Current trends in non–HDL cholesterol and LDL cholesterol levels in adults with atherosclerotic cardiovascular disease

Open AccessPublished:May 27, 2019DOI:https://doi.org/10.1016/j.jacl.2019.05.012

      Highlights

      • Trends in non–high-density lipoprotein and low-density lipoprotein levels were tracked for 17 years in subjects with atherosclerotic cardiovascular disease.
      • Non–high-density lipoprotein and low-density lipoprotein cholesterol decreased by 21% and 24%, respectively.
      • Intake of cholesterol-lowering drugs increased from 37% to 69% over 17 years.
      • New treatment strategies of patients with atherosclerotic cardiovascular disease are needed to optimize risk reduction.

      Background

      Low-density lipoprotein cholesterol (LDL-C) and non–high-density lipoprotein cholesterol (non–HDL-C) are targets for prevention of atherosclerotic cardiovascular disease (ASCVD). The American Heart Association and American College of Cardiology recently modified recommendations for clinical management of cholesterol in secondary and primary prevention. Accordingly, the present article examines the need for cholesterol-lowering drugs in the U.S. population with ASCVD.

      Objective

      This study examines trends in non–HDL-C and LDL-C levels in a free living population of ASCVD subjects between 1999 and 2016.

      Methods

      National Health and Nutrition Examination Surveys database included 4920 adults with ASCVD aged 40 to 85 years. Complete data were available for 4226. Trend analysis of changes in lipids is shown in box plots.

      Results

      Mean age was 67 years with 57% males. Over 17 years, LDL-C decreased significantly by 24% and non–HDL-C by 21%. Over the period of study, reported intake of cholesterol-lowering drugs rose from 37% in 1999-2000 to 69% in 2015 to 2016. Over this same period, serum triglycerides decreased by 29% (P < .001) and HDL-C rose by 6%.

      Conclusions

      The changes in LDL-C and non–HDL-C in patients with ASCVD over a 17-year period probably are related to increased treatment with statins. However, the changes are too small to be explained by widespread use of high-intensity statins, which is the current recommendation for patients with ASCVD. These findings pose a challenge for professional education to support implementation of current guidelines for cholesterol-lowering therapies.

      Keywords

      Introduction

      The introduction of cholesterol-lowering drugs will substantially reduce the risk for atherosclerotic cardiovascular disease (ASCVD). Most clinical trials have been carried out in patients with established ASCVD.
      • Grundy S.M.
      • Stone N.J.
      • Bailey A.L.
      • et al.
      2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA guideline on the management of blood cholesterol.
      In these patients, the greatest risk reduction with statin therapy has occurred with high-intensity statins. Moderate-intensity statins reduce low-density lipoprotein cholesterol (LDL-C) by 30% to 45%, and randomized clinical trials (RCTs) show a corresponding 25% to 35% reduction in risk. High-intensity statins lower LDL-C levels ≥ 50%, which yields a 15% to 20% greater risk reduction compared with moderate-intensity statins.
      • Grundy S.M.
      • Stone N.J.
      • Bailey A.L.
      • et al.
      2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA guideline on the management of blood cholesterol.
      This accounts for the recommendation for high-intensity statins in patients with established ASCVD. Recently, RCTs have been carried out using ezetimibe or proprotein convertase subtilsin-kexin type 9 inhibitors as add-on drugs to statin therapy in very-high-risk patients with ASCVD. Both types of drugs added to statin therapy showed incremental risk reduction.
      • Grundy S.M.
      • Stone N.J.
      • Bailey A.L.
      • et al.
      2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA guideline on the management of blood cholesterol.
      The current analysis was carried out in patients with ASCVD from the National Health and Nutrition Examination Surveys (NHANES) database. The purpose of the study was to determine trends in cholesterol levels in atherogenic lipoproteins (LDL and non–high-density lipoprotein [non-HDL]) over 17 years (1999–2001 through 2016). During this period, the benefits of increasing statin intensity that yield greater lowering of LDL-C and non–high-density lipoprotein cholesterol (non–HDL-C) have become apparent.
      • Boekholdt S.M.
      • Hovingh G.K.
      • Mora S.
      • et al.
      Very low levels of atherogenic lipoproteins and the risk for cardiovascular events: a meta-analysis of statin trials.
      Recently, thanks to RCTs with newer cholesterol-lowering drugs, there is a greater recognition that most of the benefit from statin therapy comes from reduction of atherogenic lipoproteins.

