What the NLA says the targets of CVD treatment should be

NLA guideline update 2017  link

"Targets of intervention in dyslipidemia management

Jump to SectionBackground and conceptual framework for formulation of the NLA Expert Panel recommendations  Major conclusions of the NLA Expert Panel  Importance of lifestyle therapies  Usefulness of treatment goalsScreening and classification of initial lipoprotein lipid levelsTargets of intervention in dyslipidemia management  Non–HDL-C and LDL-C  Apolipoprotein B  Triglycerides  High-density lipoprotein cholesterol  Metabolic syndrome  Secondary causes of dyslipidemiaASCVD risk assessment and treatment goals based on risk category  Additional information about the 4 risk categories    Very high risk    High risk    Moderate risk    Low riskApplication of lifestyle and drug therapies intended to reduce morbidity and mortality associated with dyslipidemia  Lifestyle therapies    Visit 1    Visit 2    Visit 3  Cholesterol-lowering drug therapies    Patient-centered approach    Thresholds for consideration of drug therapy    Initiation of drug therapy    Follow-up visits    Management of patients with hypertriglyceridemia    Statin intolerance and side effects    Combination drug therapy  Treatment of patients with severe hypercholesterolemia  Treatment of patients with progressive atherosclerosis, or recurrent events, despite evidence-based therapyUpdates to this documentAcknowledgmentsFinancial disclosuresReferences

Non–HDL-C and LDL-C

When intervention beyond public health recommendations for long-term ASCVD risk reduction is used, levels of atherogenic cholesterol (non–HDL-C and LDL-C) should be the primary targets for therapies. LDL is the major atherogenic lipoprotein carrying cholesterol in a majority of patients, and LDL-C comprises ∼75% of the cholesterol in circulation carried by lipoprotein particles other than HDL, although this percentage may be lower in those with hypertriglyceridemia. Although LDL-C has traditionally been the primary target of therapy in previous lipid guidelines and in the practice of clinical lipidology, the NLA Expert Panel's consensus view is that non–HDL-C is a better primary target for modification than LDL-C. Non–HDL-C comprises the cholesterol carried by all potentially atherogenic particles, including LDL, IDL, VLDL and VLDL remnants, chylomicron particles and chylomicron remnants, and Lp (a). Epidemiologic studies have shown that non–HDL-C is a stronger predictor of ASCVD morbidity and mortality than LDL-C.31, 34, 146, 147, 148, 149, 150, 151, 152 Pooled analyses of data from intervention studies have shown that non–HDL-C changes and levels during treatment are at least as strongly associated with risk for CHD as changes in LDL-C or on-treatment levels of LDL-C.152, 153 Moreover, when on-treatment values are discordant (ie, only 1 of the 2 is elevated), risk is more closely aligned with non–HDL-C than LDL-C (Fig. 9).153, 154

Figure 9

Risk of major cardiovascular events by low-density lipoprotein cholesterol (LDL-C) and non–high-density lipoprotein cholesterol (non-HDL-C) categories.153 Data markers indicate hazard ratios (HRs) and 95% confidence intervals (CIs) for risk of major cardiovascular events. Results are shown for 4 categories of statin-treated patients based on whether or not they reached the LDL-C target of 100 mg/dL and the non–HDL-C target of 130 mg/dL. HRs were adjusted for sex, age, smoking, diabetes, systolic blood pressure, and trial. Taken from Boekholdt SM et al.153 with permission. Copyright © (2012) American Medical Association. All rights reserved.

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Possible explanations for the superiority of non–HDL-C over LDL-C for predicting ASCVD event risk in those who are untreated and those receiving lipid-altering therapy include (1) as with LDL, some triglyceride-rich lipoprotein particles (remnants) enter the arterial wall and thus contribute to the initiation and progression of atherosclerosis; (2) non–HDL-C correlates more closely than LDL-C with apo B, thus may be a better indicator of the total burden of atherogenic particles155, 156, 157; (3) elevated levels of triglycerides and triglyceride-rich lipoprotein cholesterol indicate hepatic production of particles with greater atherogenic potential, such as those having poor interactivity with hepatic receptors, resulting in longer residence time in the circulation158; and (4) elevated levels of triglyceride-rich lipoproteins, particularly in the postprandial state, may trigger an inflammatory response by monocytes, increasing their propensity to become macrophages.159

