ABSTRACT

The LDL-C hypothesis holds that high blood LDL-C levels are a major risk factor for atherosclerosis cardiovascular disease (ASCVD) and lowering LDL-C levels will reduce the risk for ASCVD. This hypothesis is based on epidemiological evidence that both within and between populations higher LDL-C levels increase the risk for ASCVD, and conversely, randomized clinical trials (RCTs) demonstrating that lowering LDL-C levels will reduce ASCVD risk. LDL-C levels can be reduced by both lifestyle interventions and cholesterol-lowering drugs. Widely used LDL-C lowering drugs are statins, ezetimibe, bempedoic acid, and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors. In this chapter we discuss the information provided in the two major guidelines on how to select and treat patients to lower LDL-C levels; the 2018 AHA/ACC/Multi-Society report and the European Society of Cardiology (ESC), the European Atherosclerosis Society (EAS), and representatives from other European organizations guidelines published in 2020. Additionally, we discuss the key principles that clinicians should utilize when deciding who to treat and how aggressively to treat hypercholesterolemia to lower the risk of ASCVD. Specifically, 1) the sooner one initiates LDL-C lowering therapy the greater the benefit, 2) the greater the decrease in LDL-C the greater the benefit, 3) the higher the LDL-C level the greater the benefit, and 4) the higher the absolute risk of ASCVD the greater the benefit. Following these general principles will help clinicians make informed decisions in deciding on their approach to lowering LDL-C levels and will facilitate discussions with patients on the benefits and risks of treatment. These decisions need to balance the benefits of treatment vs. the potential side effects and cost and the preferences of individual patients. For complete coverage of all related areas of Endocrinology, please visit our on-line FREE web-text, WWW.ENDOTEXT.ORG.

INTRODUCTION

Atherosclerotic cardiovascular disease (ASCVD) remains the foremost cause of death among chronic diseases. An aging population combined with an atherogenic lifestyle increases the risk of ASCVD. Even so, mortality from ASCVD has been declining in most developed countries. This decline comes from improvements in preventive measures and better clinical interventions. One of the most important advances in the cardiovascular field resulted from identifying 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, VLDL, Lp(a), and remnants) 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 (for example, 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 also affect ASCVD risk through other ways not yet understood (2).

THE CHOLESTEROL HYPOTHESIS AND CHOLESTEROL-LOWERING THERAPY

There is now indisputable evidence that elevated serum cholesterol levels increase the risk of ASCVD. The first evidence for a connection between serum cholesterol levels and atherosclerosis came from studies in laboratory animals (3). Feeding cholesterol to various animal species raises serum cholesterol and causes deposition of cholesterol in the arterial wall (3). The latter recapitulates the early stages of human atherosclerosis. Subsequently, in humans, severe hereditary hypercholesterolemia was observed to cause premature atherosclerosis and ASCVD (3). Later, population surveys uncovered a positive association between serum cholesterol levels and ASCVD (4,5). Finally, clinical trials with cholesterol-lowering agents documented that lowering serum cholesterol levels reduces the risk for ASCVD (6). These findings have convincing proven the cholesterol hypothesis. 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. 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 have demonstrated that lowering cholesterol levels will reduce the risk for ASCVD. This bidirectional relationship between cholesterol levels and ASCVD provides ample support for the cholesterol hypothesis.

PRIOR U.S. GUIDELINES FOR CHOLESTEROL MANAGEMENT

2018 AHA/ACC/MULTI-SOCIETY REPORT

2013 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. These guidelines proposed a top 10 list of recommendations to highlight the key points. These key points will be examined.

Secondary Prevention

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

The strongest evidence for efficacy of statin therapy is a 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 (39mg/dL) 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 the use of high-intensity statins. But, if high-intensity statins are not tolerated, similar LDL-C lowering can be attained by combining a moderate-intensity statin with ezetimibe (15,16). The RACING trial, a randomized trial that compared rosuvastatin 10 mg plus ezetimibe 10 mg vs. rosuvastatin 20 mg, demonstrated a similar effect on ASCVD events (41). An approach to lowering LDL-C in patients with ASCVD is shown in Figure 2.

Figure 2.

Secondary Prevention in Patients with Clinical ASCVD (1).

VERY HIGH-RISK PATIENTS WITH ASCVD

3) In very high-risk patients with ASCVD first use a maximally tolerated statin +/- ezetimibe to achieve an LDL-C goal of < 70mg/dL (<1.8mMol/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 4). This definition is based in large part on subgroup analysis of the IMPROVE-IT trial (16,17).