      Methods

      This is a report of a secondary analysis of data collected for the NHANES in the United States
      Centers for Disease Control and Prevention, National Health and Nutrition Examination Survey.
      . The surveys conducted biannually starting from 1999 through 2016 were analyzed. NHANES records from 4920 subjects with ASCVD were retrieved for analysis. These records included data on clinical history of ASCVD defined by history of coronary heart disease, stroke, angina, heart attack. Other data consisted of subject demography, anthropometry, and history of other risk factors for cardiovascular disease such as smoking and hypertension. Results of clinical chemistry laboratory tests, serum total cholesterol (TC), HDL-C, and triglycerides and calculated values of LDL-C and non–HDL-C, are also included. In addition, survey results of medication intake for cholesterol-lowering drugs were included in the analysis. A total of 4226 records had the information needed for the analysis.
      NHANES surveys are conducted in a population of noninstitutionalized civilians residing in the United States of America.
      Centers for Disease Control and Prevention, National Health and Nutrition Examination Survey.
      The surveys include health and socioeconomic questionnaires during a home visit followed by detailed clinical examination conducted in a mobile examination center. Detailed description of methods used for randomized sampling of the population and collection of data for the NHANES surveys are available at https://wwwn.cdc.gov/nchs/nhanes/Default.aspx.
      Laboratory procedures are also detailed under NHANES databases (https://wwwn.cdc.gov/nchs/nhanes/Default.aspx). Briefly, TC was measured calorimetrically using the peroxidase end point. HDL-C was measured by the PEG-oxidase method either in a Hitachi 717 and Hitachi 912 (Roche Diagnostics, 9115 Hague Road, Indianapolis, IN 46250) or the Roche Modular P chemistry analyzer (Roche Diagnostics; 9115, Hague Road, Indianapolis, IN, 46250). LDL-C was calculated as triglycerides/5 minus HDL-C with serum triglycerides less than 400 mg/dL
      • Friedewald W.T.
      • Levy R.I.
      • Fredrickson D.S.
      Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge.
      and by direct LDL-C for triglycerides ≥ 400 mg/dL. Non–HDL-C was calculated as the difference between TC and HDL-C. Serum triglycerides also were measured calorimetrically using an enzymatic kit.

       Statistical analysis

      Data for lipid parameters are summarized in a series of box plots depicting the 10th, 25th, 50th, 75th, and 90th percentile as a function of time. LDL-C and triglyceride data are presented from 1999 through 2014 because complete data are not available for 2015 through 2016 at the time of this analysis. In the present study, the non–HDL-C data were available for the interval of time between 1999 to 2000 and 2015 to 2016, but data for LDL-C were only available up to 2013 to 2014. Thus, tracking of trends in temporal changes in non–HDL-C was more robust than for LDL-C. Descriptive statistics was used for subject characteristics. A balanced design ANOVA adjusted for age was used to compare levels of parameters over the period of observation. The NCSS v 9.0.22 statistical software (https://www.ncss.com/software/ncss/ncss-documentation/) was used for the analyses.

