CVD is a leading cause of morbidity with the prevalence projected to increase1

CVD represents one of the leading causes of morbidity worldwide with heart disease, stroke and hypertension ranking among the top causes of functional morbidity in the US.1 Many patients with established CVD remain at risk for subsequent ischemic events.2

Risk for a recurrent CV event in patients with history of MI or stroke ~1 in 3.2

Hyperlipidemia and accumulating number of other risk factors increase the risk for CV events16,19,20

Effective management of CVD requires individualized risk assessment and personalized treatment as recommended by current guidelines. Age, hyperlipidemia, a previous history of major CV events including recent acute coronary syndrome (ACS), history of MI, ischemic stroke, and symptomatic peripheral arterial disease, or other high-risk conditions such as diabetes, hypertension, chronic kidney disease, heterozygous familial hypercholesterolemia (HeFH), history of congestive heart failure (HF), history of prior coronary artery bypass surgery or percutaneous coronary intervention (PCI) outside of the major CVD events and smoking represent major risk factors for the development of CVD with the risk increasing with rising number of risk factors and advancing age.16,19,20,23 LDL-C levels are one of the strongest modifiable risk factors independently associated with the development of atherosclerosis, even in patients with optimal risk profiles (defined as having blood pressure < 120/80 mmHg, fasting glucose < 100 mg/dl, glycosylated hemoglobin <5.7%, and total cholesterol (<200 mg/dL).23 Optimal reduction of LDL-C and associated CV risk requires assessment of the patient’s absolute risk and evaluation to exclude secondary causes of hyperlipidemia.29

LDL-C levels are one of the strongest modifiable risk factors independently associated with the development of CVD. CVD risk increases with rising number of risk factors and advancing age.16,20,23

Risk of recurrent events

Patients with a history of prior ischemic events are at higher risk of experiencing subsequent CV events especially within the first year of the index event.2

Even patients who are event-free in the year following the index event remain at significant risk for future events, with event rates after MI increasing even years after the index event.30,31,32,33

A prior history of CV events is one of the strongest predictors of future ischemic events2

Figure 4: Recurrent CV event rates are highest in patients with prior event occurring within 1 year2

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Data from the REACH registry showed that high-risk patients such as those with a recent history of MI experienced significantly higher rates of recurrent CV events compared to patients with stable atherosclerosis and no prior ischemic events.2

Figure 5: Event rates increase even years after the first event32

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Peripheral Arterial Disease (PAD)

PAD is a clinical manifestation of atherosclerosis affecting the lower limbs.34 While intermittent claudication—exertional calf pain that resolves with rest—has traditionally been considered the hallmark symptom of PAD, an estimated 50% of patients present with a variety of leg symptoms different from classic claudication that complicate diagnosis.1,35 As a result, PAD is largely underdiagnosed in primary care.36 The resting ankle-brachial index (ABI) represents the most commonly used screening tool for the detection and diagnosis of PAD.37

PAD is a marker of systemic atherosclerosis.37 A large imaging study (1,779) showed that subclinical atherosclerosis occurs even in the absence of conventional CV risk factors in nearly half (49.7%) of patients between 40 and 54 years of age.23 A low ABI (<0.9) is associated with increased risk of acute limb ischemia, major amputation, and increased risk for major CV events.37,38,39

PAD affects an estimated 8.5 million Americans who are 40 years of age or older.1 However, the true PAD prevalence cannot be estimated due to the lack of studies using standardized diagnostic tests and the high number of underdiagnosed patients.34, 36

PAD is associated with significant functional impairment, such as impaired ability to perform daily activities, even in patients who do not experience lower limb symptoms.1,35

Risk in patients with established CVD and type 2 diabetes

CVD is the leading cause of morbidity among patients with type 2 diabetes (T2D), many of whom often demonstrate poorly controlled LDL-C and non-HDL-C levels, despite treatment with statins.5,40,41

Diabetes represents one of the major modifiable risk factors for the development of CVD with the incidence of both first and recurrent CV events being significantly higher in patients with diabetes compared to those without.4,19,40,42,43,44

Patients with T2D and established CVD are the least likely to reach their LDL-C goal45

