BMJ Openbmjopen.bmj.com/content/bmjopen/6/6/e010401.draft-revisions.pdf · The Association Between Low-Density Lipoprotein Cholesterol and Mortality in the Elderly. A systematic review

For peer review only

The Association Between Low-Density Lipoprotein

Cholesterol and Mortality in the Elderly. A systematic review

Journal: BMJ Open

Manuscript ID bmjopen-2015-010401

Article Type: Research

Date Submitted by the Author: 05-Nov-2015

Complete List of Authors: Ravnskov, Uffe; I am an independent researcher Diamond, David; University of South Florida, Department of Molecular Pharmacology and Physiology. Department of Psychology Hama, Rokuro; Japan Institute of Pharmacovigilance, Director Hamazaki, Tomohito ; Toyama Jonan Onsen Daini Hospital. University of Toyama, , Department of Internal Medicine Hammarskjöld, Björn; Strömstad Academy Hynes, Niamh ; National University of Ireland, Galway Clinic; Galway

University Hospitals, Western Vascular Institute Kendrick, Malcolm; Intermediate Care Team Langsjoen, Peter; Solo Practice in Cardiology Malhotra, Aseem; Royal Free Hospital, Cardiology Mascitelli, Luca ; Comando Brigata alpina Julia/Multinational Land Force, Medical Service McCully, Kilmer; VA Boston Healthcare System, Pathology and Laboratory Medicine Service Ogushi, Yoichi; Tokai University Okuyama, Harumi; Nagoya City University ; Kinjo Gakuin University,, Institute for Consumer Science and Human Life

Rosch, Paul; New York Medical College, American Institute of Stress, Medicine, Psychiatry Schersten, Tore; University of Gothenburg, Sahlgren's Academy Sultan, Sherif; National University of Ireland, Galway Clinic; Galway University Hospitals, Western Vascular Institute Sundberg, Ralf; Slottsstadens Läkarhus

<b>Primary Subject Heading</b>:

Cardiovascular medicine

Secondary Subject Heading: Geriatric medicine, Cardiovascular medicine

Keywords:

Risk factor, LDL-cholesterol, cardiovascular mortality, total mortality, elderly,, Adult cardiology < CARDIOLOGY, Myocardial infarction < CARDIOLOGY, GERIATRIC MEDICINE, PREVENTIVE MEDICINE,

EPIDEMIOLOGY

For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml

BMJ Open on 8 N

ovember 2018 by guest. P

rotected by copyright.http://bm

jopen.bmj.com

/B

MJ O

pen: first published as 10.1136/bmjopen-2015-010401 on 12 June 2016. D

ownloaded from

http://bmjopen.bmj.com/


Page 1 of 14


BMJ Open

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960

on 8 Novem

ber 2018 by guest. Protected by copyright.

http://bmjopen.bm

j.com/

BM

J Open: first published as 10.1136/bm

jopen-2015-010401 on 12 June 2016. Dow

nloaded from



2 1

The Association Between Low-Density Lipoprotein Cholesterol and Mortality in the Elderly. A review Uffe Ravnskov1, PhD David M Diamond,2 PhD Rokura Hama3, MD Tomohito Hamazaki4, MD Björn Hammarskjöld5, PhD Niamh Hynes6,16, MD Malcolm Kendrick7, MbChB Peter H. Langsjoen8, MD Aseem Malhotra9, Honorary consultant cardiologist Luca Mascitelli10, MD Kilmer S. McCully11, MD Yoichi Ogushi12, MS Harumi Okuyama13, PhD Paul J. Rosch14, MD Tore Schersten15, PhD Sherif Sultan6,16, PhD Ralf Sundberg17, PhD

Author affiliations

1. No affiliation. 2. Department of Psychology, Department of Molecular Pharmacology and Physiology,

University of South Florida. Research and Development Service, J.A. Haley Veterans Hospital, 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. Galway Clinic, National University of Ireland, Galway. Ireland. 7. East Cheshire Trust, Macclesfield District General Hospital, Macclesfield, Cheshire,

England.

Page 2 of 14


BMJ Open

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960

on 8 November 2018 by guest. Protected by copyright. http://bmjopen.bmj.com/ BMJ Open: first published as 10.1136/bmjopen-2015-010401 on 12 June 2016. Downloaded from



2

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. Western Vascular Institute, Galway University Hospitals, National University of Ireland,

Newcastle Road, Galway, Ireland. 17. Slottsstadens Läkarhus, Malmö, Sweden.

Corresponding author: Uffe Ravnskov, Magle Stora Kyrkogata 9, 22350 Lund, Sweden; tel. +46-702580416 or +46-46145022 [email protected]

Keywords: Risk factor, LDL-cholesterol, cardiovascular mortality, total mortality, elderly,

Number of words: 2183

ABSTRACT Objective. To investigate the role of low-density-lipoprotein cholesterol (LDL-C) as a risk factor for mortality in the elderly. Setting. A systematic literature review of all cohort studies, where LDL-C has been investigated as a risk factor for total and/or CVD mortality in populations above the age of 60 years. Results. In 17 studies including 28 cohorts with 66,346 participants, total mortality was recorded in 26 cohorts and CVD mortality was recorded in 8 cohorts. In 27 cohorts total and/or CVD mortality was not associated with or inversely associated with LDL-C.

Page 3 of 14


BMJ Open

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960




2 3

Conclusions. As elderly people with high LDL-C obviously live just as long or even longer than elderly people with low LDL-C, there is reason to question the validity of the cholesterol hypothesis, and the guidelines for cardiovascular prevention should be re-evaluated. STRENGTH AND LIMITATIONS OF THIS STUDY

∗ As fara s we know this is the first study ever to systematically evaluate cohort studies where LDL-C has been analysed as a risk factor for total and/or CVD mortality in elderly people

∗ The results went in the same direction in more than 98 % of the number of participants included in the studies.

∗ We may have overlooked studies, where an evaluation of LDL-C as a risk factor for mortality has been performed without mentioning it in the title or in the abstract.

INTRODUCTION For decades, the mainstream view has been that the major cause of atherosclerosis and CVD is hypercholesterolemia. There are major contradictions to this view, however. First, neither TC or LDL-C are associated with the degree of atherosclerosis. In an early study of people who had died suddenly as a result of physical trauma (thereby eliminating chronic disease as a cause of death), Landé and Sperry found no correlation between TC and degree of atherosclerosis.1 Since that work was published many other studies, both of TC and LDL-C, have confirmed their findings.2 Another contradiction is that high TC is not a risk factor for stroke and a weak risk factor for total mortality. For instance, in a recent thorough review of the cholesterol hypothesis Hamazaki et al. found that only one of several large Japanese cohort studies has found a significant association between TC and total mortality and only when the values of both men and women were combined.3 Meven any other studies have shown that TC is inversely associated with total mortality irrespective of age and sex.3

In a recent meta-analysis, performed by the Prospective Studies Collaboration (PSC), there was a clear association between TC and CVD mortality in all ages and in both sexes.4 However, even in this analysis, the risk decreased with increasing age and became minimal after the age of 80. As atherosclerosis and CVD are mainly diseases of

Page 4 of 14


BMJ Open

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960




4

the elderly, the cholesterol hypothesis would have predicted a stronger association between CVD mortality and TC in the elderly compared with younger individuals. There may be a bias in these studies however, because TC includes HDL-C, and many studies have shown that a high level of HDL-C is associated with a lower risk of CVD. Therefore, it seems more relevant to analyse LDL-C as a risk factor in elderly people. If Goldstein and Brown’s recent statement were correct; eg. that “the essential causative agent is cholesterol-carrying low-density lipoprotein”, 5 then LDL-C should be a strong risk factor for CVD in elderly people.

METHODS A PubMed, EMBASE and Ovid search was conducted independently by two f the authors using the search terms LDL-cholesterol AND risk factor AND (old OR elderly) AND (cardiovascular disease OR coronary heart disease) in the title or abstract seeking for studies in the English language examining LDL-C as a risk factor for total and/or CVD mortality in populations above the age of 60 years and published up to February 1 2015. Information was extracted including sample size, age of the individuals, exclusion criteria, follow-up time, outcome measure and risk data for all-cause and/or CVD mortality as a function of LDL-C.

RESULTS We identified 17 relevant studies including 28 cohorts with 66,346 participants where total mortality was recorded in 24 cohorts and CVD mortality was recorded in 8 cohorts (table 1). 6-22 In only one of the cohorts (including men only) total mortality was associated with LDL-C (HR: 1.16; p<0.05);13 in 10 cohorts no association was found; in 13 cohorts the association was inverse; in 10 of them with statistical significance (table 1). In one of the studies12 the inverse association was also present among subjects aged 50-60. The authors of that study had additionally evaluated the risk separately for people on statin treatment. Although the risk was lower than among participants with the lowest LDL-C, it was higher than for those with the highest LDL-C. In the cohort where LDL-C was associated with total mortality, it was also associated with CVD mortality (hazard ratio 1.19, p<0.01). In the other 7 cohorts no association was found with total mortality (table 1). There are no additional unpublished data.

Page 5 of 14


BMJ Open

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960




2 5

Table 1. Association between LDL-C and total mortality and CVD mortality, respectively in 16 studies including 28 cohorts with 64465 individuals above the age of 60. Except for Blekkenhorst et al.21 all hazard ratios have been calculated by the authors using Cox proportional hazards regression.

Authors¶ n Age Obs. years

Total mortality CVD mortality Exclusion criteria

LDL-C tertiles or quartiles (Hazard ratios)

LDL-C-quartiles (Hazard ratios)

I II III IV I II III IV

Zimetbaum et al. 19926 350 75-85 6.3 No association n.i. None

Kronmal et al. 19937 1134 747

56-75 >75

30 No association No association

n.i. n.i.

Räihä et al. 19978 347 65+ 11 n.i. No association Living in an institution Chyou & Eaker 20009 Men

Women

367 622

65+ 8-10 No association No association

n.i. None

Weverling-Rijnsburger et al. 200310 599 85+ 4 1.0 0.57 0.71 No association None

Psaty et al. 200411 Men

Women

5201 65+ 7.5 No association No association

n.i. CHD, stroke, heart failure

Schupf et al. 200512 2277 65+ 3 1.0 0.80 0.60* 0.50** n.i. Dementia

Tikhonoff et al. 200513 Men Women

1233 1887

65+ 11.1 1.0 0.84 0.99 1.16** 1.0 0.90 1.03 1.19* None

No association No association

Störk et al. 200614 Men 403 70+ 4 No association No association None

Akerblom et al. 200815

Caucasians African-merican

Hispanic

705 797 1054

65+ 3.4 1.0 1.0 1.0

0.89 0.79 0.79

0.72 0.58 0.79

0.56* 0.53* 0.71

n.i.

First year deaths

Nilsson et al. 200916 Men Women

210 222

75 10 No association No association

n.i. None

Werle et al. 201117 187 80+ 8.7 No association No association None

Cabrera et al 201218 800 60-85 12 1.0 0.69* 0.73* n.i. First 2 years deaths, cancer

Bathum et al. 201319 Men¶¶ Women¶¶

13733 7493 14298 9142

60-70 70+ 60-70 70+

1-9 1.0 1.0 1.0 1.0

0.67*** 0.71*** 0.56*** 0.66***

0.49*** 0.60*** 0.45*** 0.52***

0.45*** 0.52*** 0.47*** 0.46***

n.i. Terminal disease, CVD, diabetes

Takata et. al. 201420 207 85+ 10 Survivors 3.2 mmol/l, No association None

Page 6 of 14


BMJ Open

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960




6

n.i.: No information. ¶ Where nothing is mentioned, both sexes were included. ¶¶ HR for 7415 men and 8314 women on statin treatment was 0.63 and 0.61, respectively. * p<0.05; ** p<0.01, *** p<0.001.

In our literature search we also identified five studies that included individuals younger than 60 years with similar results. A study of 3,499 Thai people aged 35-54 years found no association between LDL-C and CVD mortality after 17 years of follow-up.23 A Finnish study of 1799 men aged 42-60 found no association between LDL-C and acute myocardial infarction after a follow-up of 4.5 years.24 In the Ibaraki Prefecture Health Study, which included 91,219 Japanese people followed for 10.3 years both total and CVD mortality was inversely associated with LDL-C.25 In the Lipid Research Clinic Prevalence study, where 1405 women age 50-69 years were followed for 14.5 years, the highest CVD mortality was seen in the lowest LDL-C tertile.26

DISCUSSION Our review of the literature revealed a notable absence of a relation between LDL-C levels and mortality. LDL-C was only associated with total and CVD mortality in one of the cohorts, which included 1233 individuals or 1.8 % of the total number of individuals; and the hazard ratio in the fourth quartile was only 1.16. That LDL-C in elderly people was not associated or inversely associated with total and/or CVD mortality in most cohorts provides a paradoxical contradiction to the cholesterol hypothesis. As atherosclerosis appears to start mainly in middle-aged people and becomes more pronounced with increasing age, the cholesterol hypothesis should predict an even stronger association between LDL-C levels and CVD mortality because it is mainly elderly people who die from CVD. Our results raise several relevant questions. Why is high TC a risk factor for young and middle-aged people only? The risk is particularly high according to the PSC analysis. Why is it that elderly people with high LDL-C live longer than elderly people

non-survivors: 2.9 mmol/l*

Lv et al 201521 Men Women

266 596

80+ 3 1.0 1.0

0.71 0.68*

0.41 0.58**

0.40 0.66

n.i. First year deaths

Blekkenhorst et al. 201522 Women 1469 70+ 10 n.i. No association None

Page 7 of 14


BMJ Open

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960




2 7

with low LDL-C? If high LDL-C is actually beneficial for the elderly, then why is cholesterol-lowering treatment able to lower the risk of cardiovascular mortality? In the following we provide potential explanations for these challenging questions. Why high cholesterol is a risk factor in young and middle-aged people. Multiple studies, mainly in young individuals, have shown that mental stress is able to increase TC from 8 to 65% in the course of less than an hour;27 and this is the case later in life as well. In a study of 199 middle-aged men and women both TC and LDL-C rose after a performance of moderately stressful behavioural tasks. At a screening session three years later those whose lipids had raised the most at the stress test also had significantly higher LDL-C and TC than the others.28 Mental stress may facilitate cardiovascular events through a number of mechanisms unrelated to cholesterol. The reason why high TC is a weaker risk factor with increasing age may be that old people have developed better coping mechanisms to deal with stress and are more resilient than young people; in particular compared with young males in the midst of their careers. Another explanation may be that studies of younger people include a higher proportion of patients with familial hypercholesterolemia (FH). There is a large variability of relative risks observed among different study populations, which may be due to the differences in the proportions of patients with FH. For instance, most of the participants in the Lipid Research Clinics Mortality Follow-up Study, which was included in the PSC analysis, had FH because all of them had a TC of 6.8 mmol/l or higher and an LDL-C of 4.9 mmol/l or higher.29 As CHD mortality before the age of 60 in people without FH is very low, it means that in studies of young and middle-aged people, the percentage of individuals with FH among those who die from CHD is much higher than the percentage in the total population. For instance, according to a study by the Simon Broome Register group CHD mortality among men and women with FH between 20-39 years is about 100 times higher than in the general population of the same age.30 Inverse causation. A common argument to explain why low lipid values are associated with an increased mortality is inverse causation, meaning that serious diseases cause low cholesterol. But this is not a likely explanation, because in four of the studies in table 1 terminal disease and mortality during the first years of observation were

