Dyslipidemia is one of the major risk factors for the development of cardiovascular disease (CVD). However, which lipoproteins to measure and what cut-off points to use in order to accurately assess this risk remains debatable.

by Mohamed S. Elgendy and Dr Mohamed B. Elshazly

Cardiovascular disease (CVD) mortality in the US in 2011 was estimated at 786 641 deaths representing approximately 33% of total annual deaths [1]. It remains the leading cause of mortality and morbidity in the developed world. Over many years of study, dyslipidemia has been identified as one of the major risk factors for developing CVD that can be modified through behavioral modifications as well as medications.

Lipoproteins
Lipoproteins are small particles formed of lipids and proteins, which play an important role in the transport and metabolism of cholesterol. Based on their relative density, they are divided into five major categories: high-density lipoprotein (HDL), low-density lipoprotein (LDL), intermediate density lipoprotein (IDL), very low-density lipoprotein (VLDL), and chylomicrons. LDL carries 60–70% of total serum cholesterol, HDL carries 20–30%, and VLDL carries 10–15% [2]. The remaining lipoproteins, namely triglyceride-rich lipoproteins such as VLDL, remnants and IDL, in addition to lipoprotein(a), carry a relatively small fraction of total cholesterol. Numerous studies have shown that LDL is the most atherogenic lipoprotein particle and lowering its levels has been the cornerstone of dyslipidemia management and CVD risk reduction in recent years. However, there is emerging evidence indicating that other lipoproteins also play a significant role in the process atherogenesis [23].

Relationship between lipoproteins and CVD risk
Several studies have reported a continuous relationship between LDL reduction and CVD risk reduction [3]. No threshold was identified below which a lower LDL concentration is not associated with lower risk [4]. For example, in the recent IMPROVE-IT trial, the incidence of CVD morbidity and mortality was lower in the ezetimibe/simvastatin group (with a median LDL-C follow-up of 53.7 mg/dL) compared to the simvastatin-alone group (with a median LDL-C follow-up of 69.5 mg/dL) [5]. In another study, individuals with hypobetalipoproteinemia, who have LDL-C levels less than 70 mg/dL, show prolonged longevity and very minimal rates of myocardial infarctions [6]. All of this supports the notion of ‘lower is better’.

