The Next Recommendation on Lowering Cholesterol May be to Start Earlier

The clinical work on lowering blood cholesterol that has taken place over recent years has demonstrated that if there is a lower limit beyond which low cholesterol levels become harmful, then that limit is very low indeed. Certainly below 10% of the normal human level. There are a number of uncommon mutations that produce individuals with up to half of the normal amount of blood cholesterol, people who exhibit significantly reduced risk of cardiovascular disease as a result of this difference from the norm. This is all quite interesting: why did we evolve to have the blood cholesterol that we do, if we need only a small fraction of it?

The reason why lowering blood cholesterol lowers the risk of cardiovascular disease is that atherosclerosis is caused by the dysfunction of macrophage cells in an environment rich in oxidized lipids. Atherosclerosis is age-related because oxidative stress, and thus amounts of oxidized lipids, rise with age. A lesser degree of all blood lipids means a lesser degree of oxidized lipids in the blood stream, entering blood vessel walls to aggravate and kill macrophages. This in turn results in a slowed progression of atherosclerosis. Unfortunately it really doesn't help all that much to remove existing fatty lesions produced by the processe of atherosclerosis, and it doesn't do more than slow the progression of the condition. Lowered blood cholesterol only raises the odds of avoiding the consequences of atherosclerosis, meaning stroke and heart attack when a weakened artery or large lesion ruptures, because a few years of delay are enough to allow some other consequence of aging to kill the patient first.

The advent of new and very efficient tools for lowering blood cholesterol, such as PCSK9 inhibitors, present the medical community with something of a quandary. The technology for lowering blood cholesterol has reached its natural limit. One really can't go much lower, and yet it isn't enough. It still only slows atherosclerosis, and cannot meaningfully reverse the corroded state of arteries and their fatty lesions. The research community is investigating other avenues beyond the lowering of blood cholesterol typified by statins and PCKS9 inhibitors, but in the meanwhile what should the medical community focus on? The next logical step appears to be starting treatment earlier, with an even greater focus on prevention and target metrics in healthier individuals, rather than on treating the manifestations of clinical disease.

Cholesterol lowering: to live longer, start younger?

Cardiovascular disease, particularly coronary heart disease and stroke, is a major cause of death globally. Since older age is an independent predictor of increased cardiovascular risk, the global burden of cardiovascular disease increases as populations age. Lowering low density lipoprotein (LDL) cholesterol has become an important strategy for reducing the risk of atherosclerotic cardiovascular disease (ASCVD). Recent evidence has shown that the benefits of this approach extend to patients over 75 years. Though LDL lowering is beneficial across middle to older age, two questions still arise: how early in the disease process should LDL lowering be initiated; and, are the currently recommended LDL targets ambitious enough?

It has been estimated 10-year ASCVD risk for an untreated 50 year old Caucasian male with a systolic/diastolic blood pressure of 140/90 mmHg and LDL cholesterol level of 3.4 mmol/L, is 5.3%. A 60 year old male with the same risk factors has a 10-year ASCVD risk of 11.8%, which increases to 22.6% at age 70. Older age appears to be a marker of the cumulative exposure to LDL cholesterol, along with other traditional cardiovascular risk factors. Delaying treatment until the cardiovascular risk is above a certain threshold will lead to additional years of exposure to this cumulative burden. Initiating statin therapy at say, the age of 50 rather than 60 years old, will prevent an additional 10 mmol/L/year LDL cholesterol exposure, or in other words, provide an additional 10 mmol/L/year of LDL cholesterol reduction.

More complex and older atheromatous plaques only partially regress with LDL lowering therapies, which means delayed treatment will leave older individuals at considerable residual risk of ASCVD. It makes sense to advocate for a greater focus on the lifetime exposure to elevated LDL and the benefit of LDL cholesterol lowering over longer periods of time. A primordial prevention strategy would target the development of atherosclerosis rather than simply preventing its complications. This hypothesis is supported by cohort studies which showed exposure to elevated blood pressure and cholesterol levels during young adulthood is associated with a greater risk of ASCVD later in life, independent of later adult exposures.

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