Lipid testing and cardiovascular risk assessment: cut-off points

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