LDL-C levels in the range of 25–60 mg/dL are considered physiologically adequate [7]. Even levels below 25 mg/dL have failed to show any adverse effects in a couple of recent trials [8, 9]. Although adverse effects of very low LDL, like hemorrhagic stroke and neurocognitive deficits, have been reported in some studies, they were neither significant nor consistent [10, 11]. Therefore, the benefits of achieving very low levels of LDL outweigh the risks. On the one hand, the lack of randomized clinical trials comparing the outcome of different LDL goals has made it difficult to reach a consensus among different guidelines on the optimal goals for high-risk patients or those with coronary disease equivalents with the commonly used target still being <70 mg/dL [12–14]. On the other hand, in the most recent American College of Cardiology (ACC)/American Heart Association (AHA) guidelines, targets were abandoned because of the notion that the benefit of statin is independent of LDL level [15]. Despite these differences, we believe that the conglomerate of evidence suggests that your LDL can never be too low although data examining patients with extremely low levels <25 mg/dL is still limited. The potential re-establishment of new even lower LDL targets in upcoming guidelines will require careful examination of data from proprotein convertase subtilisin kexin-9 (PCSK-9) trials to identify specific LDL levels below which risk outweighs benefit. Other factors contribute to total atherogenic risk
Despite the established recognition of LDL as the most atherogenic lipoprotein, it is not representative of total atherogenic risk. Elevated triglycerides were found to be associated with increased risk for CVD and this suggests that triglyceride-rich lipoproteins (TGRLs), especially the remnants, are atherogenic. These lipoproteins include VLDL, IDL, and chylomicrons (only in the non-fasting state). As LDL standard measurement by the Friedewald formula [Total cholesterol – HDL – triglycerides/5] [1] only includes LDL-C and lipoprotein(a), non-HDL has been proposed as a more inclusive parameter of atherogenic risk because it also incorporates VLDL-C, IDL-C and remnants in addition to LDL-C. In fact, several studies have demonstrated that non-HDL-C is more strongly associated with CVD than LDL-C and is a more powerful risk predictor [16–21]. Moreover, non-HDL measurement comes at no extra cost, as it is calculated from the standard lipid profile by subtracting HDL from total cholesterol, and does not require prior fasting. Nevertheless, due to the smaller number of studies examining non-HDL as a target of therapy, compared to that examining LDL, most of the current guidelines recommend non-HDL as a secondary target of therapy [2, 12, 14, 22]. Only the National Lipid Association recommends non-HDL as a primary target of therapy as well as LDL [22]. We believe this current situation represents a transitional phase toward using non-HDL as a primary target of therapy, just like the past transition from total cholesterol to LDL-C. This is most important when discordance exists between LDL and non-HDL levels within individuals, a relatively common finding particularly in patients with low LDL and high triglyceride levels [23]. The currently recommended non-HDL treatment goal is 30 mg/dL higher than that of LDL-C based on the rationale that ‘normal’ VLDL exists when triglycerides level is <150 mg/dL, which is <30 mg/dL [2]. However, in a recent study of 1.3 million US adults, non-HDL level of 93 mg/dL was percentile equivalent to LDL of 70 mg/dL [23] suggesting that a lower non-HDL goal should be targeted. Particle-based measures such as apolipoprotein-B (Apo-B) and LDL particle concentration (LDL-P) also have the potential to replace cholesterol-based measures such as LDL or non-HDL as predictors of risk and targets of therapy. Apo-B constitutes the protein component of almost all the known atherogenic lipoproteins: VLDL, IDL, and LDL,;therefore, Apo-B measurement has been suggested to better estimate particle concentration, a more accurate reflection of subendothelial atherogenesis. Apo-B has been shown to be a better risk marker than LDL in multiple studies [17, 21, 24–29]. Many guidelines currently recommend Apo-B as an optional risk marker and target of therapy [12, 14, 22, 30]. Similarly, almost all the studies comparing LDL-P to LDL-C have shown superiority of particle concentration in terms of CVD risk assessment [31–34]. In the LUNAR trial and Framingham Offspring Study, there was a strong correlation between Apo-B and LDL-P with non-HDL, respectively, suggesting that non-HDL, available from the standard lipid profile, can be used satisfactorily for risk assessment [31, 35] keeping in mind that Apo-B may be superior in instances when discordance exists [36]. Whereas individual lipid parameters are important in risk prediction, summary estimates that assess the ratio of pro-atherogenic to anti-atherogenic lipoproteins also add important prognostic information regarding CVD risk. Out of the ratios that have been considered, total cholesterol to HDL cholesterol ratio (TC/HDL) and Apo-B/A1 are the most propitious. Despite TC/HDLs strong association with CVD risk [37–43], some have argued against any additional benefit this ratio might have, given that its two variables are included in estimating LDL by the Friedewald formula, in calculating non-HDL-C and in CVD risk estimation scores in addition to the contentiousness of HDL raising therapeutic strategies. However, in a recent 1.3 million population study, it has been documented that there is significant TC/HDL patient-level discordance in relation to LDL and non-HDL [44, 45]. This implies that TC/HDL may carry additional information reflecting atherogenic particle size and concentration [44, 45]. Notably, a TC/HDL ratio of 2.6 was percentile equivalent to an LDL level of 70 mg/dL (Table 1). Outcome data examining the clinical impact of TC/HDL discordance is still in progress and thus current guidelines do not currently recommend using TC/HDL. Summary
There is no doubt that the field of dyslipidemia management has been one of the most dynamic fields in cardiology over the last 3 decades. With the recent advent of PCSK-9 inhibitors, we need to re-evaluate our understanding of lipoprotein reduction and ask ourselves important questions: Should guidelines re-establish treatment targets? What is the best lipoprotein parameter for predicting risk? Is it one parameter that is superior or is it the input of multiple parameters? What do we do when discordance between lipid parameters within individuals exists? Although a lot of data necessary to answer these questions is still a work in progress, recent data may be able to provide some insightful answers. First, LDL-C is not the optimal marker for total atherogenic risk. Second, instead of evaluating the performance of individual lipid parameters at a population level, we should evaluate their performance at an individual level where identifying discordance within individuals is key to understanding which marker may be superior. Third, particle-based measures such as Apo-B and LDL-P may be superior to cholesterol-based measures; however, summary estimates such as TC/HDL or Apo-B/A1 ratios also add significant information to individual parameters. Fourth, identifying new lipoprotein treatment goals is dependent on identifying certain lipoprotein levels below which risk may outweigh benefit. Therefore, it seems likely that a future where very low percentile-equivalent cut-off points of several lipoprotein parameters and ratios may be set as simultaneous goals for treatment.

