Higher Cholesterol Is Associated With Longer Life
Is it possible that mainstream medicine got cholesterol all wrong? That not only does cholesterol have no connection to heart disease, but that high cholesterol is actually a good thing? Yes, it’s more than possible — here I’ll show some evidence that higher cholesterol is associated with longer life.
All-cause mortality vs heart disease
Obviously, people die from many causes, whether natural, such as heart disease, cancer, or infection, or unnatural, such as from homicide, suicide, or accidents.
Should we be concerned about what cause we die from?
Yes, and no. On the one hand, if you’re dead, you’re dead, no matter from what. On the other, dying in your sleep in old age may be preferable to a long, lingering illness.
Nevertheless, from a public health standpoint, it seems a mistake to focus on changing something that lowers the risk of death from one cause only to raise that risk from another.
While total cholesterol is a poor if not utterly worthless risk marker for heart disease, doctors have focused on it to the exclusion of how it might affect other causes of death. It does you little good to save yourself from heart disease if it means that you increase your risk of death from cancer.
All-cause mortality — death from anything — is the most appropriate measure to use when looking at risk factors.
Older people with higher cholesterol live longer
Population studies in Japan show that people of all ages with higher cholesterol live longer.1
Overall, an inverse trend is found [in Japan] between all-cause mortality and total (or low density lipoprotein [LDL]) cholesterol levels: mortality is highest in the lowest cholesterol group without exception. If limited to elderly people, this trend is universal. As discussed in Section 2, elderly people with the highest cholesterol levels have the highest survival rates irrespective of where they live in the world.
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Consider the chart above, taken from the paper. It shows all-cause mortality by cholesterol levels, men on the left, women on the right.
Current guidelines call for keeping cholesterol at 200 mg/dl or lower, yet higher levels meant lower death rates.
What about outside Japan? The following chart shows cumulative all-cause mortality of people older than 85 in Leiden, The Netherlands, by cholesterol level.
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The cohort with an average cholesterol of 252 mg/dl, the highest, had the lowest death rates.
The following shows data from elderly people in Finland. Those with cholesterol greater than 232 mg/dl had the lowest death rates.
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The data from Japan is for all ages; the data from outside Japan is for the elderly. What about the data for all ages, outside of Japan? The authors believe that the presence of people with familial hypercholesterolemia, which causes a very high cholesterol level and which raises the risk of death, in the highest cholesterol categories, accounts for higher death rates in those categories. They also argue that cholesterol levels in that disorder are not the cause of increased death rates.
A recent review in the prominent medical journal BMJ regarding LDL cholesterol, the risk marker considered most significant, found either no association or an inverse association between LDL and death rates.2
High LDL-C is inversely associated with mortality in most people over 60 years. This finding is inconsistent with the cholesterol hypothesis (ie, that cholesterol, particularly LDL-C, is inherently atherogenic). Since elderly people with high LDL-C live as long or longer than those with low LDL-C, our analysis provides reason to question the validity of the cholesterol hypothesis. Moreover, our study provides the rationale for a re-evaluation of guidelines recommending pharmacological reduction of LDL-C in the elderly as a component of cardiovascular disease prevention strategies.
The Honolulu Heart Program was one of the first studies to find this inverse relation between total cholesterol and death rates in elderly people, aged 71 to 93. It found that compared to the lowest quartile (fourth) of cholesterol level, increasing quartiles of cholesterol had cholesterol had 28%, 40%, and 35% decreased death rates, respectively.
Furthermore, the Honolulu study seems to provide evidence that actually raising cholesterol is protective, since “Only the group with low cholesterol concentration at both examinations had a significant association with mortality.”
The authors of the study concluded, “We have been unable to explain our results. These data cast doubt on the scientific justification for lowering cholesterol to very low concentrations (<4.65 mmol/L) [<180 mg/dl] in elderly people.”
Is high cholesterol protective?
Why would people with low cholesterol die at higher rates than those with higher cholesterol?
Several things could be going on.
Cholesterol may protect against infections and atherosclerosis.3
Cholesterol may protect against cancer.4
A strong association was found between low cholesterol and violence. Odds ratio of violence for cholesterol of <180 mg/dl was 15.49. 5
Several studies have found an association between low cholesterol and suicide. For instance, one study found that those in the lowest quartile (fourth) of cholesterol concentration had more than 6 times the risk of suicide as those in the highest quartile.6
A number of studies have found that, at least in people older than 60, high cholesterol is associated with lower death rates.
This fact casts considerable doubt on the cholesterol hypothesis of heart disease.
