Skip to main content

Minimizing the Burden of Cardiovascular Disease: A Need for Lipid-Lowering Strategies Beyond Statins

Download PDF

Cardiovascular disease (CVD) remains the leading cause of death in the United States,1-3 despite public health initiatives and measures to reduce modifiable risk factors.4 Approximately 1 in 4 deaths in the United States are caused by CVD,3,5 and an estimated 10% of the adult US population has atherosclerotic CVD (ASCVD).4 Most recent data estimated the direct and indirect annual cost of CVD in the United States was $378 billion.3 The largest proportion (~44%) of direct costs is attributed to inpatient hospitalizations for acute events3; a smaller proportion (~4.1%) is attributed to hospital emergency department visits.3

One of the major risk factors for the development of CVD is dyslipidemia, often called hyperlipidemia.3,6 The major lipids in humans are cholesterol and triglycerides.7 Because they are insoluble in water, these lipids are transported in the circulatory system in complex particles known as lipoproteins, which are classified based on size and composition.8 Low-density lipoprotein cholesterol (LDL-C) is thought to be the primary driver of atherosclerosis.9 Four of the other lipoprotein classes—intermediate-density lipoprotein, very low-density lipoprotein, lipoprotein(a), and chylomicron remnants—are also known to be atherogenic.8 Conversely, high-density lipoprotein cholesterol is antiatherogenic.8

Role of LDL-C in Development of Atherosclerosis

The process of atherosclerosis is initiated when mechanical stimuli affect vulnerable areas of the arterial lining, resulting in compromised barrier integrity.10 This allows atherogenic lipoproteins, such as LDL particles and other remnant lipid particles, to move into the subendothelial space.10 The retained lipoproteins undergo biological modification through a variety of mechanisms,10 and the modified LDL particles are engulfed by macrophages and smooth muscle cells. Subsequent release of growth factors and cytokines attracts additional monocytes. Foam-cell accumulation and smooth-muscle–cell proliferation result in formation of plaques on the arterial wall.10 These plaques may become vulnerable and prone to rupture.10 Plaque rupture results in thrombus formation, which accounts for the majority of clinical events in ASCVD, ie, myocardial infarction (MI), unstable angina, sudden cardiac death, and stroke.10

LDL-C is a driver of atherosclerosis as the development of atherosclerotic plaques increases in a dose-dependent manner with increasing LDL-C levels.11,12 LDL particles are the key deliverer of cholesterol to the arterial wall and the most abundant atherogenic lipoprotein in plasma.12 Generally, the higher the LDL-C level, the faster the plaques evolve.13 Plaque formation is also accelerated by other risk factors such as smoking, high blood pressure, and diabetes.13-15

Role of Elevated LDL-C in Cardiovascular Risk

LDL-C was first identified as a risk factor for coronary heart disease (CHD) in the mid-1950s by John Gofman, MD, PhD, of the University of California at Berkeley.13 Since that time, numerous investigations including epidemiologic studies, genetic studies, and clinical trials in humans have all confirmed that LDL-C has a direct association with, and is causally related to, ASCVD, and that reduction in plasma LDL-C levels is associated with fewer adverse cardiovascular events.9

Separate meta-analyses of more than 200 prospective cohort studies, Mendelian randomization studies, and randomized trials including more than 150,000 cardiovascular events and more than 2 million participants show a consistent and remarkable log-linear association between the magnitude of vascular exposure to LDL-C and risk of ASCVD; this effect appears to increase as duration of exposure to LDL-C increases.9

Randomized clinical trials have shown that reducing LDL-C decreases risk of ASCVD.4,6,16,17 One of the earliest clinical trials, the Coronary Primary Prevention Trial, published in 1984, assigned patients with elevated cholesterol and no history of ASCVD to cholestyramine or placebo. Mean LDL-C decreased by 20.3% with cholestyramine and by 7.7% with placebo.18 For each 11% reduction in LDL-C, a 19% (P <.001) decrease in CHD events was seen.19 Since then, numerous clinical trials evaluating risk reduction of major vascular events with statins have been conducted. A 2012 meta-analysis of 27 randomized statin trials conducted by the Cholesterol Treatment Trialists Collaboration (CTTC) showed that for each 38-mg/dL (1.0-mmol/L) decrease in LDL-C, risk of major vascular events fell by 21% (relative risk, 0.79).20 This meta-analysis included both patients without known ASCVD (primary prevention) and those with established ASCVD (secondary prevention). A separate 2016 meta-regression analysis by Silverman and colleagues included 49 trials (both primary and secondary prevention trials) incorporating 9 different treatment modalities.11 This study showed that with treatments that act predominantly through upregulation of LDL-receptor activity (ie, statins, ezetimibe, bile acid sequetrants, ileal bypass, and diet), for each 38-mg/dL (1.0-mmol/L) decrease in LDL-C, risk of major vascular events decreased by 23% (relative risk, 0.77; P <.001).11

Genetic studies also offer powerful evidence that lower LDL-C levels are associated with a lower risk of CHD. Mendelian randomization studies have repeatedly shown that genetic variants associated with lower LDL-C levels are also associated with a correspondingly lower rate of CHD.21-23

