ABSTRACT

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), very low-density lipoproteins (VLDL), and remnants. 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, bempedoic acid, 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 for 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 < 55-70 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 or lifetime 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.

INTRODUCTION

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 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 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).

HISTORY OF THE CHOLESTEROL HYPOTHESIS AND CHOLESTEROL-LOWERING THERAPY

The first evidence for a connection between serum cholesterol levels and atherosclerosis came from 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 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 of serum cholesterol levels reduces the risk for ASCVD (6). 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. 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.

HISTORY OF U.S. GUIDELINES FOR CHOLESTEROL MANAGEMENT

2018 AHA/ACC/MULTI-SOCIETY REPORT

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 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 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 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% (11). 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 (18). 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)

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 (18,19).

Table 5.

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 addition of non-statins to statin therapy can enhance risk reduction. These RCTs (and their add-on drugs) were IMPROVE-IT (ezetimibe) (18), FOURIER (evolocumab) (34), and ODYSSEY OUTCOMES (alirocumab) (35). 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, 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 (34,35)

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. An analysis of cost-effectiveness has shown that at current prices in very high-risk patients PCSK9 inhibitors can be cost-effective (52). Another analysis (53) 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

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 (54,55). 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 (56,57). 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 (58). 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 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 (14). 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)

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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 7.

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

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 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 (59) (https://www.acc.org/guidelines/hubs/blood-cholesterol). Estimation of lifetime risk is also useful, particularly in younger individuals. 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.

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 manifestation (figure 4). In patients with high cholesterol levels (homozygous and heterozygous familial hypercholesterolemia) ASCVD can occur early in life whereas in patients with loss of function mutations in PCSK9 and low cholesterol 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 (60).

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 (61). 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.

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 (62). 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)

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.

9. 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 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 (63). 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.

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 these focuses on 10-year risk and a CAC score in this range in a younger individual is predictive of long-term risk (64)).

c.

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

Monitoring

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 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 (76). A task force appointed by these organizations have published an update on dyslipidemia management (77). 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.

KEY PRINCIPLES

There are certain key principles that clinicians should remember when deciding who to treat and how aggressively to treat hypercholesterolemia.

1.

The Sooner the Better- atherosclerosis begins early in life and progresses overtime with LDL-C levels playing a major role in the rate of development. 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.

2.

The Lower the Better- studies have clearly demonstrated that the lower the LDL-C levels the greater the decrease in ASCVD events. Clinicians need to balance the benefits of more aggressively lowering LDL-C levels with the risks and costs of high dose or additional drug therapy. It should be recognized that statins and ezetimibe are generic drugs and very inexpensive. In contrast, PCSK9 inhibitors and bempedoic acid are expensive. In many patients using high-intensity statin therapy in combination with ezetimibe can lead to marked reductions in LDL-C levels with minimal risk and at low cost.

3.

The Higher the LDL-C the Greater the Benefit- if the baseline LDL-C is high the magnitude of the reduction in LDL-C will be greater leading to a larger decrease in ASCVD events. Clinicians should be more aggressive in patients with high LDL-C levels.

4.

The Greater the Risk of ASCVD the Greater the Absolute Reduction in ASCVD- clinicians should identify patients at higher risk for ASCVD and more aggressively treat these patients.

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. For an in-depth discussion of these key principles see the following references (79,80).

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 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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