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.

Nonstandard Abbreviations and Acronyms

AHA

American Heart Association

CIMT

carotid artery intimal medial thickness

CLTI

chronic limb threatening ischemia

CVD

cerebrovascular disease

FOURIER

Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk

LDL‐P

low‐density lipoprotein particle

MACE

major adverse cardiovascular event

MALE

major adverse limb outcomes

TC

total cholesterol

Peripheral artery disease (PAD) is an atherosclerotic syndrome defined by stenosis or occlusion of the extremities (particularly the lower extremities) and affects 200 million individuals worldwide, with an estimated 12 million adults affected in the United States alone. ¹ It is the third leading cause of atherosclerotic morbidity after coronary artery disease (CAD) 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 (MACE) and have a higher all‐cause mortality than those without disease. ² The global 5‐year survival rate for those with chronic limb threatening ischemia (CLTI) in the setting of PAD is <30%, with a 20% to 25% mortality rate in the first year after diagnosis alone. More than 25% of patients with CLTI will ultimately require amputations. Risk factors for development and progression of PAD mirror CAD, with smoking being the most important risk factor. However, the relative impact of other risk factors—hypertension, hypercholesterolemia, and type 2 diabetes—on PAD outcomes is less clear. ³

Distinct differences in the pathophysiology of both PAD and CAD have been identified, which have led to reappraisal of risk factors for PAD and differences in management of these diseases. Perhaps surprisingly, research on the role of lipids and lipid subcomponents, specifically low‐density lipoprotein cholesterol (LDL‐C), in the development of PAD is not well established. Data regarding lipid management among patients with established PAD are similarly not as robust as one may assume. The most recent update of the American Heart Association (AHA)/American College of Cardiology lipid management guidelines recommend lipid‐lowering therapy with a high‐dose statin for all patients with established atherosclerotic cardiovascular disease (CAD, cerebrovascular disease [CVD], and PAD). ⁴ The CTT's (Cholesterol Treatment Trialists') meta‐analysis of 170 000 patients from 26 trials showed that increasing reductions in LDL‐C increasingly reduced the incidence of heart attack, revascularization, and ischemic stroke. ⁵ The results of the CTT meta‐analysis are presumed to hold true for all patients with atherosclerotic disease including those with PAD; however, a minority of patients in the studies included in the meta‐analysis had PAD, and prespecified PAD outcomes were not adjudicated as end points. Patients with PAD have a 2‐ to 3‐fold higher risk of myocardial infarction (MI) and stroke compared with those without PAD, and statins are known to reduce this risk, just as in patients with CAD. ⁶ However, the impact of lipid‐lowering therapy on limb outcomes remains a critical knowledge gap.

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.

METHODS

A search of the existing evidence on the role of lipids in the pathophysiology of PAD, the effectiveness of lipid‐lowering therapies in PAD, and imaging modalities for detection and quantification of lipid burden in PAD was conducted to inform the scope of this paper. The PubMed database was searched using the terms (‘PAD’) AND (‘lipids’) AND (‘medical therapy’, ‘imaging’, OR ‘pathophysiology’) for all full‐text articles published in English between January 1, 1990, and December 31, 2024. Search results yielded 366 articles published in this time period. No additional filters or limits were used. Articles not directly pertaining to lipids as they relate to the pathophysiology or treatment of PAD were discarded. Key articles not directly identified in the search results but that were either instrumental in this field or cited multiple times by other articles in the original search results were also included. There were no specific end points of interest that were evaluated given the comprehensive nature of this review including epidemiology, pathophysiology, treatment, and identification of PAD/lipids.

Atherosclerotic Burden in PAD

Approximately 30% to 50% of patients with known PAD also have known CAD. Conversely, patients with CAD and concomitant PAD have more extensive coronary atherosclerosis with a significantly increased burden of calcified disease compared with those without PAD. ⁷ Studies have shown that a history of MI was 2.5 times more prevalent in patients with an ankle‐brachial index (ABI) <0.9 and PAD was 2.1 times more prevalent in patients with a history of MI in the Cardiovascular Health Study. ⁸ Additionally, the progression of CAD in patients with PAD is greater than in those without. Despite the higher atherosclerotic cardiovascular disease (ASCVD) burden, and evidence of decreased ASCVD risk with lipid modification, lipid undertreatment and nontreatment remain common among patients with diagnosed PAD (Figure 1, ⁹ , ¹⁰ , ¹¹ , ¹² , ¹³ , ¹⁴ , ¹⁵ , ¹⁶ ).

