Cardiovascular disease is the underlying cause for 17.3 million deaths yearly worldwide, with 8.2 million due to ischemic heart disease and 6.5 million due to stroke.² Epidemiological data suggest that individuals with long-term exposure to even moderately elevated levels of low density lipoprotein cholesterol (LDL-C) are at increased risk of developing atherosclerotic cardiovascular disease (ASCVD) later in life.³ Furthermore, randomized controlled trials of lipid lowering agents have demonstrated that reduction in the risk of ASCVD events is directly proportional to the absolute reduction in LDL-C levels.³

Therefore, periodic assessment of LDL-C levels is important in monitoring patients' cardiovascular health. In particular, the lipid profile is of critical importance for the assessment of overall cardiovascular risk in adults. In addition, the clinical encounter for discussion of blood cholesterol levels constitutes an important opportunity to address lifestyle habits and other interventions for ASCVD prevention, such as smoking cessation, exercise, blood pressure control, healthy diet and psychosocial stressors.

Of note, direct measurement of LDL-C levels with preparative ultracentrifugation is an expensive, impractical and not widely available method. As a result, LDL-C levels are derived indirectly from mathematical calculations. Traditionally, the Friedewald equation was used for this purpose. This formula assumes a fixed ratio between very-low density lipoproteins (VLDL) and triglycerides (TG). In reality, however, this ratio is not always the same. A recently developed formula that utilizes a variable VLDL:TG ratio has been shown to provide better accuracy for LDL-C estimation and is quickly gaining widespread acceptance.^4,5

The novel Martin/Hopkins method for LDL-C calculation is particularly more accurate in patients with low levels of LDL-C. Approximately 20% of individuals with Friedewald-estimated LDL-C <70 mg/dL have a more accurate value of ≥70 mg/dL using the novel equation.⁵ As a result, it has been adopted by several laboratories, such as our own laboratory at Johns Hopkins, and more widely by Quest diagnostics throughout their laboratories inside and outside the US, as the standard-of-care for LDL-C estimation.^4,5 Importantly, atherogenic plasma lipoproteins are mostly of hepatic origin and suffer little variation between fasting and nonfasting levels. Therefore, nonfasting levels are acceptable for better patient comfort without negative diagnostic or prognostic implications unless the triglycerides are known to be very high.⁶

Global Risk Assessment

Though LDL-C levels are of significant importance when assessing the role of lipid lowering therapies in primary prevention, the global ASCVD risk assessment also plays a critical role in that decision, at least for patients without familial hypercholesterolemia (FH). Several risk assessment tools are available in the literature and recommended by different professional cardiovascular societies worldwide. The American College of Cardiology, American Heart Association and US Preventive Services Task Force recommend the Pooled Cohort Equations (PCE);^7,8 the European Society of Cardiology recommends the Systematic Coronary Risk Evaluation (SCORE) charts;⁹ the Canadian Cardiovascular Society recommends the use of the Framingham Risk Score (FRS);¹⁰ whereas the United Kingdom National Institute for Health and Care Excellence (NICE) recommends the QRisk2 calculator.¹¹ These risk prediction models are summarized in Table 1.

Table 1: Risk Prediction Tools Recommended in European, UK and US Guidelines

	QRISK2 – UK11	PCE – US8	SCORE – Europe9	Modified FRS – Canada10
Population	1993-2001 GP databases	4 studies – ARIC, CHS, CARDIA, FHS	12 studies; 1972-1991; 11 countries, Europe	FHS and Framingham offspring study
Sample size	2.29 million	10,745 men 13,881 women	117,098 men 80,080 women	3969 men 4522 women
Outcome	10-year ASCVD, lifetime risk	10-year ASCVD, lifetime risk	10-year risk of CV mortality	10-year ASCVD
Age range (years)	35-74	20-79	40-65	30-75
Variables	Age, gender, TC/HDL, SBP/HTN, smoking, DM, zip code, FH, BMI, ethnicity, AF, RA	Age, sex, race, TC, HDL-C, SBP/HTN, DM, smoking	Sex, age, total cholesterol, SBP, smoking	Sex, age, total cholesterol, HDL-C, SBP, smoking status, DM, SBP/HTN
Comments	-	Overestimation of risk in most external cohorts	Versions for use in high and low-risk countries	-

A primordial step in the care of all patients with elevated blood cholesterol levels is to address lifestyle changes as a critical component of ASCVD risk reduction. These patients should be counseled on adhering to a heart healthy diet, weight loss and/or maintenance of a healthy weight, routine moderate or vigorous physical activity, and smoking cessation. In addition to lifestyle improvements, some patients with elevated LDL-C but no previous clinical ASCVD events will also require lipid lowering pharmacotherapy for primary prevention.

