The Problematic Paradigm of LDL-C, Part 3

LDL Studies and the Association Between LDL-C and Heart Disease, pt. 2

Previous - Part 2 - LDL Studies and the Association Between LDL-C and Heart Disease, pt. 1

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 al. Lack of an association or an inverse association between low-density-lipoprotein 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

16.         Knekt P, Reunanen A, Aromaa A, Heliövaara M, Hakulinen T, Hakama M. Serum cholesterol and risk of cancer in a cohort of 39,000 men and women. J Clin Epidemiol. 1988;41(6):519-530. doi:10.1016/0895-4356(88)90056-x

17.         NHANES - National Health and Nutrition Examination Survey Homepage. Published December 9, 2022. Accessed December 14, 2022. https://www.cdc.gov/nchs/nhanes/index.htm