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) ⁹ ; within 3 months of incident diagnosis of either CAD or PAD ¹⁰ ; within 18 months of incident diagnosis of either CAD or PAD ¹⁰ ; prevalent statin use in all patients with PAD as compared with those with PAD+CAD or PAD+CVD ¹¹ ; PAD compared with PAD+CAD over 8‐year follow‐up period in an outpatient setting ¹² ; prevalent statin use in PAD alone compared with either CAD or CVD alone ¹³ ; prevalent use of lipid‐lowering therapy, majority statin, including 20.5% on high‐intensity and 39.5% on low‐intensity lipid‐lowering therapy ¹⁴ ; prevalent use of at least 1 lipid‐lowering medication ¹⁵ ; prevalent statin use in chronic limb‐threatening ischemia undergoing peripheral vascular intervention. ¹⁶ 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.

The PARTNERS trial (Peripheral Arterial Disease Awareness, Risk, and Treatment: New Resources for Survival) in 1999 found that in a primary care setting, only 44% of patients with a new diagnosis of PAD and 56% with a prior diagnosis of PAD were treated for hyperlipidemia. ⁹ In the large international REACH (Reduction of Atherothrombosis for Continued Health) registry of patients with established ASCVD, 62.2% of patients with PAD were on statins (74.5% in patients with concomitant CAD, 64% with concomitant CVD). Disparities seemed to be more pronounced when the primary enrolling physician was not a cardiologist. For instance, only 30.2% of patients enrolled by vascular surgeons were on a statin if they did not also have CAD. ¹¹ More recent studies have shown improvements in statin usage rates for patients with PAD. ¹⁵ , ¹⁶

These disparities are important because patients with PAD have at least the risk of MACE of patients with CAD and patients with polyvascular disease have almost double the risk. ¹⁷ As such, lipid management guidelines for PAD are similar if not more intensive when compared with CAD; the current European guidelines recommend targeting LDL reduction of ≥50% from baseline and <55 mg/dL in patients with PAD. ¹⁸ Guidelines from the AHA/American College of Cardiology recommend statin use in all patients with diagnosed PAD. ²

Pathophysiology/Plaque Types

PAD can be categorized into intermittent claudication (stable peripheral disease), CLTI, and acute limb ischemia. Both CLTI and acute limb ischemia carry a massive morbidity and mortality burden, although there are significant differences in the clinical presentation, diagnosis, and treatment of these 2 entities. Little is known about plaque composition and pathophysiology regarding progression of artery disease in PAD and until recently both were thought to mirror CAD. ¹⁹ Luminal thrombosis is the central pathologic cause of events in both CAD and PAD; however, the underlying substrate differs between the 2 diseases and is dependent on anatomic site. ²⁰ For CAD, the common clinical manifestation is that of an acute ischemic event causing luminal thrombosis in the setting of plaque rupture or erosion. Thrombotic occlusion in PAD comprises a mixture of both acute and chronic thrombosis, but chronic thrombosis is more commonly observed in those arteries without significant underlying atherosclerosis. ²¹ The more subacute/chronic clinical presentation of ischemia in PAD likely owes to these differences in pathophysiology, with CLTI commonly demonstrating severe intimal thickening or chronic thrombus. ²² In CLTI, disease involves distal, small vessel and typically manifests as medial calcification and intimal fibrosis. In comparison, acute limb events are thought to be the result of in situ thrombosis or embolism from cardiac or more proximal peripheral sources as opposed to plaque rupture. ²³ In patients with prior intervention, graft occlusion is also a significant cause of acute limb ischemia. Overall, acute thrombosis is less common in the infrapopliteal arteries, and chronic thrombosis plays a much larger role in PAD than plaque rupture and acute thrombosis.

In contrast to CAD pathology in which fibroatheromas and fibrocalcific lesions lead to luminal thrombosis through plaque rupture, in PAD, more “stable” phenotypes such as pathologic intimal thickening are present in which a lipid core begins to develop in the setting of smooth muscle cell accumulation but without necrosis of this core. A study of pathologic specimens of patients with CLTI by Narula et al. showed that in lower extremity vessels with ≥70% stenosis, only 25% of stenoses were due to significant atherosclerosis without thrombi, and 73% of arteries had thrombi contributing to the luminal stenosis. ²⁴ In 67% of those arteries with thrombi, the thrombotic occlusion was not associated with any significant atherosclerosis. In the same study, only 40% of infrapopliteal arteries in postamputation limbs showed any significant atherosclerosis, as opposed to ~66% in patients with femoral or popliteal disease. ²⁴