As observed in meta-analyses of clinical trials, nonstatin therapies that lower LDL-C also reduce cardiovascular risk. Studies have shown a linear relationship with LDL-C lowering and decreased cardiovascular events when adjunctive nonstatin therapy is added to background statin therapy. The IMPROVE-IT trial evaluated ezetimibe plus a statin versus statin monotherapy in patients with recent acute coronary syndrome. During a 6-year follow-up, the ezetimibe plus statin group had a mean LDL-C of 53.7 mg/dL compared with 69.5 mg/dL in the statin-only group.24 The rate of the primary end point (death from cardiovascular causes, nonfatal MI, unstable angina requiring rehospitalization, coronary revascularization, or nonfatal stroke) at 7 years was 32.7% in the ezetimibe plus statin group versus 34.7% in the statin-only group (hazard ratio [HR], 0.936; P = .016).24

Cardiovascular outcome trials of proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors have also shown significant reduction in cardiovascular risk. The FOURIER trial evaluated evolocumab plus statin therapy versus statin monotherapy in patients with known ASCVD. The addition of evolocumab reduced LDL-C by a mean of 56 mg/dL.25 During 2.2 years of follow-up, the primary end point (composite of cardiovascular death, MI, stroke, hospitalization for unstable angina, or coronary revascularization) was 9.8% in the evolocumab plus statin group versus 11.3% in the placebo group (HR, 0.85; P <.001).25 Similarly, the ODYSSEY OUTCOMES trial evaluated the PCSK9 inhibitor alirocumab plus maximally tolerated statin therapy compared with placebo plus maximally tolerated statin therapy in patients with acute coronary syndrome within the previous 12 months. Alirocumab reduced LDL-C by a mean of 44 mg/dL at 12 months versus an increase of 4 mg/dL in the placebo group.26 During the median follow-up period of 2.8 years, the primary end point (a composite of death from CHD, nonfatal MI, fatal or nonfatal ischemic stroke, or unstable angina requiring hospitalization) was 9.5% in the alirocumab group versus 11.1% in the placebo group (HR, 0.85; P <.001).26

Even in patients with low baseline levels of LDL-C, further reduction in LDL-C is associated with reduction in major vascular events. A 2010 meta-analysis (which included 26 prospective statin trials) showed that in studies of more intensive versus less intensive statin therapy (5 trials), when baseline LDL-C was <77 mg/dL (2.0 mmol/L), each 38-mg/dL (1.0-mmol/L) reduction in LDL-C led to a 29% decrease in major vascular events27; when baseline LDL-C was <70 mg/dL (1.8 mmol/L), a 37% reduction in major vascular events occurred with each 38-mg/dL (1.0-mmol/L) reduction in LDL-C.16,27

This substantial body of evidence demonstrates that the most important consideration in reducing cardiovascular risk is how much, when, and for how long LDL-C reduction is achieved, rather than by what pathway it is achieved.17

Role of Inflammation and Comorbidities in Contributing to Cardiovascular Risk

A growing body of evidence suggests that underlying inflammation may contribute to the development of atherosclerosis.28 Common comorbid conditions, such as diabetes,29,30 hypertension,31 and obesity,30 are associated with inflammation and are known cardiovascular risk factors.32 Chronic kidney disease is also associated with persistent low-grade inflammation33 and doubles the risk for cardiovascular events34,35; diabetes also doubles the risk.34,36 When diabetes and chronic kidney disease coexist, the risk for cardiovascular events increases even further.34

Patients with ASCVD, who are already at high risk for recurrent events, often have complex comorbidities involving diabetes, cardiorenal, and/or metabolic (DCRM) diseases,34 which further heighten their risk. Such patients may benefit from a holistic, multidisciplinary approach to treat both ASCVD and DCRM comorbidites.34 This approach may be feasible, as several recent cardiovascular outcome trials have shown that therapies developed for one condition also improve outcomes across several conditions, such as the proven benefits of sodium glucose cotransporter 2 inhibitors and long-acting glucagon-like peptide 1 receptor agonists on cardiovascular outcomes.34

Peripheral artery disease (PAD), an extracardiac manifestation of atherosclerosis, also increases the risk of cardiovascular events especially when present with other cardiovascular conditions.37 In a retrospective analysis of commercial and Medicare claims data, Colantonio and colleagues evaluated more than 940,000 patients with a diagnosis of PAD, CHD, or cerebrovascular disease (2014-2017).37 The subsequent ASCVD event rate (per 1000 patient-years) was 42.2 for patients with CHD, 34.7 for patients with PAD, 72.8 for patients with both PAD and CHD, and 119.5 for patients with all 3 conditions.37 In fact, lower extremity PAD has been described as a CHD risk equivalent.38

MACE as a Composite End Point

Many clinical trials describe cardiovascular outcomes using a composite end point known as MACE (major adverse cardiovascular events).39 Definitions of MACE can vary. Traditional 3-point, 4-point, and 5-point MACE include, respectively40:

  • Acute myocardial infarction (AMI), stroke, or cardiovascular death
  • AMI, stroke, cardiovascular death, and unstable angina
  • AMI, stroke, cardiovascular death, unstable angina, and heart failure

Various other definitions of MACE are also common.39 For example:

  • AMI and stroke40
  • AMI, stroke, and all-cause death40
  • Cardiovascular death, nonfatal MI, unstable angina requiring rehospitalization, coronary revascularization, or nonfatal stroke24

Consensus Guidelines
Cardiovascular Risk Categories

The initial step in managing dyslipidemia is to categorize each patient’s risk for cardiovascular events. Risk category is determined based on the presence of patient comorbidities and major risk factors and may also include the calculation of the patient’s 10-year ASCVD risk score. Risk calculators such as ASCVD Risk Estimator Plus, Framingham Risk Score, and Reynolds Risk Score are widely used to calculate the 10-year risk for cardiovascular events.41 These risk estimators are easy to use and are available in the public domain on the Internet, downloaded as mobile apps, or integrated into electronic medical records systems.

