Role of Lipid-Lowering Therapy in Peripheral Artery Disease

Abstract

Atherosclerosis is a multifactorial, lipoprotein-driven condition that leads to plaque formation within the arterial tree, leading to subsequent arterial stenosis and thrombosis that accounts for a large burden of cardiovascular morbidity and mortality globally. Atherosclerosis of the lower extremities is called peripheral artery disease and is a major cause of loss in mobility, amputation, and critical limb ischemia. Peripheral artery disease is a common condition with a gamut of clinical manifestations that affects an estimated 10 million people in the United States of America and 200 million people worldwide. The role of apolipoprotein B-containing lipoproteins, such as LDL and remnant lipoproteins in the development and progression of atherosclerosis, is well-established. The focus of this paper is to review existing data on lipid-lowering therapies in lower extremity atherosclerotic peripheral artery disease.

Keywords: PCSK9 inhibitors; amputation; atherosclerosis; critical limb ischemia; icosapent ethyl; inclisiran; intermittent claudication; lipoprotein; peripheral artery disease; statin.

Figure 1

Left panel: Adjusted hazard ratio of lipids and apolipoproteins and PAD in the Physicians’ Health Study. Note relative risk and 95% confidence intervals for the top and bottom quartile of various lipid and lipoprotein levels after adjustment for smoking status, age, body mass index, frequency of exercise, presence of diabetes and hypertension, and family history of premature atherosclerotic disease. Right panel: Women’s Health Study with hazard ratios and 95% confidence intervals for the top versus bottom tertile of various lipid and lipoprotein levels after adjustment for number of packs smoked over the years, age, body mass index, high-sensitivity C-reactive protein, and presence of hypertension, metabolic syndrome, prior lipid-lowering therapy, and hormonal therapy [12].

Figure 2

Role of oxidized lipoproteins in the development of atherosclerosis, with specific targets and mechanism of action of statins, ezetimibe, and PCSK9 inhibitors. HMGCR: 3-β-Hydroxy β-methylglutaryl-CoA reductase, LDL: Low-density lipoprotein, LDL-C: Low-density lipoprotein cholesterol, LDL-R: Low-density lipoprotein receptor, NP1C1R: Niemann–Pick C1-like 1 receptor, PCSK9: Proprotein Convertase Subtilisin/Kexin Type 9.

Figure 3

University of Louisville approach to PAD treatment based on current guidelines. * ASCVD disease includes CAD, PAD, TIA, stroke, history of myocardial infarction, aortic aneurysm, carotid atherosclerotic disease, history of coronary artery bypass grafting, or percutaneous coronary intervention. Risk factors include HTN, HLD, DM, age ≥70 years, LDL-C >100 mg/dL, high-sensitivity CRP > 2 mg/dL, chronic kidney disease, and Lp(a) > 125 nmol/L. ** High-intensity statins include atorvastatin 40–80 mg and rosuvastatin 20–40 mg. Moderate-intensity statins include atorvastatin 10–20 mg, rosuvastatin 5–10 mg, simvastatin 20–40 mg, and pravastatin 40–80 mg. ^& Bempedoic acid may also be considered, but it is pending data from an ongoing cardiovascular outcomes trial. ^# LDL-C > 55 mg/dL if in a very-high risk group as defined in the 2019 ESC guidelines [7]. CAD: Coronary artery disease, PAD: Peripheral artery disease, HTN: Hypertension, HLD: Hyperlipidemia, DM: Diabetes Mellitus, MetS: Metabolic syndrome, TIA: Transient ischemic attack, LDL-C: Low-density lipoprotein cholesterol, ASCVD: Atherosclerotic cardiovascular disease, TG: Triglycerides, IPE: icosapent ethyl, PCSK9: Proprotein Convertase Subtilisin/Kexin Type 9.