LDL Studies and the Association Between LDL-C and Heart Disease, pt. 2
This is the third installment overall in our investigation
of lipids and cholesterol, and the second part of our look at studies that
compare fat consumption, LDL cholesterol levels, and disease.
Framingham Offspring Analysis
As noted previously, the Framingham Heart Study is a
decades-long initiative. The graphics below reflect a follow-up cohort of more
than two decades, assessing cardiovascular disease as a function of cholesterol
levels. To be clear, those who ultimately suffered cardiovascular disease did
in fact have higher levels of LDL-C on average. However, an important note is
that this relationship is not retained when stratifying by HDL-C and
triglyceride levels. In fact, a person with low LDL-C may be at greatly
elevated OR reduced risk depending on these other markers. There is simply no
way to know based on LDL-C alone. Conversely, no person with high HDL-C levels
is ever at elevated risk, regardless of how high LDL-C levels are. These
observations will ultimately serve as much of the backbone for our future
exploration of the underlying mechanisms of cardiovascular disease and
dyslipidemia.1
For now, it is sufficient to know that this occurs because
low HDL-C and high triglycerides are strong, direct markers of the poor
metabolic function that underlies cardiovascular and other chronic disease. One
manner by which LDL-C can be elevated is as a downstream effect of that same
metabolic dysfunction. In fact, the frequency of metabolic dysfunction in
modern populations is the very reason the general association between LDL-C and
cardiovascular disease tends to exist. Elevated LDL-C levels don’t portend a
rise in cardiovascular disease risk in a person with optimal metabolic markers but
they do help suggest increasing metabolic dysfunction when metabolic
markers are suboptimal or poor. This phenomenon will be explored in great depth
in future posts.
LEFT: HDL-C levels strongly predict cardiovascular disease,
while LDL-C levels lose predictive value in those with good metabolic health. RIGHT:
Relative cardiovascular risks for individuals with given levels of LDL-C,
HDL-C, and triglycerides. Note the odds ratios (OR) that represent an increase
or decrease in disease risk.
Studies Comparing LDL-C and Cardiovascular Disease
Additional modern studies confirm the general association
between elevated LDL-C levels and increased risk of cardiovascular disease.2–4 For example, one study found
a 25% increased risk of coronary heart disease in those with long-term elevated
LDL-C:
“We estimated a relative CHD risk of 1.25 for 16-years of
exposure to LDL-cholesterol>190 mg/dL compared with 16 years of
LDL-cholesterol<130 mg/dL”2
While another found the risk of cardiovascular disease death
to be basically double in men with significantly elevated LDL-C levels.4 Interestingly, this same
study found that both men and women with above average LDL-C levels suffered
the lowest rates of death from all causes, which we will touch on next.
Studies Comparing LDL-C and All-Cause Mortality
There may be obvious, logical reasons to be concerned with
cardiovascular disease in an individual with a history of such disease, but it
perhaps makes less sense to place a myopic focus on heart disease alone in a
seemingly healthy population. To that end, the relationship between LDL-C and
all-cause mortality does not support the notion that elevated LDL-C is a risk
factor for overall death and disease, and if anything supports the opposite –
Those with the lowest LDL-C are, in fact, those who suffer the most disease and
die the most frequently.4–11
Yes, the preponderance of evidence suggests that it is those
with low, not high, LDL-C levels who are most at risk of adverse health events
and death, especially as people age. Take the following data from a massive
study of healthy Danish individuals over the age of 50:
It is not the individuals with the recommended sub-100 mg/dl
LDL-C levels, but those with LDL-C levels in the 130-160 mg/dl range that have
the best survival rates.8 This finding is common across
a number of studies. The reason for this finding may be that
lipoproteins are highly involved in cellular repair. In fact, there is really
no other manner by which the major components of the cellular repair mechanism
– phospholipids and cholesterol that help form and maintain cell structure and
function– can move to reach the cells of the body. The trafficking of these
components is one of the main functions of the lipoprotein system in the body,
so a deficit of this system could very reasonably play a role in
susceptibility to cancer, infection, and other disease.
