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      Lack of an association or an inverse association between low-density-lipoprotein cholesterol and mortality in the elderly: a systematic review

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          Abstract

          Objective

          It is well known that total cholesterol becomes less of a risk factor or not at all for all-cause and cardiovascular (CV) mortality with increasing age, but as little is known as to whether low-density lipoprotein cholesterol (LDL-C), one component of total cholesterol, is associated with mortality in the elderly, we decided to investigate this issue.

          Setting, participants and outcome measures

          We sought PubMed for cohort studies, where LDL-C had been investigated as a risk factor for all-cause and/or CV mortality in individuals ≥60 years from the general population.

          Results

          We identified 19 cohort studies including 30 cohorts with a total of 68 094 elderly people, where all-cause mortality was recorded in 28 cohorts and CV mortality in 9 cohorts. Inverse association between all-cause mortality and LDL-C was seen in 16 cohorts (in 14 with statistical significance) representing 92% of the number of participants, where this association was recorded. In the rest, no association was found. In two cohorts, CV mortality was highest in the lowest LDL-C quartile and with statistical significance; in seven cohorts, no association was found.

          Conclusions

          High LDL-C is inversely associated with mortality in most people over 60 years. This finding is inconsistent with the cholesterol hypothesis (ie, that cholesterol, particularly LDL-C, is inherently atherogenic). Since elderly people with high LDL-C live as long or longer than those with low LDL-C, our analysis provides reason to question the validity of the cholesterol hypothesis. Moreover, our study provides the rationale for a re-evaluation of guidelines recommending pharmacological reduction of LDL-C in the elderly as a component of cardiovascular disease prevention strategies.

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          Most cited references31

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          Report of the Conference on Low Blood Cholesterol: Mortality Associations.

          A National Heart, Lung, and Blood Institute (NHLBI) Conference was held October 9-10, 1990, to review and discuss existing data on U-shaped relations found between mortality rates and blood total cholesterol levels (TC) in some but not other studies. Presentations were given from 19 cohort studies from the United States, Europe, Israel, and Japan. A representative of each study presented its findings and also submitted tables of proportional hazards regression coefficients for entry TC levels in regard to death, and these were incorporated into a formal statistical overview adjusted for age, diastolic blood pressure, cigarette smoking, body mass index, and alcohol intake, as available. The U-shape for total mortality in men and the flat relation in women resulted largely from a positive relation of TC with coronary heart disease death and an inverse relation with deaths caused by some cancers (e.g., lung but not colon), respiratory disease, digestive disease, trauma, and residual deaths. Risk for combined noncardiovascular, noncancer causes of death decreased steadily across the range of TC. The conference considered possible explanations for the statistical associations found between low TC levels or active TC lowering and certain causes of death. One is that TC is lowered by some disease conditions themselves, such as wasting in chronic pulmonary disease or reduced production and secretion of cholesterol-bearing lipoproteins with liver disease. In this sort of situation, the TC:mortality association found in observational studies may be due to preexisting disease. This was addressed by excluding early deaths from the analysis, which did not change the results. The conference considered as well the biological function of cholesterol, which, if seriously deranged, might hypothetically cause a wide variety of diseases and dysfunction. The conference also considered the biological functions that might provide plausible mechanisms for the associations found. Definitive interpretation of the associations observed was not possible, although most participants considered it likely that many of the statistical associations of low or lowered TC level are explainable by confounding in one form or another. The conference focused on the apparent existence and nature of these associations and on the need to understand their source rather than on any pertinence of the findings for public health policy. Further research is recommended to explain the observed associations of low TC levels (and TC lowering) with certain noncardiovascular diseases. This includes studies of the time course of TC change in disease, the relation of TC to morbidity, further studies of possible epidemiological confounding, monitoring of population trends in TC and mortality, further studies of the relations in women, auditing of noncardiovascular events in trials, studies of cell membrane, genetic and molecular links to cholesterol metabolism, TC level and disease, studies of disease manifestations in specific lipid disorders, and further study of the proposed causal mechanisms linking low TC and hemorrhagic stroke.
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            Lipid levels in patients hospitalized with coronary artery disease: an analysis of 136,905 hospitalizations in Get With The Guidelines.

            Lipid levels among contemporary patients hospitalized with coronary artery disease (CAD) have not been well studied. This study aimed to analyze admission lipid levels in a broad contemporary population of patients hospitalized with CAD. The Get With The Guidelines database was analyzed for CAD hospitalizations from 2000 to 2006 with documented lipid levels in the first 24 hours of admission. Patients were divided into low-density lipoprotein cholesterol (LDL), high-density lipoprotein cholesterol (HDL), and triglyceride categories. Factors associated with LDL and HDL levels were assessed along with temporal trends. Of 231,986 hospitalizations from 541 hospitals, admission lipid levels were documented in 136,905 (59.0%). Mean lipid levels were LDL 104.9 +/- 39.8, HDL 39.7 +/- 13.2, and triglyceride 161 +/- 128 mg/dL. Low-density lipoprotein cholesterol or =60 mg/dL) in only 1.4%. High-density lipoprotein cholesterol was or =60 mg/dL. These findings may provide further support for recent guideline revisions with even lower LDL goals and for developing effective treatments to raise HDL.
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              Relationship between plasma lipids and all-cause mortality in nondemented elderly.