Although both non–HDL-C and LDL-C are termed atherogenic cholesterol, non–HDL-C is listed first to emphasize its primary importance. Both non–HDL-C and LDL-C are considered targets for lipid-altering therapy, and goals for therapy have been defined for both (Table 2, Table 3). Using non–HDL-C as a target for intervention also simplifies the management of patients with high triglycerides (200–499 mg/dL). An elevated triglyceride concentration confounds the relationship between LDL-C and ASCVD risk, even in cases when the triglyceride elevation is borderline, but this appears to be less of an issue with non–HDL-C.29, 160, 161, 162 Non–HDL-C incorporates the triglyceride level indirectly because the triglyceride concentration is highly correlated with the concentration of triglyceride-rich lipoprotein cholesterol.27, 36 Non–HDL-C testing is also preferable because it is calculated as the difference between 2 stable and easily measured parameters, total-C and HDL-C, and thus is less subject to artifact than LDL-C measurement or calculation.29, 144, 148, 163, 164, 165, 166, 167 Furthermore, non–HDL-C is more accurately measured in the nonfasting state compared with LDL-C.29, 168 Goal levels of non–HDL-C may be attained by targeting either or both of the main components of non–HDL-C: LDL-C and VLDL-C. However, it should be emphasized that goal thresholds apply to both non–HDL-C and LDL-C, because discordance may occur, and effective management of atherogenic cholesterol would ideally result in achieving goal levels for both.

Table 2Treatment goals for non–HDL-C, LDL-C, and Apo B in mg/dL

Risk category	Treatment goal
	Non–HDL-C	LDL-C	Apo B∗
Low	<130 td="">	<100 td="">	<90 td="">
Moderate	<130 td="">	<100 td="">	<90 td="">
High	<130 td="">	<100 td="">	<90 td="">
Very high	<100 td="">	<70 td="">	<80 td="">

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Apo, apolipoprotein; LDL-C, low-density lipoprotein cholesterol; Non–HDL-C, non–high-density lipoprotein cholesterol.

∗Apo B is a secondary, optional target of treatment.

Table 3Criteria for ASCVD risk assessment, treatment goals for atherogenic cholesterol, and levels at which to consider drug therapy

Risk category	Criteria	Treatment goal	Consider drug therapy
		Non–HDL-C, mg/dL LDL-C, mg/dL	Non–HDL-C, mg/dL LDL-C, mg/dL
Low	• 0–1 major ASCVD risk factors • Consider other risk indicators, if known	<130 br=""> <100 td="">	≥190 ≥160
Moderate	• 2 major ASCVD risk factors • Consider quantitative risk scoring • Consider other risk indicators∗	<130 br=""> <100 td="">	≥160 ≥130
High	• ≥3 major ASCVD risk factors • Diabetes mellitus (type 1 or 2)† ○ 0–1 other major ASCVD risk factors and ○ No evidence of end-organ damage • Chronic kidney disease stage 3B or 4‡ • LDL-C of ≥190 mg/dL (severe hypercholesterolemia)§ • Quantitative risk score reaching the high-risk threshold|||	<130 br=""> <100 td="">	≥130 ≥100
Very high	• ASCVD • Diabetes mellitus (type 1 or 2) ○ ≥2 other major ASCVD risk factors or ○ Evidence of end-organ damage¶	<100 br=""> <70 td="">	≥100 ≥70
For patients with ASCVD or diabetes mellitus, consideration should be given to use of moderate or high-intensity statin therapy, irrespective of baseline atherogenic cholesterol levels.

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ASCVD, atherosclerotic cardiovascular disease; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol.

∗For those at moderate risk, additional testing may be considered for some patients to assist with decisions about risk stratification. See Table 4, Table 11 and text for additional details.