Table 4.

Very High Risk of Future ASCVD Events (1)

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Major ASCVD Events

Recent ACS (within the past 12 months) 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 Hypertension 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 the addition of non-statins to statin therapy can enhance risk reduction. These RCTs (and their add-on drugs) were IMPROVE-IT (ezetimibe) (16), FOURIER (evolocumab) (19), and ODYSSEY OUTCOMES (alirocumab) (20). 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 70 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, the duration of therapy was only about 3 years. A marked additional LDL lowering was achieved. In both trials, the 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 (or non-HDL-C > 100mg/dL) during treatment with maximally tolerated statin plus ezetimibe (Figure 3). This latter threshold LDL-C was chosen because it was a recruitment criterion for PCSK9 inhibitor therapy in reported RTCs (19,20)

An important question about the 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, and one can anticipate that the price will continue to decrease. An analysis of cost-effectiveness has shown that at current prices in very high-risk patients PCSK9 inhibitors can be cost-effective (42). Another analysis (43) 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.

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

Primary Prevention

SEVERE PRIMARY HYPERCHOLESTEROLEMIA

1.

In patients with severe primary hypercholesterolemia (LDL-C greater than 190mg/dL (>4.9mMol/L)) without concomitant ASCVD begin high-intensity statin therapy (or moderate intensity statin + ezetimibe) to achieve an LDL-C goal of < 100mg/dL; if this goal is not achieved consider adding a 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 (44,45). 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.

PATIENTS WITH DIABETES

2.

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 therapy (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 (48). 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 the pooled cohort equation (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 (12). Hence, most middle-aged patients with diabetes deserve statin therapy. With progression of age and accumulation of multiple risk factors, increasing the intensity of statin therapy or adding ezetimibe seems prudent (Tables 5 and 6). It is not necessary to measure 10-year risk before initiation of statin therapy in these patients with diabetes.

Table 5.

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

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

ABI indicates ankle-brachial index.

Table 6.

ASCVD Risk Enhancers (1)

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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

*

Chronic kidney disease definition- eGFR 15–59 mL/min/1.73 m2 with or without albuminuria.

**

Metabolic syndrome definition- increased waist circumference, elevated triglycerides [>175 mg/dL], elevated blood pressure, elevated glucose, and low HDL-C [<40 mg/dL in men; <50 in women mg/dL] are factors; tally of 3 makes the diagnosis).

Other factors that can increase the risk of ASCVD include social deprivation, physical inactivity,

psychosocial stress, major psychiatric disorders, obstructive sleep apnea syndrome, and metabolic associated fatty liver disease (38).

PRIMARY PREVENTION PATIENT WITHOUT OTHER FACTORS

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

This discussion is necessary to put a patient’s total risk status in 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 pooled cohort equation (PCE) risk calculator (49) (https://tools.acc.org/ASCVD-Risk-Estimator-Plus/#!/calculate/estimate/). Estimation of lifetime risk is also useful, particularly in younger individuals who often have a low 10-year risk but a high lifetime risk. 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) and should be obtained in younger individuals. 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 the 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.

Patients should also recognize that atherosclerosis begins early in life and progresses overtime before manifesting as clinical disease. The cumulative LDL-C levels (“LDL-C years”) strongly influence the timing of clinical manifestations (figure 4). In patients with high LDL-C levels (homozygous and heterozygous familial hypercholesterolemia) ASCVD can occur early in life whereas in patients with loss of function mutations in PCSK9 and low LDL-C level have a reduced occurrence of ASCVD.

Figure 4.

Relationship between cumulative LDL-C exposure, age, and the development of the clinical manifestations of ASCVD. Figure from reference (50).

Additionally, patients should be appraised of comparisons of the reduction in ASCVD events in individuals with genetic variations resulting in life-long reductions in LDL-C levels vs. individuals treated with statins to lower LDL-C later in life. Variants in the HMG-CoA reductase, NPC1L1, PCSK9, ATP citrate lyase, and LDL receptor genes result in a lifelong decrease in LDL-C and a 10mg/dL decrease in LDL-C with any of these genetic variants was associated with a 16-18% decrease in ASCVD events (51). As noted above, a 39mg/dL decrease in LDL-C in the statin trials resulted in a 22% decrease in ASCVD events. Thus, a life-long decrease in LDL-C levels results in a decrease in ASCVD events that is three to four times as great as that seen with short-term LDL-C lowering with drugs later in life suggesting that the sooner the LDL-C level is lowered the better the prevention of cardiovascular events.