Another important aspect in the pathogenesis of PAD is the presence and quantification of medial calcification, which represents the bulk of vascular calcification present in the lower extremities (as opposed to intimal calcification), but it is beyond the scope of this review. ²²

Lipids as Risk Factors for PAD

There are several widely supported, established risk factors for the development of PAD. Smoking, hypertension, hypercholesterolemia, and type 2 diabetes account for the majority of the risk of developing PAD, and these risk factors are seemingly additive (incident rates lowest for zero risk factors [9 cases/100 000 person‐years] with a progressive increase with all 4 risk factors [186 cases/100000 person‐years]). ³ At least 1 of these risk factors is present in 80% of individuals with CAD, but as high as 95% of cases of severe PAD. ³ The Cardiovascular Health Study is one of few studies that suggests lipid markers are associated with progression of PAD. ²⁵ In this study, dyslipidemia was among several other independent risk factors for disease progression (age, diabetes, and cigarette smoking).

Lipids as they relate to PAD can be addressed from 2 angles: as risk factors for incident PAD (primary prevention) and as a treatment target for patients with established PAD (secondary prevention). Much of the data regarding risk factors for PAD development are based on cross‐sectional associations and analyses as many of these studies define a relationship with PAD based on incident disease (MI, stroke, etc.) and not from time of development of PAD based on ABI. ²⁶ These studies must adjust for multiple risk factors to estimate the contribution from a single factor as there is significant interplay among the known risk factors for PAD.

The exact relationship between lipid levels and PAD is less clear than it is in other atherosclerotic diseases. As such there are significantly fewer studies examining the role of lipids in the pathogenesis of PAD as compared with CAD. ²⁷ It is evident however that lipid risk profiles in PAD are markedly different than those for CAD or CVD. ²⁸ LDL and apolipoprotein B are among the strongest lipid markers for CAD and CVD, whereas the strongest lipid markers for PAD may be high‐density lipoprotein (HDL), total cholesterol (TC):HDL, and specific lipid subfractions (such as small dense LDL). ²⁸ This section further discusses individual lipids and subcomponents as they relate to PAD. A summary of lipid markers as they relate to PAD end points is provided in Table 1. ³ , ⁸ , ²⁵ , ²⁸ , ²⁹ , ³⁰ , ³¹ , ³² , ³³ , ³⁴ , ³⁵ , ³⁶ , ³⁷ , ³⁸ , ³⁹ , ⁴⁰ , ⁴¹ , ⁴² , ⁴³ , ⁴⁴ , ⁴⁵

Table 1.