†For patients with diabetes plus 1 major ASCVD risk factor, treating to a non–HDL-C goal of <100 a="" considered="" div="" dl="" is="" mg="" nbsp="" of="" option.="" therapeutic="">

‡For patients with chronic kidney disease (CKD) stage 3B (estimated glomerular filtration rate [eGFR], 30–44 mL/min/1.73 m2) or stage 4 (eGFR, 15–29 mL/min/1.73 m2) risk calculators should not be used because they may underestimate risk. Stage 5 CKD (or on hemodialysis) is a very high-risk condition, but results from randomized, controlled trials of lipid-altering therapies have not provided convincing evidence of reduced ASCVD events in such patients. Therefore, no treatment goals for lipid therapy have been defined for stage 5 CKD.

§If LDL-C is ≥190 mg/dL, consider severe hypercholesterolemia phenotype, which includes familial hypercholesterolemia. Lifestyle intervention and pharmacotherapy are recommended for adults with the severe hypercholesterolemia phenotype. If it is not possible to attain desirable levels of atherogenic cholesterol, a reduction of at least 50% is recommended. For familial hypercholesterolemia patients with multiple or poorly controlled other major ASCVD risk factors, clinicians may consider attaining even lower levels of atherogenic cholesterol. Risk calculators should not be used in such patients.

||High-risk threshold is defined as ≥10% using Adult Treatment Panel III Framingham Risk Score for hard coronary heart disease (CHD; myocardial infarction or CHD death), ≥15% using the 2013 Pooled Cohort Equations for hard ASCVD (myocardial infarction, stroke, or death from CHD or stroke), or ≥45% using the Framingham long-term cardiovascular disease (myocardial infarction, CHD death or stroke) risk calculation. Clinicians may prefer to use other risk calculators, but should be aware that quantitative risk calculators vary in the clinical outcomes predicted (eg, CHD events, ASCVD events, cardiovascular mortality); the risk factors included in their calculation; and the timeframe for their prediction (eg, 5 years, 10 years, or long-term or lifetime). Such calculators may omit certain risk indicators that can be very important in individual patients, provide only an approximate risk estimate, and require clinical judgment for interpretation.

¶End-organ damage indicated by increased albumin-to-creatinine ratio (≥30 mg/g), CKD (eGFR, <60 m="" min="" ml="" nbsp="" span="" style="font-size: 9px; line-height: 0; position: relative; top: -0.5em; vertical-align: baseline;">2

), or retinopathy.

Desirable levels of atherogenic cholesterol for primary prevention (ie, those without clinical evidence of ASCVD or other very high-risk conditions) are <130 a="" and="" are="" class="figureLink" desirable="" dl="" for="" high="" href="https://www.lipidjournal.com/article/S1933-2874(15)00059-8/fulltext#tbl2" id="back-tbl2" ldl-c="" levels="" mg="" nbsp="" non="" patients="" risk="" style="color: #336699;" the="" very="">Table 2

, Table 3). Support for these thresholds derives primarily from observational evidence showing low ASCVD incidence rates in groups with levels in these ranges.4, 8 In several studies, the risk for CHD was shown to decrease progressively to a total-C concentration of ∼150 mg/dL, and populations with total-C below this level have low ASCVD morbidity and mortality.4, 50, 53 This corresponds to an LDL-C concentration of ∼100 mg/dL. Examination of genetic variants that result in below-average levels of atherogenic cholesterol throughout life also support an LDL-C concentration of <100 a="" and="" ascvd.="" class="bibRef" dl="" for="" level="" mg="" nbsp="" non="" of="" prevention="" span="" style="position: relative;">56, 57, 58, 68,169, 170, 171, 172 Data from RCTs show that risk for ASCVD events is reduced with a variety of atherogenic cholesterol–lowering interventions, including cholesterol-lowering drugs and dietary modification, in a pattern that is generally consistent with expectations based on observational evidence.8, 37, 83, 116, 173, 174 An examination of the pravastatin-to-simvastatin conversion lipid optimization program cohort indicated that lipid-lowering therapy which reduced LDL-C to ≤100 mg/dL was associated with a significantly lower percentage of total and CHD-related deaths (40% vs 61%) compared with patients with LDL-C of >100 mg/dL.175 The relationship between lower levels of atherogenic cholesterol with lower risk for ASCVD events has been shown to be present to LDL-C values of <55 class="bibRef" dl.="" mg="" nbsp="" span="" style="position: relative;">80, 81, 82, 83, 176, 177, 178, 179