      Results

      Lipid and demographic data from 4226 adults (58% males) identified as having ASCVD during the time interval of 1999 to 2016 were selected for study. ASCVD was defined by positive history of coronary heart disease, stroke, angina, or heart attack. Subject characteristics are summarized in Table 1. Most of the study population consisted of non-Hispanic whites. Age for each time interval ranged between 66 and 68.6 years. About 20% of the subjects were between 40 and 59 years old. Average BMI was in the obese range. Fifty-three percent of the subjects reported taking cholesterol-lowering medication (Table 1). The percentage of subjects reporting cholesterol medication started at 37.1% for the year 1999 to 2000 and increased to 69.2% by 2015 to 2016.
      Table 1Characteristics of study population with ASCVD per year of study
      CharacteristicMean/Proportion (SD)
      Total number of ASCVD subjects4226
      Number of subjects with ASCVD per year of study
      Average number of subjects with ASCVD per yearly survey from 1999 to 2016.
      470 (54)
      % Men per year of study57 (2)
      Age (y)67 (1)
      % Subjects in the age range 40 to 59 y20 (3)
      BMI (kg/m2)30 (1)
      ASCVD conditions (% of total per year of study)
       Heart attacks43.2 (1.6)
       Coronary heart disease41.3 (1.9)
       Stroke37.9 (3.4)
       Angina29.6 (4.5)
       % Subjects reporting intake of “cholesterol medication”
      Average percent of subjects reporting yearly intake of cholesterol-lowering or hypertension for surveys from 1999 to 2016.
      53 (12)
       % Subjects reporting hypertension
      Average percent of subjects reporting yearly intake of cholesterol-lowering or hypertension for surveys from 1999 to 2016.
      39 (4)
       % Smokers20 (4)
      Ethnic background
       % Non-Hispanic white57 (8)
       % African American20 (4)
       % Hispanic18 (5)
       % Other5 (3)
      ASCVD, atherosclerotic cardiovascular disease.
      Average number of subjects with ASCVD per yearly survey from 1999 to 2016.
      Average percent of subjects reporting yearly intake of cholesterol-lowering or hypertension for surveys from 1999 to 2016.
      The mean non–HDL-C level sampled in 1999 to 2000 was 158 ± 40 mg/dL (±SD). The mean non–HDL-C levels for the population sampled in 2015 to 2016 were 125 ± 43 mg/dL (–21%) (P < .001). Median (interquartile) levels of non–HDL-C were reduced significantly (P < .001) during the time interval of observation. The median non–HDL-C level during 1999 to 2000 was 151 mg/dL (131, 182) and fell to 119 mg/dL (93, 150) mg/dL (–21%) during last survey. Box plots for medium non–HDL-C for each yearly survey are shown in Figure 1A. Lines link the non–HDL-C levels at the 50th, 25th, and the 75th percentile levels for each year of the survey between 1999 and 2016.
      Figure thumbnail gr1
      Figure 1Box plot of non–HDL cholesterol (panel A) and LDL cholesterol (panel B) levels in subjects with ASCVD per year. The lines connect the trajectory of lipoprotein cholesterol levels at the 25th, 50th, and 75th percentile for each distribution. Significant trend for reduction is noted for non–HDL cholesterol and LDL cholesterol (P < .001). ASCVD, atherosclerotic cardiovascular disease; non–HDL-C, non–high-density lipoprotein cholesterol; LDL, low-density lipoprotein.
      The mean LDL-C level sampled in 1999 to 2000 was 124 ± 37 mg/dL (±SD) and in 2013 to 2014 was 95 ± 34 mg/dL (–23%) (P < .001). Median (interquartile) levels of LDL-C were reduced significantly (P < .001) during the time interval (116 mg/dL [99,148] vs 88 mg/dL [68,119]) (–24%) (P < .001). Box plots for medium LDL-C for each yearly survey are shown in Figure 1B.
      Modest but significant increases in levels of HDL-C (6.8%; P < .001) were noted from 1999 through 2016 (Fig. 2A). The 1999 to 2000 median levels were 44 (32, 52) mg/dL and rose significantly to 47 (39, 59) mg/dL (P < .001). Box plots for serum triglyceride levels between 1999 and 2014 are shown in Figure 2B. Median levels fell from 147 (116, 216) mg/dL to 106 (72, 159) mg/dL (−28%; P < .001).
      Figure thumbnail gr2
      Figure 2Box plots over time for levels of HDL cholesterol (panel A) and triglyceride (panel B). HDL cholesterol increased over time (P < .001) and triglyceride was also reduced over the period of analyses (P < .001). HDL, high-density lipoprotein cholesterol.

