Low-Density Lipoprotein Cholesterol
2018; Lippincott Williams & Wilkins; Volume: 138; Issue: 21 Linguagem: Inglês
10.1161/circulationaha.118.034922
ISSN1524-4539
AutoresSalim S. Virani, Christie M. Ballantyne,
Tópico(s)Cancer, Lipids, and Metabolism
ResumoHomeCirculationVol. 138, No. 21Low-Density Lipoprotein Cholesterol Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBLow-Density Lipoprotein CholesterolIs 160 the New 190? Salim S. Virani, MD, PhD and Christie M. Ballantyne, MD Salim S. ViraniSalim S. Virani Health Policy, Quality & Informatics Program (S.S.V.), Michael E. DeBakey Veterans Affairs Medical Center, Houston, TX. Section of Cardiology (S.S.V.), Michael E. DeBakey Veterans Affairs Medical Center, Houston, TX. Department of Medicine, Sections of Cardiovascular Research and Cardiology (S.S.V., C.M.B.), Baylor College of Medicine, Houston, TX. Center for Cardiometabolic Disease Prevention (S.S.V., C.M.B.), Baylor College of Medicine, Houston, TX. and Christie M. BallantyneChristie M. Ballantyne Christie M. Ballantyne, MD, Baylor College of Medicine, One Baylor Plaza, MS BCM285, Houston, TX 77030. Email E-mail Address: [email protected] Department of Medicine, Sections of Cardiovascular Research and Cardiology (S.S.V., C.M.B.), Baylor College of Medicine, Houston, TX. Center for Cardiometabolic Disease Prevention (S.S.V., C.M.B.), Baylor College of Medicine, Houston, TX. Originally published20 Aug 2018https://doi.org/10.1161/CIRCULATIONAHA.118.034922Circulation. 2018;138:2326–2329This article is a commentary on the followingLong-Term Association of Low-Density Lipoprotein Cholesterol With Cardiovascular Mortality in Individuals at Low 10-Year Risk of Atherosclerotic Cardiovascular DiseaseOther version(s) of this articleYou are viewing the most recent version of this article. Previous versions: August 20, 2018: Ahead of Print Article, see p 2315Low-density lipoprotein cholesterol (LDL-C) has long been recognized as a risk factor for atherosclerotic cardiovascular disease (ASCVD). Although the current treatment guidelines clearly state that formal global cardiovascular disease (CVD) assessment should be performed in most individuals without established ASCVD, the guidelines do not recommend risk assessment in those with marked elevation of LDL-C levels.1 Marked elevation in LDL-C is generally defined as ≥190 mg/dL (mean LDL-C level in US adults is 113 mg/dL2). The risk of coronary heart disease (CHD) is accelerated by 10 to 20 years in men and 20 to 30 years in women with LDL-C levels ≥190 mg/dL.3 Although the risk of CHD events has been described as 22-fold higher among those with familial hypercholesterolemia–defining mutations (because of a lifetime exposure to elevated LDL-C levels), the future risk of CHD remains 6-fold higher in those with LDL-C ≥190 mg/dL and no familial hypercholesterolemia–related mutations.4 Statin therapy significantly lowers the risk of ASCVD events in these patients.5 It is important to note that although the prevalence of heterozygous familial hypercholesterolemia may be 1 in 250, the prevalence of LDL-C ≥190 mg/dL may be as high as 5% to 7% in the general population.3,6Long-term ASCVD risk associated with more moderate elevations in LDL-C levels is not well described, especially among young individuals and those without other major ASCVD risk factors. In this population, 10-year ASCVD risk using current risk assessment tools may be low.What Does This Study Show?The study by Abdullah et al7 in this issue of Circulation fills this gap. In a group of relatively low-risk individuals (n=36 375) with 10-year ASCVD risk <7.5% (median 1.3% 10-year ASCVD risk) using the Pooled Cohort Risk Equation and without a history of ASCVD or diabetes mellitus at baseline, the association between fasting LDL-C (or non–high-density lipoprotein cholesterol [non-HDL-C]) levels and ASCVD mortality was evaluated over a median follow-up of 26.8 years. Compared with those with LDL-C <100 mg/dL, individuals with LDL-C levels of 160 to 189 mg/dL (hazard ratio [HR], 1.7; 95% CI, 1.4–2.2) and those with LDL-C ≥190 mg/dL (HR, 1.5; 95% CI, 1.2–2.1) had increased risk for CVD mortality. This would roughly equate to mean reductions in years free of CVD death of 4.3 and 3.9, respectively. Similarly, non-HDL-C