**I suspect significant seed oil consumption (canola, soybean, corn, etc.) may also
play a role in this relationship, but that’s a long conversation for another
day
For this and other reasons, it is highly common for these
studies to exclude those with preexisting cardiovascular disease, diabetes, or
other disease, and to exclude deaths that occur in the first year or two of
follow-up. This seems an obvious choice, in order to avoid or minimize the
potential confounding factors we just discussed. However, the predictive value
of low LDL-C persists. Consider the findings of a study that excluded those
with most underlying disease and those that died in the first year of
follow-up:
“All-cause mortality was lower in the groups with TC or
LDL-C above the recommended levels…These associations indicate that high
lipoprotein levels do not seem to be definitely harmful in the general
population”10
50- to 60-year-olds with LDL-C below 97 mg/dl were more than
50% more likely to have died compared those with higher LDL-C levels. Another
study that excluded those with existing cancer diagnosis and those who died
within two years of follow-up found “high mortality among older adults with
lower TC” and a twenty percent decrease in mortality for those with LDL-C above
130 mg/dl.9
Despite efforts to mitigate any potential methodological
issues, the common argument against these findings remains the notion that
terminal or other serious disease (Usually cancer - Although it is important to
note that low LDL-C is associated with other unfavorable outcomes such as
stroke as well 12,13) acts in some way to lower
LDL-C, and that this effect confounds the data. To be clear – there is some
evidence that individuals with cancer tend to have lower cholesterol levels.14 However, this makes clear
only an association between cancer and low LDL-C levels. The association does
not inherently support the second implicit argument – that cancer or other
disease causes the decrease in LDL-C. In fact, the argument holds
extremely little or no weight whatsoever. As just discussed, it is just as
inherently likely that low LDL-C plays a role in the development of cancer than
the other way around. Based on the available evidence, this may be the more
likely reality.
One major problem with this argument, then, is that it
necessarily flies in the face of the belief that low LDL-C levels are something
to be desired. Scientists and healthcare professionals who champion very low
LDL-C levels always or nearly always write off these findings by the argument
outlined above. But even if this were true – if low LDL-C levels are so
strongly predictive of future death by cancer or infection that the eventual
disease shows up on a cholesterol panel many years in advance – it would
necessarily be a cause for concern rather than a cause for celebration.
Regardless of the underlying cause, adults with low LDL-C tend to die at a
significantly increased rate in the years that follow. It is intellectually
incongruent to hand-waive this observation away with the “cancer lowers LDL”
argument while also high-fiving the patient for their supposedly optimal
health.
The other major problem with this argument is that it is
unsupported by the evidence. Again, cancer patients may have lower LDL-C
levels. However, the evidence is better that low LDL-C predates and possibly
influences the development of cancer than the other way around. On top of the
typical measures taken by researchers to minimize any effects of preexisting
disease, studies show low LDL-C levels predate an elevated risk of cancer by
many years.15,16 Consider the following
statement from the American College of Cardiology, discussing a study
demonstrating a strong association between low LDL-C levels and increased
cancer incidence an average of 18 years later:
“Researchers reviewed data at four points in time prior to cancer
diagnosis and found that LDL cholesterol values were lower in cancer subjects
than matched controls at each point of assessment throughout an average of 18.7
years prior to diagnosis (p = .038). The trend for lower LDL-C in cancer
patients compared with those who were cancer-free was consistent throughout the
duration of the study.”15
This again
suggests that low LDL-C is more likely to influence cancer development than the
other way around. It also very strongly suggests that, if it increases the risk
of death and can help predict cancer nearly twenty years out, a low LDL-C level
needs to be taken seriously as a disease risk rather than celebrated as a sign
of health.
NHANES Data
NHANES, the National Health and Nutrition Examination Survey, is a long term CDC tracking project that records the lifestyle habits, health markers and outcomes of thousands of Americans.17 The most recent set of results, detailing a fifteen year period ending in 2014, demonstrates a very similar relationship between LDL-C and all-cause mortality to that which we’ve already seen in the research. This can be seen below. The top graph shows calculated all-cause mortality risk as a function of LDL-C levels, while the bottom charts show the same risk stratified by LDL-C level and either adjusted for age (left) or adjusted for a variety of risk factors (right). Again, it is quite clear that it is those with low LDL-C levels, rather than those with elevated levels, who proved most likely to die (average age of subjects was 46 years old at the beginning of the tracking period).11
While opinions on the underlying
reasons for the relationship differ, it is clear both that individuals with
very low LDL cholesterol are at elevated risk of medium-term death and that
individuals with high LDL cholesterol tend to be at only minor excess risk of death
compared to those with average levels. Furthermore, the relationship between
LDL cholesterol and cardiovascular disease is highly dependent on the
presence or absence of reasonable metabolic health. This observation will drive
much of our future discussion on the nature of lipids and cholesterol. Before
diving in, though, we’ll first take a good look at what words like “cholesterol”
really mean while explaining the relevant components of the lipid system.