      Discussion

      The present study was carried out to compare trends of non–HDL-C and LDL-C tracked during the NHANES surveys conducted between 1999 and 2016. Non–HDL-C is given priority because it is a measure of all atherogenic lipoproteins, that is, LDL and its precursors very low density lipoprotein and intermediate density lipoprotein including remnant lipoproteins. Moreover, non–HDL-C correlates highly with total apolipoprotein B levels.
      • Ballantyne C.M.
      • Andrews T.C.
      • Hsia J.A.
      • Kramer J.H.
      • Shear C.
      Correlation of non-high-density lipoprotein cholesterol with apolipoprotein B: effect of 5 hydroxymethylglutaryl coenzyme A reductase inhibitors on non-high-density lipoprotein cholesterol levels.
      For many years, treatment guidelines have focused on LDL-C; but in fact, non–HDL-C is more strongly correlated with cardiovascular risk in patients with ASCVD treated with statins than is LDL-C.
      • Boekholdt S.M.
      • Arsenault B.J.
      • Mora S.
      • et al.
      Association of LDL cholesterol, non-HDL cholesterol, and apolipoprotein B levels with risk of cardiovascular events among patients treated with statins: a meta-analysis.
      In addition, the lipoprotein database for NHANES is more complete for non–HDL-C than for LDL-C, so for these several reasons, non–HDL-C appears to be the preferred lipid measurement when evaluating ASCVD risk.
      The data showed that over the period of observation, non–HDL-C fell by 21%. Over a somewhat shorter period of observation, average LDL-C levels fell by 24%. It is interesting to compare these results with recommendations for LDL-C management in patients with ASCVD as recommended by 2018 American Heart Association (AHA)/American College of Cardiologists (ACC)/Multisociety Cholesterol Guideline.
      • Grundy S.M.
      • Stone N.J.
      • Bailey A.L.
      • et al.
      2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA guideline on the management of blood cholesterol.
      The basic recommendation for patients with ASCVD is to use high-intensity statin therapy. This recommendation is based on available RCTs in patients with atherosclerotic disease. In patients with ASCVD, high-intensity statins reduce cardiovascular events more than do moderate-intensity statins.
      • Friedewald W.T.
      • Levy R.I.
      • Fredrickson D.S.
      Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge.
      • Ballantyne C.M.
      • Andrews T.C.
      • Hsia J.A.
      • Kramer J.H.
      • Shear C.
      Correlation of non-high-density lipoprotein cholesterol with apolipoprotein B: effect of 5 hydroxymethylglutaryl coenzyme A reductase inhibitors on non-high-density lipoprotein cholesterol levels.
      • Boekholdt S.M.
      • Arsenault B.J.
      • Mora S.
      • et al.
      Association of LDL cholesterol, non-HDL cholesterol, and apolipoprotein B levels with risk of cardiovascular events among patients treated with statins: a meta-analysis.
      • Cannon C.P.
      • Braunwald E.
      • McCabe C.H.
      • et al.
      Intensive versus moderate lipid lowering with statins after acute coronary syndromes.
      • LaRosa J.C.
      • Grundy S.M.
      • Waters D.D.
      • et al.
      Intensive lipid lowering with atorvastatin in patients with stable coronary disease.
      • Pedersen T.R.
      • Faergeman O.
      • Kastelein J.J.
      • et al.
      High-dose atorvastatin vs usual-dose simvastatin for secondary prevention after myocardial infarction: the IDEAL study: a randomized controlled trial.
      • Baigent C.
      • Blackwell L.
      • Emberson J.
      • et al.
      Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials.
      High-intensity statins typically reduce LDL-C by ≥ 50%.
      • Grundy S.M.
      • Stone N.J.
      • Bailey A.L.
      • et al.
      2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA guideline on the management of blood cholesterol.
      Current
      • Grundy S.M.
      • Stone N.J.
      • Bailey A.L.
      • et al.
      2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA guideline on the management of blood cholesterol.
      and previous
      • Stone N.J.
      • Robinson J.G.
      • Lichtenstein A.H.
      • 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.
      AHA/ACC cholesterol guidelines did not identify a specific LDL-C level as treatment target. Such a target is not warranted by available RCTs. In 2001 guidelines,
      • Grundy S.M.
      • Cleeman J.I.
      • Merz C.N.
      • et al.
      Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III Guidelines.
      an LDL-C was set as < 100 mg/dL, but the Heart Protection Study
      MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial.
      showed that initiation of statin therapy in ASCVD patients with LDL-C of 100 mg/dL gives further risk reduction. Moreover, at any level of LDL-C, a given dose of statins reduces LDL-C by a similar percentage. These considerations led the 2018 Guideline to adopt the ≥50% reduction as the LDL-C goal for secondary prevention. Corresponding reductions in non–HDL-C are 3% to 5% less, that is, 45% to 48%.
      • Ballantyne C.M.
      • Raichlen J.S.
      • Cain V.A.
      Statin therapy alters the relationship between apolipoprotein B and low-density lipoprotein cholesterol and non-high-density lipoprotein cholesterol targets in high-risk patients: the MERCURY II (Measuring Effective Reductions in Cholesterol Using Rosuvastatin) trial.
      NHANES data confirm that in the period 1999 to 2016, non–HDL-C declined significantly by approximately 21%. This value is just under half the current recommendation for reduction of 45% to 48% based on recommendation of high-intensity statin therapy. No doubt there is widespread use of statins in patients with ASCVD. In the NHANES population, reported use of cholesterol-lowering drugs rose from 37% in 1999 to 2000 to 69% in 2015 to 2016. Recently, Pokharel et al.
      • Pokharel Y.
      • Tang F.
      • Jones P.G.
      • et al.
      Adoption of the 2013 American College of Cardiology/American Heart Association Cholesterol Management Guideline in Cardiology Practices Nationwide.
      examined adoption of the 2013 ACC/AHA guideline
      • Stone N.J.
      • Robinson J.G.
      • Lichtenstein A.H.
      • 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.
      in 161 U.S. cardiology practices (the ACC Practice Innovation and Clinical Excellence Registry), which included 1,116,472 postguideline patients. The use of moderate-intensity to high-intensity statin therapy was 66.6% (after publication of the guideline). Apparently, one-third of patients received no statin therapy. Among those who were treated with statins, it is likely that the majority received moderate-intensity statin therapy. The findings of Pokharel et al.
      • Pokharel Y.
      • Tang F.
      • Jones P.G.
      • et al.
      Adoption of the 2013 American College of Cardiology/American Heart Association Cholesterol Management Guideline in Cardiology Practices Nationwide.
      thus appear consistent with the results of the present study. If 2018 guidelines represent optimal therapy for most patients with ASCVD, there is a need for greater use of statins and increased adoption of high-intensity therapy.
      Finally, along with the gradual reduction in non–HDL-C, triglyceride levels were also reduced by 28%. In the NHANES as a whole, serum triglycerides have declined 21%,
      • Carroll M.D.
      • Kit B.K.
      • Lacher D.A.
      • Shero S.T.
      • Mussolino M.E.
      Trends in lipids and lipoproteins in US adults, 1988-2010.
      whereas in the NHANES patients with ASCVD, triglycerides declined by 28%. Previous authors
      • Carroll M.D.
      • Kit B.K.
      • Lacher D.A.
      • Shero S.T.
      • Mussolino M.E.
      Trends in lipids and lipoproteins in US adults, 1988-2010.
      attributed the change in triglycerides to nutritional factors. More likely, in the cohort with ASCVD, the fall in triglycerides was likely due in part to increased statin therapy.