levels of 160 to 189 mg/dL (HR, 1.3; 95% CI, 1.1–1.6), 190 to 219 mg/dL (HR, 1.8; 95% CI, 1.4–2.2), and ≥220 mg/dL (HR, 1.5; 95% CI, 1.2–2.0) were significantly associated with CVD death compared with non-HDL-C levels <130 mg/dL. Results were qualitatively similar when analyses were restricted to those with 10-year ASCVD risk ≤5% (89% of the cohort).Several observations can be made from these important analyses in otherwise low-risk individuals. First, even moderately elevated LDL-C levels in the range of 160 to 189 mg/dL over a 27-year follow-up were associated with an increased risk of CVD death, with roughly 4.3 years' reduction in years free of CVD. Second, non-HDL-C levels showed an association with CVD death (and all-cause mortality) that was more robust at even lower levels compared with the corresponding LDL-C levels. This finding is not surprising because non-HDL-C includes the cholesterol content of all atherogenic lipoproteins, including low-density lipoprotein, intermediate-density lipoprotein, very-low-density lipoprotein, lipoprotein(a), and chylomicron remnants.8 Therefore, non-HDL-C calculation captures the risk associated with both cholesterol-rich lipoproteins and triglyceride-rich remnant lipoproteins. This observation reemphasizes that non-HDL-C is superior to LDL-C in identifying future ASCVD risk.These results should be interpreted in the context of the limitations of the analyses. No information on baseline or follow-up lipid-lowering therapies was available. Also, age was not adjusted for in the main analyses because of violation of the proportional-hazards assumption. It is quite possible that given such a long follow-up, some would reach a threshold of 7.5% 10-year ASCVD risk because of age or the development of age-dependent risk factors and, therefore, would meet the guideline-recommended risk threshold of 7.5% 10-year ASCVD risk for discussion regarding statin therapy.What Are the Implications of the Findings?First, these analyses indicate that there is no "threshold" at which atherogenic lipoproteins increase ASCVD risk. Even moderate elevations in atherogenic lipoproteins, without other risk factors and with a low 10-year ASCVD risk, are associated with increased long-term risk of CVD mortality and possibly all-cause mortality. This finding raises questions of whether 10-year or lifetime ASCVD risk assessment should be performed first in individuals with LDL-C 160 to 189 mg/dL or whether they should begin lipid-lowering treatments based on long-term risk similar to individuals with LDL-C levels ≥190 mg/dL. As noted in the current analyses, the association between LDL-C levels and CHD mortality (or CVD mortality) was not significant when analyses were truncated at 10 years.Second, should patients with LDL-C 160 to 189 mg/dL be treated early? Most primary-prevention trials9–11 (Table) included a low-risk population, and some included patients with LDL-C ≥160 mg/dL; however, the baseline age in those trials was higher than the mean of 42 years in the current study. Although treating those with LDL-C 160 to 189 mg/dL but low 10-year ASCVD risk early in life sounds promising, it would lead to treating a much larger number of individuals than the current recommendation of treating those with LDL-C ≥190 mg/dL. For example, individuals with LDL-C 160 to 189 mg/dL comprised 13% of the overall study population. The 2013 American College of Cardiology/American Heart Association cholesterol guideline notes that statin therapy may be considered (class IIb recommendation with level of evidence C) in individuals with LDL-C ≥160 mg/dL who are otherwise not considered for statin therapy based on the statin benefit groups.1 The current analyses could substantiate updating the level of evidence for this recommendation, which, when combined with clinical trial evidence (Table), could support early initiation of statin therapy in at least some of these individuals. At least 2 of these primary-prevention trials9,11 (Table) showed benefit in individuals with LDL-C levels ≈160 mg/dL and 10-year ASCVD risk <7.5%. It is unlikely that clinical trials of statin therapy will be performed in a population of this age with few risk factors because of the large sample size and long-term