The designation of non–HDL-C treatment targets as 30 mg/dL more than the LDL-C concentration is based on the assumption that “normal” VLDL-C concentration when triglycerides are <150 and="" are="" dl="" elevated="" is="" mg="" nbsp="" triglycerides="" typically="" vldl-c="" when="">30 mg/dL.4, 180 In observational studies, each 1 mg/dL increment in triglyceride-rich lipoprotein cholesterol is associated with an increment in ASCVD event risk at least as large as that for each 1 mg/dL increase in LDL-C.27, 31, 34, 62, 147 As further research is conducted to investigate the atherogenic properties of triglyceride-rich lipoproteins, including VLDL particles, the accepted values for typical VLDL-C and associated non–HDL-C targets may be modified.181

Jump to SectionBackground and conceptual framework for formulation of the NLA Expert Panel recommendations  Major conclusions of the NLA Expert Panel  Importance of lifestyle therapies  Usefulness of treatment goalsScreening and classification of initial lipoprotein lipid levelsTargets of intervention in dyslipidemia management  Non–HDL-C and LDL-C  Apolipoprotein B  Triglycerides  High-density lipoprotein cholesterol  Metabolic syndrome  Secondary causes of dyslipidemiaASCVD risk assessment and treatment goals based on risk category  Additional information about the 4 risk categories    Very high risk    High risk    Moderate risk    Low riskApplication of lifestyle and drug therapies intended to reduce morbidity and mortality associated with dyslipidemia  Lifestyle therapies    Visit 1    Visit 2    Visit 3  Cholesterol-lowering drug therapies    Patient-centered approach    Thresholds for consideration of drug therapy    Initiation of drug therapy    Follow-up visits    Management of patients with hypertriglyceridemia    Statin intolerance and side effects    Combination drug therapy  Treatment of patients with severe hypercholesterolemia  Treatment of patients with progressive atherosclerosis, or recurrent events, despite evidence-based therapyUpdates to this documentAcknowledgmentsFinancial disclosuresReferences

Apolipoprotein B

Apo B is considered an optional, secondary target for treatment. Epidemiologic studies have generally shown that both apo B and non–HDL-C are better predictors of ASCVD risk than LDL-C.147, 152 Because each potentially atherogenic lipoprotein particle contains a single molecule of apo B, the apo B concentration is a direct indicator of the number of circulating particles with atherogenic potential. Apo B and non–HDL-C share the advantage that neither requires fasting for accurate assessment. Non–HDL-C is favored over apo B by the NLA Expert Panel because it is universally available, requiring no additional expense compared with the standard lipid profile, and because apo B has not been consistently superior to non–HDL-C in predicting ASCVD event risk (Fig. 10).36, 153, 173

Figure 10

Hazard ratios for coronary heart disease across quintile of non–high-density lipoprotein cholesterol (non-HDL-C), apolipoprotein (apo) B, HDL-C, and apo A1.36 Analyses were based on 91,307 participants (involving 4499 cases) from 22 studies. Regression analyses were stratified, where appropriate, by sex and trial group and adjusted for age, systolic blood pressure, smoking status, history of diabetes mellitus, and body mass index; furthermore, analyses of non–HDL-C were adjusted for HDL-C and loge triglyceride, analyses of apo B were adjusted for apo AI and loge triglyceride, analyses of HDL-C were adjusted for non–HDL-C and loge triglyceride, and analysis of apo AI were adjusted for apo B and loge triglyceride. Studies with fewer than 10 cases were excluded from analysis. Sizes of data markers are proportional to the inverse of the variance of the hazard ratios. Referent groups are lowest fifths. Lines are fitted by first-degree fractional polynomial regression of log hazard ratios on mean SD score. Error bars indicate 95% confidence intervals. The y-axis is shown on a log scale. The x-axis is shown on a Z-transformed scale. Taken from Emerging Risk Factors Collaboration36 with permission. Copyright © (2009) American Medical Association. All rights reserved. SD, standard deviation.