Page 8 of 14


BMJ Open

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960




8

excluded. In spite of that, all four studies showed that the highest mortality was seen among those with the lowest initial LDL-C. There is much evidence that low LDL-C is not a consequence of serious disease but the very cause. Based on animal and laboratory experiments more than a dozen research groups have shown that LDL binds to and inactivates almost all kinds of microorganisms and their toxic products.31 Diseases caused or aggravated by microorganisms may therefore occur more often in people with low cholesterol, and this is also what has been observed in many studies.32 In a meta-analysis of 19 cohort studies for instance including 68,406 deaths performed by the National Heart, Lung, and Blood Institute,33 TC was inversely associated with mortality from respiratory and gastrointestinal diseases, most of which are of an infectious origin. It is unlikely that these diseases caused the low TC because the associations remained after the exclusion of deaths occurring during the first 5 years. In a study by Iribarren et al. more than 100,000 healthy individuals were followed for 15 years. At follow-up those whose cholesterol was lowest at the start had been admitted significantly more often to hospital because of an infectious disease during these 15 years.34 Evidently, low cholesterol, recorded at a time when these people were healthy, could not have been caused by a disease they had not yet encountered. High cholesterol also appears to protect against cancer. The reason may be that many cancer types are caused by viruses.35 In accordance, nine cohort studies including more than 140,000 individuals followed for 10-<30 years have found an inverse association between cancer and TC measured at the start, even after excluding cancer deaths that occurred during the first 4 years.36 Furthermore, most cholesterol-lowering experiments on rodents have resulted in cancer, and in several case-control studies of cancer patients and controls matched for age and sex, significantly more cancer patients have been on cholesterol-lowering treatment.36 In accordance, cancer mortality is significantly lower in individuals with FH.37 An apparent contradiction is that several studies have shown that statin-treated patients suffer less from cancer and other diseases. However, this view is based on cohort studies where statin-treated patients have been compared with non-treated individuals. There is a serious bias in such studies, because most statin-treated patients have lived most of their life with high cholesterol and many of them stop the treatment by themselves, whereas many untreated people may have had low cholesterol during

Page 9 of 14


BMJ Open

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960




2 9

most of their life, and as mentioned above, low LDL-C is associated with a higher risk of cancer.

Cholesterol-lowering treatment. The strongest argument for the cholesterol hypothesis is the benefit from statin treatment. However, the effect may be due to the non-lipid-lowering effects of the statins because with one exception, exposure-response, calculated correctly, has not been found in any angiographic or clinical cholesterol-lowering trial; e.g. the effect, if any, is the same whether cholesterol is lowered maximally or only a little.2 Furthermore, in three trials the cholesterol-lowering effect of simvastatin was improved by the use of ezetimibe, but in all of them CVD and total mortality did not differ significantly between the treatment and the control groups although LDL-C was 26-63% lower in the former.38-40

Another hypothesis. A crucial question is why both TC and LDL-C of patients with acute myocardial infarction are lower than normal. This has been documented repeatedly without a reasonable explanation.41-43 In one of the studies43 the authors concluded that cholesterol evidently should be lowered even more, and this was what they did, but at a follow-up three years later mortality was twice as high among those whose cholesterol had been lowered the most compared with those whose cholesterol was lowered only a little.

More than 100 years ago the “Father of Modern Medicine”, the renowned pathologist William Osler suggested that atherosclerosis was an infectious disease44 and since then numerous reviews have pointed to the strong association between infectious diseases and atherosclerosis.45 Today inflammation is seen as a cause of atherosclerosis, but if microorganisms play a causal role, the inflammation may in fact be beneficial. In support of this interpretation is that many trials with anti-inflammatory drugs have resulted in an increased coronary mortality.46 There is indeed much evidence that an invasion of microorganisms may be a primary cause in many cases, and a likely mechanism has been presented as well.31,47

CONCLUSIONS This work provides the first comprehensive analysis of the literature on the relation between LDL-C levels and mortality in the elderly. As the main goal with prevention of deadly diseases is to prolong life, total mortality is the most important outcome. Total

Page 10 of 14


BMJ Open

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960




10

mortality is also most easily defined and least subject to bias. The cholesterol hypothesis predicts that high levels of LDL-C would be associated with a high rate of CVD and all-cause mortality. Instead, we report the opposite finding: High levels of LDL-C are associated with greater longevity in elderly people. The cholesterol hypothesis, therefore, is in conflict with most of Bradford Hill´s criteria for causation. Most deviant is its lack of consistency, biological gradient and coherence. Our work provides the basis for a re-evaluation of the guidelines for cardiovascular prevention, which recommends a reduction of LDL levels in older people, in particular because the benefit from statin treatment has been exaggerated.48

Contributors. UR and RS performed the paper search. UR wrote the first draft of the manuscript. All authors have made improvements of the content and the wording. Funding. The study has not been funded Data sharing statement. Raw data from this project can be made available by a request to the corresponding author. Competing interests. TH has received speaker fees from Nissui Pharmaceutical and Nippon Suisan Kaisha. KSM has a US patent pending for homocysteine protocol; RH, ZH, HO, RS, UR have written books with criticism of the cholesterol hypothesis. DMD, JN, BH, NH, AM, PHL, LM, YO, PJR, SS and TS have no competing interests.

REFERENCES

1. Landé KE, Sperry WM. Human atherosclerosis in relation to the cholesterol content of the blood serum. Arch Pathol 1936;22:301-12.

2. Ravnskov U. Is atherosclerosis caused by high cholesterol? Q J M 2002;95:397-403. 3. Hamazaki T, Okuyama H, Ogushi Y, Hama R. Towards a paradigm shift in cholesterol

treatment -- a re-examination of the cholesterol Issue in Japan. Ann Nutr Metab 2015; 66 Suppl 4:1-116.

4. Prospective Studies Collaboration. Blood cholesterol and vascular mortality by age, sex, and blood pressure: a meta-analysis of individual data from 61 prospective studies with 55 000 vascular deaths. Lancet 2007;370:1829-39.

5. Goldstein JL, Brown MS. A Century of Cholesterol and Coronaries: From plaques to

Page 11 of 14


BMJ Open

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960




2 11

genes to statins. Cell 2015;161:161-72. 6. Zimetbaum P, Frishman WH, Ooi WL, et al. Plasma lipids and lipoproteins and the

incidence of cardiovascular disease in the very elderly: The Bronx Aging Study. Arterioscler Thromb 1992;12:416–23.

7. Kronmal RA, Cain KC, Ye Z, Omenn GS. Total serum cholesterol levels and mortality risk as a function of age. A report based on the Framingham data. Arch Intern Med 1993;153:1065-73.

8. Räihä I1, Marniemi J, Puukka P, Toikka T, Ehnholm C, Sourander L. Effect of serum lipids, lipoproteins, and apolipoproteins on vascular and nonvascular mortality in the elderly. Arterioscler Thromb Vasc Biol 1997;17:1224-32.

9. Chyou PH, Eaker ED. Serum cholesterol concentrations and all-cause mortality in older people. Age Ageing 2000;29:69-74.

10. Weverling-Rijnsburger AW, Jonkers IJ, van Exel E, Gussekloo J, Westendorp RG. High-density vs low-density lipoprotein cholesterol as the risk factor for coronary artery disease and stroke in old age. Arch Intern Med 2003;163:1549-54.

11. Psaty BM, Anderson M, Kronmal RA, et al. The association between lipid levels and the risks of incident myocardial infarction, stroke, and total mortality: The Cardiovascular Health Study. J Am Geriatr Soc 2004;52:1639-47.

12. Schupf N1, Costa R, Luchsinger J, Tang MX, Lee JH, Mayeux R. Relationship between plasma lipids and all-cause mortality in nondemented elderly. J Am Geriatr Soc 2005;53:219-26

13. Tikhonoff V, Casiglia E, Mazza A, et al. Low-density lipoprotein cholesterol and mortality in older people. J Amer Geriatr Soc 2005;53:2159-64.

14. Störk S, Feelders RA, van den Beld AW, Steyerberg EW, et al. Prediction of mortality risk in the elderly. Am J Med 2006;119:519-25.

15. Akerblom JL, Costa R, Luchsinger JA, Manly JJ, et al. Relation of plasma lipids to all-cause mortality in Caucasian, African-American and Hispanic elders. Age Ageing 2008;37:207-13.

16. Nilsson G, Ohrvik J, Lonnberg I, Hedberg P. Ten-year survival in 75-year-old men and women: Predictive ability of total cholesterol, HDL-C, and LDL-C. Curr Gerontol Geriatr Res Published Online First: 27 April 2009. doi: 10.1155/2009/158425.

17. Werle MH, Moriguchi E, Fuchs SC, Bruscato NM, de Carli W, Fuchs FD. Risk factors for cardiovascular disease in the very elderly: results of a cohort study in a city in southern Brazil. Eur J Cardiovasc Prev Rehabil 2011;18:369-77.

Page 12 of 14


BMJ Open

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960




12

18. Cabrera MA, de Andrade SM, Dip RM. Lipids and all-cause mortality among older adults: a 12-year follow-up study. ScientificWorldJournal Published Online First: 1 May 2012. doi: 10.1100/2012/930139

19. Bathum L, Depont Christensen R, Engers Pedersen L, Lyngsie Pedersen P, Larsen J, Nexøe J. Association of lipoprotein levels with mortality in subjects aged 50 + without previous diabetes or cardiovascular disease: A population-based register study. Scand J Prim Health Care 2013;31:172-80

20. Takata Y, Ansai T, Soh I, Awano S, et al. Serum total cholesterol concentration and 10-year mortality in an 85-year-old population. Clin Interv Aging 2014;9:293-300

21. Lv YB, Yin ZX, Chei CL, et al. Low-density lipoprotein cholesterol was inversely associated with 3-year all-cause mortality among Chinese oldest old: Data from the Chinese Longitudinal Healthy Longevity Survey. Atherosclerosis 2015;239:137-42.

22. Blekkenhorst LC, Prince RL, Hodgson JM, et al. Dietary saturated fat intake and atherosclerotic vascular disease mortality in elderly women: a prospective cohort study. Am J Clin Nutr 2015;101:1263-8.

23. Sritara P, Patoomanunt P, Woodward M, et al. Associations between serum lipids and causes of mortality in a cohort of 3,499 urban Thais: The Electricity Generating Authority of Thailand (EGAT) study. Angiology 2007;58:757-63.

24. Salonen JT, Salonen R, Seppänen K, Rauramaa R, Tuomilehto J. HDL, HDL2, and HDL3 subfractions, and the risk of acute myocardial infarction. A prospective population study in eastern Finnish men. Circulation 1991;84:129-39.

25. Noda H, Iso H, Irie F, Sairenchi T, Ohtaka E, Ohta H. Gender difference of association between LDL cholesterol concentrations and mortality from coronary heart disease amongst Japanese: the Ibaraki Prefectural Health Study. J Intern Med 2010;267:576–87.

26. Bass KM, Newschaffer CJ, Klag MJ, Bush TL. Plasma lipoprotein levels as predictors of cardiovascular death in women. Arch Intern Med 1993;153:2209-16.

27. Dimsdale JE, Herd A. Variability of plasma lipids in response to emotional arousal. Psychosom Med 1982;44:413-30.

28. Steptoe A, Brydon L. Associations between acute lipid responses and fasting lipid levels 3 years later. Health Psychol 2005;24:601-7

29. The Lipid Research Clinic's coronary primary prevention trial results. 1. Reduction in incidence of coronary heart disease. JAMA 1984;251:351-64.

30. Scientific Steering Committee on behalf of the Simon Broome Register Group. Risk of

Page 13 of 14


BMJ Open

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960




2 13

fatal coronary heart disease in familial hypercholesterolaemia. BMJ 1991;303:893-6. 31. Ravnskov U, McCully KS. Vulnerable plaque formation from obstruction of vasa

vasorum by homocysteinylated and oxidized lipoprotein aggregates complexed with microbial remnants and LDL autoantibodies. Ann Clin Lab Sci 2009;39:3-16

32. Ravnskov U. High cholesterol may protect against infections and atherosclerosis. Q J M 2003;96:927-34

33. Jacobs D, Blackburn H, Higgins M e,t al. Report of the conference on low blood cholesterol: Mortality associations. Circulation 1992;86:1046–60.

34. Iribarren C, Jacobs DR Jr, Sidney S, Claxton AJ, Feingold KR. Cohort study of serum total cholesterol and in-hospital incidence of infectious diseases. Epidemiol Infect 1998;121:335-47.

35. Read SA, Douglas MW. Virus induced inflammation and cancer development. Cancer Lett 2014;345:174-81.

36. Ravnskov U, McCully KS, Rosch PJ. The statin-low cholesterol-cancer conundrum. Q J M 2012;105:383-8.

37. Neil HA, Hawkins MM, Durrington PN, et al. Non-coronary heart disease mortality and risk of fatal cancer in patients with treated heterozygous familial hypercholesterolaemia. Atherosclerosis 2005;179:293–7.

38. Kastelein JP, Akdim F, Stroes ES, et al. Simvastatin with or without ezetimibe in familial hypercholesterolemia. N Engl J Med 2008;358:1431-43.

39. Cannon CP, Blazing MA, Giugliano RP, et al. Ezetimibe added to statin therapy after acute coronary syndromes. N Engl J Med 2015;372:2387-97.

40. Rossebø AB, Pedersen TR, Boman K, et al. Intensive lipid lowering with simvastatin and ezetimibe in aortic stenosis. N Engl J Med 2008;359:1343-56.

41. Reddy VS, Bui QT, Jacobs JR, Begelman SM, Miller DP, French WJ et al. Relationship between serum low-density lipoprotein cholesterol and In-hospital mortality following acute myocardial infarction (The lipid paradox). Am J Cardiol 2015;115:557-62.

