primary or secondary prevention. For very high-risk patients, the goal is an LDL-C of < 1.4 mmol/L (55 mg/dL). For moderate-risk patients in primary prevention, the goal is LDL-C <2.6 mmol/L (100 mg/dL). The guideline task force presumably believed that having defined LDL-C goals facilitates cholesterol-lowering therapy in clinical practice.

Table 11.

ESC/EAS LDL Cholesterol Goals

Very High RiskLDL-C reduction of >50% from baseline and an LDL-C goal of <1.4 mmol/L (<55 mg/dL) is recommended
High RiskLDL-C reduction of >50% from baseline and an LDL-C goal of <1.8 mmol/L (<70 mg/dL) is recommended
Moderate RiskLDL-C goal of <2.6 mmol/L (<100 mg/dL) should be considered
Low RiskLDL-C goal <3.0 mmol/L (<116 mg/dL) may be considered.

Risk estimation for primary prevention

AHA/ACC employed a pooled cohort equation (PCE) developed from five large population groups in the USA to estimate 10-year risk (and lifetime risk) for ASCVD events. ESC/EAS for several years has employed a SCORE algorithm based on risk for ASCVD mortality in European populations. Both PCE and SCORE are used to define “statin eligibility” for primary prevention. A recent report suggests that more people are “eligible” for statin therapy using PCE compared to SCORE (63). If this finding can be confirmed, it suggests that ESC/EAS guidelines are less aggressive for reducing LDL-C in lower risk individuals (compared to AHA/ACC guidelines). In contrast, ESC/EAS appears to be more aggressive in use of non-statins for LDL lowering in higher risk patients than is AHA/ACC.

Risk enhancing factors

AHA/ACC proposed that several risk enhancing factors favor the decision to use statin therapy in patients at intermediate risk. Although European guidelines did not specify a list of such factors, most were considered to justify more intensive therapy. Notable among risk enhancing factors were apolipoprotein B (apoB) and lipoprotein (a) (Lp[a]). ESC/EAS seemingly placed more emphasis on these two factors for adjusting intensity of therapy; this report’s recommendations can be taken to mean that apoB and Lp(a) should be measured more frequently in risk assessment than stated by AHA/ACC. In fact, neither guideline was highly specific as to when to exercise the option of their measurements. This option depends largely on clinical judgment.

Subclinical atherosclerosis

AHA/ACC propose that CAC measurement can assist in deciding whether to use statin therapy in patients at intermediate risk. AHA/ACC in particular noted that the absence of CAC justifies delaying statin therapy. No other modalities of measurement of subclinical atherosclerosis were advocated by AHA/ACC. In contrast, ESC/EAS supported use of different modes of cardiovascular imaging to assist in decisions about intensity of LDL-C lowering therapy. Beyond this, however, recommendations for cardiovascular imaging were not highly specific. Nonetheless, these guidelines suggest that the finding of substantial subclinical atherosclerosis in any arterial bed elevates a patient’s risk to the category of established ASCVD and can justify adding non-statin therapy to statins in such patients.

Guideline specificity

AHA/ACC guidelines place great emphasis on data from RCTs to justify its recommendations. However, RTC’s related to specific questions typically are limited in number. AHA/ACC recommendations are highly codified and kept to a minimum. ESC/EAS in contrast bases its recommendations both on clinical trials and other types of evidence. It explores available evidence in greater detail, and many of its recommendations are more nuanced. This approach to guideline development has its advantages and disadvantages. For example, it gives the reader a broader base of information to assist in clinical decisions. On the other hand, many of its recommendations are made outside of an RCT-evidence base. Without doubt, cholesterol management in all age and gender groups with various risk factor profiles is complex. The ESC/EAS attempts to provide a rationale for management of this complexity. The AHA/ACC, on the other hand, simplifies management as much as possible; it is written specifically for the practitioner, and leaves the complexities of management to a lipid specialist. ESC/EAS delves into the complexities in more detail so that its recommendations are applicable to both practitioner and specialist.


Advances in drug therapy of elevated cholesterol levels offer great potential for reducing both new-onset ASCVD and recurrent ASCVD events in those with established disease. This benefit can be enhanced by judicious use of lifestyle intervention. But among drugs, statins are first-line therapy. They are generally safe and inexpensive. They have been shown to reduce ASCVD events in both secondary and primary prevention. Ezetimibe has about half the LDL-lowering efficacy of statins; it too is generally safe, and is a generic relatively inexpensive drug. Ezetimibe can be used as an add-on drug to moderate intensity statins, especially for those who do not tolerate a high-intensity statin. PCSK9 inhibitors are powerful LDL-lowering drugs, and they appear to be largely safe. The major drawback is cost. If the cost of these inhibitors can be reduced, they too have the potential for wide usage, especially in patients who are “statin intolerant”. The major challenge for use of cholesterol-lowering drugs is the problem of long-term non-adherence. Improving adherence will require fundamental changes in the current healthcare system in which patient monitoring and follow-up is often not a high priority.


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