Why, with so much evidence against it, does the cholesterol theory still have so much traction? To quote the authors in the first cited study, it’s all about the money:
We believe the answer is very simple: for the side defending this so-called cholesterol theory, the amount of money at stake is too much to lose the fight.
Update: I hadn’t seen this before I wrote this article, but Uffe Ravnskov, a co-author of some of the above-cited studies, has a good article with many relevant citations, The Benefits of High Cholesterol.
Ann Nutr Metab 2015;66(suppl 4):1–116 DOI: 10.1159/000381654
Ravnskov, Uffe, et al. “Lack of an association or an inverse association between low-density-lipoprotein cholesterol and mortality in the elderly: a systematic review.” BMJ open 6.6 (2016): e010401.
Ravnskov, Uffe. “High cholesterol may protect against infections and atherosclerosis.” Qjm96.12 (2003): 927–934.
Ravnskov, U., K. S. McCully, and P. J. Rosch. “The statin-low cholesterol-cancer conundrum.”QJM (2011): hcr243.
Mufti, Rizwan M., Richard Balon, and Cynthia L. Arfken. “Low cholesterol and violence.”Psychiatric services (2006).
Ellison, Larry F., and Howard I. Morrison. “Low serum cholesterol concentration and risk of suicide.” Epidemiology 12.2 (2001): 168–172.
High and low cholesterol levels seem to raise death risk, study finds
17-Aug-2016 – Last updated on 18-Aug-2016 at 12:55 GMT
The findings further fuel the argument as to whether raised levels of the “good” HDL cholesterol are beneficial. ©iStock
RELATED TAGS: Cholesterol
Healthy cholesterol levels are a fine balancing act as a new study has revealed both high and low levels can increase chances of an early death.
Writing in the Clinical Journal of the American Society of Nephrology the key finding identified a ‘U-shaped’ relationship between high-density lipoprotein (HDL-C) cholesterol and mortality rates.
The researchers from Washington University School of Medicine also found that this relationship was affected by cardiovascular disease and estimated glomerular filtration rate (eGFR) – a measure of kidney function and efficiency.
The findings further fuel the argument as to whether raised levels of the “good” HDL-C cholesterol are beneficial.
In equal measure, low levels of HDL-C cholesterol have been linked to an elevated risk of early death, especially in individuals in kidney disease.
Margarine plant sterols
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Margarines in particular have incorporated these plant compounds as a key ingredient as a way of lowering cholesterol.©iStock
Much of the food industry’s focus has been on raising HDL-C cholesterol levels and lowering “bad” LDL-C cholesterol levels.
One of the ways LDL-C cholesterol levels may be lowered is by consuming plant sterols and stanols (phytosterols), which are found naturally in plants and are structurally similar to cholesterol.
Margarines in particular have incorporated these plant compounds as a key ingredient. In the UK, Flora margarine spread was the subject of a new marketing campaign that highlighted its plant-based health credentials. Flora’s makers Unilever, also launched a dairy-free version.
The study began by identifying 1,764,986 men with at least one eGFR value recorded between October of 2003 and September of 2004.
These men were monitored for their kidney function and HDL-C cholesterol levels until September of 2013 or death, a duration of approximately nine years.
Data analysis revealed that compared with low levels of HDL-C (less than 25 mg/dl), intermediate HDL-C levels (HDL-C between 25 and 50 mg/dl) were linked to a reduced risk of all-cause mortality.
Risk of death in patients with high HDL-C (more than 50 mg/dl) was comparable with that of patients with low HDL-C (lower than 25 mg/dl).
In other words, the risk of death was highest in those with very low and very high HDL-C levels.
“The findings may explain why clinical trials aimed at increasing HDL cholesterol levels failed to show improved outcomes,” said Dr Ziyad Al-Aly, an assistant professor of medicine at Washington University and the study’s senior author.
These findings regarding HDL-C cholesterol and premature death were not found in other large epidemiologic studies, he added.
Al-Aly was referring to one study that evaluated the relationship of HDL-C and mortality in 3307 patients and confirmed a lack of association between higher HDL-C and lower mortality in patients with chronic kidney disease.
Another study found that reduced kidney function was linked with lower concentrations of large LDL-C particles, and lower concentrations of HDL-C.
The study commented that HDL-C may have a biphasic effect (at low and high concentrations). High concentrations could well impair specific cell and blood vessel formation, suggesting loss of a protective effect.
“The findings from these studies support the notion that there may be a range of HDL-C values where HDL-C may have a helpful effect, beyond which higher HDL-C may not be beneficial and may be associated with untoward outcomes.”