Guidelines Around the Globe

Guidelines across the globe recommend lipid lowering treatment, for which statins are the cornerstone pharmacotherapy, for primary prevention in patients with elevated baseline cardiovascular risk. In the ACC/AHA guidelines, these would be patients aged 40-75 years old with either a 10-year estimated ASCVD risk ≥7.5% or those with diabetes and a baseline LDL-C ≥70 mg/dL, after a clinician patient risk discussion.¹⁰

In the Canadian Guidelines, patients are recommended statin therapy if they have: 1) diabetes and are >40 years of age or have microvascular complications; 2) chronic kidney disease with estimated glomerular filtration rate <60 ml/min/m²; 3) modified FRS ≥20%; or 4) modified FRS 10-19% with LDL-C ≥130 mg/dL.¹⁰

The European Guidelines advise drug treatment for LDL-C in patients at very high-risk (diabetes with organ damage, chronic kidney disease with glomerular filtration rate <30 ml/min/m², or a SCORE 10-year risk of coronary mortality ≥10%); high-risk (diabetics, chronic kidney disease with glomerular filtration rate 30-60 ml/min/m² or a SCORE 10-year risk of coronary mortality 5-10%) if LDL-C ≥70 mg/dL; and moderate-risk (SCORE 10-year risk of coronary mortality 1-5%) if LDL-C ≥100 mg/dL.⁹

Importantly, primary care practitioners and cardiovascular specialists should be well equipped to identify patients with familial dyslipidemias based on family history patterns, physical examination findings and lipid testing. Heterozygous FH has an estimated prevalence of 1:250 individuals. Different criteria are available for diagnosis, and FH should be suspected in patients with LDL-C ≥190 mg/dL and a personal or family history of premature ASCVD. In these individuals, lipid lowering therapy, typically a combination of statin and non-statin therapy, is recommended in addition to lifestyle modifications.^{1, 8-10}

Non-Statin Therapies

Randomized trials of the non-statin therapies ezetimibe and proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitors were primarily conducted in a population with a previous ASCVD clinical event (secondary prevention). Nevertheless, these therapies are recommended for selected high risk primary prevention patients who do not achieve their LDL-C goals on maximally tolerated statin therapy, particularly for patients with suspected or confirmed FH.^7,10,12 In those patients, the decision between ezetimibe and PCSK9 inhibitors should be guided by costs, route of administration, pill burden, patient preferences and degree of additional LDL-C lowering desired. Patients who require <25% additional lowering of LDL-C to get within goal levels usually do well with generic ezetimibe, whereas those who require >25% LDL-C lowering to reach target levels may eventually need PCSK9 inhibition if more extensive lifestyle improvements are not sufficient in lowering the LDL-C.

References

1. Ryan A, Heath S, Cook P. Managing dyslipidaemia for the primary prevention of cardiovascular disease. BMJ 2018;360.
2. Benjamin EJ, Blaha MJ, Chiuve SE, et al. Heart disease and stroke statistics-2017 update: a report from the American Heart Association. Circulation 2017;135:e146-603.
3. Collins R, Reith C, Emberson J, et al. Interpretation of the evidence for the efficacy and safety of statin therapy. Lancet 2016;388:2532-61.
4. Martin SS, Blaha MJ, Elshazly MB, et al. Comparison of a novel method vs the Friedewald equation for estimating low-density lipoprotein cholesterol levels from the standard lipid profile. JAMA 2013;310:2061-8.
5. Whelton SP, Meeusen JW, Donato LJ, et al. Evaluating the atherogenic burden of individuals with a Friedewald-estimated low-density lipoprotein cholesterol <79 mg/dL compared with a novel low-density lipoprotein estimation method. J Clin Lipidol 2017;11:1065-72.
6. Nordestgaard BG. A test in context: lipid profile, fasting versus nonfasting. J Am Coll Cardiol 2017;70:1637-46.
7. Lloyd-Jones DM, Morris PB, Ballantyne CM, et al. 2017 focused update of the 2016 ACC expert consensus decision pathway on the role of non-statin therapies for ldl-cholesterol lowering in the management of atherosclerotic cardiovascular disease risk: a report of the American College of Cardiology task force on expert consensus decision pathways. J Am Coll Cardiol 2017;70:1785-1822.
8. 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. J Am Coll Cardiol 2014;63:2889-934.
9. Piepoli MF, Hoes AW, Agewall S, et al. 2016 European guidelines on cardiovascular disease prevention in clinical practice: the sixth joint task force of the European Society of Cardiology and other societies on cardiovascular disease prevention in clinical practice (constituted by representatives of 10 societies and by invited experts) developed with the special contribution of the European Association for Cardiovascular Prevention & Rehabilitation (EACPR). Eur Heart J 2016;37:2315-81.
10. Anderson TJ, Gregoire J, Pearson GJ, et al. 2016 Canadian Cardiovascular Society guidelines for the management of dyslipidemia for the prevention of cardiovascular disease in the adult. Can J Cardiol 2016;32:1263-82.
11. NICE. Cardiovascular disease: risk assessment and reduction, including lipid modification. 2014. Available at https://www.nice.org.uk/guidance/cg181. Accessed April 28, 2018.
12. Landmesser U, Chapman MJ, Stock JK, et al. 2017 update of ESC/EAS task force on practical clinical guidance for proprotein convertase subtilisin/kexin type 9 in patients with atherosclerotic cardiovascular disease or in familial hypercholesterolaemia. Eur Heart J 2018;39:1131-43.

Keywords: Dyslipidemias, Primary Prevention, Cholesterol, LDL, Hyperlipoproteinemia Type II, Triglycerides, Cardiovascular Diseases, Blood Pressure, Smoking Cessation, Risk Factors, Atherosclerosis, Coronary Artery Disease, Hypolipidemic Agents, Lipoproteins, VLDL, Risk Assessment, Stroke, Ultracentrifugation

< Back to Listings