5) 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 (52). 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 5.

Figure 5.

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

6) 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 6.

7) IF A DECISION ABOUT STATIN THERAPY IS UNCERTAIN IN ADULTS 40 TO 75 YEARS OF AGE WITHOUT DIABETES MELLITUS, WITH LDL-C LEVELS ≥ 70 MG/DL, AND WITH A 10 YEAR ASCVD RISK OF ≥ 7.5% TO 19.9% (INTERMEDIATE RISK) CONSIDER MEASURING Coronary Artery Calcium (CAC).

CAC measurements are a safe and inexpensive method to assess severity of coronary atherosclerosis. CAC scores generally reflect lifetime exposure to coronary risk factors and therefore in young individuals (men < 40 years of age; women < 50 years of age) the long-term predictive value is limited because the CAC score is often 0. Studies show that CAC accumulation is a strong predictor of probability of ASCVD events (53). A CAC core of zero generally is accompanied by few if any ASCVD events over the subsequent decade. Reevaluation in 5-10 years is indicated. 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. CAC > 300-400 is equivalent to clinical ASCVD. Data such as these led to the following recommendation of 2018 guidelines for patients at intermediate risk by PCE.

a. If CAC is zero, treatment with statin therapy may be withheld or delayed, except in cigarette smokers, those with diabetes mellitus, those with a strong family history of premature ASCVD, and possibly chronic inflammatory conditions such as HIV.

b. 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 (note this focuses on 10-year risk and a CAC score in this range in a younger individual is predictive of an increased long-term risk (54)).

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

Monitoring

8) 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 an 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 a 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 6). 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 6.

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.

EUROPEAN GUIDELINES FOR CHOLESTEROL MANAGEMENT

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 (65). A task force appointed by these organizations have published an update on dyslipidemia management (38). 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.

Differences Between AHA/ACC and ESC/EAS Guidelines

DEFINITION OF VERY HIGH RISK

This definition is important because it sets the stage for considering intensive LDL-C lowering and the use of 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 considers all patients with clinical ASCVD or ASCVD on imaging as very high risk. Additionally, 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 (table 9). Overall, 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 (43) showed that only about 10% of patients with established ASCVD will be eligible for PCSK9 inhibitors by AHA/ACC recommendations.

Table 9.

ESC/EAS Cardiovascular Risk Categories

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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, 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

SCORE= Systematic Coronary Risk Estimation. * Total CVD event risk is approximately three times higher than the 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 the 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) (table 10). 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. Additionally, following the ESC/EAS LDL-C goals will most likely result in lower LDL-C levels in many patients.

Table 10.

ESC/EAS LDL Cholesterol Goals

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

In patients with ASCVD who experience a second vascular event within 2 years while on maximally tolerated statin therapy an LDL-C goal of < 1mMol/L (40mg/dL) may be considered.

In addition, the ESC/EAS also provided goals for non-HDL-C and apolipoprotein B (table 11).

Table 11.

ESC/EAS Goals of Therapy

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	Non-HDL-C	Apo B
Very High Risk	<85mg/d;	<65mg/dL
High Risk	<100mg/dL	<80mg/dL
Moderate Risk	<130mg/dL	<100mg/dL

Figure 7 provides an overview of the ESC/EAS recommended treatment based on risk and baseline LDL-C levels.

Figure 7.

ESC/EAS treatment recommendations based on risk and baseline LDL-C levels.

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 study suggests that more people are “eligible” for statin therapy using PCE compared to SCORE (66). 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. The European guidelines provide a similar list of factors that should be considered in determining risk and modifying the SCORE result. Notable among risk enhancing factors were apolipoprotein B (apoB) and lipoprotein (a) (Lp[a]).

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 both CAC and carotid or femoral plaque burden on ultrasonography to determine risk. 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 general 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 the general practitioner and specialist.

IMPORTANT CHANGES SINCE THESE GUIDELINES WERE PUBLISHED

KEY PRINCIPLES

There are certain key principles that clinicians should utilize when deciding who to treat and how aggressively to treat hypercholesterolemia. Understanding these principles will allow clinicians to help their patients decide on the best approach to LDL-C lowering.

