Role of Lipids and Lipid Management Therapy Among Patients With Peripheral Artery Disease: A Reappraisal of the Current Evidence and Future Directions

Abstract

Peripheral artery disease (PAD), defined by stenosis or occlusion of the extremities (particularly the lower extremities), affects 200 million individuals worldwide, including an estimated 7% of adults in the United States alone. It is the third leading cause of atherosclerotic morbidity after coronary artery disease and stroke. Regardless of symptoms, individuals with PAD are known to be at a significantly increased risk for development of a major adverse cardiovascular event and have a higher all-cause mortality than those without disease. Despite PAD underdiagnosis, higher atherosclerotic cardiovascular disease burden, and evidence of decreased atherosclerotic cardiovascular disease risk with lipid modification, lipid undertreatment and nontreatment remain common among patients with PAD. This review addresses (1) the role of lipids in the pathophysiology of incident PAD and in adverse outcomes in those with PAD, (2) the role of lipid-modifying therapies in primary and secondary prevention of PAD, and (3) insights regarding future directions of the study of lipids as it relates to PAD.

Keywords: atherosclerotic cardiovascular disease; chronic limb threatening ischemia; lipids; lipid‐modifying therapies; peripheral artery disease.

Figure 1. Statin use among patients with varying forms of ASCVD.

Prevalent use, compared with 73% statin use in patients with cardiovascular disease (atherosclerotic coronary, cerebral, or abdominal aortic aneurysmal disease); within 3 months of incident diagnosis of either CAD or PAD; within 18 months of incident diagnosis of either CAD or PAD; prevalent statin use in all patients with PAD as compared with those with PAD+CAD or PAD+CVD; PAD compared with PAD+CAD over 8‐year follow‐up period in an outpatient setting; prevalent statin use in PAD alone compared with either CAD or CVD alone; prevalent use of lipid‐lowering therapy, majority statin, including 20.5% on high‐intensity and 39.5% on low‐intensity lipid‐lowering therapy; prevalent use of at least 1 lipid‐lowering medication; prevalent statin use in chronic limb‐threatening ischemia undergoing peripheral vascular intervention. ASCVD indicates atherosclerotic cardiovascular disease; BEST‐CLI, Best Endovascular vs Best Surgical Therapy in Patients with Critical Limb Ischemia; CAD, coronary artery disease; CVD, cerebrovascular disease; PAD, peripheral artery disease; PARTNERS, Peripheral Arterial Disease Awareness, Risk, and Treatment: New Resources for Survival; and REACH, Reduction of Atherothrombosis for Continued Health.

Figure 2. Summary of evidence of cholesterol fractions and other lipid biomarkers as PAD risk factors.

Red ovals represent lipid particles that have a negative impact on PAD and green ovals represent lipid particles that have a positive impact on PAD. HDL‐C, high‐density lipoprotein cholesterol; LDL‐C, low‐density lipoprotein cholesterol; PAD, peripheral artery disease; TG, triglycerides; and VLDL‐C, very low‐density lipoprotein cholesterol.

Figure 3. Lipid lower therapy and impact on MACE and MALE events.

A, Forest plot summarizing lipid lowering studies and MACE outcomes with further details in Table 2. B, Forest plot summarizing lipid lowering studies and MALE outcomes with further details in Table 2. aHR indicates adjusted hazard ratio; AIM‐HIGH, Atherothrombosis Intervention in Metabolic Syndrome With Low HDL/High Triglycerides: Impact on Global Health Outcomes; HR, hazard ratio; MACE, major adverse cardiovascular event; MALE, major adverse limb event; OR, odds ratio; PAD, peripheral artery disease; and RR, relative risk.