follow-up required. How, then, should observational data such as found in this study be used for joint decision-making with our patients?Table. Randomized Clinical Trials of Statin Monotherapy as Primary PreventionTrialTreatmentAge/Sex Eligibility CriteriaLipid/Other Eligibility Criteria (mg/dL)Mean LDL-C Reduction and Absolute Reduction Versus Placebo at 1 yRRR for ASCVDEstimated 10-Year Hard ASCVD RiskMEGAPravastatin 10–20 mgMen 40–70 years of age; postmenopausal women 40–70 years of ageTotal cholesterol 220–279(LDL-C ≈160–210)–17%; 128 vs. 156 (–28 mg/dL)24%5.1%AFCAPS/TexCAPSLovastatin 20–40 mgMen 45–73 years of age; postmenopausal women 55–73 years of ageLDL-C 130–190; triglycerides <400; HDL-C <45 for men and 50 years of age; women ≥60 years of agehs-CRP >2 mg/L; LDL-C <130; triglycerides <500–50%; 55 vs. 110(–55 mg/dL)44%7.6%AFCAPS/TexCAPS indicates Air Force/Texas Coronary Atherosclerosis Prevention Study9; ASCVD, atherosclerotic cardiovascular disease; JUPITER, Justification for the Use of Statins in Primary Prevention: An Intervention Trial Evaluating Rosuvastatin10; HDL-C, high-density lipoprotein cholesterol; hs-CRP, high-sensitivity C-reactive protein; LDL-C, low-density lipoprotein cholesterol; MEGA, Management of Elevated Cholesterol in the Primary Prevention Group of Adult Japanese11; and RRR, relative risk reduction.Adapted from the supplement to the 2013 American College of Cardiology/American Heart Association Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Disease in Adults.1Third, these analyses reemphasize the importance of calculating non-HDL-C. Although the Adult Treatment Panel III guideline recommended non-HDL-C as a secondary treatment target especially among individuals with elevated triglycerides,12 the 2013 American College of Cardiology/American Heart Association cholesterol guideline did not include non-HDL-C for treatment decisions because trials of statin therapy mostly used LDL-C levels for eligibility.1 The analyses in the current study show that non-HDL-C levels were associated with CHD and CVD mortality at much lower levels (130–159 mg/dL) than the corresponding LDL-C levels. It is important to note that all recent outcomes trials of PCSK9 inhibitors (most of which included secondary-prevention patients) used both LDL-C and non-HDL-C thresholds for eligibility13,14 and could therefore include patients with elevated non-HDL-C levels despite LDL-C levels below the eligibility criterion. Should clinicians use non-HDL-C in addition to LDL-C when making decisions regarding lipid-lowering therapy?What Are the Remaining Gaps?Although the authors evaluated elevation of LDL-C and non-HDL-C levels in midlife, there are other clinical circumstances in which LDL-C levels may be elevated but the duration of exposure may not be as long. One example would be perimenopausal elevation of LDL-C.15 Menopause can lead to elevated LDL-C, which in some cases may approach 160 to 189 mg/dL. Should these women be treated with lipid-lowering therapy? Although these women may have elevated LDL-C levels, their risk may not be as high as individuals in the current analyses because overall risk is likely a combination of the degree of elevation of atherogenic lipoproteins and the duration of exposure (shorter in women with perimenopausal LDL-C elevation). Last, although imaging, especially coronary calcium score, has been shown to stratify risk in intermediate-risk individuals,16 can imaging be used for risk stratification in individuals with moderate LDL-C elevation? Can therapy be withheld with a coronary calcium score of 0 when LDL-C levels are 160 to 189 mg/dL, especially when one considers the limitations of coronary calcium scores in young individuals? This finding would be important given the considerable number of individuals with LDL-C 160 to 189 mg/dL, the need for lifelong treatment once lipid-lowering therapy is started, and possibly a higher risk for statin-associated side effects given the longer duration of therapy.In conclusion, these analyses solidify the evidence that even moderately elevated atherogenic lipoprotein levels, especially when present over a long-term follow-up, are associated with an increased risk of CVD death and possibly overall mortality.Sources of