Based on the clinical and/or 10-year ASCVD risk assessment, patients are determined to be at low risk to very high risk or extreme risk for developing ASCVD, and treatment targets and lipid-lowering therapy are adjusted accordingly. Guidelines from the American College of Cardiology/American Heart Association (ACC/AHA)42 and the American Association of Clinical Endocrinologists/American College of Endocrinology (AACE/ACE)16 differ somewhat in the risk categories (Table 1 and Table 2) and treatment recommendations, but both recommend intensification of treatment as cardiovascular risk increases.

Table 1
Table 2

Indeed, over the past 20 years since the inception of lipid targets in the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III),43 guidelines have generally evolved to include lower LDL-C treatment targets in patients with established ASCVD, in recognition of the role of LDL-C in atherosclerosis and the increasing evidence of LDL-C lowering and cardiovascular-risk reduction in this high-risk patient population (Table 3). The ACC/AHA guidelines from 2013 and 2018, however, are largely based on evidence from randomized controlled trials, most of which used statins at a fixed, prespecified dose (as opposed to statin dose titration designed to achieve an LDL-C target goal).42,44 As a result, recommendations of these guidelines focus on the use of statins at dosages utilized in the randomized controlled trials and establish percentage reduction in LDL-C (rather than an absolute LDL-C level) as a target goal.

Table 3

Treatment Recommendations and LDL-C Goals

The most recent 2018 ACC/AHA Guideline on the Management of Blood Cholesterol recommends the initiation of moderate-intensity or high-intensity statin therapy in patients in certain risk categories (Table 1), including42:

  • Individuals with LDL-C ≥190 mg/dL
  • Individuals aged 40 to 75 years with diabetes and LDL-C 70 mg/dL to 189 mg/dL
  • Individuals aged 40 to 75 years with LDL-C 70 mg/dL to 189 mg/dL and estimated 10-year ASCVD risk ≥7.5%
  • Individuals with clinical ASCVD

Likewise, the AACE/ACE consensus statement outlines specific LDL-C target goals for each risk category (Table 3).16 As patient risk for ASCVD increases, the consensus statement recommends more aggressive goals for lipid-lowering therapy (Table 2). For high-risk patients with LDL-C ≥70 mg/dL despite maximally tolerated statin therapy, adjunct therapy should be considered.42

Key primary prevention recommendations for both the 2018 ACC/AHA guidelines and the 2020 AACE/ACE consensus statement are described and compared16,42 in Table 4. Those for secondary prevention are described in Table 5. Together, these consensus guidelines recommend more aggressive LDL-C treatment goals in patients with established ASCVD and increased cardiovascular risk.

Table 4
Table 5

Guideline Recommendations for Comorbidities

As described previously, the presence of comorbidities, especially cardiometabolic conditions, substantially increases cardiovascular risk. In 2022, a multispecialty task force published a consensus document on the comprehensive management of patients with complicated metabolic disease.34 In the DCRM Multispecialty Practice Recommendations, patients with diabetes are considered high risk, and the risk category increases with additional comorbid conditions.34 It states, “[a]ll patients at elevated ASCVD risk should receive a statin at the maximally tolerated dose unless there is a contraindication.”34 The 2022 Scientific Statement from AHA provides a similar recommendation that patients with diabetes aged 40 to 75 years should receive at least a moderate-dose statin in order to prevent cardiovascular events, and patients with diabetes and multiple ASCVD risk factors, risk-modifying factors, or diabetes-specific risk-enhancing factors should receive high-intensity statin therapy.45

For patients with established ASCVD (secondary prevention), all guidelines agree that the presence of comorbid diabetes warrants aggressive LDL-C lowering to reduce cardiovascular risk.

2018 ACC/AHA Guideline Recommendations for the Elderly, Aged ≥75 Years42

Advanced age should be considered in the management of dyslipidemia, as these patients (≥75 years) may be at higher risk for adverse effects of therapy due to comorbid conditions, and potential drug–drug interactions. Continuation of the highest intensity statin dose tolerated is considered reasonable after evaluating the benefits, potential adverse effects, and life-limiting comorbidities.

Primary Prevention:

  • In patients with LDL-C 70 mg/dL to 189 mg/dL, it is reasonable to initiate moderate-intensity statin therapy.
  • In patients aged 76 to 80 years with LDL-C 70 mg/dL to 189 mg/dL, it may be reasonable to measure coronary artery calcium (CAC) to avoid statin therapy in those with a CAC score of zero.
  • In patients with functional decline (physical or cognitive), multimorbidity, frailty, or reduced life expectancy which limits the potential benefits of statin therapy, it is reasonable to discontinue statin therapy.
  • In patients with diabetes mellitus who are already on statin therapy, it is reasonable to continue statin therapy.
  • In patients with diabetes, it may be reasonable to initiate statin therapy after a clinician–patient discussion of potential benefits and risks.

