There was a time when it was actually believed that there was no benefit to lowering cholesterol. There were many studies which in fact cautioned against lowering cholesterol with the belief that very low cholesterol may lead to enhanced mortality. In the last few decades, however, the concept has slowly shifted towards low, lower, and lowest possible levels of LDL (low-density lipoprotein) cholesterol.

The reason is that as LDL cholesterol is lowered to new nadirs, there is a continuous linear decline in cardiovascular events as well. Unlike hypertension and diabetes, there is no J curve in dyslipidaemia correction. It is a linear correlation!

LDL and cardiovascular disease

1. LDL has been casually implicated in cardiovascular disease and it has been seen that this is one of the most important entities for cardiovascular disease pathogenesis. Very high levels result in early and severe coronary artery disease. Most of the time there are non-hereditary acquired causes of such high and dangerous levels of LDL. 
2. There is a reason to believe that we developed these lethal levels of LDL over the last many centuries to reach the current levels. These atherosclerotic LDL values were attained by eating a diet rich in refined sugars, processed foods, trans fats and carbonated drinks.
3. Perhaps the biggest single culprit food could be plain refined sugar. Not to mention the additive effects of pollution, stress, smoking and allied risk factors. Anthropological and historical data has shown that, nearly 10,000 years ago, the early human who was a hunter-gatherer, primarily depended on a wildlife diet consisting mostly of nuts, fruits, vegetables, and flesh of wild animals.
4. These nomads were free from atherosclerosis with an average total cholesterol level of about 50–75 mg/dl. Tragically, it took only 500 further generations, for Atherosclerotic vascular disease based on the LDL foundation to become the predominant cause of global mortality.
5. The average total cholesterol of modern humans has now jumped to be approximately 200 mg/dl. Part of this dubious credit is shared by the agricultural green revolution that happened and the rest of the lifestyle changes and poor dietary choices we had made. 
6. Unfortunately, this colossal dietary transformation happened too quickly over the years, without letting the evolution of genetic adaptation take place. These sweeping changes in our diet without genetic adaptations are primarily responsible for the rise of serum LDL levels and increased incidence of atherosclerotic cardiovascular diseases.

Zero LDL hypothesis 

1. The Cholesterol Treatment Trialists’ Collaboration meta-analysis has shown that there is a continuous linear correlation between LDL reduction and cardiovascular benefits. Thus lowering the LDL cholesterol lower is the cardiovascular events. Similarly, in the FOURIER trial, For example, it was shown that when there was a significant reduction of LDL from a baseline value of 92 mg/dl to 30 mg/dl with Evolocumab, which was well tolerated and there was a significant decrease in the risk of major cardiovascular events without any major increase in the adverse events.

2. There was a 17% decrease in the primary endpoints of cardiovascular death, myocardial infarction, and stroke on lowering the LDL to 43 mg/dl and when the LDL levels were further reduced to 22 mg/dl, there was further lowering of the cardiovascular risk to 20%. Additionally, there were consistent clinical improvements per unit reduction in LDL. In the same manner, a post hoc analysis of ODYSSEY trials comparing Alirocumab with the control indicated that low LDL-C was associated with a lower incidence of major adverse cardiovascular events with no significant increase in the therapy associated adverse reactions.

3. Very recently, a prespecified safety analysis of the IMPROVE-IT trial involving 15 281 patients showed that of 971 patients with LDL levels below 30 mg/dl, there were no increased adverse events over six years of follow-up.

Encouraged by these well designed and executed randomised controlled trials, there is growing scientific consensus that LDL cholesterol should in fact be zero or as low as possible.

This has been met with guarded assessment by the experts as critics point out that there are serious flaws in this hypothesis. 

1. There is no long-term data on living with very low LDL available. We have at best safety data available for 5 to 7 years.
2. There have been safety concerns about some diseases which are associated with very low LDL cholesterol though never been proven till now. Very low levels of LDL cholesterol may be associated with an increased risk of cancer, haemorrhagic stroke, depression and preterm births in hypolipidemic mothers.
3. The side effects of the treating drugs may come into play when LDL is lowered to such a low level. Due to increased catabolism low LDL levels should not be compared with those due to low production rates, as in hypobeta - and abetalipoproteinemia, diseases characterised by severe symptoms because of apolipoprotein B deficiency.

The recently updated guidelines for the management of dyslipidaemia from the European Society of Cardiology (ESC) and European Atherosclerosis Society (EAS) have revised the targets accordingly and thus have recommended aggressive goals for LDL.

The amended goals are mentioned below:

1. For patients at high risk of atherosclerotic cardiovascular disease (ASCVD) = <70 mg/dl
2. For patients at very high risk or with clinically evident ASCVD = <55 mg/dl
3. For very high-risk patients who experienced a second vascular event within 2 years = <40 mg/dL

The authors thus believe that there is no level of LDL-C below which ‘benefit ceases or harm occurs has been defined’.

Why zero LDL hypothesis could be right?

Cholesterol is an essential molecule with many important cellular functions. However, a number of physiological and clinical observations have supported the fact of zero LDL blood levels.

1. All human cells can synthesise LDL for themselves if there is a need. Presumably, as this pathway is available to all tissues, very low levels of LDL are not associated with any known metabolic abnormalities or health concerns.
2. There are certain populations, where LDL cholesterol is found to be extremely low. Additionally, all of us are born with LDL levels below 1.0 mmol/L (40 mg/dl)—a concentration sufficient to support neonatal organ formation during which cholesterol requirements are very high.
3. Lifelong LDL-C levels below 1.3 mmol/L(50 mg/dl) have been observed in hunter-gatherer societies with no evidence of related health risks.
4. Hereditary conditions, such as PCSK9 loss of function which promote LDL removal and LDL levels are <0.39 mmol/L (15 mg/dl) have not been shown to be associated with adverse ASCVD events.
5. In the FOURIER study of Evolocumab, 10% (n=2669/25 982) of patients reached LDL levels <0.5 mmol/L (19 mg/dL). This subgroup exhibited the lowest risk of cardiovascular events, and there was no significant difference in adverse events compared with those who had higher LDL on treatment (whether on active drug or placebo). In the same study, neurological and neurocognitive events were evaluated in subjects with very low LDL levels and no difference was observed with those with higher levels.
6. In IMPROVE-IT, more than 5000 patients receiving ezetimibe plus statin achieved an LDL-C <1.3 mmol/L (50 mg/dl), with approximately 1000 patients achieving levels <0.8 mmol/L (30 mg/dl). Over 7 years of follow-up, neither subgroup showed an increased frequency of side effects, including new-onset diabetes, haemorrhagic stroke or neurocognitive dysfunction.

Disclaimer- The views and opinions expressed in this article are those of the authors and do not necessarily reflect the official policy or position of M3 India.

The author, Dr Arun Kochar is a Senior Interventional Cardiologist practising in Mohali.