FundingThis work was supported by a Department of Veterans Affairs Health Services Research & Development Service Investigator-Initiated grant (IIR 16–072), American Heart Association Beginning Grant-in-Aid (14BGIA20460366), American Diabetes Association Clinical Science and Epidemiology award (1-14-CE-44), Houston VA Health Services Research & Development Center for Innovations grant (HFP 90-020), and National Institutes of Health grant (R01-HL134320).DisclosuresDr Virani received honoraria from the American College of Cardiology (Associate Editor for Innovations, acc.org) and the National Lipid Association, and is on the steering committee for the Patient and Provider Assessment of Lipid Management Registry at the Duke Clinical Research Institute (no financial remuneration). Dr Ballantyne received grant/research support (all paid to the institution, not the individual) from Amgen, Esperion, Regeneron, and Sanofi-Synthelabo; and is a consultant for Amgen, Esperion, Merck, Regeneron, and Sanofi-Synthelabo.FootnotesThe opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.https://www.ahajournals.org/journal/circGuest Editor for this manuscript was Vera Bittner, MD, MSPH.The views expressed in this editorial are those of the authors and do not necessarily represent the views of the Department of Veterans Affairs.Christie M. Ballantyne, MD, Baylor College of Medicine, One Baylor Plaza, MS BCM285, Houston, TX 77030. Email [email protected]eduReferences1. 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Stein R, Ferrari F and Martins V (2022) Blood lipids and molecular pathways of atherogenesis Cholesterol, 10.1016/B978-0-323-85857-1.00021-3, (623-637), . Al Rifai M, Blumenthal R, Stone N, Schofield R, Orringer C, Michos E, Heidenreich P, Braun L, Birtcher K, Smith S, Nambi V, Grundy S and Virani S (2021) Department of Veterans Affairs (VA) and U.S. Department of Defense (DoD) guidelines for management of dyslipidemia and cardiovascular disease risk reduction: Putting evidence in context, Progress in Cardiovascular Diseases, 10.1016/j.pcad.2021.08.001, 68, (2-6), Online publication date: 1-Sep-2021. Lee M, Mahtta D, Alam M, Ullah W, Nasir K, Hanif B and Virani S (2021) Contemporary outcomes studies to identify and mitigate the risk in patients with premature cardiovascular disease, Expert Review of Pharmacoeconomics & Outcomes Research, 10.1080/14737167.2021.1888718, 21:4, (559-570), Online publication date: 4-Jul-2021. Park J, Kim D, Lee H, Lee H, Hwang I, Yoon Y, Park H, Lee S, Choi S, Kim Y, Cho G, Han K and Kim H (2021) Effect of Moderately but Persistently Elevated Lipid Levels on Risks of Stroke and Myocardial Infarction in Young Korean Adults, Journal of the American Heart Association, 10:12, Online publication date: 15-Jun-2021. Levinson S (2019) Non–High-Density Lipoprotein Cholesterol and Guidelines for Cholesterol Lowering in Recent History, Laboratory Medicine, 10.1093/labmed/lmz032, 51:1, (14-23), Online publication date: 2-Jan-2020. Kim M, Han K, Joung H, Baek K, Song K and Kwon H (2019) Cholesterol levels and development of cardiovascular disease in Koreans with type 2 diabetes mellitus and without pre-existing cardiovascular disease, Cardiovascular Diabetology, 10.1186/s12933-019-0943-9, 18:1, Online publication date: 1-Dec-2019. Agarwala A, Liu J, Ballantyne C and Virani S (2019) The Use of Risk-Enhancing Factors to Personalize ASCVD Risk Assessment: Evidence and Recommendations from the 2018 AHA/ACC Multi-Society Cholesterol Guidelines, Current Cardiovascular Risk Reports, 10.1007/s12170-019-0616-y, 13:7, Online publication date: 1-Jul-2019. Related articlesLong-Term Association of Low-Density Lipoprotein Cholesterol With Cardiovascular Mortality in Individuals at Low 10-Year Risk of Atherosclerotic Cardiovascular DiseaseShuaib M. Abdullah, et al. Circulation. 2018;138:2315-2325 November 20, 2018Vol 138, Issue 21 Advertisement Article InformationMetrics © 2018 American Heart Association, Inc.https://doi.org/10.1161/CIRCULATIONAHA.118.034922PMID: 30571588 Originally publishedAugust 20, 2018 KeywordsLDL cholesterolEditorialscardiovascular diseasesPDF download Advertisement SubjectsCardiovascular DiseaseLipids and CholesterolRisk Factors
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