Secondary Prevention:

  • In patients with clinical ASCVD, it is reasonable to initiate moderate- or high-intensity statin therapy after evaluating the potential for ASCVD risk reduction, adverse effects, and drug–drug interactions, as well as patient frailty and patient preferences.
  • In patients with clinical ASCVD who are tolerating high-intensity statin therapy, it is reasonable to continue high-intensity statin therapy after evaluating the potential for ASCVD risk reduction, adverse effects, and drug–drug interactions, as well as patient frailty and patient preferences.

Introduction to Treatment Options
Statins as Initial Therapy

Statins are considered the cornerstone of lipid-lowering therapy.42 Unless contraindicated, a statin should be used as initial therapy for lowering LDL-C.16,42,46 Evidence supports a moderate- to high-intensity statin. CTTC conducted a meta-analysis of 21 trials and found that moderate-

intensity statins lowered LDL-C by 41.38 mg/dL and ASCVD risk by 22% (relative risk, 0.78) during a mean follow-up of 4.8 years.27 A parallel meta-analysis of 5 trials found that high-intensity statin therapy led to a further mean LDL-C reduction of 19.72 mg/dL and a 15% further reduction in major vascular events.27

In addition, ≥30 years of evidence, beginning with US Food and Drug Administration approval of lovastatin in 1987, have shown that statins are safe and well-tolerated by the majority of patients. However, in clinical practice, some patients are unable to take high-intensity statin therapy, either because of contraindications (eg, active hepatic disease, pregnancy) or adverse effects (statin intolerance). The most common adverse effects from statins are skeletal muscle–related symptoms: myalgias, soreness, cramps, stiffness, or weakness.47 The development of more severe myopathy leading to rhabdomyolysis is rare but requires discontinuation of statin therapy.16 The National Lipid Association (NLA) defines statin intolerance as47:

. . . [O]ne or more adverse effects associated with statin therapy, which resolves or improves with dose reduction or discontinuation, and can be classified as complete inability to tolerate any dose of a statin or partial intolerance, with inability to tolerate the dose necessary to achieve the patient-specific therapeutic objective. To classify a patient as having statin intolerance, a minimum of two statins should have been attempted, including at least one at the lowest approved daily dosage.

The NLA states that even patients who are statin-intolerant should keep trying statins in an effort to find a tolerable statin regimen, which may include another statin medication, a reduced dose (low- or moderate-intensity), or an alternate dosing regimen (eg, every other day).47 It is also notable that, in patients at high and very high risk who have statin intolerance, the NLA statement recommends that clinicians consider initiating nonstatin therapy while further attempts are made to identify a tolerable statin to minimize the duration of exposure to high levels of atherogenic cholesterol.47

Historically, women are often under-treated with statin therapy and receive less-aggressive lipid management than men with hyperlipidemia. Sex differences in statin treatment and guideline-recommended statin dosing were analyzed using the Patient and Provider Assessment of Lipid Management Registry, which is a nationwide registry of outpatients with or at risk for ASCVD. A total of 5693 participants were analyzed (43% of whom were women), and it was seen that 67% of women versus 78.4% of men eligible for ACC/AHA guideline-recommended statin treatment were prescribed any statin treatment at all (P <.001).48 In addition, only 36.7% of women versus 45.2% of men received a statin at guideline-recommended intensity (P <.001).48 Women were also more likely to report never having been offered statin therapy, declined statin therapy, or discontinued statin therapy.48 Another study evaluating 10,138 patients using the Understanding Statin Use in America and Gaps in Patient Education (USAGE) survey demonstrated that women are more likely to stop or switch statin therapy compared with men, mainly due to new or worsening muscle symptoms.49 The USAGE survey is an Internet-based questionnaire of patients diagnosed with high cholesterol who are current or former users of a statin. Analysis from the survey showed that 31% of women reported new or worsening muscle symptoms with statin therapy compared with 26% of men (P <.01).49 Women were also more likely to stop a statin due to muscle symptoms and were more likely to try ≥3 statins; however, they were less likely to use an alternative lipid-lowering treatment compared with men.49 Finally, it was observed that women were more likely than men to be dissatisfied with their statin and how clinicians described the treatment and were less adherent to the statin regimen.49

Need for Adjunct Lipid-Lowering Therapy

Even with aggressive statin therapy, however, many patients are not able to achieve adequate lowering of LDL-C,16,50,51 particularly those with familial hypercholesterolemia (FH), a genetic cause of elevated cholesterol and LDL-C.6,52 Heterozygous familial hypercholesterolemia (HeFH) is an autosomal codominant disorder usually due to a mutation in the LDL-receptor gene and is characterized by very high LDL-C levels (>190 mg/dL). HeFH has been estimated to occur in approximately 1 out of 212 people,53 and is significantly underdiagnosed.54 Estimates suggest that 90%, or 1.1 million people, in the United States with FH are undiagnosed.55,56 A genome sequencing study of 50,726 US participants in a single healthcare system demonstrated that only 15% of those found to have FH by genetic testing had evidence of a previous diagnosis of FH, ie, an ICD-10 (International Classification of Diseases, Tenth Edition) diagnosis code for pure hypercholesterolemia or previous visit to a lipid clinic.57 The homozygous form of FH is rare and associated with severe disease; patients often experience MI in early childhood.58,59

