There is evidence of positive relationships between cholesterol concentration and risk of cardiovascular diseases.
However, higher mortality in patients with a low cholesterol level has been reported and is referred to as the cholesterol paradox.
The cholesterol paradox generally refers to seemingly contradictory observations about cholesterol and health outcomes, particularly in certain populations or conditions. Key aspects include:
The reverse epidemiology seen in some chronic conditions where higher cholesterol levels are associated with better survival outcomes, particularly in:
Elderly populations Patients with chronic heart failure Those undergoing dialysis People with chronic inflammatory conditions
Some studies have found that lower cholesterol levels can be associated with: Higher all-cause mortality in certain populations Increased risk of certain non-cardiovascular conditions Better outcomes in some acute illness scenarios
Patients with total cholesterol in the lower quartile and LDL-C < 70 mg/dl had greater risk of the outcomes measured than individuals with a TC level in the remaining quartiles and LDL-C ≥ 70 mg/dl.
Moreover, patients with TC in the highest quartile, and LDL-C ≥ 115 mg/dl, had the lowest all-cause in-hospital mortality.
A low cholesterol level should be interpreted as a biomarker of illness severity.
During a very long-term, up to a maximum of 46 years, follow-up of 3277 midlife healthy men in the Helsinki Businessmen Study, a baseline total cholesterol blood concentration below 154 mg/dl was related to the lowest mortality and a higher score in the RAND-36 physical functioning scale in old age.
Hypolipemic therapy, mainly with statins and recently with inhibitors of proprotein convertase subtilisin/kexin type 9 (PCSK9), decreases overall and cardiovascular mortality, reduces risk of CVE and has established a goal for low-density lipoprotein (LDL) cholesterol (LDL-C) of lower than 70 mg/dl in patients with a very high risk.
It is also reported that patients with low TC and LDL-C plasma concentrations have a worse prognosis, in what is called the “cholesterol paradox”.
The LDL cholesterol paradox is a reduction in CVE risk related to a decrease in LDL-C blood concentration which is not concomitant with a decrease in total mortality.
The “cholesterol paradox” refers to the counterintuitive observation that, in certain populations, lower cholesterol levels are associated with worse clinical outcomes, contrary to the traditional understanding that lower cholesterol is generally beneficial for cardiovascular health.
In patients with acute myocardial infarction (AMI), lower low-density lipoprotein cholesterol (LDL-C) levels have been associated with higher in-hospital mortality, suggesting that low cholesterol may reflect an advanced disease state or other underlying health issues.
In patients with chronic heart failure (HF), higher cholesterol levels have been linked to improved survival, while lower levels are associated with increased mortality.
There is an inverse relationship in their scientific statement on hyperlipidemia and heart failure.
The cholesterol paradox has been observed in older adults with type 2 diabetes mellitus, where lower cholesterol levels were associated with higher prevalence of diabetes and impaired cognitive and daily functioning, regardless of lipid-lowering drug use.
The cholesterol paradox may be influenced by malnutrition, reverse causality, and the acute-phase response in severe illnesses, which can lower cholesterol levels and confound the association with mortality.
The better prognosis in patients with hypercholesterolemia may be related to (a) favorable effects of the “obesity paradox”: improved hemodynamic stability in the obese, adipokine protection against tumor necrosis factor-α, lipoprotein protection against endotoxins, lipophilic toxin sequestration by adipose tissue, and the modulation of inflammatory processes: b) an earlier start of contact with health care professionals; and (c) the evidence of favorable and pleiotropic effect of hypolipidemic drugs recommended for patients with prior diagnosed hypercholesterolemia which is treated without meeting the recommended goals.
The “cholesterol paradox” may be an effect of “reverse causality”, in which poor prognosis in patients with low cholesterol blood concentration results not from the lack of the aforementioned favorable effects of hyperlipidemia, but from (d) unfavorable effects of comorbidities, such as systemic inflammation, malnutrition, malabsorption syndrome, neoplasm, end-stage liver disease, end-stage kidney disease, chronic obstructive pulmonary disease (COPD), and cardiac heart failure and/or (e) potential harmful effects of aggressive hypolipidemic therapy when hypercholesterolemia was diagnosed earlier and cholesterol was lowered too aggressively.
The cholesterol paradox has been noted among geriatric patients and in several acute (myocardial infarction and chronic conditions, such as stable coronary artery disease, end-stage renal disease requiring dialysis, chronic heart failure, atrial fibrillation, peripheral artery disease, stroke, COPD, rheumatoid arthritis, and AIDS.
In our study, performed on a large, non-selected population of consecutive inpatients at a university hospital, the existence of a “lipid paradox” or “cholesterol paradox” was suggested only by univariate analysis.
A neutral effect of plasma lipid levels on the risk of the outcomes measured, which suggests that this paradox is an effect of reverse causality, and higher blood cholesterol concentration is not a biomarker of better prognosis, but an effect of the better general condition of the patient and a lower severity of illness.
Patients with higher TC, LDL-C and HDL-C blood concentrations had a lower risk of all the outcomes measured than their counterparts, both in the whole of the population studied and in the analysis limited only to patients with a diagnosis of CVD or cancer.
Analysis identified a worse prognosis for hospitalized patients with the lowest TC, LDL-C and TG, which, although contrary to findings in outpatient studies and in the general literature, corroborated results of recent, experimental, randomized and controlled trials.
Recently, a few studies have failed to show a cardiovascular benefit of the aggressive lowering of LDL-C and raising of HDL-C blood concentrations.
These studies showed the lack of the assumed clinical importance of an increase in HDL-C and a large reduction in LDL-C.
It is also possible that such aggressive therapy may lead to non-cardiovascular mortality, secondary to still undiagnosed adverse effects e.g. similar to statins, which cause a dose-dependent increase in the risk of diabetes mellitus.
Analysis revealed better outcomes in hospitalized patients with hyperlipidemia, which was also consistent with the results of observational studies.