Research & Education

New Questions About the Role of LDL-C in Cardiovascular Disease

“If you’re still looking at LDL as the ‘bad’ cholesterol, then you’re about thirty years out of date.” (Ken Sikaris, MD, quoted in Cholesterol Clarity)

“The least accurate way of estimating your atherogenic risk on a standard cholesterol panel would be to look at total cholesterol or LDL cholesterol.” (Thomas Dayspring, MD, Ibid)


A recent paper fired a major shot across the bow of researchers and medical professionals who adamantly stand by the notion that LDL cholesterol, by itself, is independently causal for cardiovascular disease (CVD). The paper, LDL-C does not cause cardiovascular disease: a comprehensive review of the current literature, detailed several shortcomings and weaknesses of research on LDL and statin drugs and raises important questions regarding the role of LDL in CVD.

As the authors state, “If high total cholesterol (TC) causes atherosclerosis, people with high TC should have more atherosclerosis than people with low TC.” Several studies have shown this not to be the case, and most cardiologists can verify that individuals who have CVD and who suffer heart attacks run the gamut from low LDL to high, and everything in between. If “high” LDL were a major causal factor, then we would expect far more heart disease and heart attacks among those with high LDL.

Moreover, if high LDL is causal in heart disease, then LDL-C of untreated heart disease patients should be higher than normal. On the contrary, in an analysis of over 130,000 patients hospitalized with coronary artery disease (CAD), nearly half had admission LDL levels <100 mg/dL, and almost 18% had LDL-C <70 mg/dL. We could speculate, as the authors of this analysis did, that treatment guidelines should be revised to support lowering LDL-C even further, or, we could consider the possibility that high LDL-C is not actually a driving factor in heart disease. It certainly wouldn’t be the first time a deeply held belief was questioned and possibly proven wrong.

It should be noted that in this analysis, mean lipid levels were LDL-C 104.9 (+/- 39.8), HDL-C 39.7 (+/- 13.2), and triglyceride 161 (+/- 128 mg/dL). More than half the patients had HDL-C <40 mg/dL. So rather than focusing solely on LDL-C, it might be more telling to look at the triglyceride:HDL ratio, as more practitioners are coming around to doing.

Moving on to the issue of lifespan and mortality, the authors of the paper questioning the role of LDL-C in CVD noted that if high LDL-C was the major cause of atherosclerosis and CVD, then people with the highest LDL-C should have shorter lives than people with low LDL-C. Notably, in a systematic review of 19 cohort studies that included over 68,000 older people (>60 years of age), the opposite was found: high LDL-C was inversely associated with mortality.

If LDL-C is not a primary cause of CVD, then it may be misguided—and worse, potentially harmful—to lower it using pharmaceutical drugs that bring with them unwanted and dangerous side-effects. In the case of statins, these drugs may actively worsen cardiovascular health, as one paper asserted.

The authors of the paper questioning the role of LDL-C in CVD wrote, “As cholesterol is a vital substance for the renewal of all cells, and since statins also block the production of other molecules necessary for normal cell function, it is not surprising that statin treatment may result in side effects from many different organs.”

It’s well documented that among some patients, statins induce muscle pain and weakness, depression, and may result in elevated blood glucose. Additionally, they may have a negative impact on cognitive function. Numerous studies have found a positive association between serum cholesterol and cognition among the elderly: the higher cholesterol (including LDL-C), the better the cognitive performance. In fact, researchers have written that low cholesterol might someday be considered a risk factor for cognitive impairment in the elderly. A study comparing patients with Alzheimer’s disease and healthy age-matched controls found that the cerebrospinal fluid of those with Alzheimer’s had significantly lower levels of cholesterol compared to the controls.     

This is not intended as an across-the-board indictment of statin drugs, nor a complete vindication of LDL-C as a causative agent in cardiovascular disease. There may be patient populations for whom statin therapy is warranted, and it’s possible that LDL-C may be problematic when combined with other risk factors for CVD, such as type 2 diabetes or insulin resistance. It’s increasingly evident, however, that LDL, independently of anything else, looks less and less like a major driver of CVD, and for some patients, lowering it without prejudice may be doing more harm than good.

By Amy Berger, MS, CNS


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