Because patients with FH often present with very high baseline LDL-C levels (≥190 mg/dL), they may not be able to achieve LDL-C goals with statin therapy alone. A study by Duell and colleagues based on the CASCADE-FH Registry, which includes 1900 patients with FH, demonstrated that although 93% received lipid-lowering therapy, only 48% achieved LDL-C <100 mg/dL.60 A study published in 2019 described 20-year follow-up of patients with FH who had been enrolled in a pravastatin trial as children.61 At the time of follow-up, 146 (79%) of 184 were using lipid-lowering therapy, and 86 (47%) of 184 were on high-intensity statin therapy,61 yet the mean LDL-C for the entire cohort was 160.7 mg/dL (standard deviation, 72.6 mg/dL).61 Thus, the majority of patients with FH were far from the goal for LDL-C.

Patients with established ASCVD, including those with recent hospitalization for acute coronary syndrome, represent another high-risk group who may have difficulty achieving LDL-C targets with statin therapy alone. In the clinical trial setting, 1 in 4 patients receiving high-intensity statins were not able to achieve LDL-C <70 mg/dL.50,51

  • In the PROVE-IT TIMI-22 trial, 3745 patients with recent acute coronary syndrome were randomized to high-intensity (atorvastatin 80 mg daily) or moderate-intensity (pravastatin 40 mg daily) statin therapy and followed for a mean of 2.5 years.50 Among the high-intensity group, 28% did not achieve LDL-C below 70 mg/dL. In the moderate-intensity group, 78% did not achieve LDL-C below 70 mg/dL.50
  • In the A to Z trial (phase Z), 4497 patients with recent acute coronary syndrome were randomized to high-intensity (simvastatin 80 mg daily) or moderate-intensity statin therapy (simvastatin 20 mg daily) and followed for approximately 2 years.51 In the high-intensity group, LDL-C exceeded 82 mg/dL in 25% of patients at 2 years of follow-up, and 34% of subjects had discontinued the study drug prematurely.51 In the moderate-intensity group, LDL-C exceeded 81 mg/dL in 50% of patients, and 32% had discontinued the study drug prematurely.

In the real-world setting, LDL-C goal attainment is even lower. In the GOULD prospective observational registry of 5006 patients with ASCVD, only 1 in 3 patients on lipid-lowering therapy achieved an LDL-C <70 mg/dL.62 Despite the low level of goal attainment, only 17.1% of patients in the GOULD registry underwent intensification of lipid-lowering therapy during the 2-year follow-up period. Similarly, a recent retrospective analysis of >25,000 patients with ASCVD from a large US administrative claims database found that the majority of patients were not at the guideline-recommended LDL-C goal, and, most distressingly, 41% of ASCVD patients were not on any lipid-lowering therapy.4 Likewise, almost 50% of all patients with established ASCVD identified in a large commercial health plan data set (2018 to 2019) were not on any statin therapy, and only 22.5% were on guideline-recommended high-intensity statin therapy.63 Only 19% of patients had evidence of any change to their statin therapy, half of which were treatment de-escalations.63 In addition, a nationwide analysis, using 2017 to 2018 electronic health record data (Cerner Real World Data) from 384,109 patients with ASCVD in 94 US health systems, found that only 44.4% of patients on a high-intensity statin had an LDL-C <70 mg/dL.64 These real-world studies demonstrate that many patients at high or very high risk for CVD are not receiving appropriate therapy, and for many patients, statin monotherapy is not sufficient to achieve treatment goals.

Role of Adjunctive Lipid-Lowering Therapies

As these studies demonstrate, statin treatment alone may not be sufficient to get patients’ LDL-C levels to goal. Indeed, guidelines recommend adding nonstatin therapies to maximally tolerated statin therapy in order to achieve further LDL-C lowering in high-risk patients not at goal. Maximally tolerated statin therapy may mean no statin (for patients with complete statin intolerance), low- or moderate-intensity statin (for patients with partial statin intolerance), or high-intensity statin, yet patients on a high-intensity statin may require further LDL-C lowering to achieve goal.

The ACC/AHA 2018 guideline recommends consideration of adjunct lipid-lowering therapy in patients with severe hypercholesterolemia (baseline LDL-C ≥190 mg/dL, including those with HeFH) whose LDL-C remains ≥100 mg/dL despite maximally tolerated statin therapy, and in those with clinical ASCVD with LDL-C ≥70 mg/dL despite maximally tolerated statin therapy.42

Adjunct therapy is recommended by the 2020 AACE/ACE consensus statement for patients in all risk categories who have not achieved their LDL-C goal (Tables 4 and 5) with statin monotherapy, after addressing statin adherence.16 The selection of a specific agent may be influenced by the level of required LDL-C lowering. A third agent should be added if the LDL-C goal is still not achieved with combination therapy.16 When intensification of lipid-lowering therapy is required, several complementary therapies are available and recommended in the guidelines.42 These therapies will be described in greater detail in the upcoming Part 2 of this series.


