A recent study on the health risks posed by “very high” levels of high-density lipoprotein cholesterol (HDL-C) has caused consternation in the world of medicine. It looked at associations between health outcomes and HDL-C by using two large databases of blood samples stored in UK and US biobanks and disease-related data which were recorded in those cohorts. Total mortality and cardiovascular death rates were compared in persons with HDL-C levels up to 80 mg% and those with higher levels.
HDL-C is regarded as the protective fraction of cholesterol, essentially, “good cholesterol”. It prevents deposition of cholesterol in tissues, especially in blood vessel walls. In most cohort studies around the world, low levels of HDL-C have been shown to be associated with an increased risk of heart attacks and strokes. High rates of heart attacks in persons of Indian ethnicity across different countries have especially been linked to low HDL-C levels. However, the UK-US Biobank study published in 2022 surprised many doctors by revealing that persons with HDL levels over 80mg% were two times more prone to all-cause mortality and a 71% higher risk of cardiovascular mortality, compared to those with lower levels. There was a U-shaped relationship: persons having very low levels of HDL-C also had higher cardiovascular death rates. Both extremes were clearly bad.
This should not come as a complete surprise. Some earlier studies with smaller sample sizes had also suggested an increased risk of death in persons with very high levels of HDL-C. Further, drug trials with agents that increase HDL-C levels in blood were uniformly unsuccessful in providing the hoped for protection against major cardiovascular events. While a fall in HDL-C due to smoking, physical inactivity or diabetes was bad for the heart, boosting it through medicines did not help. An increased risk of osteoporosis (where bones become weak and brittle) and bone fractures has also been reported in persons with HDL-C levels above 74mg%.
A similar warning about simplistic predictions of risk came from a 2023 study from South Korea, which studied low-density lipoprotein cholesterol (LDL-C) levels in persons with diabetes. LDL-C is the globally incriminated villain (“bad cholesterol”) that causes atherosclerotic cardiovascular disease. Drugs that lower LDL-C, such as statins, have been shown to be very effective in prevention of events related to coronary heart disease. Yet, the Korean study, which identified 26,341 cases of sudden cardiac arrest (SCA), found there was an increase in the risk of SCA when LDL-C levels were below 70mg%. That level of risk was only second to the risk observed in persons whose LDL-C was above 160 mg%.
In the Japanese Nomura community-based cohort study (2021) involving 3,684 participants, all-cause mortality was noted to be 2.5 times higher in persons with LDL-C below 70 mg% compared to those with levels over 144 mg%. There are likely to be ethnic variations between populations. Nevertheless, these studies challenge the conventional wisdom of cardiology which affirmed that “lower the LDL-C, the better it is for heart health”. These findings should really not surprise us. We know through various cohort studies that many physiological variables have a U-shaped or a J-shaped relationship with health risks. Both beyond and below a relatively safe range, the risk of adverse health events progressively increases. This is true for body temperature, body weight, blood pressure, blood sugar and blood lipid levels. We are in trouble if haemoglobin levels, platelet counts or white blood cell counts are too low or too high. Even for a protective feature like immunity, very low or very high levels of antibodies can be harmful!
The human body has evolved to function best within those safe bands. There will be some variations in the span of those bands, between populations and among individuals. Risk of adverse health events, especially those involving cardiovascular disease, is determined by a composite of risk factors rather than by the level of a single risk factor. For heart attacks and strokes, the “absolute risk” of a major cardiovascular adverse event (death, non-fatal heart attack or stroke) is predicated on an individual’s family history, sex, age, smoking habits, blood pressure, body mass index, waist-hip ratio, blood sugar, blood lipid profile, stress levels and sleep patterns, among others. Dietary patterns and exercise levels influence many of the biologic risk factors which combine to produce insulin resistance, inflammation, vascular injury, atherosclerosis and thrombosis.
Amid this complexity, doctors still try to assess risk by looking at levels of major risk factors. While doing so, it would be wise to recognise that nature abhors both extremes and has used the anvil of evolution to craft our bodies to perform best in a physiologically optimal middle zone. Healthy diets and moderate physical exercise keep most physiological variables in that safe zone.
For extraneous factors that do not occur naturally and are introduced into human bodies which are not physiologically programmed for them, their relationship with health risks is likely to be linear rather than U-shaped. Toxic chemicals in polluted air or tobacco smoke and additives in ultra-processed foods or micro-plastics do not have a U-shaped relationship with human health. They pose rising levels of danger with an increase in doses or duration of exposure. Not only is human physiology unfamiliar with such artificially introduced chemicals, but the trillions of friendly bacteria that constitute our body’s supportive mechanism (microbiome) are also challenged when we consume them.
What the body needs for its physiological functions it accepts willingly in moderation. When we unwisely dump into it things it does not need or use, it suffers damage in a linear dose-response relationship. Even when dealing with familiar physiologic variables, it does not tolerate a harmful combination of multiple risk factors even if they are only modestly elevated, since the cumulative risk is high. For example, risks of blood pressure are compounded by smoking, raised blood cholesterol or diabetes. The evolved wisdom of our bodies value moderation and our physiological sensors shun extremes. It is time to become aware and realise that moderation is the word!
(Views are personal)
Dr K Srinath Reddy
Cardiologist, epidemiologist and Distinguished Professor of Public Health, PHFI