      Conclusion

      The trends in non–HDL-C and LDL-C lowering observed in free-living population of patients with ASCVD in the past 17 years show a significant lowering. Nonetheless, it is still a challenge to implement more intense treatment in the ASCVD population to optimize risk reduction as demonstrated in a large number of clinical trials. The 2018 Guideline
      • Grundy S.M.
      • Stone N.J.
      • Bailey A.L.
      • et al.
      2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA guideline on the management of blood cholesterol.
      reviewed in some detail various approaches. Before statin therapy is initiated, a clinician-patient discussion is needed to promote shared decision-making and to obtain patient commitment to adherence. In the clinical setting, a health care team will facilitate a multifaceted approach to integrated, multidisciplinary educational activities with pharmacist intervention. A health care system needs to be established to monitor quality of clinical care and implementation of therapy. In selected patients with ASCVD at very high risk, consideration can be given to supplementing high-intensity statin therapy with newer nonstatin drugs (ezetimibe and proprotein convertase subtilsin-kexin type 9 inhibitors).
      Measures of quality performance in patients with ASCVD include intervention on all major risk factors, percentage intervention with statin therapy and with high-intensity statins, add-on ezetimibe to moderate-intensity statins, identification of very-high-risk patients, and use of nonstatins in very-high-risk patients.