In conclusion, CVD is the leading cause of mortality in the United States and is estimated to affect 10% of the adult population. It is associated with significant economic burden; the largest portion of direct costs are attributed to inpatient hospitalizations for acute vascular events. LDL-C plays a causal role in the pathogenesis of atherosclerosis and is the principal driver of atherosclerosis. Reduction in LDL-C reduces the risk of atherosclerotic events, especially in patients with established ASCVD. Inflammation may be another underlying and causative factor in the development of atherosclerosis. Major risk factors and comorbidities, such as diabetes, hypertension, and smoking, are inflammatory and are known to increase the risk of CVD. Since NCEP ATP III was published in 2002, cholesterol guidelines have evolved concomitantly with the scientific evidence, which unequivocally indicates that lower LDL-C levels are related to lower risk for subsequent ASCVD events. Statins are the cornerstone of lipid-lowering therapy to achieve low LDL-C levels and subsequent risk reduction; however, statin therapy alone is often not sufficient for patients with ASCVD or FH to achieve LDL-C targets. Over the past several years, additional adjunct therapies have become available and are increasingly being incorporated into guidelines to help patients achieve treatment goals. There remains a need for identifying these patients who may benefit from adjunct therapy, either due to the need for further LDL-C lowering beyond what is achievable with statin therapy or due to statin intolerance.

Esperion Therapeutics would like to acknowledge John Welz, MPH, and Abbey Stackpole, PharmD, of Amplity Health for their contributions in developing this article.