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The authors
Mohamed S. Elgendy¹ and Mohamed B. Elshazly*² MD
¹Kasr Al Ainy School of Medicine, Cairo University, Cairo, Egypt
²Cleveland Clinic, Heart and Vascular Institute, Cleveland, OH 44195, USA

*Corresponding author
E-mail: elshazm@ccf.org

Cardiovascular disease (CVD) carries considerable morbidity and mortality and poses a large economic cost on societies. Screening for CVD in order to identify high-risk individuals who may then be treated has been shown to be an effective way of alleviating the associated burden of disease. Numerous risk factors have been identified, of which lipids are a major modifiable factor.

by Dr Ravinder Sodi, Jarlath Eastwood, Dr Ian M. Godber

Cardiovascular disease (CVD), which manifests as coronary artery disease, peripheral vascular disease and cerebrovascular disease, accounts for approximately one-third of deaths worldwide [1], with three-quarters of them occurring in middle- and low-income countries [2]. The assessment of risk factors helps to determine those who are at high risk for CVD, which may then lead to lifestyle and dietary modifications as well as the use of medications in an attempt to mitigate the risk of associated mortality and morbidity. The primary aim of lipid measurements in the clinical setting is to aid in cardiovascular disease risk estimation. In the United Kingdom (UK), the National Institute for Health and Care Excellence (NICE) has issued guidance on the cardiovascular risk assessment and the modification of blood lipids to prevent CVD [3].

Clinical indications for screening
The clinical indication for screening is to identify high-risk individuals for the primary (first event) prevention of CVD. The most recent NICE guidance [3] recommends screening all individuals aged 40–74 years and/or with type 2 diabetes mellitus (DM) using the QRISK2 screening tool [3]. If the 10-year risk is ≥20%, a full, formal risk assessment should be undertaken; otherwise reviewing on an ongoing basis is suggested. The guidelines state ‘offer atorvastatin 20 mg for the primary prevention of cardiovascular disease (CVD) to people who  have a 10% or greater 10-year risk of developing CVD’ [3]. This recommendation has not yet been widely adopted and has been critiqued as it would mean that a considerable proportion of the general population would require lipid-lowering therapy [4]. If the 10-year risk is ≥20%, lifestyle changes as well as lipid-lowering medications should be considered. The use of clinical judgement and pragmatism is advised. The QRISK2 is not applicable in those ≥85 years; with type 1 DM; an estimated glomerular filtration rate (eGFR) <60 mL/min/1.73m², albuminuria or both; pre-existing CVD; and, family history of dyslipidemia. These patients are already at high risk and as such screening is of no further benefit. It is important to bear in mind that CVD risk may be underestimated in people treated for HIV, those with serious mental health issues, medications causing dyslipidemias, systemic inflammatory disorders, those on anti-hypertensives or lipid-lowering drugs, those who are severely obese (body mass index, BMI >40 kg/m²) and those who have recently stopped smoking. In general, for both primary and secondary prevention of CVD, the cardio-protective diet, physical activity, weight management, reduced alcohol consumption and smoking cessation are recommended together with lipid modification therapy, as applicable.

Risk factors for cardiovascular disease
There are numerous modifiable, partly modifiable and unmodifiable risk factors for CVD as shown in Table 1 [5]. The major modifiable risk factors for CVD are cigarette smoking, hypertension, dyslipidemia and depending on the presence of chronic complications of hyperglycemia, DM may be a partly modifiable factor. CVD risk increases with age and is higher in males than females, with the exception of postmenopausal women who smoke [6]. CVD is more common in those with a family history of the same and appears to be more common in Indians compared to Caucasians [1, 7]. Partly modifiable risk factors may be difficult to modulate as these may be beyond the control of both patient and clinician.