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Cholesterol-lowering drug therapies, especially statins, alter the relationship between atherogenic cholesterol and apo B, often lowering the cholesterol concentration more than the apo B level. Apo B is a potential contributor to residual ASCVD risk because it may remain elevated in some individuals who have attained their treatment goals for non–HDL-C and LDL-C (discussed in the following section), particularly in patients with high triglycerides and low HDL-C levels.70, 161 A clinical trial assessing the ability of more aggressive lipid management to lower residual risk in patients on statin therapy, but with residual elevation in apo B (and/or LDL particle concentration), is needed. An examination of LDL-C, non–HDL-C, apo B, and LDL particle concentrations among 27,533 apparently healthy women in the Women's Health Study demonstrated reasonably high correlations between LDL-C and each of the alternate measures (non–HDL-C, apo B, and LDL particle concentration), but substantial discordance between measurements in some individuals (Fig. 11).70 For those with concordant levels of LDL-C and non–HDL-C, apo B, or LDL particle concentration, the clinical utility of these measures for estimating coronary risk was similar. However, among the subgroups of subjects with discordance of LDL-C with another atherogenic lipoprotein-related measure such as non–HDL-C, apo B, or LDL particle concentration (11%-24% depending on the measure used), ASCVD risk was either overestimated or underestimated by 20% to 50% compared with LDL-C alone. Discordance has been defined variably in research conducted to date (eg, median cut points or guideline cut points).70, 153, 182, 183, 184, 185 Additional research will be needed to further elucidate the clinical importance of discordance between measures of atherogenic lipoprotein burden.

Figure 11

Hazard ratios (HR) ad 95% confidence intervals (CIs) for an incident coronary heart disease (CHD) event among women discordant for low-density lipoprotein cholesterol (LDL-C) and alternate measures of atherogenic lipoprotein burden.70 Apo, apolipoprotein; LDL-P, low-density lipoprotein particle concentration; Non–HDL-C, non–high-density lipoprotein cholesterol.

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If apo B is used as an optional target for treatment, goals are <90 a="" although="" and="" apo="" atherogenic="" b="" been="" cholesterol="" class="figureLink" dl="" for="" generally="" goal="" has="" her="" high="" his="" href="https://www.lipidjournal.com/article/S1933-2874(15)00059-8/fulltext#tbl2" id="back-tbl2" is="" levels="" measurement="" mg="" nbsp="" necessary="" not="" of="" or="" patient="" prevention="" primary="" risk="" style="color: #336699;" the="" those="" to="" treated="" until="" very="" with="">Table 2

).186, 187, 188 The thresholds for these cut points represent the panel's consensus based on an evaluation of the available evidence and are consistent with those recommended previously by the American Diabetes Association/ACC Foundation.186 Treatment with statins and other cholesterol-lowering drug therapies appears to alter the relationship between atherogenic cholesterol and apo B concentrations.155, 189, 190, 191 In an analysis of data from the Limiting Undertreatment of Lipids in ACS with Rosuvastatin (LUNAR) trial, Ballantyne et al190 reported that during statin therapy, an apo B concentration of 90 mg/dL was associated with mean LDL-C and non–HDL-C concentrations of 85 and 105 mg/dL, respectively. The corresponding mean values associated with an apo B concentration of 80 mg/dL were 74 mg/dL for LDL-C and 92 mg/dL for non–HDL-C. As discussed previously, patients who remain above the apo B goals, despite having reached their atherogenic cholesterol goals, are discordant and may therefore have residual risk related to an elevated concentration of circulating particles with atherogenic potential.

Clinicians may consider measuring LDL particle concentration as an alternative to apo B.161, 183, 188 Apo B and LDL particle concentration have been reported to perform similarly with regard to the prediction of increased ASCVD risk.154, 188 The NLA Expert Panel acknowledges that measurement of LDL particle concentration can be useful clinically, particularly once non–HDL-C and LDL-C goals have been attained, as another potential indicator of residual risk for ASCVD. The Centers for Disease Control–National Heart, Lung, and Blood Institute has standardization programs for LDL-C, non–HDL-C, and apo B measurements. A similar standardization program for LDL particle concentration has not yet been established. Most studies of LDL particle concentration published to date have used a proprietary nuclear magnetic resonance method,183, 188 but other proprietary methodologies for LDL particle concentration quantification are also available. These various methods appear to have variable agreement in terms of LDL particle size,192, 193, 194 and their performance for predicting ASCVD risk has not been directly compared. Accordingly, the NLA Expert Panel did not recommend treatment goals for LDL particle concentration. Additional information about the clinical use of LDL particle concentration may be found in a report issued by another panel of NLA experts: Clinical Utility of Inflammatory Markers and Advanced Lipop–rotein Testing: Advice from an Expert Panel of Lipid Specialists.161