Many patients with T2D do not reach their LDL-C targets despite optimized treatment with statins.5,40 Large epidemiological studies have shown that 42–66% of patients with T2D do not meet the predefined LDL-C threshold of 70mg/dL despite treatment.5,41 Patients with T2D and clinical CVD are the least likely to reach their LDL-C goals.45

Many high-risk patients do not achieve the recommended LDL-C thresholds, where additional therapy is indicated5,45

Numerous clinical and epidemiological studies have consistently shown that the majority of patients at high risk for CV events do not achieve the recommended LDL-C goals. Reports from several studies document persistently low rates of LDL-C goal attainment (an average of 82% of patients not achieving levels <70 mg/dL) among patients with established CVD.45

In the U.S. alone, between 71% and 99% of 1,677 adults representing 62.6 million patients eligible for statin therapy were not at LDL-C goal (as defined by the National Lipid Association). Among patients with established CVD an estimated 79.7% did not achieve the recommended LDL-C <70 mg/dL despite treatment with lipid lowering therapy.5

Figure 6: Many adults with established CVD in the U.S.* are not achieving prespecifed LDL-C levels, despite treatments5

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Many patients with established CVD remain at significant risk for future events despite achieving recommended LDL-C goals6

Studies show despite optimal treatment with lipid-lowering agents including statins, niacin and fibrates, significant residual CV risk remains regardless of dose and treatment setting.6

Landmark statin trials demonstrated that while further reductions in LDL-C, following high intensity lipid lowering treatment, are associated with additional reductions in CV risk in patients with established CVD, even those achieving LDL-C levels 62–81 mg/dL remain at risk for future events (Figure 8).6,24,46,47,48

Figure 7: In clinical studies, residual CV risk remains despite treatment for

Figure 7 Figure 7

Figure 8: Residual CV risk remains even in those receiving treatment with high-intensity statins46,47,48

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Lowest achieved LDL-C levels translate into lower risk for major CV events with the benefit accumulating with every subsequent year of treatment49

Meta-analyses of studies evaluating the effects of lipid-lowering treatments on CV outcomes, including the Cholesterol Treatment Trialists Collaboration analyses have shown that:

1. More intensive LDL-C lowering is associated with further reductions in CV event rates and that these reductions are safe and beneficial even for individuals with low baseline LDL levels (70 mg/dL).24

2. The percentage CV risk reduction per 39 mg/dL LDL-C reduction is independent of baseline LDL-C levels and dependent on the absolute reduction in LDL-C24,26,49

3. The clinical benefits of LDL-C lowering on CV risk reduction extend to patients with very low baseline LDL-C levels and are greatest in those with the lowest achieved LDL-C levels24,49

4. The beneficial effect of LDL-C lowering on CV risk reduction increases with time with maximum risk reduction occurring with over 4 years of treatment24,26

The lack of a documented lower threshold at which LDL lowering is no longer beneficial, as suggested by epidemiological, genetic and clinical studies, has led to the hypothesis that intensive LDL-C lowering, beyond recommended thresholds could provide additional benefits, especially for very high-risk patients.24,25

Figure 9: Very low achieved LDL-C levels (<50 mg/dL) are associated with further reductions in risk for major CV events49

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Updated guidelines recognize that lower is better

Recognizing the need for further LDL-C reductions in very high-risk patients, lipid-lowering trials have achieved lower LDL-C levels over time (Figure 10) resulting in further reductions in CV risk and guideline recommendations for more intensive LDL-C lowering in patients with established CVD.19, 20,50

The importance of achieving further LDL-C reductions to minimize the risk for recurrent events in secondary prevention patients is reflected in the updated, widely endorsed ACC/AHA 2018 clinical practice guidelines on the management of blood cholesterol. The updated guidelines recognize that lower is better, and that an LDL-C of 70 mg/dL or higher, in very-high risk patients, is a threshold for additional, more aggressive therapy (Figure 12).20

Figure 10: Over time lipid-lowering trials have achieved lower LDL-C levels50

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Figure 11: AACE: Risk Categories and LDL-C Target Treatment Levels for Secondary Prevention19

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Figure 12: 2018 AHA/ACC Guideline Overview of Cholesterol Management: LDL-C > 70 mg/dL is a threshold to intensify lipid-lowering therapy in very high-risk ASCVD20

Figure 12 Open