Association of Lipid Markers With PAD End Points

Lipid marker	Study	No.	Population	Outcome measure	Results	Prospective or cross‐sectional
TC	Ingolfsson et al. 1994 29	9141	Icelandic men born from 1907 to 1934	Prevalent cases of intermittent claudication	OR per mg/dL of TC: 1.009, P<0.001	Cross‐sectional
	Ingolfsson et al. 1994 29	8045	Icelandic men born from 1907 to 1934	Incident cases of intermittent claudication	Rate ratio per mg/dL of TC: 1.007. P<0.01	Prospective 1968–1986
	Murabito et al. 1997 30	5209	Men and women aged 28–62 y	Intermittent claudication	OR per 40 mg/dL, 1.2 (95% CI, 1.1–1.3), P=0.0001	Prospective over 38‐year follow‐up
	Newman et al. 1993 8	5084	Medicare recipients age ≥65 y from 4 US communities	ABI <0.9	RR per 10 mg/dL, 1.1 (95% CI, 1.06–1.14), P<0.0001	Cross‐sectional
	Meijer et al. 2000 31	6450	Men and women age ≥ 55 y from Netherlands	ABI <0.9	Multivariate OR per mmol/L, 1.19 (95% CI, 1.05–1.36)	Prospective 1990–1995
	Curb et al. 1996 32	3450	Japanese‐American men age 45–68 y	ABI <0.9	Multivariate OR for 80th compared with 20th percentile, 1.36 (95% CI, 1.12–1.68)	Cross‐sectional
	Curb et al. 1996 32	3450	Japanese‐American men age 45–68 y	ABI <0.9	Multivariate OR for 80th compared with 20th percentile, 1.40 (95% CI, 1.18–1.67)	Prospective 1965–1968
	Bainton et al. 1994 33	2094	Men aged 45–59 y	Intermittent claudication	Mean difference adjusted for age and smoking per mmol/L, +0.27 (95% CI, 0.01–0.54), P<0.05	Prospective over 11 years
	Joosten et al. 2012 3	44 985	US, male health professionals aged 40–70 y without history of CVD	Limb amputation or revascularization, ≥50% obstruction on angiogram, ABI <0.9, physician‐diagnosed PAD	P value for linear trend according to duration of hypercholesterolemia =0.05	Prospective 1986–2011
	Aday et al. 2018 28	27 888	Women ≥45 y free of CVD at baseline	Intermittent claudication or revascularization	Multivariate HR for top vs bottom tertile of standard lipid measure 0.99 (95% CI, 0.63–1.55), P=0.77	Prospective over median 15.1 years
	Ridker et al. 2001 34	14 916	Healthy US male physicians aged 40–84 y	Intermittent claudication, hospitalization for revascularization	Adjusted RR highest vs lowest quartile, 3.1 (95% CI, 1.5–6.5), P<0.001	Prospective over average 9 years
	Murabito et al. 2002 35	3313	Men and women age ≥ 40 y (offspring from Framingham Heart Study and spouses)	ABI <0.9	Sex and age‐adjusted OR per mg/dL, 1.7 (1.1–2.4) Multivariable‐adjusted OR per mg/dL, nonsignificant	Cross‐sectional
	Bowlin et al. 1994 36	8253	Israeli men aged 40–65 y	Intermittent claudication defined by questionnaire	Multiple logistic regression OR per 50 mg/dL difference, 1.35 (95% CI, 1.18–1.54)	Prospective over 5 years
	Miyata et al. 2019 37	6565	Patients with PAD (ABI <0.9) across medical clinics in Japan	MALE defined by amputation, development of chronic limb threatening ischemia, and acute limb ischemia	Adjusted multivariate HR, 0.68 (95% CI, 0.46–1.01)	Prospective over 2 years
HDL‐C	Meijer et al. 2000 31	6450	Men and women age ≥ 55 y from Netherlands	ABI <0.9	Multivariate OR per mmol/L, 0.58 95% CI, (0.35–0.99)	Prospective 1990–1995
	Curb et al. 1996 32	3450	Japanese‐American men aged 45–68 y	ABI <0.9	Multivariate OR for 80th compared with 20th percentile, 0.68 (95% CI, 0.53–0.88)	Cross‐sectional
	Bainton et al. 1994 33	2094	Men aged 45–59 y	Intermittent claudication	Mean difference adjusted for age and smoking per mmol/L, −0.03 (−0.11 to 0.06), P nonsignificant	Prospective over 11 years
	Ness et al. 2000 38	1911	Geriatric men and women from a single practice	Symptomatic PAD (defined as intermittent claudication, ischemic rest pain, exam findings consistent with PAD)	OR, 0.965 (95% CI, 0.946–0.984), P=0.001 for women; 0.948 (95% CI, 0.907–0.990), P=0.017 for men	Cross‐sectional