Jump to SectionBackground and conceptual framework for formulation of the NLA Expert Panel recommendations  Major conclusions of the NLA Expert Panel  Importance of lifestyle therapies  Usefulness of treatment goalsScreening and classification of initial lipoprotein lipid levelsTargets of intervention in dyslipidemia management  Non–HDL-C and LDL-C  Apolipoprotein B  Triglycerides  High-density lipoprotein cholesterol  Metabolic syndrome  Secondary causes of dyslipidemiaASCVD risk assessment and treatment goals based on risk category  Additional information about the 4 risk categories    Very high risk    High risk    Moderate risk    Low riskApplication of lifestyle and drug therapies intended to reduce morbidity and mortality associated with dyslipidemia  Lifestyle therapies    Visit 1    Visit 2    Visit 3  Cholesterol-lowering drug therapies    Patient-centered approach    Thresholds for consideration of drug therapy    Initiation of drug therapy    Follow-up visits    Management of patients with hypertriglyceridemia    Statin intolerance and side effects    Combination drug therapy  Treatment of patients with severe hypercholesterolemia  Treatment of patients with progressive atherosclerosis, or recurrent events, despite evidence-based therapyUpdates to this documentAcknowledgmentsFinancial disclosuresReferences

Triglycerides

Prospective epidemiologic studies and meta-analyses have demonstrated a positive relationship between serum triglyceride levels and incidence of ASCVD,195, 196, 197 although the mechanisms responsible for this association are not fully understood.198 Possible pathophysiological links include (1) the atherogenicity of smaller species of triglyceride-rich remnant lipoprotein particles that may enter the subendothelial space; (2) elevated triglycerides may act a marker of increased concentrations of atherogenic particles (apo B–containing, apo C3–containing, small dense LDL particles); and (3) triglycerides are associated with other metabolic disturbances (insulin resistance, inflammation, endothelial dysfunction, hypercoagulation, and lower reverse cholesterol transport).198,199, 200 An elevated triglyceride concentration is also a component of the metabolic syndrome.200 The NLA Expert Panel agreed that an elevated triglyceride level is not a target of therapy per se, except when very high (≥500 mg/dL). When triglycerides are between 200 and 499 mg/dL, the targets of therapy are non–HDL-C and LDL-C.

Fasting triglyceride levels of ≥500 mg/dL (and especially ≥1000 mg/dL) are associated with increased risk of acute pancreatitis.201 Although significant chylomicronemia generally does not occur until the fasting triglyceride level is substantially higher than 500 mg/dL (∼750 mg/dL), there is no single threshold of triglyceride concentration above which pancreatitis may occur, and it can be exacerbated by other risk factors. A threshold of ≥500 mg/dL was selected to define very high triglycerides because the triglyceride level fluctuates markedly and such individuals are at risk for developing more severe hypertriglyceridemia.

A cohort study that examined the risk for acute pancreatitis according to the degree of hypertriglyceridemia (triglycerides <150 150="" dl="" in="" mg="" nbsp="" or="">65,000 subjects found a significant dose-response relationship between triglyceride concentration and incident acute pancreatitis during 15 years of follow-up. The risk increased 4% for each 100 mg/dL increase in triglyceride level (after adjustment for covariates and removal of patients hospitalized for gallstones, chronic pancreatitis, alcohol-related comorbidities, renal failure, and other biliary diseases).202

Thus, when the triglyceride concentration is very high (≥500 mg/dL, and especially if ≥1000 mg/dL), reducing the concentration to <500 are="" becomes="" benefits="" class="bibRef" clinical="" data="" dl="" for="" goal="" limited="" mg="" nbsp="" of="" pancreatitis.="" pancreatitis="" prevent="" primary="" reducing="" risk="" span="" style="position: relative;" support="" the="" therapy.="" therapy="" there="" to="" trial="" triglyceride-lowering="">203