  1. Centers for Disease Control and Prevention. Leading Causes of Death. Updated January 13, 2022. Accessed May 30, 2022.
  2. Centers for Disease Control and Prevention. National Center for Health Statistics Data Brief 427. Mortality in the US, 2020. Accessed May 30, 2022.
  3. Tsao CW, Aday AW, Almarzooq ZI, et al. Heart disease and stroke statistics-2022 update: a report from the American Heart Association. Circulation. 2022;145(8):e153-e639.
  4. Gu J, Sanchez R, Chauhan A, Fazio S, Wong N. Lipid treatment status and goal attainment among patients with atherosclerotic cardiovascular disease in the United States: a 2019 update. Am J Prev Cardiol. 2022;10:100336.
  5. Centers for Disease Control and Statistics. Heart Disease Facts. Updated February 7, 2022. Accessed May 30, 2022.
  6. Tokgozoglu L, Orringer C, Ginsberg HN, Catapano AL. The year in cardiovascular medicine 2021: dyslipidaemia. Eur Heart J. 2022;43(8):807-817.
  7. Ference BA, Kastelein JJP, Catapano AL. Lipids and lipoproteins in 2020. JAMA. 2020;324(6):595-596.
  8. Feingold KR. Introduction to Lipids and Lipoproteins. In: Feingold KR, Anawalt B, Boyce A, et al, eds. Endotext. South Dartmouth (MA):, Inc.; 2021.
  9. Ference BA, Ginsberg HN, Graham I, et al. Low-density lipoproteins cause atherosclerotic cardiovascular disease. Evidence from genetic, epidemiologic, and clinical studies. A consensus statement from the European Atherosclerosis Society Consensus Panel. Eur Heart J. 2017;38(32):2459-2472.
  10. Linton MRF, Yancey PG, Davies SS, et al. The Role of Lipids and Lipoproteins in Atherosclerosis. In: Feingold KR, Anawalt B, Boyce A, et al, eds. Endotext. South Dartmouth (MA):, Inc.; January 3, 2019.
  11. Silverman MG, Ference BA, Im K, et al. Association between lowering LDL-C and cardiovascular risk reduction among different therapeutic interventions: a systematic review and meta-analysis. JAMA. 2016;316(12):1289-1297.
  12. Boren J, Chapman MJ, Krauss RM, et al. Low-density lipoproteins cause atherosclerotic cardiovascular disease: pathophysiological, genetic, and therapeutic insights: a consensus statement from the European Atherosclerosis Society Consensus Panel. Eur Heart J. 2020;41(24):2313-2330.
  13. Goldstein JL, Brown MS. A century of cholesterol and coronaries: from plaques to genes to statins. Cell. 2015;161(1):161-172.
  14. Glass CK, Witztum JL. Atherosclerosis. the road ahead. Cell. 2001;104(4):503-516.
  15. Faxon DP, Fuster V, Libby P, et al. Atherosclerotic vascular disease conference: Writing Group III: pathophysiology. Circulation. 2004;109(21):2617-2625.
  16. Handelsman Y, Jellinger PS, Guerin CK, et al. Consensus statement by the American Association of Clinical Endocrinologists and American College of Endocrinology on the management of dyslipidemia and prevention of cardiovascular disease algorithm-2020 executive summary. Endocr Pract. 2020;26(10):1196-1224.
  17. Ray KK, Reeskamp LF, Laufs U, et al. Combination lipid-lowering therapy as first-line strategy in very high-risk patients. Eur Heart J. 2022;43(8):830-833.
  18. The Lipid Research Clinics Coronary Primary Prevention Trial results. I. Reduction in incidence of coronary heart disease. JAMA. 1984;251(3):351-364.
  19. The Lipid Research Clinics Coronary Primary Prevention Trial results. II. The relationship of reduction in incidence of coronary heart disease to cholesterol lowering. JAMA. 1984;251(3):365-374.
  20. Cholesterol Treatment Trialists’ (CTT) Collaborators, Mihaylova B, Emberson J, et al. The effects of lowering LDL cholesterol with statin therapy in people at low risk of vascular disease: meta-analysis of individual data from 27 randomised trials. Lancet. 2012;380(9841):581-590.
  21. Cohen JC, Boerwinkle E, Mosley TH, Jr., Hobbs HH. Sequence variations in PCSK9, low LDL, and protection against coronary heart disease. N Engl J Med. 2006;354(12):1264-1272.
  22. Ference BA, Yoo W, Alesh I, et al. Effect of long-term exposure to lower low-density lipoprotein cholesterol beginning early in life on the risk of coronary heart disease: a Mendelian randomization analysis. J Am Coll Cardiol. 2012;60(25):2631-2639.
  23. Linsel-Nitschke P, Gotz A, Erdmann J, et al. Lifelong reduction in LDL-cholesterol related to a common variant in the LDL-receptor gene decreases the risk of coronary artery disease-a Mendelian randomisation study. PLoS ONE. 2008;3(8):e2986.
  24. Cannon CP, Blazing MA, Giugliano RP, et al. Ezetimibe added to statin therapy after acute coronary syndromes. N Engl J Med. 2015;372(25):2387-2397.
  25. Sabatine MS, Giugliano RP, Keech AC, et al. Evolocumab and clinical outcomes in patients with cardiovascular disease. N Engl J Med. 2017;376(18):1713-1722.
  26. Schwartz GG, Steg PG, Szarek M, et al. Alirocumab and cardiovascular outcomes after acute coronary syndrome. N Engl J Med. 2018;379(22):2097-2107.
  27. Cholesterol Treatment Trialists’ Collaboration, Baigent C, Blackwell L, et al. Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials. Lancet. 2010;376(9753):1670-1681.
  28. Soehnlein O, Libby P. Targeting inflammation in atherosclerosis-from experimental insights to the clinic. Nat Rev Drug Discov. 2021;20(8):589-610.
  29. Poznyak A, Grechko AV, Poggio P, Myasoedova VA, Alfieri V, Orekhov AN. The diabetes mellitus-atherosclerosis connection: the role of lipid and glucose metabolism and chronic inflammation. Int J Mol Sci. 2020;21(5):1835.
  30. Rohm TV, Meier DT, Olefsky JM, Donath MY. Inflammation in obesity, diabetes, and related disorders. Immunity. 2022;55(1):31-55.
  31. Madhur MS, Elijovich F, Alexander MR, et al. Hypertension: do inflammation and immunity hold the key to solving this epidemic? Circ Res. 2021;128(7):908-933.
  32. Centers for Disease Control and Prevention. Know Your Risk for Heart Disease. Updated December 9, 2019. Accessed June 3, 2022.
  33. Ebert T, Pawelzik SC, Witasp A, et al. Inflammation and premature ageing in chronic kidney disease. Toxins (Basel). 2020;12(4):227.
  34. Handelsman Y, Anderson JE, Bakris GL, et al. DCRM multispecialty practice recommendations for the management of diabetes, cardiorenal, and metabolic diseases. J Diabetes Complications. 2022;36(2):108101.
  35. Collins AJ, Li S, Gilbertson DT, et al. Chronic kidney disease and cardiovascular disease in the Medicare population. Kidney Int Suppl. 2003;(87):S24-S31.
  36. Centers for Disease Control and Prevention. Diabetes and Your Heart. Updated May 7, 2021. Accessed June 3, 2022.
  37. Colantonio LD, Hubbard D, Monda KL, et al. Atherosclerotic risk and statin use among patients with peripheral artery disease. J Am Coll Cardiol. 2020;76(3):251-264.