Lipid variables and cardiovascular disease risk
An elevated plasma concentration of low-density lipoprotein (LDL)-cholesterol has been shown to be a strong independent predictor of CVD [8]. Lipid-lowering guidelines have recommended LDL-cholesterol as the main target of treatment with lipid-lowering drugs. Astonishingly, the Friedewald formula (Table 2) used to determine the LDL-cholesterol in most clinical laboratories [9] has never been validated for use in patients treated with lipid-lowering medications. This information is not always available to laboratories when reporting lipid results. Moreover, this formula is only valid in individuals with triglycerides <4.5 mmol/L, necessitating an overnight fast before its determination and is inaccurate in those with low LDL-concentrations. As there are three variables required to determine LDL-cholesterol using the Friedewald formula, it is subject to three sources of inherent bias and imprecision. It also assumes that the cholesterol content of the very-low density lipoprotein (VLDL)-cholesterol is constant and does not account for other atherogenic lipoproteins and, therefore, is not valid in those with familial dysbetalipoproteinemia (type III hyperlipoproteinemia, broad-beta disease or remnant removal disease) where the LDL-cholesterol is overestimated [10]. Finally, it must be pointed out that the recommended QRISK2 tool does not require LDL-cholesterol as a variable to determine CVD risk but requires total-cholesterol and high-density lipoprotein (HDL)-cholesterol as separate variables [11]. HDL-cholesterol is a powerful independent cardiovascular risk factor with an inverse relationship with atherosclerotic disease (with risk rising sharply when levels are <1.04 mmol/L) [12]. However, Total-cholesterol/HDL-cholesterol ratio has been shown to be a better measure of CVD risk than individual components [13]. Total-cholesterol and high-density lipoprotein (HDL)-cholesterol are included in the QRISK2 tool as separate entities in determining CVD risk [3, 11]. Non-HDL-cholesterol (Table 2) has long been known to be a better predictor of CVD risk than LDL-cholesterol, but is as good as apolipoprotein-B [14]. It is known that many patients who achieve their LDL-cholesterol targets still develop CVD due in part to the residual risk not identified by LDL-cholesterol. Non-HDL-cholesterol serves as an index of all atherogenic, apolipoprotein-B containing lipoproteins: LDL, VLDL, intermediate-density-lipoprotein (IDL), lipoprotein(a). Most important, from a pragmatic stance, it does not require patients to be fasted overnight and can be used in those with high triglycerides. In addition, the recent NICE guidelines endorse the use of non-HDL-cholesterol recommending specialist referral if it is >7.5 mmol/L. Non-HDL cholesterol is particularly of importance in DM, where LDL-cholesterol may not be raised but the risk of CVD is considerable. Moreover, it has been shown that in DM, non-HDL cholesterol is a stronger predictor of mortality from CVD than LDL-cholesterol [15]. The prediction of CVD in those on lipid-lowering therapy remains an important goal and non-HDL-cholesterol may help address this. One disadvantage of non-HDL-cholesterol is that the positive bias in HDL-cholesterol measurement seen in cases of hypertriglyceridemia may mitigate any benefits [16]. However, taken together, non-HDL cholesterol provides an accurate alternative to LDL-cholesterol and there is a compelling case to include it in the laboratory test repertoire especially given that no additional reagent is required other than a simple calculation.

Elevated triglycerides concentrations are also an independent risk factor for CVD although it is weaker than LDL-cholesterol [17]. A high triglyceride level is a component of the metabolic syndrome, which is associated with high risk of CVD. Severe hypertriglyceridemia also increases the risk of pancreatitis [18]. Secondary causes of hypertriglyceridemia include: alcohol excess, medication-related (thiazides, beta-blockers, estrogens, corticosteroids, antiretroviral protease inhibitors, immunosuppressants, antipsychotics), untreated DM, renal disease, liver disease, pregnancy and some autoimmune disorders [18].

Apolipoproteins-B, -A1, low-density lipoprotein particle number and size have all been advocated as markers of CVD risk but offer no advantage over routine lipid parameters discussed above, are expensive requiring additional reagents but may be useful in identifying patients with dysbetalipoproteinemia [19]. At present in the UK, they are only measured in specialist laboratories.

Conclusion
Lipid testing offers a simple and cost-effective mode of determining CVD risk. Clinical laboratories should make every effort to start reporting non-HDL-cholesterol as part of their lipid profiles. It requires no additional reagent other than software configurations for calculation, obviates the need for fasting and requires no knowledge of lipid-lowering medications.

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The authors
Ravinder Sodi* ^1,2 PhD, CSci, FRCPath; Jarlath Eastwood¹ BSc, Ian M. Godber² PhD, CSci, FRCPath
¹Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, UK
²Department of Clinical Biochemistry, NHS Lanarkshire, Wishaw General
Hospital, Wishaw, UK

*Corresponding author
E-mail: ravsodi@yahoo.com