42. Sachdeva A, Cannon CP, Deedwania PC, et al. Lipid levels in patients hospitalized with coronary artery disease: an analysis of 136,905 hospitalizations in Get With The Guidelines. Am Heart J 2009;157:111-7

43. Al-Mallah MH, Hatahet H, Cavalcante JL, Khanal S. Low admission LDL-cholesterol is associated with increased 3-year all-cause mortality in patients with non ST segment elevation myocardial infarction. Cardiol J 2009;16:227-33

44. Osler W. Diseases of the arteries. In: Modern Medicine: its Practice and Theory (Osler

Page 14 of 14


BMJ Open

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960




14

W, Ed), Lea & Fibiger, Philadelphia, 1908; pp 426-47. . 45. Khovidhunkit W, Kim MS, Memon RA, et al. infection and inflammation on lipid and

lipoprotein metabolism: mechanisms and consequences to the host. J Lipid Res 2004;45:1169-96.

46. Johnsen SP, Larsson H, Tarone RE, et al. Risk of myocardial infarction among users of rofecoxib, celecoxib, and other NSAIDs: a population- based case-control study. Arch Intern Med 2005;165:978-84.

47. Ravnskov U, McCully KS. Infections may be causal in the pathogenesis of atherosclerosis. Am J Med Sci 2012;344:391-4.

48. Kristensen ML, Christensen PM, Hallas J. The effect of statins on average survival in randomised trials, an analysis of end point postponement. BMJ Open 2015; 5(9):e007118. doi: 10.1136/bmjopen-2014-007118.

Page 15 of 14


BMJ Open

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960






Journal: BMJ Open

Manuscript ID bmjopen-2015-010401.R1


Date Submitted by the Author: 04-Feb-2016







Keywords:


EPIDEMIOLOGY


BMJ Open on 8 N



jopen.bmj.com

/B

MJ O


ownloaded from



Page 1 of 18


BMJ Open

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960

on 8 Novem


http://bmjopen.bm

j.com/

BM


jopen-2015-010401 on 12 June 2016. Dow

nloaded from



2 1

The Association Between Low-Density-Lipoprotein Cholesterol and Mortality in the Elderly. A Systematic Review. Uffe Ravnskov1, PhD David M Diamond,2 PhD Rokura Hama3, MD Tomohito Hamazaki4, MD Björn Hammarskjöld5, PhD Niamh Hynes6,16, MD Malcolm Kendrick7, MbChB Peter H. Langsjoen8, MD Aseem Malhotra9, Honorary consultant cardiologist Luca Mascitelli10, MD Kilmer S. McCully11, MD Yoichi Ogushi12, MS Harumi Okuyama13, PhD Paul J. Rosch14, MD Tore Schersten15, PhD Sherif Sultan6,16, PhD Ralf Sundberg17, PhD

Author affiliations





England.

Page 2 of 18


BMJ Open

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960




2










Page 3 of 18


BMJ Open

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960




2 3

ABSTRACT Background It is well known that total cholesterol becomes less of a risk factor or not at all for total and cardiovascular mortality with increasing age, but little is known as to whether low-density lipoprotein cholesterol (LDL-C), one component of total cholesterol, is associated with mortality in the elderly.. Objective. To investigate low-density-lipoprotein cholesterol (LDL-C) as a risk factor for total and cardiovascular mortality in the elderly. Setting and participants. We sought PubMed for cohort studies, where LDL-C had been investigated as a risk factor for total and/or CVD mortality in individuals age ≥60 years from the general population. Results. We identified 20 studies including 30 cohorts with a total of 74113 elderly people, where total mortality was recorded in 28 cohorts and CVD mortality in 9 cohorts. LDL-C was associated with total and/or CVD mortality in one of the cohorts including only 1.8 % of the total number of investigated individuals. In 15 cohorts LDL-C was inversely associated with total mortality; in 13 of the cohorts the negative association was statistically significant. In 8 of the 9 remaining cohorts, no association was found. In eight of the nine cohorts recording CVD mortality no association was found with LDL-C. Conclusions. As elderly people with high LDL-C live just as long or longer than controls with low LDL-C, there is reason to question the validity of the cholesterol hypothesis (i.e., that cholesterol is inherently atherogenic). In addition the guidelines for cardiovascular prevention in the elderly should be re-evaluated. STRENGTH AND LIMITATIONS OF THIS STUDY

∗ This is the first systematic review of cohort studies where LDL-C has been analysed as a risk factor for total and/or CVD mortality in elderly people

∗ Lack of an association or an inverse association between LDL-C and mortality was present in more than 98 % of the participants.

∗ We may have overlooked studies, where an evaluation of LDL-C as a risk factor for mortality has been performed without mention in the title or in the abstract. Minor errors may be present because the authors may not have adjusted LDL-C by the same risk factors.

∗ Some of the participants with high LDL-C may have started cholesterol-lowering treatment during the observation period and in this way may have added a longer life to

Page 4 of 18


BMJ Open

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960




4

the group with high LDL-C. However, this effect must have been minimal, because almost all statin trials have lowered mortality by only two percentage points at most; whereas the 4-year mortality in the included cohorts was lowered between 12 and 36%. Furthermore, in the largest study that included 2/3 of the participants, the risk was lower among those with the highest LDL-C than among those on statin treatment.

INTRODUCTION For decades, the mainstream view has been that the major cause of atherosclerosis and CVD is hypercholesterolemia. There are several contradictions to this view, however. No study of unselected people has found an association between total cholesterol (TC) and degree of atherosclerosis;1 in most of the Japanese epidemiological studies high TC is not a risk factor for stroke and an inverse risk factor for total mortality irrespective of age and sex.2 In a recent meta-analysis, performed by the Prospective Studies Collaboration (PSC), there was an association between TC and CVD mortality in all ages and in both sexes.3 However, even in this analysis, the risk decreased with increasing age and became minimal after the age of 80. As atherosclerosis and CVD are mainly diseases of the elderly, the cholesterol hypothesis predicts that the association between CVD mortality and TC should be at least as strong in the elderly as in young people.. There may be a bias in these studies however, because TC includes HDL-C, and multiple studies have shown that a high level of HDL-C is associated with a lower risk of CVD. Therefore, it seems relevant to analyse LDL-C as a risk factor in elderly people. If Goldstein and Brown’s recent statement that “the essential causative agent is cholesterol-carrying low-density lipoprotein”4 is correct, then LDL-C should be a strong risk factor for CVD in elderly people.

METHODS A PubMed search was conducted independently by two of the authors using the search terms “lipoprotein AND (old OR elderly) AND mortality NOT animal NOT trial” where the authors have examined LDL-C as a risk factor for total and/or CVD mortality in individuals from the general population age 60 years and older published up to December 17, 2015. We excluded studies not written in English and studies with irrelevant issues. Studies where the title or abstract indicated that they might include LDL-C data of elderly people were read in full.

Page 5 of 18


BMJ Open

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960




2 5

RESULTS Our search gave 2894 hits. We excluded 2632 studies because they were either irrelevant for our study or they were published in languages other than English. After having read the full text of the remaining 262 papers, we identified 20 relevant studies including 30 cohorts with a total of 74113 participants. Total mortality was recorded in 28 cohorts and CVD mortality in 9 cohorts (table 1). 5-24 In one of the cohorts representing only 1.7 % of the total number of participants, total mortality was associated with LDL-C (HR: 1.16; p<0.05).12 In 14 cohorts no association was found; in 15 cohorts the association was inverse; in 12 of them, including 76% of the total number of participants, the inverse association was statistically significant (Table 1). In one of the studies19 the inverse association was also present among subjects aged 50-60. The authors of that study had additionally evaluated the risk separately for people on statin treatment. Although the risk was lower than among participants with the lowest LDL-C, it was higher than for those with the highest LDL-C. In the cohort where LDL-C was associated with total mortality, LDL-C was also associated with CVD mortality (hazard ratio 1.19, p<0.01). In the other eight cohorts no association was found (Table 1).

Table 1. Association between LDL-C and total mortality and CVD mortality, respectively in 20 studies including 30 cohorts with 74113 individuals from the general population above the age of 60. With one exception24 all hazard ratios have been adjusted by the authors for various baseline risk factors using Cox proportional hazards regression models.

Authors¶ n Age; years

Obs. years

Total mortality CVD mortality Exclusion criteria

LDL-C tertiles or quartiles (Hazard ratios)

LDL-C-quartiles (Hazard ratios)


Zimetbaum et al. 19925 350 75-85 6.3 No association n.i. Absence of terminal illness, dementia

Kronmal et al. 19936 1134 747

66-75 >75

30 No association No association

n.i. n.i.

None

Räihä et al. 19977 347 ≥65 11 n.i. No association Living in an institution

Fried et al. 19988 5101 ≥65 5 Inversely associated *** n.i. Wheel-chair bound; cancer treatment

Chyou & Eaker 20009 Men 367 ≥65 8-10 No association n.i. None

Page 6 of 18


BMJ Open

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960




6

n.i.: No information. ¶ Where nothing is mentioned, both sexes were included. ¶¶ HR for 7415 men and 8314 women on statin treatment was 0.63 and 0.61, respectively. * p<0.05; ** p<0.01, *** p<0.001.

In our literature search we also identified several studies including individuals younger than 60 years and with similar results. A study of 3,499 Thai people aged 35-54 years found no association between LDL-C and CVD mortality after 17 years of follow-up.25 A

Women 622 No association

Weverling-Rijnsburger et al. 200310 599 ≥85 4 1.0 0.57 0.71 No association None

Psaty et al. 200411 Men Women

5201 ≥65 7.5 No association No association

n.i. CHD, stroke, heart failure

Schupf et al. 200512 2277 ≥65 3 1.0 0.80 0.60* 0.50** n.i. Dementia

Tikhonoff et al. 200513 Men Women

1233 1887

65 11.1 1.0 0.84 0.99 1.16** 1.0 0.90 1.03 1.19* None


Störk et al. 200614 Men 403 4 No association No association None


Caucasians African-merican

Hispanic

705 797 1054

≥65 3.4 1.0 1.0 1.0

0.89 0.79 0.79

0.72 0.58 0.79

0.56* 0.53* 0.71

n.i.

First year deaths

Upmeier et al. 200916 1032 70 12 1.0 0.61* 0.58* 0.47* No association None

Nilsson et al. 200917 Men Women

210 222

75 10 No association No association

n.i. None

Werle et al. 201118 187 ≥80 8.7 No association No association None

Bathum et al. 201319 Men¶¶ Women¶¶

13733 7493 14298 9142

60-70 ≥70

60-70 ≥70

1-9 1.0 1.0 1.0 1.0

0.67*** 0.71*** 0.56*** 0.66***

0.49*** 0.60*** 0.45*** 0.52***

0.45*** 0.52*** 0.47*** 0.46***

n.i. Terminal disease, CVD, diabetes

Linna et al. 201320 1260 ≥64 10 Inverse association** n.i. None

Jacobs et al. 201321 512 702

78-85 85-90

8 5


n.i. None

Takata et. al. 201422 207 ≥85 10 Survivors 3.2 mmol/l, non-survivors: 2.9 mmol/l*

No association None

Lv et al 201523 Men Women

266 596

≥80 3 1.0 1.0

0.71 0.68*

0.41 0.58**

0.40 0.66

n.i. First year deaths

Blekkenhorst et al. 201524 Women 1469 ≥70 10 n.i. No association None

Page 7 of 18


BMJ Open

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960




2 7

Finnish study of 1799 men aged 42-60 found no association between LDL-C and acute myocardial infarction after a follow-up of 4.5 years.26 In the Ibaraki Prefecture Health Study, which included 91,219 Japanese people followed for 10.3 years both total and CVD mortality was inversely associated with LDL-C.27 In the Lipid Research Clinic Prevalence study, where 1405 women age 50-69 years were followed for 14.5 years, the highest CVD mortality was seen in the lowest LDL-C tertile.28

DISCUSSION Our review of the literature revealed a notable absence of an association between LDL-C levels and mortality. LDL-C was only associated with total and CVD mortality in one of the cohorts, which included a small minority of the total number of individuals included in our review; and the hazard ratio in the fourth LDL-C quartile of that study was only 1.16 as regards total mortality and 1.19 as regards CVD mortality. Furthermore, in 76% of the total number of individuals, LDL-C was inversely associated with total mortality with statistical significance. These findings provide a paradoxical contradiction to the cholesterol hypothesis. As atherosclerosis commences mainly in middle-aged people and becomes more pronounced with increasing age, there should be an association between LDL-C levels and CVD mortality in old people as well. Our results raise several relevant questions. Why is high TC a risk factor for CVD in young and middle-aged people? Why do elderly people with high LDL-C live longer than people with low LDL-C? If high LDL-C is potentially beneficial for the elderly, then why does cholesterol-lowering treatment lower the risk of cardiovascular mortality? In the following we provide potential explanations for these challenging questions. Why is high LDL-C a risk factor in young and middle-aged people? A possible explanation is that young people are more stressed than older people. Multiple studies, mainly in young individuals, have shown that mental stress is able to increase TC from 8 to 65% in the course of less than an hour;29 and this is the case later in life as well.30 Mental stress may facilitate cardiovascular events through a number of mechanisms unrelated to cholesterol. The reason that elevated total cholesterol is a weaker risk factor with increasing age may be related to better ability of the elderly to cope with stress than younger people, in particular compared with young males in the midst of their careers.

