Pharmacological Options in Atherosclerosis: A Review of the Existing Evidence

Abstract

Coronary heart disease (CHD) is the leading cause of mortality worldwide and high low-density lipoprotein (LDL) cholesterol levels have been shown to be key in the pathogenesis of this condition. Lipid control has therefore been the subject of decades of research and has led to many large and robust randomized controlled trials, as well as the highest grossing drug of all time-Lipitor (atorvastatin). Statin therapy has long been indicated for secondary and more recently primary prevention. However, despite the large-scale use of statins, CHD prevalence remains high, and some patients do not respond to statin therapy. There has been a large push to find and test alternative lipid-lowering agents, these include fibrates, cholesterol absorption inhibitors, and proprotein convertase subtilisin/kexin type 9 (PCSK-9) inhibitors. It is the aim of this review to assess the literature surrounding each of these groups of drugs.

Keywords: Cholesterol absorption inhibitor; Fibrates; LDL; Lipid; PCSK-9 inhibitor; Statin.

Fig. 1

a Atherogenic lipoproteins such as low-density lipoproteins (LDLs) entering the intima are modified, by oxidation or enzymatic activity, and aggregate within the extracellular intimal space. Unregulated uptake of these lipoproteins by macrophages generates foam cells and fatty streaks. These are usually asymptomatic. b Vascular smooth muscle cells secrete large amounts of extracellular-matrix components, such as collagen, which increase the retention and aggregation of atherogenic lipoproteins. The inflammatory state is potentiated by monocyte and leukocyte recruitment. As the plaque grows, compensatory remodeling (adaptive intimal thickening) occurs to preserve the lumen diameter. c Foam cells eventually die and release cellular debris, which forms a necrotic core. Smooth muscle cells form a fibrous cap beneath the endothelium, which walls off the plaque from the blood. d The advanced lesion can either rupture or continue to grow, eventually leading to clinically significant obstructive disease. Reproduced by permission from Springer Nature, Nature, Translating molecular discoveries into new therapies for atherosclerosis, Daniel J. Radar & Alan Daugherty (2008, Vol 451, 904-913)

Fig. 2

Kaplan–Meier estimates of the incidence of major secondary outcomes in the pravastatin and placebo groups. a Mortality from all causes. b Death due to coronary heart disease (CHD) or nonfatal myocardial infarction (MI). c Stroke of any type. The graphs show a reduction in risk in the pravastatin group for all-cause mortality, cardiovascular events, and stroke. For every 1000 patients in the pravastatin group, the analysis showed that death from any cause was avoided in 30 patients, death due to CHD or nonfatal MI in 35 patients, and stroke in eight patients. Reproduced by permission from Elsevier, NEJM, Prevention of Cardiovascular Events and Death with Pravastatin in Patients with Coronary Heart Disease and a Broad Range of Initial Cholesterol Levels. The Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group 1998;Vol 339(19):1349–1357