              To investigate the relationship between plasma lipids and risk of death from all causes in nondemented elderly. Prospective cohort study. Community-based sample of Medicare recipients, aged 65 years and older, residing in northern Manhattan. Two thousand two hundred seventy-seven nondemented elderly, aged 65 to 98; 672 (29.5%) white/non-Hispanic, 699 (30.7%) black/non-Hispanic, 876 (38.5%) Hispanic, and 30 (1.3%) other. Anthropometric measures: fasting plasma total cholesterol, triglyceride, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and non-HDL-C, body mass index, and apolipoprotein E (APOE) genotype. clinical measures: neuropsychological, neurological, medical, and functional assessments; medical history of diabetes mellitus, heart disease, hypertension, stroke, and treatment with lipid-lowering drugs. Vital status measure: National Death Index date of death. Survival methods were used to examine the relationship between plasma lipids and subsequent mortality in younger and older nondemented elderly, adjusting for potential confounders. Nondemented elderly with levels of total cholesterol, non-HDL-C, and LDL-C in the lowest quartile were approximately twice as likely to die as those in the highest quartile (rate ratio (RR)=1.8, 95% confidence interval (CI)=1.3-2.4). These results did not vary when analyses were adjusted for body mass index, APOE genotype, diabetes mellitus, heart disease, hypertension, stroke, diagnosis of cancer, current smoking status, or demographic variables. The association between lipid levels and risk of death was attenuated when subjects with less than 1 year of follow-up were excluded (RR=1.4, 95% CI=1.0-2.1). The relationship between total cholesterol, non-HDL-C, HDL-C, and triglycerides and risk of death did not differ for older (>or=75) and younger participants (>75), whereas the relationship between LDL-C and risk of death was stronger in younger than older participants (RR=2.4, 95% CI=1.2-4.9 vs RR=1.6, 95% CI=1.02-2.6, respectively). Overall, women had higher mean lipid levels than men and lower mortality risk, but the risk of death was comparable for men and women with comparable low lipid levels. Low cholesterol level is a robust predictor of mortality in the nondemented elderly and may be a surrogate of frailty or subclinical disease. More research is needed to understand these associations.
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                Author and article information

                Journal
                BMJ Open
                BMJ Open
                bmjopen
                bmjopen
                BMJ Open
                BMJ Publishing Group (BMA House, Tavistock Square, London, WC1H 9JR )
                2044-6055
                2016
                2 June 2016
                : 6
                : 6
                : e010401
                Affiliations
                [1 ]Magle Stora Kyrkogata 9, 22350 Lund, Sweden
                [2 ]Department of Psychology, Department of Molecular Pharmacology and Physiology, Center for Preclinical and Clinical Research on PTSD, University of South Florida , Tampa, Florida, USA
                [3 ]NPO Japan Institute of Pharmacovigilance , Osaka, Japan
                [4 ]Department of Internal Medicine, Toyama Jonan Onsen Daini Hospital, University of Toyama , Toyama City, Japan
                [5 ]Strömstad Academy , Strömstad, Sweden
                [6 ]Western Vascular Institute, University Hospital Galway & Galway Clinic , National University of Ireland & Royal college of Surgeons of Ireland affiliated Hospital, Galway, Ireland
                [7 ]East Cheshire Trust, Macclesfield District General Hospital, Macclesfield, Cheshire , England
                [8 ]Solo Practice in Cardiology, Tyler, Texas 75701 , USA
                [9 ]Department of cardiology , Frimley Park Hospital, Portsmouth road, Surrey GU16 7UJ, UK
                [10 ]Medical Service, Comando Brigata Alpina “Julia”/Multinational Land Force, Udine , Italy
                [11 ]Pathology and Laboratory Medicine Service , VA Boston Healthcare System, West Roxbury; Harvard Medical School, Boston, Massachusetts
                [12 ]Tokai University, Daikancho, Hiratsuka, Kanagawa , Japan 254-0807
                [13 ]Nagoya City University and Institute for Consumer Science and Human Life, Kinjo Gakuin University , Nagoya, Japan
                [14 ]New York Medical College; The American Institute of Stress
                [15 ]Sahlgren's Academy, University of Gothenburg, Sweden, and Colombia University, NY , USA
                [16 ]Slottsstadens Läkarhus, Malmö , Gothenburg, Sweden
                Author notes
                [Correspondence to ] Dr Uffe Ravnskov; ravnskov@ 123456tele2.se
                Article
                bmjopen-2015-010401
                10.1136/bmjopen-2015-010401
                4908872
                27292972
                98624dc0-1696-4029-959d-065861cb9983
                Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

                This is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/

                History
                : 5 November 2015
                : 21 April 2016
                : 11 May 2016
                Categories
                Cardiovascular Medicine
                Research
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                1698
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                Medicine
                risk factor, ldl-cholesterol, cardiovascular mortality, total mortality, elderly,,geriatric medicine,preventive medicine,epidemiology

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