Page 8 of 18


BMJ Open

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960




8

Another explanation may be that according to a study by Kario et al. stress does not raise cholesterol in elderly people. They had examined elderly hypertensive patients before and after a catastrophic earthquake and found that various coagulation factors had increased significantly, whereas their lipid profile was unchanged.31

Inverse causation. A common argument to explain why low lipid values are associated with an increased mortality is inverse causation, meaning that serious diseases cause low cholesterol. But this is not a likely explanation, because in four of the studies in table 1 terminal disease and mortality during the first years of observation were excluded. In spite of that, all four studies showed that the highest mortality was seen among those with the lowest initial LDL-C. Is high LDL-C beneficial? There is much evidence that low LDL-C is not a consequence of serious disease, but the very cause. Based on animal and laboratory experiments more than a dozen research groups have shown that LDL binds to and inactivates almost all kinds of microorganisms and their toxic products.32 Diseases caused or aggravated by microorganisms may therefore occur more often in people with low cholesterol, as observed in many studies.33 In a meta-analysis of 19 cohort studies including 68,406 deaths performed by the National Heart, Lung, and Blood Institute, TC was inversely associated with mortality from respiratory and gastrointestinal diseases, most of which are of an infectious origin.34 It is unlikely that these diseases caused the low TC, because the associations remained after the exclusion of deaths occurring during the first 5 years. In a study by Iribarren et al. more than 100,000 healthy individuals were followed for 15 years. At follow-up those whose initial cholesterol level was lowest had been hospitalized significantly more often because of an infectious disease during these 15 years.35 Evidently, low cholesterol, recorded at a time when these people were healthy, could not have been caused by a disease they had not yet encountered. High cholesterol also appears to protect against cancer. The reason may be that many cancer types are caused by viruses.36 Nine cohort studies including more than 140,000 individuals followed for 10 to 30 years have found an inverse association between cancer and TC measured at the beginning of the study, even after excluding deaths that occurred during the first 4 years.37 Furthermore, most cholesterol-lowering experiments on rodents have resulted in cancer, and in several case-control studies of cancer patients and controls matched for age and sex, significantly more cancer

Page 9 of 18


BMJ Open

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960




2 9

patients have been on cholesterol-lowering treatment.37 In agreement with these studies, cancer mortality is significantly lower in individuals with FH.38 Several studies have shown that statin-treated patients suffer less from cancer and other diseases, an apparent contradiction to the assumption that high LDL-C is beneficial. However, this view is based on cohort studies where statin-treated patients have been compared with non-treated individuals. There is a serious bias in such studies because most statin-treated patients have lived most of their lives with high cholesterol, which may render them less susceptible to developing cancer, independent of later statin treatment. Cholesterol-lowering treatment. The strongest argument for a medical hypothesis according to which a disease is said to be caused by factor X is experiments where absence of factor X is able to prevent the disease or improve its course. Many researchers consider that statin treatment fulfil these conditions. It is true that statin treatment is able to lower the risk of CVD, but this is most likely due to their pleiotropic effects because with one exception, exposure-response has not been found in any angiographic or clinical cholesterol-lowering trial;1 e.g. the beneficial effect of statin therapy, if any, is the same whether cholesterol is lowered maximally or only a little. Furthermore, in three trials the cholesterol-lowering effect of simvastatin was improved by the use of ezetimibe, but in all of them CVD and total mortality did not differ significantly between the treatment and the control groups although LDL-C was 26-63% lower in the former.39-41 A surprising finding is that LDL-C is lower than normal in patients with acute myocardial infarction. This has been documented repeatedly without a reasonable explanation.42-44 In one of the studies44 the authors concluded that cholesterol evidently should be lowered even more, but at a follow-up three years later mortality was twice as high among those whose LDL-C had been lowered the most compared with those whose cholesterol was unchanged or lowered only a little. If high LDL-C were the cause, the effect should have been the opposite.

CONCLUSIONS Our review provides the first comprehensive analysis of the literature about the association between LDL-C and mortality in the elderly. As the main goal of prevention of disease is prolongation of life, total mortality is the most important outcome. Total mortality is also the most easily defined outcome and the least subject to bias. The

Page 10 of 18


BMJ Open

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960




10

cholesterol hypothesis predicts that LDL-C will be associated with increased total and CVD mortality. Our review documents that almost all studies have demonstrated either an inverse association or no association between LDL-C and total mortality, as well as a lack of an association with CVD mortality. The cholesterol hypothesis seems to be in conflict with most of Bradford Hill´s criteria for causation, because of its lack of consistency, biological gradient and coherence. Our review provides the basis for more research about the cause of atherosclerosis and CVD and also for a re-evaluation of the guidelines for cardiovascular prevention, in particular because the benefits from statin treatment have been exaggerated.45-46

Contributors. UR and RS performed the paper search. UR wrote the first draft of the manuscript. All authors have made improvements of the content and the wording. Funding. The study has not been funded Data sharing statement. Raw data from this project can be made available by a request to the corresponding author. Competing interests. TH has received speaker fees from Nissui Pharmaceutical and Nippon Suisan Kaisha. KSM has a US patent for a homocysteine-lowering protocol; RH, ZH, HO, RS, UR have written books with criticism of the cholesterol hypothesis. DMD, JN, BH, NH, AM, PHL, LM, YO, PJR, SS and TS have no competing interests.

REFERENCES

1. Ravnskov U. Is atherosclerosis caused by high cholesterol? Q J M 2002;95:397-403. 2. Hamazaki T, Okuyama H, Ogushi Y, Hama R. Towards a paradigm shift in cholesterol



4. Goldstein JL, Brown MS. A Century of Cholesterol and Coronaries: From plaques to genes to statins. Cell 2015;161:161-72.

Page 11 of 18


BMJ Open

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960




2 11

5. Zimetbaum P, Frishman WH, Ooi WL, et al. Plasma lipids and lipoproteins and the incidence of cardiovascular disease in the very elderly: The Bronx Aging Study. Arterioscler Thromb 1992;12:416–23.


7. Räihä I1, Marniemi J, Puukka P, Toikka T, Ehnholm C, Sourander L. Effect of serum lipids, lipoproteins, and apolipoproteins on vascular and nonvascular mortality in the elderly. Arterioscler Thromb Vasc Biol 1997;17:1224-32.

8. Fried LP, Kronmal RA, Newman AB et al. Risk factors for 5-year mortality in older adults: the Cardiovascular Health Study. JAMA 1998;279:585-92.




12. Schupf N1, Costa R, Luchsinger J, Tang MX, Lee JH, Mayeux R. Relationship between plasma lipids and all-cause mortality in nondemented elderly. J Am Geriatr Soc 2005;53:219-26




16. Upmeier E, Lavonius S, Lehtonen A, Viitanen M, Isoaho H, Arve S. Serum lipids and their association with mortality in the elderly: a prospective cohort study. Aging Clin Exp Res. 2009;21:424-30.

17. Nilsson G, Ohrvik J, Lonnberg I, Hedberg P. Ten-year survival in 75-year-old men and women: Predictive ability of total cholesterol, HDL-C, and LDL-C. Curr Gerontol Geriatr

Page 12 of 18


BMJ Open

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960




12

Res Published Online First: 27 April 2009. doi: 10.1155/2009/158425. 18. Werle MH, Moriguchi E, Fuchs SC, Bruscato NM, de Carli W, Fuchs FD. Risk factors for

cardiovascular disease in the very elderly: results of a cohort study in a city in southern Brazil. Eur J Cardiovasc Prev Rehabil 2011;18:369-77.


20. Linna M, Ahotupa M, Löppönen MK, Irjala K, Vasankari T. Circulating oxidised LDL lipids, when proportioned to HDL-c, emerged as a risk factor of all-cause mortality in a population-based survival study. Age Ageing 2013;42:110-3

21. Jacobs JM, Cohen A, Ein-Mor E, Stessman J. Cholesterol, statins, and longevity from age 70 to 90 years. J Am Med Dir Assoc 2013;14:883-8.

22. Takata Y, Ansai T, Soh I et al. Serum total cholesterol concentration and 10-year mortality in an 85-year-old population. Clin Interv Aging 2014;9:293-300.







29. Dimsdale JE, Herd A. Variability of plasma lipids in response to emotional arousal.

Page 13 of 18


BMJ Open

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960




2 13

Psychosom Med 1982;44:413-30. 30. Steptoe A, Brydon L. Associations between acute lipid responses and fasting lipid

levels 3 years later. Health Psychol 2005;24:601-7. 31. Kario K, Matsuo T, Kobayashi H, Yamamoto K, Shimada K. Earthquake-induced

potentiation of acute risk factors in hypertensive elderly patients: possible triggering of cardiovascular events after a major earthquake. J Am Coll Cardiol 1997;29:926-33.

32. Ravnskov U, McCully KS. Vulnerable plaque formation from obstruction of vasa vasorum by homocysteinylated and oxidized lipoprotein aggregates complexed with microbial remnants and LDL autoantibodies. Ann Clin Lab Sci 2009;39:3-16

33. Ravnskov U. High cholesterol may protect against infections and atherosclerosis. Q J M 2003;96:927-34.

34. Jacobs D, Blackburn H, Higgins M et al. Report of the conference on low blood cholesterol: Mortality associations. Circulation 1992;86:1046–60.









43. Sachdeva A, Cannon CP, Deedwania PC, et al. Lipid levels in patients hospitalized with coronary artery disease: an analysis of 136,905 hospitalizations in get with the

Page 14 of 18


BMJ Open

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960




14

guidelines. Am Heart J 2009;157:111-7 44. Al-Mallah MH, Hatahet H, Cavalcante JL, Khanal S. Low admission LDL-cholesterol is

associated with increased 3-year all-cause mortality in patients with non ST segment elevation myocardial infarction. Cardiol J 2009;16:227-33

45. Diamond DM, Ravnskov U. How statistical deception created the appearance that statins are safe and effective in primary and secondary prevention of cardiovascular disease. Expert Rev Clin Pharmacol 2015;8:201-10.


Page 15 of 18


BMJ Open

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960




Section/topic # Checklist item Reported

on page

My comments

Title 1 Identify the report as a systematic review,

meta-analysis, or both.

1

Abstract 2 Provide a structured summary including,

as applicable: background; objectives; data

sources; study eligibility criteria,

participants, and interventions; study

appraisal and synthesis methods; results;

limitations; conclusions and implications of

key findings; systematic review

registration number.

2-3 We have no systematic review number because

from the section Methods it should be easy to see

how we have collected our data

Introduction

Rationale 3 Describe the rationale for the review in the

context of what is already known.

3

Objectives 4 Provide an explicit statement of questions

being addressed with reference to

participants, interventions, comparisons,

outcomes, and study design (PICOS).

4

Methods

Protocol and

registration

5 Indicate if a review protocol exists, if and

where it can be accessed (e.g., Web

address), and, if available, provide

registration information including


4 We have no review protocol

Eligibility

criteria

6 Specify study characteristics (e.g., PICOS,

length of follow-up) and report

characteristics (e.g., years considered,

language, publication status) used as

criteria for eligibility, giving rationale

4

Information 7 Describe all information sources (e.g., 4

Page 16 of 18


BMJ Open

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960




sources databases with dates of coverage, contact

with study authors to identify additional

studies) in the search and date last

searched.

Search 8 Present full electronic search strategy for

at least one database, including any limits

used, such that it could be repeated.

4

Study

selection

9 State the process for selecting studies (i.e.,

screening, eligibility, included in

systematic review, and, if applicable,

included in the meta-analysis).

4

Data collection

process

10 Describe method of data extraction from

reports (e.g., piloted forms, independently,

in duplicate) and any processes for

obtaining and confirming data from

investigators.

4

Data items 11 List and define all variables for which data

were sought (e.g., PICOS, funding sources)

and any assumptions and simplifications

made.

All data were presented clearly in the studies we

have reviewed and we found no evidence of bias

in any of them.

Risk of bias in

individual

studies

12 Describe methods used for assessing risk

of bias of individual studies (including

specification of whether this was done at

the study or outcome level), and how this

information is to be used in any data

synthesis.

3,4 See also #11

Summary

measures

13 State the principal summary measures

(e.g., risk ratio, difference in means).

5

Synthesis of

results

14 Describe the methods of handling data and

combining results of studies, if done,

including measures of consistency (e.g., I2)

See Table 1

Page 17 of 18


BMJ Open

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960




for each meta-analysis.

Risk of bias

across studies

15 Specify any assessment of risk of bias that

may affect the cumulative evidence (e.g.,

publication bias, selective reporting within

studies).

We have not found any indications of bias

Additional

analyses

16 Describe methods of additional analyses

(e.g., sensitivity or subgroup analyses,

meta-regression), if done, indicating which

were pre-specified.

We have not made any further analyses because

with one exception the association between LDL-

C and total and CVD mortality and baseline

selected risk factors was analyzed in all the

studies by means of Cox proportional hazards

regression models.

Results Study selection

17 Give numbers of studies screened, assessed

for eligibility, and included in the review,

with reasons for exclusions at each stage,

ideally with a flow diagram.

4-6

Study characteristics

18 For each study, present characteristics for

which data were extracted (e.g., study size,

PICOS, follow-up period) and provide the

citations.

See Table 1

Risk of bias within studies

19 For all outcomes considered (benefits or

harms), present, for each study: (a) simple

summary data for each intervention group

(b) effect estimates and confidence

intervals, ideally with a forest plot

See Table 1

Results of individual studies





intervals, ideally with a forest plot.

See Table 1

Synthesis of 21 Present results of each meta-analysis done, See Table 1

Page 18 of 18


BMJ Open

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960




results including confidence intervals and

measures of consistency.

Risk of bias

across studies

22 Present results of any assessment of risk of

bias across studies (see Item 15).

See above

Additional

analysis

23 Give results of additional analyses, if done


meta-regression [see Item 16]).

Irrelevant for our study

Discussion 24

Summary of

evidence

24 Summarize the main findings including the

strength of evidence for each main

outcome; consider their relevance to key

groups (e.g., healthcare providers, users,

and policy makers).

10

Limitations 25 Discuss limitations at study and outcome

level (e.g., risk of bias), and at review-level

(e.g., incomplete retrieval of identified

research, reporting bias).

3

Conclusions 26 Provide a general interpretation of the

results in the context of other evidence,

and implications for future research.

10

Funding 27 Describe sources of funding for the

systematic review and other support (e.g.,

supply of data); role of funders for the

systematic review.

There is no funding of our study

Page 19 of 18


BMJ Open

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960






Journal: BMJ Open



Date Submitted by the Author: 29-Mar-2016







Keywords:


EPIDEMIOLOGY


BMJ Open on 8 N



jopen.bmj.com

/B

MJ O


ownloaded from



Page 1 of 18


BMJ Open

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960

on 8 Novem


http://bmjopen.bm

j.com/

BM


jopen-2015-010401 on 12 June 2016. Dow

nloaded from



2 1

The Association Between Low-Density-Lipoprotein Cholesterol and Mortality in the Elderly. A Systematic Review. Uffe Ravnskov1, PhD David M Diamond,2 PhD Rokura Hama3, MD Tomohito Hamazaki4, MD Björn Hammarskjöld5, PhD Niamh Hynes6,16, MD Malcolm Kendrick7, MbChB Peter H. Langsjoen8, MD Aseem Malhotra9, Honorary consultant cardiologist Luca Mascitelli10, MD Kilmer S. McCully11, MD Yoichi Ogushi12, MS Harumi Okuyama13, PhD Paul J. Rosch14, MD Tore Schersten15, PhD Sherif Sultan6,16, PhD Ralf Sundberg17, PhD

Author affiliations





England.

Page 2 of 18


BMJ Open

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960




2









Number of words: 2959 ABSTRACT Objective. It is well known that total cholesterol becomes less of a risk factor or not at all for total and cardiovascular mortality with increasing age, but little is known as to whether low-density lipoprotein cholesterol (LDL-C), one component of total cholesterol, is associated with mortality in the elderly. Therefore we decided to investigate whether low-density-lipoprotein cholesterol (LDL-C) is a risk factor for total and cardiovascular mortality in the elderly.