Part 4 - Lipids and Cholesterol: Who Are the Players and What Are We Really Measuring?
1. Is Isolated Low High-Density
Lipoprotein Cholesterol a Cardiovascular Disease Risk Factor?
doi:10.1161/CIRCOUTCOMES.115.002436
2. Ueda P, Gulayin P, Danaei G.
Long-term moderately elevated LDL-cholesterol and blood pressure and risk of
coronary heart disease. PLOS ONE. 2018;13(7):e0200017. doi:10.1371/journal.pone.0200017
3. Mortensen MB, Nordestgaard BG.
Elevated LDL cholesterol and increased risk of myocardial infarction and
atherosclerotic cardiovascular disease in individuals aged 70–100 years: a
contemporary primary prevention cohort. The Lancet.
2020;396(10263):1644-1652. doi:10.1016/S0140-6736(20)32233-9
4. Gender difference of association
between LDL cholesterol concentrations and mortality from coronary heart
disease amongst Japanese: the Ibaraki Prefectural Health Study - Noda - 2010 -
Journal of Internal Medicine - Wiley Online Library. Accessed August 7, 2022.
https://onlinelibrary.wiley.com/doi/full/10.1111/j.1365-2796.2009.02183.x
5. Ravnskov U, Diamond DM, Hama R, et
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cholesterol and mortality in the elderly: a systematic review. BMJ Open.
2016;6(6):e010401. doi:10.1136/bmjopen-2015-010401
6. Lu JM, Wu MY, Yang ZM, et al. Low
LDL-C levels are associated with risk of mortality in a Chinese cohort study. Endocrine.
2021;73(3):563-572. doi:10.1007/s12020-021-02746-6
7. Schupf N, Costa R, Luchsinger J, Tang
MX, Lee JH, Mayeux R. Relationship Between Plasma Lipids and All-Cause
Mortality in Nondemented Elderly. Journal of the American Geriatrics Society.
2005;53(2):219-226. doi:10.1111/j.1532-5415.2005.53106.x
8. Johannesen CDL, Langsted A, Mortensen
MB, Nordestgaard BG. Association between low density lipoprotein and all cause
and cause specific mortality in Denmark: prospective cohort study. BMJ. 2020;371:m4266.
doi:10.1136/bmj.m4266
9. Cabrera MAS, de Andrade SM, Dip RM.
Lipids and All-Cause Mortality among Older Adults: A 12-Year Follow-Up Study. The
Scientific World Journal. 2012;2012:e930139. doi:10.1100/2012/930139
10. 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. Scandinavian
Journal of Primary Health Care. 2013;31(3):172-180.
doi:10.3109/02813432.2013.824157
11. Liu Y, Liu F, Zhang L, et al.
Association between low density lipoprotein cholesterol and all-cause
mortality: results from the NHANES 1999–2014. Sci Rep. 2021;11(1):22111.
doi:10.1038/s41598-021-01738-w
12. Ma C, Na M, Neumann S, Gao X.
Low-Density Lipoprotein Cholesterol and Risk of Hemorrhagic Stroke: a
Systematic Review and Dose-Response Meta-analysis of Prospective Studies. Curr
Atheroscler Rep. 2019;21(12):52. doi:10.1007/s11883-019-0815-5
13. Wang X, Dong Y, Qi X, Huang C, Hou L.
Cholesterol Levels and Risk of Hemorrhagic Stroke. Stroke.
2013;44(7):1833-1839. doi:10.1161/STROKEAHA.113.001326
14. Fiorenza AM, Branchi A, Cardenà A,
Molgora M, Rovellini A, Sommariva D. Serum cholesterol levels in patients with
cancer. Relationship with nutritional status. Int J Clin Lab Res.
1996;26(1):37-42. doi:10.1007/BF02644772
15. LOW LDL CHOLESTEROL IS RELATED TO
CANCER RISK. American College of Cardiology. Accessed December 14, 2022. https://www.acc.org/about-acc/press-releases/2012/03/25/15/15/http%3a%2f%2fwww.acc.org%2fabout-acc%2fpress-releases%2f2012%2f03%2f25%2f15%2f15%2fldl_cancer
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17. NHANES - National Health and Nutrition
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