	Fowkes et al. 1992 39	1592	Scottish men and women aged 55–74 y	Intermittent claudication	Multivariate OR per 0.4 mmol/L, 0.7 (95% CI, 0.5–1.0), P<0.1	Cross‐sectional
	Aday et al. 2018 28	27 888	Women ≥45 y free of CVD at baseline	Intermittent claudication or revascularization	Multivariate HR for top vs bottom tertile of standard lipid measure, 0.30 (95% CI, 0.17–0.54), P>0.0001	Prospective over median 15.1 y
	Ridker et al. 2001 34	14 916	Healthy US male physicians aged 40–84 y	Intermittent claudication, hospitalization for revascularization	Adjusted RR, highest vs lowest quartile: 0.5 (95% CI, 0.2–0.9), P=0.03	Prospective over average 9 y
	Kennedy et al. 2005 25	218	Men and women age 65 y or older without PAD and with ABI >0.9 and <1.4 from 4 US communities	Decrease in ABI by >0.15 and to 0.9 or less	Multivariate OR for highest vs lowest quartile per mg/dL, 0.84 (95% CI, 0.49–1.45), P=0.53	Prospective over 6‐y follow‐up
	Newman et al. 1993 8	5084	Medicare recipients age ≥65 from 4 US communities	ABI <0.9	RR per 1 mg/dL, 0.99 (95% CI, 0.98–1.00), P=0.02	Cross‐sectional
	Murabito et al. 2002 35	3313	Men and women age ≥ 40 y (offspring from Framingham Heart Study and spouses)	ABI <0.9	Sex‐ and age‐adjusted OR per 5 mg/dL, 0.9 (95% CI, 0.8–0.9) Multivariable‐adjusted OR per 5 mg/dL, 0.9 (95% CI, 0.8–1.0)	Cross‐sectional
	Bowlin et al. 1994 36	8343	Israeli men aged 40–65 y	Intermittent claudication defined by questionnaire	Univariate RR of highest vs lowest quintile, 0.62 (95% CI, 0.40–0.95)	Cross‐sectional
TC:HDL‐C	Aday et al. 2018 28	27 888	Women ≥45 free of CVD at baseline	Intermittent claudication or revascularization	Multivariate HR for top vs bottom tertile of standard lipid measure, 3.11 (95% CI, 1.67–5.81), P=0.0005	Prospective over median 15.1 y
	Allison et al. 2006 40	6814	US men and women aged 45–84 y without CVD	ABI ≤0.9	Adjusted OR, 1.58 (95% CI, 1.22–2.18)	Cross‐sectional
	Ridker et al. 2001 34	14 916	Healthy US male physicians aged 40–84 y	Intermittent claudication, hospitalization for revascularization	Adjusted RR highest vs lowest quartile: 3.9 (95% CI, 1.7–8.6), P<0.001	Prospective over average 9 y
	Aboyans et al. 2006 41	403	Established patients from single‐center US hospital with prior LE arterial testing	PAD progression (LV: highest 10% ABI decline; SV: highest 10% TBI decline)	Adjusted HR per unit for ABI decrease >0.3, 1.35 (95% CI, 1.05–1.73), P=0.019 Unadjusted HR per unit for TBI decrease <0.27, 0.63 (95% CI, 0.35–1.13), P=0.121	Prospective with average follow‐up 4.6 ± 2.5 y
	Bowlin et al. 1994 36	8343	Israeli men aged 40–65 y	Intermittent claudication defined by questionnaire	Univariate RR of highest vs lowest quintile, 1.92 (95% CI, 1.26–2.91)	Cross‐sectional
Triglycerides	Bainton et al. 1994 33	2094	Men aged 45–59 y	Intermittent claudication	Mean difference adjusted for age and smoking per mmol/L, +0.33 (95% CI, 0.12–0.55), P<0.01	Prospective over 11 y
	Fowkes et al. 1992 39	1592	Scottish men and women aged 55–74 y	Intermittent claudication	Multivariate OR, 1.0 (95% CI, 0.7–1.5), Pvalue not significant	Cross‐sectional
	Aday et al. 2018 28	27 888	Women ≥45 y free of CVD at baseline	Intermittent claudication or revascularization	Multivariate HR for top vs bottom tertile of standard lipid measure, 1.46 (95% CI, 0.82–2.61), P=0.23	Prospective over median 15.1 y
	Ridker et al. 2001 34	14 916	Healthy US male physicians aged 40–84 y	Intermittent claudication, hospitalization for revascularization	Adjusted RR highest vs lowest quartile, 2.8 (95% CI, 1.3–5.9), P=0.003	Prospective over average 9 y