Page 3 of 18


BMJ Open

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960




2 3

Setting, participants and outcome measures. We sought PubMed for cohort studies, where LDL-C had been investigated as a risk factor for total and/or CVD mortality in individuals age ≥60 years from the general population. Results. We identified 20 studies including 32 cohorts with a total of 73295 elderly people, where total mortality was recorded in 30 cohorts and CVD mortality in 9 cohorts. In 16 cohorts LDL-C was inversely associated with total mortality; in 14 of them with statistical significance; in 14 cohorts no association was found. In two cohorts CVD mortality was highest in the lowest LDL-C quartile and with statistical significance; in seven cohorts no association was found. No additional data available. Conclusions. As elderly people with high LDL-C live just as long or longer than those with low LDL-C, there is reason to question the validity of the cholesterol hypothesis (i.e., that cholesterol is inherently atherogenic). In addition the guidelines for cardiovascular disease prevention in the elderly should be re-evaluated.

STRENGTH AND LIMITATIONS OF THIS STUDY

∗ This is the first systematic review of cohort studies where LDL-C has been analysed as a risk factor for total and/or CVD mortality in elderly people

∗ Lack of an association or an inverse association between LDL-C and mortality was present in all studies.

∗ We may have overlooked studies, where an evaluation of LDL-C as a risk factor for mortality has been performed without mentioning it in the title or in the abstract. Minor errors may be present because the authors have not adjusted LDL-C by the same risk factors. Taking all studies together however the results have been corrected for 50 different factors

∗ Some of the participants with high LDL-C may have started cholesterol-lowering treatment during the observation period and in this way may have added a longer life to the group with high LDL-C. However, this effect must have been minimal, because almost all statin trials have lowered mortality by only two percentage points at most; whereas the 4-year mortality in the included cohorts was lowered between 9% and 36%. Furthermore, in the largest study that included 2/3 of the participants, the risk was lower among those with the highest LDL-C than among those on statin treatment.

∗∗∗∗ We may have overlooked relevant studies because we have only searched PubMed. The reason is that in a previous version of the manuscript where we sought with another search term, we identified 17 relevant studies in PubMed, but

Page 4 of 18


BMJ Open

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960




4

only two in OVID and EMBASE, and both of them were found in PubMed as well. Furthermore, we think that it is highly unlikely to find a study with the opposite result, as the result of all of those we have identified went in the same direction. INTRODUCTION Rationale. For decades, the mainstream view has been that the major cause of atherosclerosis and CVD is hypercholesterolemia. There are several contradictions to this view, however. No study of unselected people has found an association between total cholesterol (TC) and degree of atherosclerosis;1 in most of the Japanese epidemiological studies high TC is not a risk factor for stroke and an inverse risk factor for total mortality irrespective of age and sex.2 In a recent meta-analysis, performed by the Prospective Studies Collaboration there was an association between TC and CVD mortality in all ages and in both sexes.3 However, even in this analysis, the risk decreased with increasing age and became minimal after the age of 80. As atherosclerosis and CVD are mainly diseases of the elderly, the cholesterol hypothesis predicts that the association between CVD mortality and TC should be at least as strong in the elderly as in young people. There may be a bias in these studies however, because TC includes HDL-C, and multiple studies have shown that a high level of HDL-C is associated with a lower risk of CVD. Objectives. Therefore, it seems relevant to analyse LDL-C as a risk factor in elderly people. As the definition of CVD varies considerably in the scientific literature, we have chosen to analyse the association between LDL-C and both total and CVD mortality, because mortality has the least risk of bias among all outcome measures. If Goldstein and Brown’s recent statement that “the essential causative agent is cholesterol-carrying low-density lipoprotein”4 is correct, then LDL-C should be a strong risk factor for mortality in elderly people.

METHODS Search strategy. UR and RS sysƒLinnatematically searched Pubmed independently from initial to December 17, 2015, The following keywords were used: “lipoprotein AND (old OR elderly) AND mortality NOT animal NOT trial”. We also retrieved the references in the publications so as not to miss any relevant studies. The search was limited to

Page 5 of 18


BMJ Open

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960




2 5

studies in English. Inclusion and exclusion criteria. All included studies should meet the following criteria: the study should be a cohort study of people aged 60 years or older selected randomly from the general population, or a study, where the authors had found no significant differences between the participants and the source populations demographic characteristics. The studies should include an initial analysis of LDL-C, the length of the observation time and information about total and/or cardiovascular mortality at the end of follow-up. The studies should also include information about the association between LDL-C, and total and/or CVD mortality. We excluded studies that did not represent the general population (e.g. case-control studies; case reports; studies that included patients only); studies where data about elderly people were not given separately, and studies without multivariate correction for the association between LDL-C and total and/or CVD mortality. We accepted studies where the authors had excluded patients with serious diseases or individuals who had died during the last year. Study selection, data items and extraction. Studies where the title or abstract indicated that they might include LDL-C data of elderly people, were read In full, and the relevant data were extracted by at least three of the authors, e.g. year of publication, total number of subjects, sex, length of observation time, exclusion criteria, LDL-C measured at the start, and the association between initial LDL-C and risk of total and/or CVD mortality at follow-up. When more than 1 adjusted hazard ratio (HR) was reported, the HR with the most fully adjusted model was selected. Quality assessment. Due to the design of the study it satisfies almost all points of reliability and validity according to the Newcastle Ottawa Scale (NOS) as regards selection, comparability and exposure.5 Thus, all studies represented elderly people only; ascertainness of exposure (e.g. measurement of LDL-C) was present In all studies, and outcome was unknown at the start. It can be questioned, if all of the studies represented the general population, because, as shown below, in some of them various types of disease groups were excluded. RESULTS Study selection. Our search gave 2894 hits. We excluded 160 studies in non-English

Page 6 of 18


BMJ Open

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960




6

and 2453 studies because judged from the abstract it was obvious that they were irrelevant. The rest was read in full, but 242 of these studies were excluded as well, either because the participants did not represent the general population; or because LDL-C was not measured at the start; or because follow-up information was not given for the elderly separately; or because no information was present about mortality during the observation period (fig.1). Study characteristics. The remaining 20 studies including 32 cohorts with a total of 73295 participants met the inclusion criteria (fig. 1). Total mortality was recorded in 30 cohorts. In 16 of these cohorts the association was inverse and with statistical significance in 14; in one of the cohorts the association was mirror-J-formed with the lowest risk in the highest quartile; in the rest no association was found. CVD mortality was recorded in 9 cohorts; in one of them the association was almost U-formed with the lowest risk in the highest quartile (curvilinear fit: p=0.001); in one of them the association was mirror-J-formed and also with the lowest risk in the highest quartile (curvilinear fit: p=0.03); in the other seven cohorts no association was found (table 1).

Table 1. Association between LDL-C and total mortality and CVD mortality, respectively in 20 studies including 32 cohorts with 73295 individuals

from the general population above the age of 60. In the study by Fried et al. degree of significance was not reported.

Abbreviations: M: males; F: females; n.i.: no information; *: p<0.05; **: p<0.01; ***: p<0.001; ¶: HR for 7415 men and 8314 women on statin treatment was 0.63 and 0.61, respectively.

Authors Race

if indicated

Sex N Age; years

Obs. Year

s

Total mortality LDL-C tertiles or quartiles

(Hazard ratios)

CVD mortality LDL-C-quartiles (Hazard ratios)

Exclusion criteria and other remarks


Zimetbaum et al. 19926 MF 350 75-85 6,3 No association n.i. Absence of terminal illness, dementia

Kronmal et al. 19937 MF 747 66-75

10 No association n.i.

None 176 >75 No association n.i.

Räihä et al. 19978 MF 347 ≥65 11 n.i. No association Living in an institution

Page 7 of 18


BMJ Open

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960




2 7

Fried et al. 19989 MF 5201 ≥65 5 1.0 ? ? 0.66

(signif.) n.i.

Wheel-chair bound; cancer treatment

Chyou & Eaker 200010 M 367

≥65 8-10 No association

n.i. None F 622 No association

Weverling-Rijnsburger et al. 200311

MF 599 ≥85 4 1.0 0.57 0.71

p for trend* No association None

Psaty et al. 200412 M

5201 ≥65 7,5 No association

n.i. CHD, stroke, heart failure F No association

Schupf et al. 200513 MF 2277 ≥65 3 1.0 0.79 0.63 0.53

p for trend** n.i. Dementia

Tikhonoff et al. 200514

M 1233

≥65 11,1

Mirror-J-formed association with the highest risk in the lowest quartile

Almost U-formed association with the highest risk in the lowest quartile*

Dementia

F 1887 Inverse association*

Mirror-J-formed association with the highest risk in the lowest quartile*

Störk et al. 200615 M 403 >70 4 No association No association None


Caucasians MF 705

≥65 3.5

1.0 0.89 0.72 0.56*

n.i. Dementia, first year deaths

African-Americans

MF 797 1.0 0.79 0.58 0.53*

Hispanics MF 1054 1.0 0.79 0.79 0.71

Upmeier et al. 200917 MF 1032 70 12 No association No association None

Nilsson et al. 200918 M 210

75 10 No association


Werle et al. 201119 MF 187 ≥80 8,7 No association No association None

Bathum et al. 201320 ¶

M 13733 60-70

1-9

1.0 0.67*** 0.49*** 0.45***

n.i.

Terminal disease, CVD, diabetes, subjects with a prescription of statin during the last year before test date

7493 ≥70 1.0 0.71*** 0.60*** 0.52***

F

14298 60-70 1.0 0.56*** 0.45*** 0.47***

9142 ≥70 1.0 0.66*** 0.52*** 0.46***

Page 8 of 18


BMJ Open

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960




8

Linna et al. 201321 MF 1260 ≥64 10 Inverse association** n.i. None

Jacobs et al. 201322 MF 512 78-85 8 No association

n.i. None 702 85-90 5 No association

Takata et. al. 201423 MF 207 85 10 Survivors 3.2 mmol/l; non-

survivors: 2.9 mmol/l** No association None

Lv et al 201524

M 266

≥80 3

1.0 0.67 0.43 0.41*

n.i. First year deaths F 596 1.0 0.69* 0.57** 0.59*

MF

1.0 0.72* 0.59** 0.60*

Blekkenhorst et al. 201525 F 1469 ≥70 10 n.i. No association None

Risk of bias across studies. A common argument for the increased risk of mortality among people with low cholesterol is that serious diseases may lower cholesterol. In 10 of the studies no exclusions were made and if the argument is valid, this is obviously a bias. However, in four studies participants with terminal illness or who died during the first observation year were excluded. In one of them6 LDL-C was not associated with total mortality; in the three others,16,20,24 which included about two thirds of the total number of participants in the review, LDL-C was inversely associated with total mortality and with statistical significance. A bias may arrive because the studies did not correct for the same risk factors and some of them did not inform the reader about which risk factors they have corrected for However, taking all studies together 50 different risk factors have been corrected for in the Cox analyses (table 2).

Table 2. Factors corrected for in the multifactorial analyses of each study. In studies not corrected for age all participants were of the same age.

Authors Factors corrected for

Zimetbaum et al. Age, smoking, health self-rating, BMI, BP, diabetes, MI, IQ.

Kronmal et al. Age, sex, BP, BMI, BMI squared, smoking.

Räihä et al. Age, sex, smoking, alcohol use, BMI, CHD, BP, diabetes.

Page 9 of 18


BMJ Open

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960




2 9

Fried et al. Race, height, hip and waist circumference, BMI, smoking, diastolic BP, antihypertensive and lipd-lowering treatment, TC, HDL-C, TG, diabetes, fasting insulin, factor VII and VIII, serum potassium and uric acid, asthma, emphysema, angina, MI, stroke, claudication, arthritis, renal disease, cancer, hearing and visual impairment, FEV, mitral stenosis and regurgitation, carotis stenosis

Chyou & Eaker Age, sex, CHD, stroke, cancer, diabetes, BP, BMI, smoking, alcohol consumption

Weverling-Rijnsburger et al. No information

Psaty et al. Age, sex, smoking, diabetes, systolic BP, CVD, CRP, carotid IMT

Schupf et al. Age, sex, ethnic group, BMI, level of education, APOE genotype, diabetes, heart disease, stroke, cancer, smoking

Tikhonoff et al. Age, BP, pulse rate, BMI, CV events, smoking, alcohol intake, diabetes, serum creatinine, uric acid.

Störk et al. No information

Akerblom et al. Age, sex, education, BMI, APOE genotype, heart disease, BP, diabetes, stroke, dementia, smoking.

Upmeier et al. Gender, BMI, smoking, angina pectoris, stroke, diabetes, hypertension, cancer

Nilsson et al. BMI, smoking, non-HDL-C, TG, BP, diabetes, previous MI

Werle et al. No information

Bathum et al. No information

Linna et al. Age, sex, BMI, smoking, BP, diabetes

Jacobs et al. Statin treatment, sex, CHD, BP, neoplasm, self-rated health, smoking, albumin, BMI, triglycerides.

Takata et. al. Sex, smoking, alcohol intake, stroke, heart disease, serum albumin, BMI, systolic BP

Lv et al 2015 Age, sex, marital status, smoking, alcohol drinking,

Page 10 of 18


BMJ Open

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960




10

tea drinking, central obesity, cognitive impairment, daily activity, blindness, anemia, BT, diabetes, CKD, HDL-C

Blekkenhorst et al. Age, BMI, physical activity, renal function, smoking, diabetes, CVD, low-dose aspirin, antihypertensive and statin medication, energy intake, SFA

Abbreviations: BMI: body mass index; BP: blood pressure; HDL-C: high-density lipoprotein; IMT: Intima-media thickness; CRP: C-reactive protein; MI: Myocardial infarction; CKD; chronic kidney disease In our literature search we also identified several studies including individuals younger than 60 years and with similar results. A study of 3,499 Thai people aged 35-54 years found no association between LDL-C and CVD mortality after 17 years of follow-up.26 A Finnish study of 1799 men aged 42-60 found no association between LDL-C and acute myocardial infarction after a follow-up of 4.5 years.27 In the Ibaraki Prefecture Health Study, which included 91,219 Japanese people followed for 10.3 years both total and CVD mortality was inversely associated with LDL-C.28 In the Lipid Research Clinic Prevalence study, where 1405 women age 50-69 years were followed for 14.5 years, the highest CVD mortality was seen in the lowest LDL-C tertile.29 DISCUSSION Our review of the literature revealed either an absence or an inverse association between LDL-C levels and mortality among elderly people. In 76% of the total number of individuals LDL-C was even inversely associated with total mortality and with statistical significance. These findings provide a paradoxical contradiction to the cholesterol hypothesis. As atherosclerosis commences mainly in middle-aged people and becomes more pronounced with increasing age, there should be an association between LDL-C levels and CVD mortality in old people as well. Our results raise several relevant questions. Why is high TC a risk factor for CVD in young and middle-aged people? Why do elderly people with high LDL-C live longer than people with low LDL-C? If high LDL-C is potentially beneficial for the elderly, then why does cholesterol-lowering treatment lower the risk of cardiovascular mortality? In the following we provide potential explanations for these challenging questions.