Source: Clinical Journal of the American Society of Nephrology
Published online ahead of print, doi: 10.2215/CJN.00730116
“High density lipoprotein cholesterol and the risk of all-cause mortality among U.S. veterans.”
Lipid levels are inversely associated with infectious and all-cause mortality: International MONDO study results
1 University of California Davis School of Medicine, United States;
2 Renal Research Institute, United States;
3 University of California Santa Barbara, United States;
4 Fresenius Medical Care North America, United States;
5 Fresenius Medical Care, Germany;
6 Maastricht University Medical Center, Netherlands
↵* Corresponding author; email: email@example.com
Cardiovascular events (CV) are increased 36 fold in patients with end stage renal disease. However, randomized controlled trials to lower LDL-C and TC have not shown significant mortality improvements. An inverse association of serum total cholesterol (TC) and LDL cholesterol (LDL-C) with all-cause and cardiovascular (CV) mortality has been observed in patients on chronic dialysis. Lipoproteins also may protect against infectious diseases. We used data from 37,250 patients in the international Monitoring Dialysis Outcomes (MONDO) database to evaluate the association between lipids and infection-related or CV mortality. The study began on the first day of lipid measurement and continued for up to 4 years. We applied Cox proportional models with time-varying covariates to study associations of LDL-C, HDL cholesterol (HDL-C), and TGs with all-cause, CV, infectious, and other causes of death. Overall, 6,147 patients died (19.2% from CV, 13.2% from infection, 67.6% from other causes). After multivariable adjustment, higher LDL-C, HDL-C, and TGs were independently associated with lower all-cause death risk. Neither LDL-C nor TGs were associated with CV death and HDL-C was associated with lower CV risk. Higher LDL-C and HDL-C were associated with a lower risk of death from infection or other non CV causes. LDL-C was associated with reduced all-cause and infectious, but not CV mortality, which resulted in the inverse association with all-cause mortality.
Received February 9, 2018.
Revision received June 8, 2018.
Accepted June 12, 2018.
Published under license by The American Society for Biochemistry and Molecular Biology, Inc
JAMA. 1994 Nov 2;272(17):1335-40.
Lack of association between cholesterol and coronary heart disease mortality and morbidity and all-cause mortality in persons older than 70 years.
To determine whether elevated serum cholesterol level is associated with all-cause mortality, mortality from coronary heart disease, or hospitalization for acute myocardial infarction and unstable angina in persons older than 70 years. Also, to evaluate the association between low levels of high-density lipoprotein cholesterol (HDL-C) and elevated ratio of serum cholesterol to HDL-C with these outcomes.
Prospective, community-based cohort study with yearly interviews.
A total of 997 subjects who were interviewed in 1988 as part of the New Haven, Conn, cohort of the Established Population for the Epidemiologic Study of the Elderly (EPESE) and consented to have blood drawn.
MAIN OUTCOME MEASURES:
The risk factor-adjusted odds ratios of the 4-year incidence of all-cause mortality, mortality from coronary heart disease, and hospitalization for myocardial infarction or unstable angina were calculated for the following: subjects with total serum cholesterol levels greater than or equal to 6.20 mmol/L (> or = 240 mg/dL) compared with subjects with cholesterol levels less than 5.20 mmol/L (< 200 mg/dL); subjects in the lowest tertile of HDL-C level compared with those in the highest tertile; and subjects in the highest tertile of the ratio of total serum cholesterol to HDL-C level compared with those in the lowest tertile.
Elevated total serum cholesterol level, low HDL-C, and high total serum cholesterol to HDL-C ratio were not associated with a significantly higher rate of all-cause mortality, coronary heart disease mortality, or hospitalization for myocardial infarction or unstable angina after adjustment for cardiovascular risk factors. The risk factor-adjusted odds ratio for all-cause mortality was 0.99 (95% confidence interval [CI], 0.56 to 2.69) for the group who had cholesterol levels greater than or equal to 6.20 mmol/L (> or = 240 mg/dL) compared with the group that had levels less than 5.20 mmol/L (< 200 mg/dL); 1.00 (95% CI, 0.59 to 1.70) for the group in the lowest tertile of HDL-C compared with those in the highest tertile; and 1.03 (95% CK, 0.62 to 1.71) for subjects in the highest tertile of the ratio of total serum cholesterol to HDL-C compared with those in the lowest tertile.