, 204

Jump to SectionBackground and conceptual framework for formulation of the NLA Expert Panel recommendations  Major conclusions of the NLA Expert Panel  Importance of lifestyle therapies  Usefulness of treatment goalsScreening and classification of initial lipoprotein lipid levelsTargets of intervention in dyslipidemia management  Non–HDL-C and LDL-C  Apolipoprotein B  Triglycerides  High-density lipoprotein cholesterol  Metabolic syndrome  Secondary causes of dyslipidemiaASCVD risk assessment and treatment goals based on risk category  Additional information about the 4 risk categories    Very high risk    High risk    Moderate risk    Low riskApplication of lifestyle and drug therapies intended to reduce morbidity and mortality associated with dyslipidemia  Lifestyle therapies    Visit 1    Visit 2    Visit 3  Cholesterol-lowering drug therapies    Patient-centered approach    Thresholds for consideration of drug therapy    Initiation of drug therapy    Follow-up visits    Management of patients with hypertriglyceridemia    Statin intolerance and side effects    Combination drug therapy  Treatment of patients with severe hypercholesterolemia  Treatment of patients with progressive atherosclerosis, or recurrent events, despite evidence-based therapyUpdates to this documentAcknowledgmentsFinancial disclosuresReferences

High-density lipoprotein cholesterol

Epidemiologic evidence suggests that HDL-C is inversely associated with ASCVD,64, 205, 206 and the level of HDL-C is widely accepted as an important risk indicator and used in risk factor counting and quantitative ASCVD risk assessment.4, 5, 207 Low HDL-C is also a component of the metabolic syndrome. HDL particles have several properties that are expected to provide protection against ASCVD including reverse cholesterol transport, antioxidation, endothelial protection, antiplatelet activity, and anticoagulation,208, 209 but a direct mechanistic relationship between low HDL and ASCVD is not fully understood. It has been suggested that low HDL-C levels may simply be a reflection of the presence of other atherogenic factors, such as hypertriglyceridemia, particularly the degree of postprandial hypertriglyceridemia.210, 211 A Mendelian randomization approach to examine the potential causality of the relationship between HDL-C level and reduced risk for myocardial infarction in case-control and prospective cohort studies found that single nucleotide polymorphisms that increase plasma HDL-C concentration in isolation (ie, without altering triglycerides or LDL-C) were not associated with reduced risk of myocardial infarction.212 To date, clinical trials of agents that markedly raise HDL-C, including niacin and cholesteryl ester transfer protein inhibitors, have failed to demonstrate that they reduce all cause mortality, CHD mortality, myocardial infarction, or stroke in statin-treated patients.210, 213,214, 215, 216, 217

The NLA Expert Panel did not rule out the possibility of a potential ASCVD risk-reduction benefit with raising HDL-C or promoting HDL function, but at this time, HDL-C is not recommended as a target of therapy per se. The HDL-C level is often raised as a consequence of efforts to reduce atherogenic cholesterol through lifestyle and drug therapies.

Jump to SectionBackground and conceptual framework for formulation of the NLA Expert Panel recommendations  Major conclusions of the NLA Expert Panel  Importance of lifestyle therapies  Usefulness of treatment goalsScreening and classification of initial lipoprotein lipid levelsTargets of intervention in dyslipidemia management  Non–HDL-C and LDL-C  Apolipoprotein B  Triglycerides  High-density lipoprotein cholesterol  Metabolic syndrome  Secondary causes of dyslipidemiaASCVD risk assessment and treatment goals based on risk category  Additional information about the 4 risk categories    Very high risk    High risk    Moderate risk    Low riskApplication of lifestyle and drug therapies intended to reduce morbidity and mortality associated with dyslipidemia  Lifestyle therapies    Visit 1    Visit 2    Visit 3  Cholesterol-lowering drug therapies    Patient-centered approach    Thresholds for consideration of drug therapy    Initiation of drug therapy    Follow-up visits    Management of patients with hypertriglyceridemia    Statin intolerance and side effects    Combination drug therapy  Treatment of patients with severe hypercholesterolemia  Treatment of patients with progressive atherosclerosis, or recurrent events, despite evidence-based therapyUpdates to this documentAcknowledgmentsFinancial disclosuresReferences