Page 11 of 18


BMJ Open

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960




2 11

Why is high LDL-C a risk factor in young and middle-aged people only? A possible explanation is that young people are more stressed than older people. Many studies, mainly in young individuals, have shown that mental stress is able to increase TC from 8 to 65% in the course of less than an hour;30 and this is the case later in life as well31,32 and many studies have also shown that various types of stress is a strong risk factor for CVD.33,34 Mental stress may facilitate cardiovascular events through a number of mechanisms unrelated to cholesterol. The reason that elevated total cholesterol is a weaker risk factor with increasing age may be related to better ability of the elderly to cope with stress than younger people, in particular compared with young males in the midst of their careers. Another explanation may be that according to a study by Kario et al. stress does not raise cholesterol in elderly people. They had examined elderly hypertensive patients before and after a catastrophic earthquake and found that various coagulation factors had increased significantly, whereas their lipid profile was unchanged.33

Inverse causation. A common argument to explain why low lipid values are associated with an increased mortality is inverse causation, meaning that serious diseases cause low cholesterol. But this is not a likely explanation, because in five of the studies in table 1 terminal disease and mortality during the first years of observation were excluded. In spite of that, three of them showed that the highest mortality was seen among those with the lowest initial LDL-C. Is high LDL-C beneficial? There is much evidence that low LDL-C is not a consequence of serious disease, but the very cause. Based on animal and laboratory experiments more than a dozen research groups have shown that LDL binds to and inactivates almost all kinds of microorganisms and their toxic products.35 Diseases caused or aggravated by microorganisms may therefore occur more often in people with low cholesterol, as observed in many studies.36 In a meta-analysis of 19 cohort studies for instance, performed by the National Heart, Lung, and Blood Institute and including 68,406 deaths, TC was inversely associated with mortality from respiratory and gastrointestinal diseases, most of which are of an infectious origin.37 It is unlikely that these diseases caused the low TC, because the associations remained after the exclusion of deaths occurring during the first 5 years. In a study by Iribarren et al. more

Page 12 of 18


BMJ Open

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960




12

than 100,000 healthy individuals were followed for 15 years. At follow-up those whose initial cholesterol level was lowest had been hospitalized significantly more often because of an infectious disease during these 15 years.38 Evidently, low cholesterol, recorded at a time when these people were healthy, could not have been caused by a disease they had not yet encountered. High cholesterol also appears to protect against cancer. The reason may be that many cancer types are caused by viruses.39 Nine cohort studies including more than 140,000 individuals followed for 10 to 30 years have found an inverse association between cancer and TC measured at the start of the study, even after excluding deaths that occurred during the first 4 years.40 Furthermore, most cholesterol-lowering experiments on rodents have resulted in cancer, and in several case-control studies of cancer patients and controls matched for age and sex, significantly more cancer patients have been on cholesterol-lowering treatment.40 In agreement with these studies, cancer mortality is significantly lower in individuals with FH.41 Several studies have shown that statin-treated patients suffer less from cancer and other diseases, an apparent contradiction to the assumption that high LDL-C is beneficial. However, this view is based on cohort studies where statin-treated patients have been compared with non-treated individuals. There is a serious bias in such studies because most statin-treated patients have lived most of their lives with high cholesterol, which may render them less susceptible to developing cancer, independent of later statin treatment. Cholesterol-lowering treatment. The strongest argument for a medical hypothesis according to which a disease is said to be caused by factor X is experiments where absence of factor X is able to prevent the disease or improve its course. Many researchers consider that statin treatment fulfil these conditions. It is true that statin treatment is able to lower the risk of CVD, but this is most likely due to their pleiotropic effects because with one exception, exposure-response has not been found in any angiographic or clinical cholesterol-lowering trial;1 e.g. the beneficial effect of statin therapy, if any, is the same whether cholesterol is lowered maximally or only a little. Furthermore, in three trials the cholesterol-lowering effect of simvastatin was improved by the use of ezetimibe, but in all of them CVD and total mortality did not differ significantly between the treatment and the control groups although LDL-C was 26-63% lower in the former.42-44

Page 13 of 18


BMJ Open

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960




2 13

A surprising finding is that LDL-C is lower than normal in patients with acute myocardial infarction. This has been documented repeatedly without a reasonable explanation.45-47 In one of the studies47 the authors concluded that cholesterol evidently should be lowered even more, but at a follow-up three years later mortality was twice as high among those whose LDL-C had been lowered the most compared with those whose cholesterol was unchanged or lowered only a little. If high LDL-C were the cause, the effect should of course have been the opposite.

CONCLUSIONS Our review provides the first comprehensive analysis of the literature about the association between LDL-C and mortality in the elderly. As the main goal of prevention of disease is prolongation of life, total mortality is the most important outcome, and is also the most easily defined outcome and least subject to bias. The cholesterol hypothesis predicts that LDL-C will be associated with increased total and CVD mortality. Our review has shown either no or an inverse association between LDL-C and both total and CVD mortality. The cholesterol hypothesis seems to be in conflict with most of Bradford Hill´s criteria for causation, because of its lack of consistency, biological gradient and coherence. Our review provides the basis for more research about the cause of atherosclerosis and CVD and also for a re-evaluation of the guidelines for cardiovascular prevention, in particular because the benefits from statin treatment have been exaggerated.48-50

Contributors. UR and RS performed the paper search. UR wrote the first draft of the manuscript. All authors have read the papers and made improvements of the content and the wording. The relevant data from each study have been Funding. The study has not been funded Data sharing statement. Raw data from this project can be made available by a request to the corresponding author. Competing interests. TH has received speaker fees from Nissui Pharmaceutical and Nippon Suisan Kaisha. KSM has a US patent for a homocysteine-lowering protocol; RH, ZH, HO, RS, UR have written books with criticism of the cholesterol hypothesis. DMD,

Page 14 of 18


BMJ Open

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960




14

JN, BH, NH, AM, PHL, LM, YO, PJR, SS and TS have no competing interests.

REFERENCES 1. Ravnskov U. Is atherosclerosis caused by high cholesterol? Q J M 2002;95:397-403. 2. Hamazaki T, Okuyama H, Ogushi Y, Hama R. Towards a paradigm shift in cholesterol



4. Goldstein JL, Brown MS. A Century of Cholesterol and Coronaries: From plaques to genes to statins. Cell 2015;161:161-72.

5. Stang A. Critical evaluation of the Newcastle-Ottawa scale for the assessment of the quality of nonrandomized studies in meta-analyses. Eur J Epidemiol. 2010;25:603–5.



8. Räihä I, Marniemi J, Puukka P, Toikka T, Ehnholm C, Sourander L. Effect of serum lipids, lipoproteins, and apolipoproteins on vascular and nonvascular mortality in the elderly. Arterioscler Thromb Vasc Biol 1997;17:1224-32.





Page 15 of 18


BMJ Open

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960




2 15

13. Schupf N, Costa R, Luchsinger J, Tang MX, Lee JH, Mayeux R. Relationship between plasma lipids and all-cause mortality in nondemented elderly. J Am Geriatr Soc 2005;53:219-26




17. Upmeier E, Lavonius S, Lehtonen A, Viitanen M, Isoaho H, Arve S. Serum lipids and their association with mortality in the elderly: a prospective cohort study. Aging Clin Exp Res. 2009;21:424-30.

18. Nilsson G, Ohrvik J, Lonnberg I, Hedberg P. Ten-year survival in 75-year-old men and women: Predictive ability of total cholesterol, HDL-C, and LDL-C. Curr Gerontol Geriatr Res Published Online First: 27 April 2009. doi: 10.1155/2009/158425.

19. Werle MH, Moriguchi E, Fuchs SC, Bruscato NM, de Carli W, Fuchs FD. Risk factors for cardiovascular disease in the very elderly: results of a cohort study in a city in southern Brazil. Eur J Cardiovasc Prev Rehabil 2011;18:369-77.


21. Linna M, Ahotupa M, Löppönen MK, Irjala K, Vasankari T. Circulating oxidised LDL lipids, when proportioned to HDL-c, emerged as a risk factor of all-cause mortality in a population-based survival study. Age Ageing 2013;42:110-3




25. Blekkenhorst LC, Prince RL, Hodgson JM, et al. Dietary saturated fat intake and

Page 16 of 18


BMJ Open

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960




16

atherosclerotic vascular disease mortality in elderly women: a prospective cohort study. Am J Clin Nutr 2015;101:1263-8.





30. Dimsdale JE, Herd A. Variability of plasma lipids in response to emotional arousal. Psychosom Med 1982;44:413-30.

31. Steptoe A, Brydon L. Associations between acute lipid responses and fasting lipid levels 3 years later. Health Psychol 2005;24:601-7.

32. Kario K, Matsuo T, Kobayashi H, Yamamoto K, Shimada K. Earthquake-induced potentiation of acute risk factors in hypertensive elderly patients: possible triggering of cardiovascular events after a major earthquake. J Am Coll Cardiol 1997;29:926-33.

33. Hemingway H, Marmot M. Evidence based cardiology: psychosocial factors in the aetiology and prognosis of coronary heart disease. Systematic review of prospective cohort studies. BMJ 1999;318:1460–7.

34. Rozanski A, Blumenthal JA, Davidson KW, Saab PG, Kubzansky L. The epidemiology, pathophysiology, and management of psychosocial risk factors in cardiac practice: the emerging field of behavioral cardiology. J Am Coll Cardiol 2005;45:637–51.

35. Ravnskov U, McCully KS. Vulnerable plaque formation from obstruction of vasa vasorum by homocysteinylated and oxidized lipoprotein aggregates complexed with microbial remnants and LDL autoantibodies. Ann Clin Lab Sci 2009;39:3-16



Page 17 of 18


BMJ Open

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960




2 17









46. Sachdeva A, Cannon CP, Deedwania PC, et al. Lipid levels in patients hospitalized with coronary artery disease: an analysis of 136,905 hospitalizations in get with the guidelines. Am Heart J 2009;157:111-7




50. de Lorgeril M, Rabaeus M. Beyond confusion and controversy, Can we evaluate the real efficacy and safety of cholesterol-lowering with statins? J Controversies Biomed Res 2015;1:67-92.

Page 18 of 18


BMJ Open

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960




106x150mm (300 x 300 DPI)

Page 19 of 18


BMJ Open

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960

on 8 Novem


http://bmjopen.bm

j.com/

BM


jopen-2015-010401 on 12 June 2016. Dow

nloaded from



Lack of an Association or an Inverse Association Between

Low-Density-Lipoprotein Cholesterol and Mortality in the

Elderly. A Systematic Review

Journal: BMJ Open



Date Submitted by the Author: 21-Apr-2016

Complete List of Authors: Ravnskov, Uffe; I am an independent researcher Diamond, David; University of South Florida, Department of Molecular Pharmacology and Physiology. Department of Psychology

Hama, Rokuro; Japan Institute of Pharmacovigilance, Director Hamazaki, Tomohito ; Toyama Jonan Onsen Daini Hospital. University of Toyama, , Department of Internal Medicine Hammarskjöld, Björn; Strömstad Academy Hynes, Niamh ; National University of Ireland, Galway Clinic; Galway University Hospitals, Western Vascular Institute Kendrick, Malcolm; Intermediate Care Team Langsjoen, Peter; Solo Practice in Cardiology Malhotra, Aseem; Royal Free Hospital, Cardiology Mascitelli, Luca ; Comando Brigata alpina Julia/Multinational Land Force, Medical Service McCully, Kilmer; VA Boston Healthcare System, Pathology and Laboratory

Medicine Service Ogushi, Yoichi; Tokai University Okuyama, Harumi; Nagoya City University ; Kinjo Gakuin University,, Institute for Consumer Science and Human Life Rosch, Paul; New York Medical College, American Institute of Stress, Medicine, Psychiatry Schersten, Tore; University of Gothenburg, Sahlgren's Academy Sultan, Sherif; National University of Ireland, Galway Clinic; Galway University Hospitals, Western Vascular Institute Sundberg, Ralf; Slottsstadens Läkarhus

<b>Primary Subject

Heading</b>: Cardiovascular medicine


Keywords:

Risk factor, LDL-cholesterol, cardiovascular mortality, total mortality, elderly,, Adult cardiology < CARDIOLOGY, Myocardial infarction < CARDIOLOGY, GERIATRIC MEDICINE, PREVENTIVE MEDICINE, EPIDEMIOLOGY


BMJ Open on 8 N



jopen.bmj.com

/B

MJ O


ownloaded from



Page 1 of 24


BMJ Open

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960

on 8 Novem


http://bmjopen.bm

j.com/

BM


jopen-2015-010401 on 12 June 2016. Dow

nloaded from



1

Lack of an Association or an Inverse Association Between Low-Density-Lipoprotein Cholesterol and Mortality in the Elderly. A Systematic Review. Uffe Ravnskov1, PhD David M Diamond,2 PhD Rokura Hama3, MD Tomohito Hamazaki4, MD Björn Hammarskjöld5, PhD Niamh Hynes6,16, MD Malcolm Kendrick7, MbChB Peter H. Langsjoen8, MD Aseem Malhotra9, Honorary consultant cardiologist Luca Mascitelli10, MD Kilmer S. McCully11, MD Yoichi Ogushi12, MS Harumi Okuyama13, PhD Paul J. Rosch14, MD Tore Schersten15, PhD Sherif Sultan6,16, PhD Ralf Sundberg17, PhD

Author affiliations


Center for Preclinical and Clinical Research on PTSD, University of South Florida. Tampa, Florida, USA



England.

Page 2 of 24


BMJ Open

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960




2








Keywords: Risk factor, LDL-cholesterol, cardiovascular mortality, all-cause mortality, elderly,


Page 3 of 24


BMJ Open

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960




3

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 of age 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 of age. This finding is inconsistent with the cholesterol hypothesis, (i.e., that cholesterol, particularly LDL-C, is inherently atherogenic). As 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.

Page 4 of 24


BMJ Open

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960




4

STRENGTH AND LIMITATIONS OF THIS STUDY

∗ This is the first systematic review of cohort studies where LDL-C has been analysed as a risk factor for all-cause and/or CV mortality in elderly people

∗ Lack of an association or an inverse association between LDL-C and mortality was present in all studies.