Our findings do not support the hypothesis that hypercholesterolemia or low HDL-C are important risk factors for all-cause mortality, coronary heart disease mortality, or hospitalization for myocardial infarction or unstable angina in this cohort of persons older than 70 years.
Cholesterol in the elderly. Is it important? [JAMA. 1994]
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J Thorac Dis. 2016 Dec; 8(12): E1780–E1781.
High density lipoprotein cholesterol and risk of death
Author information ► Article notes ► Copyright and License information ► Disclaimer
See the article “High Density Lipoprotein Cholesterol and the Risk of All-Cause Mortality among U.S. Veterans” in Clin J Am Soc Nephrol, volume 11 on page 1784.
This article has been cited by other articles in PMC.
We thank the editorialists Tiziomalos, and Badimon et al. for their comments on our work (Bowe et al.) (1).
Seminal findings form the Framingham Heart Study established that low levels of high density lipoprotein cholesterol (HDL-C) are associated with increased risk of cardiovascular outcomes and death. The findings lent plausibility to the hypothesis that higher levels of HDL-C would be associated with improved cardiovascular outcomes and reduced mortality. This hypothesis was never thoroughly tested in that none of the prior studies—which involved few thousand patients, where very few cohort participants had very high HDL-C levels-were powered enough to rigorously address this clinically relevant question. It was also assumed that raising HDL-C levels will lead to improved cardiovascular outcomes and reduced mortality. The assumed veracity of the hypothesis powered the undertaking of multiple randomized controlled trials including those testing niacin, and those involving cholesterol ester transfer protein (CETP) inhibitors. These pharmaceutical intervention studies successfully resulted in increased HDL-C levels, but did not result in amelioration of cardiovascular outcomes or mortality (2-4).
Recent experimental evidence suggests that HDL-C exhibits a biphasic effect (at low and high concentrations); where at high concentrations, HDL-C paradoxically promoted senescence and abrogated endothelial progenitor cell tube formation and angiogenesis. The findings indicate that the protective effect of HDL-C is vitiated at higher concentrations (5). Recent Mendelian randomization analyses show that genetic mechanisms that raise plasma HDL-C do not result in lowering the risk of myocardial infarction (6).
In a large epidemiologic study involving 1.7 million United States Veterans followed for over 9 years (16 million person-years) we evaluated the relationship between HDL-C and risk of death; we found that low HDL-C is associated with increased risk of death, and-unexpectedly-that high HDL-C is also associated with increased risk of death. The relationship between HDL-C and risk of mortality exhibited a U-shaped association where risk of death is increased at low and high HDL-C levels (1). The findings were also consistent in studies where we examined the relationship of HDL-C and risk of incident kidney disease and its progression to end stage renal disease (likely a result of microvascular injury and disease), where again the salutary effect of high HDL-C was reversed at high concentrations and risk relationship was U-shaped (7). Ko and colleagues recently reported results consistent with ours, and also showed increased cardiovascular and non-cardiovascular mortality at both low and high HDL-C levels; they noted that HDL-C is does not represent a cardiovascular specific risk factor given that it is also associated with non-cardiovascular outcomes (8).
Taken together, the constellation of findings suggests that HDL-C is a non-specific and heavily confounded measure, and represents a poor marker for cardiovascular outcomes. It should not be regarded as an independent modifiable risk factor for cardiovascular disease, and is an unreliable target for pharmaceutical interventions. Moving beyond quantitative HDL-C levels to a qualitative assessment of HDL-C size, composition, functional capacity or HDL-C subclasses may be promising (9,10).
The promise of big data in medicine
Another important lesson we learned is that foundational studies such as the Framingham Heart Studies and others significantly advanced our understanding of cardiovascular health and disease, and specifically elucidated the relationship between cholesterol parameters (and of particular relevance here: HDL-Cholesterol) and clinical outcomes. However, these studies are limited in that the number of patients in these longitudinal cohorts is relatively small compared to what could be obtained using a Big Data approach. The recent epidemiologic reports which unearthed the finding that high HDL-C is associated with increased risk of death leveraged the power of Big Data to examine the relationship across the full range of HDL-C values spectrum. This approach of using the powerful lens of Big Data to re-examine perennial questions, and challenge prior knowledge and prevailing assumptions holds significant promise and –in our opinion- will yield a more a more nuanced understanding of health and disease in the decades to come.
Provenance: This is an invited Correspondence commissioned by the Section Editor Hai-Long Dai, M.D., Ph.D (Department of Cardiology, Yan’an Affiliated Hospital of Kunming Medical University, Kunming, China).