	Kennedy et al. 2005 25	218	Men and women age 65 y or older without PAD and with ABI >0.9 and <1.4 from 4 US communities	Decrease in ABI by >0.15 and to ≤0.9	Multivariate OR for highest vs lowest quartile per mg/dL, 0.99 (95% CI, 0.60–1.62), P=0.95	Prospective over 6‐y follow‐up
	Cheng et al. 1997 42	100	Chinese patients aged 40–80 y with symptoms of peripheral arterial insufficiency	Prevalent peripheral arterial atherosclerosis confirmed in noninvasive vascular laboratory	OR per mmol/L: 3.23, P<0.001	Cross‐sectional case/control study
	Newman et al. 1993 8	5084	Medicare recipients age ≥65 y from 4 US communities	ABI <0.9	RR nonsignificant	Cross‐sectional
	Murabito et al. 2002 35	3313	Men and women age ≥ 40 y (offspring from Framingham Heart Study and spouses)	ABI <0.9	Sex‐ and age‐adjusted OR per 40 mg/dL, 1.0 (95% CI, 1.0–1.1) Multivariable‐adjusted OR (95% CI) per 40 mg/dL: nonsignificant	Cross‐sectional
LDL‐C	Ness et al. 2000 38	1911	Geriatric men and women from a single practice	Symptomatic PAD (defined as intermittent claudication, ischemic rest pain, exam findings consistent with PAD)	OR, 1.019 (95% CI, 1.013–1.025), P=0.001 for women; 1.019 (95% CI, 1.008–1.030), P=0.001 for men	Cross‐sectional
	Aday et al. 2018 28	27 888	Women ≥45 y free of CVD at baseline	Intermittent claudication or revascularization	Multivariate HR for top vs bottom tertile of standard lipid measure, 1.02 (95% CI, 0.65–1.60), P=0.76	Prospective over median 15.1 y
	Ridker et al. 2001 34	14 916	Healthy US male physicians aged 40–84 y	Intermittent claudication, hospitalization for revascularization	Adjusted RR highest vs lowest quartile, 2.3 (95% CI,1.1–4.7), P=0.003	Prospective over average 9 y
	Kennedy et al. 2005 25	218	Men and women age 65 y or older without PAD and with ABI >0.9 and <1.4 from 4 US communities	Decrease in ABI by >0.15 and to ≤0.9	Multivariate OR for highest vs lowest quartile per mg/dL, 1.60 (95% CI, 1.03–2.51), P=0.04	Prospective over 6‐y follow‐up
	Bonaca et al. 2018 43	27 564	Clinically evident atherosclerotic CVD and symptomatic PAD (intermittent claudication and ABI <0.85, history of peripheral revascularization, ischemic amputation)	Primary: composite of cardiovascular death, MI, stroke, admission for UA, coronary revascularization Secondary: composite cardiovascular death, MI, stroke Outcome of interest: MALE (ALI, major amputation, urgent peripheral revascularization for ischemia)	HR for primary end point in symptomatic PAD with evolovumab vs placebo, 0.79 (95% CI, 0.66–0.94), P=0.0098; in symptomatic PAD without prior MI/stroke, 0.67 (95% CI, 0.47–0.96), P=0.0283 HR for secondary end point in symptomatic PAD with evolovumab vs placebo, 0.73 (95% CI, 0.59–0.91), P=0.0040; in symptomatic PAD without prior MI/stroke, 0.57 (95% CI, 0.38–0.88), P=0.0095 HR for MALE in patients with PAD with evolovumab vs placebo, 0.63 (95% CI, 0.39–1.03), P=0.063; in patients with PAD and no prior MI/stroke, 0.43 (95% CI, 0.19–0.99), P=0.042	Prospective over median 2.2 y
	Schwartz et al. 2020 44	9462	Recent ACS and elevated atherogenic lipoproteins despite maximally tolerated statin treatment without addition of alirocumab (control arm of Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome trial)	Critical limb ischemia, limb revascularization, or amputation for ischemia (prespecified tertiary end point)	HR for highest vs lowest quartile LDL‐C, 1.46 (95% CI, 0.91–2.32), P trend=0.06	Prospective over median follow‐up 2.8 y
	Newman et al. 1993 8	5084	Medicare recipients age ≥ 65 y from 4 US communities	ABI <0.9	Multivariate RR nonsignificant	Cross‐sectional