∗ We may not have included studies where an evaluation of LDL-C as a risk factor for mortality was performed but where it was not mentioned in the title or in the abstract.

∗∗∗∗ We may have overlooked relevant studies because we have only searched PubMed.

∗ Minor errors may be present because some of the authors may not have adjusted LDL-C by appropriate risk factors.

∗ Some of the participants with high LDL-C may have started statin treatment during the observation period and in this way may have added a longer life to the group with high LDL-C, and some of them may have started with a diet able to influence the risk of mortality.

∗∗∗∗ We may have overlooked a small number of relevant studies because we only searched papers in English.

Page 5 of 24


BMJ Open

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960




5

INTRODUCTION Rationale. For decades, the mainstream view has been that an elevated level of total cholesterol (TC) is a primary cause of atherosclerosis and CV disease (CVD). There are several contradictions to this view, however. No study of unselected people has found an association between total cholesterol (TC) and degree of atherosclerosis.1 Moreover, in most of the Japanese epidemiological studies high TC is not a risk factor for stroke and further, there is an inverse association between TC and all-cause mortality, irrespective of age and sex.2 In a recent meta-analysis, performed by the Prospective Studies Collaboration there was an association between TC and CV mortality in all ages and in both sexes.3 However, even in this analysis, the risk decreased with increasing age and became minimal after the age of 80. As atherosclerosis and CVD are mainly diseases of the elderly, the cholesterol hypothesis predicts that the association between CV mortality and TC should be at least as strong in the elderly as in young people. There may be a confounding influence in these studies however, because TC includes HDL-C, and multiple studies have shown that a high level of HDL-C is associated with a lower risk of CVD. Objectives. We examined the literature assessing LDL-C as a risk factor for mortality in elderly people. As the definition of CVD varies considerably in the scientific literature, we have chosen to focus on the association between LDL-C and all-cause and CVD mortality, because mortality has the least risk of bias among all outcome measures. If Goldstein and Brown’s recent statement that LDL-C is “the essential causative agent” of CVD4 is correct, then we should find that LDL-C is a strong risk factor for mortality in elderly people.

METHODS Search strategy. UR and RS systematically searched Pubmed independently from initial to December 17, 2015. The following keywords were used: “lipoprotein AND (old OR elderly) AND mortality NOT animal NOT trial”. We also retrieved the references in the publications so as not to miss any relevant studies. The search was limited to studies in English. Inclusion and exclusion criteria. All included studies should meet the following

Page 6 of 24


BMJ Open

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960




6

criteria: the study should be a cohort study of people aged 60 years or older selected randomly from the general population, or a study, where the authors had found no significant differences between the participants and the source populations demographic characteristics. The studies should include an initial assessment of LDL-C levels, the length of the observation time and information about all-cause and/or cardiovascular mortality at the end of follow-up. The studies should also include information about the association between LDL-C, and all-cause and/or CVD mortality. We excluded studies that did not represent the general population (e.g. case-control studies; case reports; studies that included patients only); studies where data about elderly people were not given separately, and studies without multivariate correction for the association between LDL-C and all-cause and/or CV mortality. We accepted studies where the authors had excluded patients with serious diseases or individuals who had died during the first year. Study selection, data items and extraction. Studies where the title or abstract indicated that they might include LDL-C data of elderly people, were read In full, and the relevant data were extracted by at least three of the authors, e.g. year of publication, total number of subjects, sex, length of observation time, exclusion criteria, LDL-C measured at the start, and the association between initial LDL-C and risk of all-cause and/or CV mortality at follow-up. When more than one adjusted hazard ratio (HR) was reported, the HR with the most fully adjusted model was selected. Quality assessment. The design of the study satisfies almost all points of reliability and validity according to the Newcastle Ottawa Scale (NOS) as regards selection, comparability and exposure.5 Thus, all studies represented elderly people only; ascertainness of exposure (e.g. measurement of LDL-C) was present In all studies, and outcome was unknown at the start. It can be questioned, if all of the studies represented the general population, because, as shown below, in some of them various types of disease groups were excluded. RESULTS Study selection. Our search gave 2,894 hits. We excluded 160 studies, which were in non-English and 2,452 studies because, judged from the abstract, it was obvious that they were irrelevant.

Page 7 of 24


BMJ Open

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960




7

, The rest of the papers were read in full, 263 of these studies were excluded for the following reasons: 1) the participants did not represent the general population; 2) LDL-C was not measured at the start; 3) follow-up information was not given for the elderly separately; or 4) no information was present about mortality during the observation period (fig.1). One of the studies6 was excluded because it included the same individuals as in a previous study.7

Study characteristics. The remaining 19 studies including 30 cohorts with a total of 68,094 participants met the inclusion criteria (fig. 1). All-cause mortality was recorded in 28 cohorts. In 16 of these cohorts (representing 92% of the individuals) the association was inverse and with statistical significance in 14; in one of the cohorts the association was mirror-J-formed with the lowest risk in the highest quartile; in the rest of the papers no association was found. CV mortality was recorded in 9 cohorts; in one of them the association was almost U-shaped with the lowest risk in the highest quartile (curvilinear fit: p=0.001); in one of them the association was mirror-J-formed and also with the lowest risk in the highest quartile (curvilinear fit: p=0.03); in the other seven cohorts no association was found (table 1).

Table 1. Association between LDL-C and all-cause mortality and CVD mortality, respectively in 19 studies including 30 cohorts with 68,094 individuals from the general population above the age of 60. In the study by Fried et al. degree of significance was not reported. Abbreviations: M: males; F: females; n.i.: no information; *: p<0.05; **: p<0.01; ***: p<0.001; ¶: HR for 7,415 men and 8,314 women on statin treatment was 0.63 and 0.61, respectively.

Authors Race

if indicated

Sex N Age; years

Obs. Year

s

All-cause mortality LDL-C tertiles or quartiles

(Hazard ratios)

CV mortality LDL-C-quartiles (Hazard ratios)

Exclusion criteria


Zimetbaum et al. 19928 MF 350 75-85 6,3 No association n.i. Terminal illness, dementia

Kronmal et al. 19939 MF 747 66-75

10 No association n.i.

None 176 >75 No association n.i.

Räihä et al. 199710 MF 347 ≥65 11 n.i. No association Living in an institution

Page 8 of 24


BMJ Open

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960




8

Fried et al. 19987 MF 5,201 ≥65 4.8 1.0 ? ? 0.66

(signif.) n.i.

Wheel-chair bound; cancer treatment

Chyou & Eaker 200011 M 367

≥65 8-10 No association


Weverling-Rijnsburger et al. 200312

MF 599 ≥85 4 1.0 0.57 0.71

p for trend* No association None

Schupf et al. 200513 MF 2,277 ≥65 3 1.0 0.79 0.63 0.53

p for trend** n.i. Dementia

Tikhonoff et al. 200514

M 1,233

≥65 11,1

Mirror-J-formed association with the highest risk in the lowest quartile

Almost U-formed association with the highest risk in the lowest quartile*

Dementia

F 1,887 Inverse association*

Mirror-J-formed association with the highest risk in the lowest quartile*

Störk et al. 200615 M 403 >70 4 No association No association None


Caucasians MF 705

≥65 3.5

1.0 0.89 0.72 0.56*

n.i. Dementia, first year deaths

African-Americans

MF 797 1.0 0.79 0.58 0.53*

Hispanics MF 1,054 1.0 0.79 0.79 0.71

Upmeier et al. 200917 MF 1,032 70 12 No association No association None

Nilsson et al. 200918 M 210

75 10 No association


Werle et al. 201119 MF 187 ≥80 8,7 No association No association None

Bathum et al. 201320 ¶

M 13,733 60-70

1-9

1.0 0.67*** 0.49*** 0.45***

n.i.

Terminal disease, CVD, diabetes, subjects with a prescription of statin during the last year before test date

7,493 ≥70 1.0 0.71*** 0.60*** 0.52***

F

14,298 60-70 1.0 0.56*** 0.45*** 0.47***

9,142 ≥70 1.0 0.66*** 0.52*** 0.46***

Linna et al. 201321 MF 1,260 ≥64 10 Inverse association** n.i. None

Jacobs et al. 201322 MF 512 78-85 8 No association n.i. None

Page 9 of 24


BMJ Open

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960




9

702 85-90 5 No association

Takata et al. 201423 MF 207 85 10 Survivors 3.2 mmol/l; non-

survivors: 2.9 mmol/l** No association None

Lv et al 201524

M 266

≥80 3

1.0 0.67 0.43 0.41*

n.i. First year deaths F 596 1.0 0.69* 0.57** 0.59*

MF

1.0 0.72* 0.59** 0.60*

Blekkenhorst et al. 201525 F 1,469 ≥70 10 n.i. No association None

Risk of bias across studies. One explanation for the increased risk of mortality among people with low cholesterol is that serious diseases may lower cholesterol soon before death occurs. Evidence to support this hypothesis may be obtained from 10 of the studies in which no exclusions were made for individuals with terminal illnesses. However, in four of the studies participants with a terminal illness or who had died during the first observation year were excluded. In one of those studies8 LDL-C was not associated with all-cause mortality; in the three others,16,20,24 which included more than 70% of the total number of participants in our review, LDL-C was inversely associated with all-cause mortality and with statistical significance. Thus, there is little support for the hypothesis that our analysis is biased by end of life changes in LDL-C levels. It is also potentially relevant that all studies did not correct for the same risk factors, and some of them did not inform the reader about which risk factors they corrected for. However, taking all studies together, 50 different risk factors were corrected for in the Cox analyses (table 2).

Table 2. Factors corrected for in the multifactorial analyses of each study. In studies not corrected for age all participants were of the same age.

Authors Factors adjusted for

Zimetbaum et al. Age, smoking, health self-rating, BMI, BP, diabetes, MI, IQ.

Kronmal et al. Age, sex, BP, BMI, BMI squared, smoking.

Räihä et al. Age, sex, smoking, alcohol use, BMI, CHD, BP, diabetes.

Page 10 of 24


BMJ Open

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960




10

Fried et al. Race, height, hip and waist circumference, BMI, smoking, diastolic BP, antihypertensive and lipd-lowering treatment, TC, HDL-C, TG, diabetes, fasting insulin, factor VII and VIII, serum potassium and uric acid, asthma, emphysema, angina, MI, stroke, claudication, arthritis, renal disease, cancer, hearing and visual impairment, FEV, mitral stenosis and regurgitation, carotis stenosis

Chyou & Eaker Age, sex, CHD, stroke, cancer, diabetes, BP, BMI, smoking, alcohol consumption

Weverling-Rijnsburger et al. Comorbidities, BMI, use of β-blocking agents, thyroid dysfunction

Schupf et al. Age, sex, ethnic group, BMI, level of education, APOE genotype, diabetes, heart disease, stroke, cancer, smoking

Tikhonoff et al. Age, BP, pulse rate, BMI, CV events, smoking, alcohol intake, diabetes, serum creatinine, uric acid.

Störk et al. Cox regression analysis. No details

Akerblom et al. Age, sex, education, BMI, APOE genotype, heart disease, BP, diabetes, stroke, dementia, smoking.

Upmeier et al. Gender, BMI, smoking, angina pectoris, stroke, diabetes, hypertension, cancer

Nilsson et al. BMI, smoking, non-HDL-C, TG, BP, diabetes, previous MI

Werle et al. Factors that showed a trend for association in the univariate analyses, well-known risk factors for total mortality or cardiovascular mortality.

Bathum et al. Cox regression analysis. No details

Linna et al. Age, sex, BMI, smoking, BP, diabetes

Jacobs et al. Statin treatment, sex, CHD, BP, neoplasm, self-rated health, smoking, albumin, BMI, triglycerides.

Takata et. al. Sex, smoking, alcohol intake, stroke, heart disease, serum albumin, BMI, systolic BP

Page 11 of 24


BMJ Open

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960




11

Lv et al 2015 Age, sex, marital status, smoking, alcohol drinking, tea drinking, central obesity, cognitive impairment, daily activity, blindness, anemia, BT, diabetes, CKD, HDL-C

Blekkenhorst et al. Age, BMI, physical activity, renal function, smoking, diabetes, CVD, low-dose aspirin, antihypertensive and statin medication, energy intake, SFA

Abbreviations: BMI: body mass index; BP: blood pressure; HDL-C: high-density lipoprotein; IMT: Intima-media thickness; CRP: C-reactive protein; MI: Myocardial infarction; CKD; chronic kidney disease It is worth considering that some of the participants with high LDL-C may have started statin treatment during the observation period. Such treatment may have increased the lifespan for the group with high LDL-C. However, any beneficial effects of statins on mortality would have been minimal because most statin trials have had little effect on CVD and all-cause mortality, with a maximum reduction of mortality of two percentage points. It is therefore relevant that the 4-year mortality among those with the highest LDL-C in the included cohorts was up to 36% lower than among those with the lowest LDL-C. Furthermore, in the largest study20 that included about two-thirds of the total number of participants in our study, the risk was lower among those with the highest LDL-C than among those on statin treatment. It is also possible that those with the highest LDL-C were put on a different diet than those with low LDL-C. However, this potential bias in mortality outcomes could have gone in both directions. Some of the individuals with high LDL-C may have followed the official dietary guidelines and exchanged saturated fat with vegetable oils rich in linoleic acid. In a recent study the authors reported that among participants who were older than 65 at baseline, a 30 mg/dL decrease in serum cholesterol was associated with a higher risk of death (hazard ratio 1.35, 95% confidence interval 1.18 to 1.54).26 If applied to the general population, this finding suggests that the conventional dietary treatment for high cholesterol with vegetable oil replacing saturated fat may actually increase mortality in those individuals with high LDL-C. Thus, the lack of an association between LDL-C and mortality may have been even stronger than reported since the dietary intervention may have been counterproductive.