Conflicts of Interest: The author has no conflicts of interest to declare.
1. Bowe B, Xie Y, Xian H, et al. High Density Lipoprotein Cholesterol and the Risk of All-Cause Mortality among U.S. Veterans. Clin J Am Soc Nephrol 2016. [Epub ahead of print]. 10.2215/CJN.00730116 [PMC free article] [PubMed] [Cross Ref]
5. Huang CY, Lin FY, Shih CM, et al. Moderate to high concentrations of high-density lipoprotein from healthy subjects paradoxically impair human endothelial progenitor cells and related angiogenesis by activating Rho-associated kinase pathways. Arterioscler Thromb Vasc Biol 2012;32:2405-17. 10.1161/ATVBAHA.112.248617 [PubMed] [Cross Ref]
6. Voight BF, Peloso GM, Orho-Melander M, et al. Plasma HDL cholesterol and risk of myocardial infarction: a mendelian randomisation study. Lancet 2012;380:572-80. 10.1016/S0140-6736(12)60312-2 [PMC free article] [PubMed] [Cross Ref]
7. Bowe B, Xie Y, Xian H, et al. Low levels of high-density lipoprotein cholesterol increase the risk of incident kidney disease and its progression. Kidney Int 2016;89:886-96. 10.1016/j.kint.2015.12.034 [PubMed] [Cross Ref]
8. Ko DT, Alter DA, Guo H, et al. High-Density Lipoprotein Cholesterol and Cause-Specific Mortality in Individuals Without Previous Cardiovascular Conditions: The CANHEART Study. J Am Coll Cardiol 2016;68:2073-2083. 10.1016/j.jacc.2016.08.038 [PubMed] [Cross Ref]
How to repair HDL
The good news: Research is now finding that a healthy lifestyle can help repair HDL. Scientists at UCLA, for example, followed men attending the Pritikin Longevity Center and found that at entry, the men tended to have dysfunctional HDL. But after three weeks at Pritikin, blood tests showed that their HDL had converted from pro-inflammatory to anti-inflammatory. Dysfunctional HDL, in other words, had returned to well-functioning HDL.
Evidence-based research, for example, a trial that followed 18,144 heart patients as well as another study that treated 202 heart patients, indicate that a non-HDL less than 80 is optimal for those with clear evidence of coronary artery disease.
Lowest heart disease rates in the world
Moreover, don’t be overly concerned if you’re following a heart-healthy lifestyle like Pritikin but your HDL is lower than traditionally recommended ranges (greater than 50 or 60). Over the last four decades, studies have consistently found that populations with some of the lowest heart disease rates in the world, such as the people of Okinawa, Japan, had very low levels of HDL, in the 20s and 30s.
Studying rural Chinese populations in the 1990s, Dr. Colin Campbell of Cornell University found that their death rates from heart disease were 94% lower than that of American men. Their HDL cholesterol was about 30. Yes, very low HDL, but very good heart health.
The diet of these rural Chinese? Like the Pritikin Eating Plan, it was rich in vegetables, fruits, and other whole, unprocessed plant foods – and had three times more fiber than a typical American diet.
What are optimal levels?
Triglycerides are fats in the blood. Chronically elevated triglyceride levels (greater than 150) are associated with atherosclerosis (the build-up of plaque within the arteries) as well as a variety of other disorders, including pancreatitis. Recently, the American Heart Association recommended even lower levels: less than 100.
High levels of triglycerides can be considered an additional risk for cardiovascular disease, especially when part of a cluster of conditions now epidemic in the U.S. called the metabolic syndrome, which includes belly fat, high blood pressure, and high blood sugar.
Chylomicrons and strawberry milkshakes
Immediately after eating a fatty meal, most triglycerides are temporarily packaged in particles called chylomicrons. Blood drawn shortly after a fatty meal will appear creamy, like a strawberry milkshake. It takes hours for these fat-rich particles to be cleared from the bloodstream.
Silent but deadly
Research is now finding that high levels of chylomicrons nearly triple the risk of heart problems. Scientists refer to chylomicrons as “silent but deadly” because by the time we have a fasting blood test, their dirty work is done and they’re gone, and therefore undetected by the standard fasting blood lipid test.
Studies have found that fat- and cholesterol-rich meals can dramatically increase the production of chylomicrons and lead to greater amounts in the blood for several hours after each fat-rich meal.
Pritikin Eating Plan
The Pritikin Eating Plan, low in fat and high in unprocessed, whole foods, has been proven to dramatically lower triglyceride levels, which means it likely lowers chylomicron levels as well.