VLDL‐C	Heidemann et al. 2021 45	8057	Men and women aged 18–80 y with diagnosis of clinically manifest arterial disease from a single‐center in the Netherlands	MALE defined as major amputation or lower limb revascularization (secondary end point)	Adjusted HR for highest vs lowest quartile of VLDL‐C, 1.49 (95% CI, 1.16–1.93), P<0.05	Prospective over median 8.2 y
Non‐HDL‐C	Fowkes et al. 1992 39	1592	Scottish men and women aged 55–74 y	Intermittent claudication	Multivariate OR per 1.3 mmol/L, 1.6 (95% CI, 1.2–2.1), P<0.001	Cross‐sectional
	Aday et al. 2018 28	27 888	Women ≥45 y free of CVD at baseline	Intermittent claudication or revascularization	Multivariate HR for top vs bottom tertile of standard lipid measure, 1.21 (95% CI, 0.75–1.94), P=0.25	Prospective over median 15.1 y
	Bowlin et al. 1994 36	8343	Israeli men aged 40–65 y	Intermittent claudication defined by questionnaire	Univariate RR of highest vs lowest quintile, 2.04 (95% CI, 1.32–3.16)	Cross‐sectional
Apolipoprotein A‐1	Aday et al. 2018 28	27 888	Women ≥45 y free of CVD at baseline	Intermittent claudication or revascularization	Multivariate HR for top vs bottom tertile of standard lipid measure, 0.30 (95% CI, 0.17–0.53), P<0.0001	Prospective over median 15.1 y
	Ridker et al. 2001 34	14 916	Healthy US male physicians aged 40–84 y	Intermittent claudication, hospitalization for revascularization	Adjusted RR highest vs lowest quartile, 0.6 (95% CI, 0.3–1.1), P=0.1	Prospective over average 9 y
Apolipoprotein B	Aday et al. 2018 28	27 888	Women ≥45 y free of CVD at baseline	Intermittent claudication or revascularization	Multivariate HR for top vs bottom tertile of standard lipid measure, 1.38 (95% CI, 0.83–2.29), P=0.11	Prospective over median 15.1 y
	Ridker et al. 2001 34	14 916	Healthy US male physicians aged 40–84 y	Intermittent claudication, hospitalization for revascularization	Adjusted RR highest vs lowest quartile, 2.9 (95% CI, 1.5–6.3), P<0.001	Prospective over average 9 y
LP(a)	Ridker et al. 2001 34	14 916	Healthy US male physicians aged 40–84 y	Intermittent claudication, hospitalization for revascularization	Adjusted RR highest vs lowest quartile, 1.1 (95% CI, 0.6–2.2), P=0.6	Prospective over average 9 y
	Aboyans et al. 2006 41	403	Established patients from single‐center US hospital with prior LE arterial testing	PAD progression (LV: highest 10% ABI decline; SV: highest 10% TBI decline)	Adjusted HR per 1 mg/dL for ABI decrease >0.3, 1.37 (95% CI, 1.03–1.82), P=0.033 Nonadjusted HR per 1 mg/dL for TBI decrease >0.27, 1.38 (95% CI, 0.85–2.23), P=0.189	Prospective with average follow‐up 4.6 ± 2.5 y
	Schwartz et al. 2020 44	18 924	Recent ACS and elevated atherogenic lipoproteins despite maximally tolerated statin treatment	Critical limb ischemia, limb revascularization, amputation for ischemia (prespecified tertiary end point)	HR for highest vs lowest quartile Lipoprotein(a), 2.22 (95% CI, 1.38–3.57), P trend=0.0021	Prospective over median follow‐up 2.8 y
LDL subfractions	Aday et al. 2018 28	27 888	Women ≥45 y free of CVD at baseline	Intermittent claudication or revascularization	Multivariate HR for top vs bottom tertile of nuclear magnetic resonance lipoprotein particle subclass: Large LDL, 0.74 (v0.44–1.27), P=0.31 Medium LDL, 1.01 (95% CI, 0.59–1.74), P=0.91 Small LDL, 2.17 (95% CI, 1.10–4.27), P=0.02	Prospective over median 15.1 y
HDL subfractions	Aday et al. 2018 28	27 888	Women ≥45 y free of CVD at baseline	Intermittent claudication or revascularization	Multivariate HR for top vs bottom tertile of nuclear magnetic resonance lipoprotein particle subclass: Large HDL, 0.44 (95% CI, 0.25–0.77), P=0.004 Medium HDL, 0.43 (95% CI, 0.25–0.74), P=0.002 Small HDL, 1.30 (95% CI, 0.77–2.17), P=0.37	Prospective over median 15.1 y