Page 12 of 24


BMJ Open

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960




12

Finally, it is potentially relevant that we limited our literature search to PubMed. In preliminary searches with PubMed, OVID and EMBASE we identified 17 relevant studies in PubMed, but only two in OVID and EMBASE, and these two studies were found in PubMed as well. Therefore, it is highly unlikely that there are studies with findings with opposite results from those we have reported here, as all of them reported either no association or an inverse association between LDL-C and mortality. DISCUSSION Assessments of the association between serum cholesterol and mortality have been studied for decades, and extensive research has shown a weak association between total cholesterol and mortality in the elderly; several studies have even shown an inverse association. It is therefore surprising that there is an absence of a review of the literature on mortality and levels of LDL-C, which is routinely referred to as a causal agent in producing CVD4 and is a target of pharmacological treatment of CVD. Our literature review has revealed either a lack of an association or an inverse association between LDL-C and mortality among people older than 60 years of age. In almost 80% of the total number of individuals LDL-C was inversely associated with all-cause mortality and with statistical significance. These findings provide a paradoxical contradiction to the cholesterol hypothesis. As atherosclerosis commences mainly in middle-aged people and becomes more pronounced with increasing age, the cholesterol hypothesis would predict that there should be a cumulative atherosclerotic burden, which would be expressed as greater CVD and all-cause mortality, in elderly people with high LDL-C levels. Our results raise several relevant questions for future research. Why is high TC a risk factor for CVD in young and middle-aged, but not in elderly people? Why do a subset of elderly people with high LDL-C live longer than people with low LDL-C? If high LDL-C is potentially beneficial for the elderly, then why does cholesterol-lowering treatment lower the risk of cardiovascular mortality? In the following we have tried to address some of these questions. Inverse causation. A common argument to explain why low lipid values are associated with an increased mortality is inverse causation, meaning that serious diseases cause low cholesterol. But this is not a likely explanation, because in five of the studies in table 1 terminal disease and mortality during the first years of observation were excluded. In

Page 13 of 24


BMJ Open

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960




13

spite of that, three of them showed that the highest mortality was seen among those with the lowest initial LDL-C with statistical significance.18,20,24

Is high LDL-C beneficial? One hypothesis to address the inverse association between LDL-C and mortality is that low LDL-C increases susceptibility to fatal diseases. Support for this hypothesis is provided by animal and laboratory experiments from more than a dozen research groups which have shown that LDL binds to and inactivates a broad range of microorganisms and their toxic products.27 Diseases caused or aggravated by microorganisms may therefore occur more often in people with low cholesterol, as observed in many studies.28 In a meta-analysis of 19 cohort studies for instance, performed by the National Heart, Lung, and Blood Institute and including 68,406 deaths, TC was inversely associated with mortality from respiratory and gastrointestinal diseases, most of which are of an infectious origin.29 It is unlikely that these diseases caused the low TC, because the associations remained after the exclusion of deaths occurring during the first five years. In a study by Iribarren et al. more than 100,000 healthy individuals were followed for fifteen years. At follow-up those whose initial cholesterol level was lowest at the start had been hospitalized significantly more often because of an infectious disease that later occurred during the 15 year follow-up period.30 This study provides strong evidence that low cholesterol, recorded at a time when these people were healthy, could not have been caused by a disease they had not yet encountered. Another explanation for an inverse association between LDL-C and mortality is that high cholesterol, and therefore high LDL-C, may protect against cancer. The reason may be that many cancer types are caused by viruses.31 Nine cohort studies including more than 140,000 individuals followed for 10 to 30 years have found an inverse association between cancer and TC measured at the start of the study, even after excluding deaths that occurred during the first 4 years.32 Furthermore, cholesterol-lowering experiments on rodents have resulted in cancer,33 and in several case-control studies of cancer patients and controls matched for age and sex, significantly more cancer patients have been on cholesterol-lowering treatment.32 In agreement with these findings, cancer mortality is significantly lower in individuals with familial hypercholesterolaemia.34 That high LDL-C may be protective is in accordance with the finding that LDL-C is lower than normal in patients with acute myocardial infarction. This has been

Page 14 of 24


BMJ Open

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960




14

documented repeatedly without a reasonable explanation.35-37 In one of the studies37 the authors concluded that LDL-C evidently should be lowered even more, but at a follow-up three years later mortality was twice as high among those whose LDL-C had been lowered the most compared with those whose cholesterol was unchanged or lowered only a little. If high LDL-C were the cause, the effect should have been the opposite.

CONCLUSIONS Our review provides the first comprehensive analysis of the literature about the association between LDL-C and mortality in the elderly. As the main goal of prevention of disease is prolongation of life, all-cause mortality is the most important outcome, and is also the most easily defined outcome and least subject to bias. The cholesterol hypothesis predicts that LDL-C will be associated with increased all-cause and CV mortality. Our review has shown either a lack of an association or an inverse association between LDL-C and both all-cause and CV mortality. The cholesterol hypothesis seems to be in conflict with most of Bradford Hill´s criteria for causation, because of its lack of consistency, biological gradient and coherence. Our review provides the basis for more research about the cause of atherosclerosis and CVD and also for a re-evaluation of the guidelines for cardiovascular prevention, in particular because the benefits from statin treatment have been exaggerated.38-40

Page 15 of 24


BMJ Open

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960




15

Contributors. UR and RS performed the paper search independently. UR wrote the first draft of the manuscript. All authors have read the papers and made improvements of the content and the wording. The relevant data from each study have been examined by at least three of the authors Funding. The study has not been funded Data sharing statement. Raw data from this project can be made available by a request to the corresponding author. Competing interests. TH has received speaker fees from Nissui Pharmaceutical and Nippon Suisan Kaisha. KSM has a US patent for a homocysteine-lowering protocol; RH, HO, RS, UR have written books with criticism of the cholesterol hypothesis. DMD, JN, BH, NH, AM, PHL, LM, YO, PJR, SS and TS have no competing interests.

Page 16 of 24


BMJ Open

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960




16

REFERENCES 1. Ravnskov U. Is atherosclerosis caused by high cholesterol? QJM 2002;95:397-403. 2. Hamazaki T, Okuyama H, Ogushi Y, Hama R. Towards a paradigm shift in cholesterol


3. Prospective Studies Collaboration. Blood cholesterol and vascular mortality by age, sex, and blood pressure: a meta-analysis of individual data from 61 prospective studies with 55,000 vascular deaths. Lancet 2007;370:1829-39.

4. Goldstein JL, Brown MS. A century of cholesterol and coronaries: From plaques to genes to statins. Cell 2015;161:161-72.

5. Stang A. Critical evaluation of the Newcastle-Ottawa scale for the assessment of the quality of nonrandomized studies in meta-analyses. Eur J Epidemiol. 2010;25:603–5.





10. Räihä I, Marniemi J, Puukka P et al. Effect of serum lipids, lipoproteins, and apolipoproteins on vascular and nonvascular mortality in the elderly. Arterioscler Thromb Vasc Biol 1997;17:1224-32.


12. Weverling-Rijnsburger AW, Jonkers IJ, van Exel, E et al. High-density vs low-density lipoprotein cholesterol as the risk factor for coronary artery disease and stroke in old age. Arch Intern Med 2003;163:1549-54.

13. Schupf N, Costa R, Luchsinger J, et al. Relationship between plasma lipids and all-cause mortality in nondemented elderly. J Am Geriatr Soc 2005;53:219-26

14. Tikhonoff V, Casiglia E, Mazza A, et al. Low-density lipoprotein cholesterol and mortality

Page 17 of 24


BMJ Open

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960




17

in older people. J Amer Geriatr Soc 2005;53:2159-64. 15. Störk S, Feelders RA, van den Beld AW, et al. Prediction of mortality risk in the elderly.

Am J Med 2006;119:519-25. 16. Akerblom JL, Costa R, Luchsinger JA, et al. Relation of plasma lipids to all-cause

mortality in Caucasian, African-American and Hispanic elders. Age Ageing 2008;37:207-13.

17. Upmeier E, Lavonius S, Lehtonen A, et al. Serum lipids and their association with mortality in the elderly: a prospective cohort study. Aging Clin Exp Res. 2009;21:424-30.

18. Nilsson G, Ohrvik J, Lonnberg I, Hedberg P. Ten-year survival in 75-year-old men and women: Predictive ability of total cholesterol, HDL-C, and LDL-C. Curr Gerontol Geriatr Res 2009, doi: 10.1155/2009/158425.

19. Werle MH, Moriguchi E, Fuchs SC, et al. Risk factors for cardiovascular disease in the very elderly: results of a cohort study in a city in southern Brazil. Eur J Cardiovasc Prev Rehabil 2011;18:369-77.

20. Bathum L, Depont Christensen R, Engers Pedersen L, et al. Association of lipoprotein levels with mortality in subjects aged 50 + without previous diabetes or cardiovascular disease: A population-based register study. Scand J Prim Health Care 2013;31:172-80

21. Linna M, Ahotupa M, Löppönen MK, et al. Circulating oxidised LDL lipids, when proportioned to HDL-C emerged as a risk factor of all-cause mortality in a population-based survival study. Age Ageing 2013;42:110-3





26. Ramsden CE, Zamora D, Majchrzak-Hong S et al. Re-evaluation of the traditional diet-heart hypothesis: analysis of recovered data from Minnesota Coronary Experiment (1968-73). BMJ. 2016 Apr 12;353:i1246. doi: 10.1136/bmj.i1246.

27. Ravnskov U, McCully KS. Vulnerable plaque formation from obstruction of vasa

Page 18 of 24


BMJ Open

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960




18

vasorum by homocysteinylated and oxidized lipoprotein aggregates complexed with microbial remnants and LDL autoantibodies. Ann Clin Lab Sci 2009;39:3-16



30. Iribarren C, Jacobs DR Jr, Sidney S, et al. Cohort study of serum total cholesterol and in-hospital incidence of infectious diseases. Epidemiol Infect 1998;121:335-47.



33. Newman TB, Hulley SB. Carcinogenicity of lipid-lowering drugs. JAMA 1996; 275:55–60.


35. Reddy VS, Bui QT, Jacobs JR, et al. Relationship between serum low-density lipoprotein cholesterol and In-hospital mortality following acute myocardial infarction (The lipid paradox). Am J Cardiol 2015;115:557-62.

36. Sachdeva A, Cannon CP, Deedwania PC, et al. Lipid levels in patients hospitalized with coronary artery disease: an analysis of 136,905 hospitalizations in get with the guidelines. Am Heart J 2009;157:111-7




40. de Lorgeril M, Rabaeus M. Beyond confusion and controversy, Can we evaluate the real efficacy and safety of cholesterol-lowering with statins? J Controversies Biomed

Page 19 of 24


BMJ Open

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960




19

Res 2015;1:67-92.

Page 20 of 24


BMJ Open

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960




Flow Chart

299x424mm (300 x 300 DPI)

Page 21 of 24


BMJ Open

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960

on 8 Novem


http://bmjopen.bm

j.com/

BM


jopen-2015-010401 on 12 June 2016. Dow

nloaded from



Section/topic # Checklist item Reported

on page

My comments

Title 1 Identify the report as a systematic review,

meta-analysis, or both.

1

Abstract 2 Provide a structured summary including,

as applicable: background; objectives; data

sources; study eligibility criteria,

participants, and interventions; study

appraisal and synthesis methods; results;

limitations; conclusions and implications of

key findings; systematic review


2-3

Introduction

Rationale 3 Describe the rationale for the review in the

context of what is already known.

4

Objectives 4 Provide an explicit statement of questions

being addressed with reference to

participants, interventions, comparisons,

outcomes, and study design (PICOS).

4

Methods

Protocol and

registration

5 Indicate if a review protocol exists, if and

where it can be accessed (e.g., Web

address), and, if available, provide

registration information including


We have no review protocol

Eligibility

criteria

6 Specify study characteristics (e.g., PICOS,

length of follow-up) and report

characteristics (e.g., years considered,

language, publication status) used as

criteria for eligibility, giving rationale

4-5

Information 7 Describe all information sources (e.g., 4

Page 22 of 24


BMJ Open

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960




sources databases with dates of coverage, contact

with study authors to identify additional

studies) in the search and date last

searched.

Search 8 Present full electronic search strategy for

at least one database, including any limits

used, such that it could be repeated.

4-5; 11

Study

selection

9 State the process for selecting studies (i.e.,

screening, eligibility, included in

systematic review, and, if applicable,

included in the meta-analysis).

4-5

Data collection

process

10 Describe method of data extraction from

reports (e.g., piloted forms, independently,

in duplicate) and any processes for

obtaining and confirming data from

investigators.

4-5; 11

Data items 11 List and define all variables for which data

were sought (e.g., PICOS, funding sources)

and any assumptions and simplifications

made.

4-5;

Risk of bias in

individual

studies

12 Describe methods used for assessing risk

of bias of individual studies (including

specification of whether this was done at

the study or outcome level), and how this

information is to be used in any data

synthesis.

3, 8-10;

table 2

Summary

measures

13 State the principal summary measures

(e.g., risk ratio, difference in means).

5,6; Table 1

Synthesis of

results

14 Describe the methods of handling data and

combining results of studies, if done,

including measures of consistency (e.g., I2)

5,6; Table 1

Page 23 of 24


BMJ Open

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960




for each meta-analysis.

Risk of bias

across studies

15 Specify any assessment of risk of bias that

may affect the cumulative evidence (e.g.,

publication bias, selective reporting within

studies).

3, 8-11

Additional

analyses

16 Describe methods of additional analyses


meta-regression), if done, indicating which

were pre-specified.

We have not made any further analyses because

the association between LDL-C and total and

CVD mortality was analyzed in all of the studies

by multifactorial analyses

Results Study selection

17 Give numbers of studies screened, assessed

for eligibility, and included in the review,

with reasons for exclusions at each stage,

ideally with a flow diagram.

5, 6; fig. 1

Study characteristics

18 For each study, present characteristics for

which data were extracted (e.g., study size,

PICOS, follow-up period) and provide the

citations.

Table 1

Risk of bias within studies





intervals, ideally with a forest plot

Table 1

Results of individual studies





intervals, ideally with a forest plot.

Table 1

Synthesis of

results

21 Present results of each meta-analysis done,

including confidence intervals and

measures of consistency.

Table 1

Page 24 of 24


BMJ Open

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960




Risk of bias

across studies

22 Present results of any assessment of risk of

bias across studies (see Item 15).

See above

Additional

analysis

23 Give results of additional analyses, if done


meta-regression [see Item 16]).

Irrelevant for our study

Discussion 24

Summary of

evidence

24 Summarize the main findings including the

strength of evidence for each main

outcome; consider their relevance to key

groups (e.g., healthcare providers, users,

and policy makers).

11-13

Limitations 25 Discuss limitations at study and outcome

level (e.g., risk of bias), and at review-level

(e.g., incomplete retrieval of identified

research, reporting bias).

8-10

Conclusions 26 Provide a general interpretation of the

results in the context of other evidence,

and implications for future research.

10

Funding 27 Describe sources of funding for the

systematic review and other support (e.g.,

supply of data); role of funders for the

systematic review.

There is no funding of our study

Page 25 of 24


BMJ Open

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960



Documents

BMJ Openbmjopen.bmj.com/content/bmjopen/6/6/e010401.draft-revisions.pdf · The Association Between Low-Density Lipoprotein Cholesterol and Mortality in the Elderly. A systematic review