  38. Subherwal S, Patel MR, Kober L, et al. Peripheral artery disease is a coronary heart disease risk equivalent among both men and women: results from a nationwide study. Eur J Prev Cardiol. 2015;22(3):317-325.
  39. Kip KE, Hollabaugh K, Marroquin OC, Williams DO. The problem with composite end points in cardiovascular studies: the story of major adverse cardiac events and percutaneous coronary intervention. J Am Coll Cardiol. 2008;51(7):701-707.
  40. Bosco E, Hsueh L, McConeghy KW, Gravenstein S, Saade E. Major adverse cardiovascular event definitions used in observational analysis of administrative databases: a systematic review. BMC Med Res Methodol. 2021;21(241):1-18.
  41. Agency for Healthcare Research and Quality. Integrating Cardiovascular Disease Risk Calculators Into Primary Care. Accessed August 3, 2022.
  42. Grundy SM, Stone NJ, Bailey AL, et al. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA guideline on the management of blood cholesterol: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol. 2019;73(24):e285-e350.
  43. National Cholesterol Education Program Expert Panel on Detection Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final report. Circulation. 2002;106(25):3143-3421.
  44. Stone NJ, Robinson JG, Lichtenstein AH, et al. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation. 2014;129(25 suppl 2):S1-S45.
  45. Joseph JJ, Deedwania P, Acharya T, et al. Comprehensive management of cardiovascular risk factors for adults with type 2 diabetes: a scientific statement from the American Heart Association. Circulation. 2022;145(9):e722-e759.
  46. Jellinger PS, Handelsman Y, Rosenblit PD, et al. American Association of Clinical Endocrinologists and American College of Endocrinology guidelines for management of dyslipidemia and prevention of cardiovascular disease-executive summary. Endocr Pract. 2017;23(4):479-497.
  47. Cheeley MK, Saseen JJ, Agarwala A, et al. NLA scientific statement on statin intolerance: a new definition and key considerations for ASCVD risk reduction in the statin intolerant patient. J Clin Lipidol. 2022;16(4):361-375.
  48. Nanna MG, Wang TY, Xiang Q, et al. Sex differences in the use of statins in community practice. Circ Cardiovasc Qual Outcomes. 2019;12(8):e005562.
  49. Karalis DG, Wild RA, Maki KC, et al. Gender differences in side effects and attitudes regarding statin use in the Understanding Statin Use in America and Gaps in Patient Education (USAGE) study. J Clin Lipidol. 2016;10(4):833-841.
  50. Ridker PM, Morrow DA, Rose LM, et al. Relative efficacy of atorvastatin 80 mg and pravastatin 40 mg in achieving the dual goals of low-density lipoprotein cholesterol <70 mg/dl and C-reactive protein <2 mg/l: an analysis of the PROVE-IT TIMI-22 trial. J Am Coll Cardiol. 2005;45(10):1644-1648.
  51. de Lemos JA, Blazing MA, Wiviott SD, et al. Early intensive vs a delayed conservative simvastatin strategy in patients with acute coronary syndromes: phase Z of the A to Z trial. JAMA. 2004;292(11):1307-1316.
  52. Defesche JC, Gidding SS, Harada-Shiba M, et al. Familial hypercholesterolaemia. Nat Rev Dis Primers. 2017;3:17093.
  53. Bucholz EM, Rodday AM, Kolor K, et al. Prevalence and predictors of cholesterol screening, awareness, and statin treatment among US adults with familial hypercholesterolemia or other forms of severe dyslipidemia (1999-2014). Circulation. 2018;137(21):2218-2230.
  54. Gidding SS, Champagne MA, de Ferranti SD, et al. The agenda for familial hypercholesterolemia: a scientific statement from the American Heart Association. Circulation. 2015;132(22):2167-2192.
  55. Bellows BK, Khera AV, Zhang Y, et al. Estimated yield of screening for heterozygous familial hypercholesterolemia with and without genetic testing in US adults. J Am Heart Assoc. 2022;11(11):e025192.
  56. Knowles JW, O’Brien EC, Greendale K, et al. Reducing the burden of disease and death from familial hypercholesterolemia: a call to action. Am Heart J. 2014;168(6):807-811.
  57. Abdul-Husn NS, Manickam K, Jones LK, et al. Genetic identification of familial hypercholesterolemia within a single U.S. healthcare system. Science. 2016;354(6319):aaf7000.
  58. Goldstein JL, Brown MS. The LDL receptor. Arterioscler Thromb Vasc Biol. 2009;29(4):431-438.
  59. Goldstein JL, Hobbs HH, Brown MS. Familial hypercholesterolemia. In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds. The metabolic and molecular bases of inherited disease. 8th ed. New York: McGraw-Hill; 2001:2863-2913.
  60. Duell PB, Gidding SS, Andersen RL, et al. Longitudinal low density lipoprotein cholesterol goal achievement and cardiovascular outcomes among adult patients with familial hypercholesterolemia: the CASCADE FH registry. Atherosclerosis. 2019;289:85-93.
  61. Luirink IK, Wiegman A, Kusters DM, et al. 20-year follow-up of statins in children with familial hypercholesterolemia. N Engl J Med. 2019;381(16):1547-1556.
  62. Cannon CP, de Lemos JA, Rosenson RS, et al. Use of lipid-lowering therapies over 2 years in GOULD, a registry of patients with atherosclerotic cardiovascular disease in the US. JAMA Cardiol. 2021;6(9):1-9.
  63. Nelson AJ, Haynes K, Shambhu S, et al. High-intensity statin use among patients with atherosclerosis in the U.S. J Am Coll Cardiol. 2022;79(18):1802-1813.
  64. Kolkailah AA, Peterson ED, Gupta A, et al. Gaps in Guideline-based lipid-lowering therapy for secondary prevention in the United States: a nationwide analysis of 384,109 patients. Presented at: American College of Cardiology Scientific Sessions; April 2-4, 2022; Washington, D.C.
  65. Smith SC, Jr, Allen J, Blair SN, et al. AHA/ACC guidelines for secondary prevention for patients with coronary and other atherosclerotic vascular disease: 2006 update: endorsed by the National Heart, Lung, and Blood Institute. Circulation. 2006;113(19):2363-2372.
  66. Smith SC, Jr, Benjamin EJ, Bonow RO, et al. AHA/ACCF secondary prevention and risk reduction therapy for patients with coronary and other atherosclerotic vascular disease: 2011 update: a guideline from the American Heart Association and American College of Cardiology Foundation. Circulation. 2011;124(22):2458-2473.
  67. Reiner Z, Catapano AL, De Backer G, et al. ESC/EAS guidelines for the management of dyslipidaemias: the Task Force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS). Eur Heart J. 2011;32(14):1769-1818.
  68. Mach F, Baigent C, Catapano AL, et al. ESC/EAS guidelines for the management of dyslipidaemias: the Task Force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS). Eur Heart J. 2020;41(1):111-188.