      Acknowledgments

      The authors contributed equally to the conception of study objective, data analyses, and writing of the manuscript. The authors have approved the final article.

      Conflict of interest

      The authors have no financial disclosures for this project. This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

      References

        • Grundy S.M.
        • Stone N.J.
        • Bailey A.L.
        • et al.
        2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA guideline on the management of blood cholesterol.
        Circulation. 2018; (Cir0000000000000625)
        • Boekholdt S.M.
        • Hovingh G.K.
        • Mora S.
        • et al.
        Very low levels of atherogenic lipoproteins and the risk for cardiovascular events: a meta-analysis of statin trials.
        J Am Coll Cardiol. 2014; 64: 485-494
      1. Centers for Disease Control and Prevention, National Health and Nutrition Examination Survey.
        (Available at:)
        • Friedewald W.T.
        • Levy R.I.
        • Fredrickson D.S.
        Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge.
        Clin Chem. 1972; 18: 499-502
        • Ballantyne C.M.
        • Andrews T.C.
        • Hsia J.A.
        • Kramer J.H.
        • Shear C.
        Correlation of non-high-density lipoprotein cholesterol with apolipoprotein B: effect of 5 hydroxymethylglutaryl coenzyme A reductase inhibitors on non-high-density lipoprotein cholesterol levels.
        Am J Cardiol. 2001; 88: 265-269
        • Boekholdt S.M.
        • Arsenault B.J.
        • Mora S.
        • et al.
        Association of LDL cholesterol, non-HDL cholesterol, and apolipoprotein B levels with risk of cardiovascular events among patients treated with statins: a meta-analysis.
        JAMA. 2012; 307: 1302-1309
        • Cannon C.P.
        • Braunwald E.
        • McCabe C.H.
        • et al.
        Intensive versus moderate lipid lowering with statins after acute coronary syndromes.
        N Engl J Med. 2004; 350: 1495-1504
        • LaRosa J.C.
        • Grundy S.M.
        • Waters D.D.
        • et al.
        Intensive lipid lowering with atorvastatin in patients with stable coronary disease.
        N Engl J Med. 2005; 352: 1425-1435
        • Pedersen T.R.
        • Faergeman O.
        • Kastelein J.J.
        • et al.
        High-dose atorvastatin vs usual-dose simvastatin for secondary prevention after myocardial infarction: the IDEAL study: a randomized controlled trial.
        JAMA. 2005; 294: 2437-2445
        • Baigent C.
        • Blackwell L.
        • Emberson J.
        • et al.
        Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials.
        Lancet. 2010; 376: 1670-1681
        • Stone N.J.
        • Robinson J.G.
        • Lichtenstein A.H.
        • 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: 2889-2934
        • Grundy S.M.
        • Cleeman J.I.
        • Merz C.N.
        • et al.
        Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III Guidelines.
        J Am Coll Cardiol. 2004; 44: 720-732
      2. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial.
        Lancet. 2002; 360: 7-22
        • Ballantyne C.M.
        • Raichlen J.S.
        • Cain V.A.
        Statin therapy alters the relationship between apolipoprotein B and low-density lipoprotein cholesterol and non-high-density lipoprotein cholesterol targets in high-risk patients: the MERCURY II (Measuring Effective Reductions in Cholesterol Using Rosuvastatin) trial.
        J Am Coll Cardiol. 2008; 52: 626-632
        • Pokharel Y.
        • Tang F.
        • Jones P.G.
        • et al.
        Adoption of the 2013 American College of Cardiology/American Heart Association Cholesterol Management Guideline in Cardiology Practices Nationwide.
        JAMA Cardiol. 2017; 2: 361-369
        • Carroll M.D.
        • Kit B.K.
        • Lacher D.A.
        • Shero S.T.
        • Mussolino M.E.
        Trends in lipids and lipoproteins in US adults, 1988-2010.
        JAMA. 2012; 308: 1545-1554