The Sooner the Better

It is widely recognized that atherosclerosis begins early in life and slowly progresses ultimately resulting in clinical manifestations later in life (78). Several studies have demonstrated the presence of atherosclerosis in young individuals (79-83). The extent of the atherosclerotic lesions correlates positively with total cholesterol and LDL-C and negatively with HDL-C levels (79,80,83-90). These studies clearly demonstrate that atherosclerosis begins early in life with the prevalence increasing with age and the extent and onset of lesions is influenced by total cholesterol and LDL-C levels. Moreover, an increased total cholesterol early in life also predicted an increased risk of developing cardiovascular disease later in life (91-93).

Genetic studies have further illustrated the key role of exposure to total cholesterol and LDL-C in determining the time when clinical manifestations of ASCVD occur. In patients with homozygous familial hypercholesterolemia (FH), LDL-C are markedly elevated, and cardiovascular events can occur early in life. Greater than 50% of untreated patients with homozygous FH develop clinically significant ASCVD by the age of 30 and cardiovascular events can occur before age 10 in some patients (45). In patients with heterozygous FH LDL-C levels are elevated but not to the levels seen with homozygous FH and cardiovascular events occur later in life but still at a relatively younger age. Untreated males with heterozygous FH have a 50% risk for a fatal or non-fatal myocardial infarction by 50 years of age whereas untreated females have a 30% chance by age 60 (45). Conversely, individuals with genetic variants in PCSK9, HMG-CoA reductase, LDL receptor, NPC1L1, or ATP citrate lyase that lead to a decrease in LDL-C levels have a reduced risk of developing cardiovascular events (50,51). The relationship between genetic disorders that alter LDL-C levels and the time to develop clinical cardiovascular events is illustrated in figure 4. The figure clearly illustrates that the age when one clinically manifests ASCVD depends on the level of LDL-C. With very high LDL-C levels clinical events occur early in life and with low LDL-C levels events will occur at an older age leading to the concept of LDL years.

Of major importance is that the reduction in ASCVD events is much greater in individuals with lifelong decreases in LDL-C compared to the reductions in ASCVD events seen with statin treatment (Table 14). A lifelong 10mg/dL decrease in LDL-C due to polymorphisms in genes that affect LDL-C is associated with a 16-18% decrease in ASCVD events (51). In contrast, a decrease in LDL-C of 39mg/dL over 4-5 years with statin therapy results in only a 22% decrease in ASCVD events (6,9). Thus, a life-long decrease in LDL-C levels results in a decrease in cardiovascular events that is three to four times as great as that seen with short-term LDL-C lowering with drugs. Figure 8 illustrates the benefits of early treatment in reducing LDL-C years and delaying the development of ASCVD.

Table 14.

Effect of Reduction in LDL-C by Genetic Variants on the Risk of ASCVD

View in own window

Gene	Odds ratio for ASCVD events per 10mg/dL decrease in LDL-C (95% CI)
ATP citrate lyase	0.82 (0.78–0.87)
HMG CoA reductase	0.84 (0.82–0.87)
NPC1L1	0.84 (0.79–0.89)
PCSK9	0.83 (0.80–0.87)
LDL receptor	0.83 (0.80–0.87)

Statin treatment decreases ASCVD by approximately 22% per 39mg/dL decrease in LDL-C.

Figure 8.

The effect of early lowering of LDL-C on the development of ASCVD.

In addition to calculating the 10-year risk of ASCVD events it is important to calculate either the lifetime or 30-year risk. This is particularly important in younger individuals where the 10-year risk of ASCVD events may be relatively low, but the long-term risk may be high. In the discussion of therapy with patients they need to be aware of their long-term risk and the potential advantages of early treatment.

Lowering LDL-C levels by lifestyle changes early in life will have long-term benefits. Additionally, in selected individuals initiating drug therapy sooner rather than latter will reduce ASCVD events later in life.

SUMMARY

Advances in the 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 relatively inexpensive genetic 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 or in combination with high intensity statins to markedly decrease LDL-C levels. PCSK9 inhibitors are powerful LDL-lowering drugs, and they appear to be 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”. Bempedoic acid has been shown to reduce ASCVD events in statin intolerant patients and in combination with ezetimibe can result in significant decreases in LDL-C levels. A major challenge for use of cholesterol-lowering drugs is the problem of long-term non-adherence.

ACKNOWLEDGEMENTS

Dr. Scott Grundy who recently died was the original author of this chapter and this chapter is an update of his chapter. This chapter is dedicated to Dr. Grundy who has been an inspiration to lipidologists worldwide.

This work was supported by grants from the Northern California Institute for Research and Education.

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