New compounds able to control hepatic cholesterol metabolism: Is it possible to avoid statin treatment in aged people?

Abstract

Aging is characterized by the loss of homeostasis that leads to changes in the biochemical composition of tissues, reduced ability to respond adaptively to environmental stimuli, and increased susceptibility and vulnerability to diseases including coronary artery diseases, carotid artery disease and brain vessel disease. Hypercholesterolemia is one of the primary risk factors for these pathologies, whose incidence is highly related to aging. Almost 25% of men and 42% of women older than 65 years have a serum total cholesterol level greater than 240 mg/dL. The mechanisms behind this age-related increase in plasma cholesterol are still incompletely understood, thus, the control of plasma cholesterol content in aged people is more challenging than in adults. In this review the different pharmacological approaches to reduce plasma cholesterol levels, particularly in aged people, will be discussed. In brief, current therapies are mostly based on the prescription of statins (3-hydroxy-3-methylglutaryl-CoA reductase inhibitors) that are pretty effective but that exert several side effects. More attention should be given to potential drug interactions, potential age-related changes in drug pharmacokinetics, adverse effects such as myopathy and competing risks when statins are prescribed to old patients. In combination or in alternative to statin therapy, other agents might be required to reduce low density lipoprotein (LDL) cholesterol levels. Among the available drugs, the most commonly prescribed are those addressed to reduce cholesterol absorption, to modulate lipoprotein lipase activity and bile acid sequestrants: even these pharmacological interventions are not exempt from side effects. The use of antioxidants or organoselenium compounds and the discovery of new proteins able to modulate exclusively LDL receptor recycling such as Proprotein convertase subtilisin kexin 9 and SEC24 offer new pharmacological approaches to selectively reduce the main causes of dyslipidemia.

Keywords: Aging; Cholesterol; Hypercholesterolemia

Core tip: The strategies used to reduce plasma cholesterol levels in elderly people are mainly addressed to the inhibition of the rate limiting enzyme of cholesterol biosynthetic pathway, 3-hydroxy-3-methylglutaryl-CoA reductase (HMGR), in order to increase low density lipoprotein (LDL) receptor membrane exposure and LDL clearance from the circulation. Indeed current therapies are mostly based on the prescription of statins (HMGR inhibitors) that are pretty effective but that exert side effects. More attention should be given to potential drug interactions, potential age-related changes in drug pharmacokinetics, adverse effects such as myopathy and competing risks when statins are prescribed to elderly. Thus, new therapeutic agents should be taken into account.