Metabolic syndrome

Metabolic syndrome is recognized as a multiplex risk factor for both ASCVD and type 2 diabetes mellitus (Table 4).200 Available evidence from meta-analyses suggests that metabolic syndrome is independently associated with ASCVD risk, essentially doubling the risk.218, 219, 220, 221 The increased ASCVD risk with metabolic syndrome is generally considered to be above and beyond that associated with traditional ASCVD risk factors; the predictive value of metabolic syndrome for type 2 diabetes mellitus risk, although substantial, is less than that shown for diabetes-specific risk equations.200, 222, 223, 224 Increased adiposity and insulin resistance appear to be central pathophysiological features of this cluster of interrelated metabolic and hemodynamic disturbances including elevations in blood pressure, triglycerides and glucose, as well as depressed HDL-C. The metabolic syndrome also likely reflects ASCVD risk secondary to indicators that are often not measured clinically including increased oxidation, inflammation, endothelial dysfunction, and thrombogenicity. Some of the NLA Expert Panel members were in favor of recommending that a diagnosis of metabolic syndrome be considered for reclassification of an individual into a higher risk category (ie, for risk refinement as described later in this document). However, because of the overlap between certain ASCVD risk factors and metabolic syndrome criteria (eg, HDL-C and triglycerides), the panel as a whole did not agree that the metabolic syndrome should be labeled a high risk condition at this time. The main value of identifying the presence of the metabolic syndrome is to recognize individuals with a high potential to benefit from lifestyle therapies, particularly weight loss if overweight or obese and increased physical activity. Successful lifestyle intervention will reduce adiposity and insulin resistance, improving multiple physiological disturbances that may contribute to risk, including the metabolic syndrome components as well as indicators of inflammation, oxidation, and thrombogenicity.2, 4, 134,225, 226, 227, 228

Table 4Criteria for clinical identification of the metabolic syndrome (any 3 or more of the listed components)200

Measure	Categorical cut points
1. Elevated waist circumference∗	≥40 inches (≥102 cm) in men ≥35 inches (≥88 cm) in women
2. Elevated triglycerides (drug treatment with a triglyceride-lowering agent is an alternate indicator†)	≥150 mg/dL
3. Reduced HDL-C	<40 br="" dl="" in="" men="" mg="" nbsp=""> <50 dl="" in="" mg="" nbsp="" td="" women="">
4. Elevated blood pressure (antihypertensive drug treatment in a patient with a history of hypertension is an alternate indicator)	Systolic ≥130 mm Hg and/or diastolic ≥85 mm Hg
5. Elevated fasting glucose (drug treatment of elevated glucose is an alternate indicator‡)	≥100 mg/dL

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HDL-C, high-density lipoprotein cholesterol.

∗American Heart Association/National Heart, Lung and Blood Institute guidelines for metabolic syndrome suggest waist circumference thresholds of ≥37 inches (≥94 cm) in men and ≥32 inches (≥80 cm) in women as optional cut points for individuals or populations with increased insulin resistance, including those of Asian descent (alternate values have also been published for other groups).8

†The most commonly used drugs for elevated triglycerides are fibric acids, nicotinic acid, and high-dose long-chain omega-3 fatty acids. A patient taking any of these drugs may be presumed to have elevated triglycerides.

‡Most patients with type 2 diabetes mellitus will have the metabolic syndrome by these criteria.

Waist circumference thresholds are presented in the list of metabolic syndrome components in Table 4 because waist is generally considered to be a better indicator of abdominal obesity than body mass index (BMI).229, 230,231 However, members of the NLA Expert Panel recognized that waist is not always measured in clinical practice, whereas weight and height data for the calculation of BMI are usually available. Thus, although not the preferred indicator, BMI may be used as an alternative to waist circumference when the latter is not available.232, 233, 234Using National Health and Nutrition Examination Survey data, the cut points for BMI that produced the same population prevalence rates as the waist criteria were 25.0 kg/m2 for women and 29.0 kg/m2 in men.232, 233Lower cut points of 23.0 and 27.0 kg/m2 for women and men, respectively, may be considered for individuals or populations with increased insulin resistance, including those of East Asian, South Asian, or Native American descent.8, 200, 235, 236