PAD outcomes stratified by lipid marker as well as whether prevalent or incident.

ABI indicates ankle brachial index; ACS, acute coronary syndrome; CVD, cerebrovascular disease; HDL‐C, high‐density lipoprotein cholesterol; HR, hazard ratio; LDL‐C, low‐density lipoprotein cholesterol; LE, lower extremity; LV, large vessel; MALE, major adverse limb event; MI, myocardial infarction; OR, odds ratio; PAD, peripheral artery disease; RR, relative risk; SV, small vessel; TBI, toe brachial index; TC, total cholesterol; and VLDL‐C, very low‐density lipoprotein cholesterol;

Total Cholesterol

TC has been the most widely studied cholesterol risk factor in PAD, representing 17% of the population attributable risk for PAD. ³ Several studies have shown that TC levels are closely related to incident PAD. In a select population (men from Iceland), TC has been shown to be a stronger risk factor for PAD (defined by intermittent claudication and pulse exam) than for CAD. ²⁹ Although assessing for claudication only (and not specifically anatomic PAD), the Framingham Heart Study observed TC levels in 2336 men and 2873 women for as long as 38 years and identified 381 new cases of claudication in this cohort. ³⁰ TC was incrementally associated with incident claudication, with each 40 mg/dL increase associated with an odds ratio of 1.2 (95% CI, 1.1–1.3; P=0.0001) for claudication. Similarly, increasing TC is associated with decline in ABI measurements. ⁸ Newman et al. have previously shown that age‐ and sex‐adjusted TC and LDL increased with decreasing ABI values but that only TC and HDL emerged as independent risk factors for PAD (ABI <1.0) in adjusted analysis. ⁸ TC levels at baseline predict future PAD, with individuals who develop claudication having on average ~10 mg/dL higher TC than those who do not. ³³ The Framingham Offspring Study, the Speedwell prospective heart disease study, and a geriatric population study have shown conflicting data. ³³ , ³⁵ , ³⁸ In these studies, TC was a significant risk factor for PAD (defined as either ABI <0.9 or clinical symptoms/prior intervention depending on study) in initial analysis; however, when subjected to multivariable models including other lipid measures, TC was no longer significant. TC levels have also been associated with hard end points in PAD. When defined by limb amputation, extremity revascularization, >50% obstruction on peripheral angiogram, ABI <0.9, or a physician diagnosis of PAD, the Health Professionals Follow‐Up Study reported a 45% increased risk in those with prior elevated TC. ³

High‐Density Lipoprotein Cholesterol

HDL cholesterol (HDL‐C) is probably the second‐most studied lipid risk factor for PAD and is considered to be protective against PAD. ²⁶ Several studies have expressed HDL alone or as a ratio of TC:HDL when discussing association with PAD. In general, there is an inverse relationship between HDL‐C levels and incident PAD with a low HDL‐C among the strongest lipid markers for PAD risk. ²⁷ The Honolulu Heart study showed that prevalence of ABI <0.9 in older men decreased with increasing levels of HDL‐C (P<0.01 adjusted for traditional risk factors). ³² In multivariable models from the Women's Health Study, HDL‐C levels in the lowest tertile versus the highest tertile demonstrated a 70% lower relative risk of PAD (hazard ratio [HR], 0.3 [95% CI, 0.17–0.54] adjusted for traditional risk factors). ²⁸

As mentioned previously, TC:HDL‐C has also been studied as a measure of risk for incident PAD and may be a more discriminating measure than TC or HDL‐C alone. ²⁷ Similar to both TC and HDL‐C levels individually, TC:HDL‐C has been shown to be statistically higher in those with ABI <0.9 compared with individuals without PAD and that a TC:HDL‐C cutoff of >5 is a consistent marker for significantly increased risk of ABI <0.9. ⁴⁰ , ⁴⁶ Moreover, TC:HDL‐C was the strongest independent predictor of incident PAD (defined as intermittent claudication or hospitalization for revascularization) in the Physicians' Health Study after multivariable analysis (relative risk [RR] for highest versus lowest quartile, 3.9 [95% CI, 1.7–8.6] when compared with standard lipid measures). ³⁴ Although data are sparse, TC:HDL‐C is one of few lipid markers that has been associated with PAD progression in large arteries (along with current smoking, high‐sensitivity C‐reactive protein, and lipoprotein(a)). ⁴¹

HDL Subfractions

Nuclear magnetic resonance spectroscopy derived HDL particle subclasses are inversely related to presence of PAD (claudication or revascularization) when stratified by size. ²⁸ Higher concentrations of large and medium‐sized HDL particle were associated with freedom from PAD events (2100 nmol/L versus 1600 nmol/L, P=0.0002 for large and 5300 nmol/L versus 3850 nmol/L, P≤0.0001 for those without versus with PAD, respectively), whereas a numerically higher concentration of small HDL particle was seen in those who developed PAD. In a study of 63 male patients with PAD (defined by claudication) compared with 63 healthy controls, those with PAD had reduced large particle size HDL (HDL2b) and increased small HDL (HDL3c) levels. ⁴⁶

Low‐Density Lipoprotein Cholesterol

Unlike CAD, LDL‐C has not been shown to be as consistent or strong a risk factor for PAD. ⁴⁷ Many early studies of PAD risk unfortunately did not include LDL‐C measures. However, even in those that have subsequently incorporated measured or calculated LDL‐C, there is variability in reported association with PAD. ²⁷ In a cohort of men in the Physicians' Health Study, LDL‐C was shown as a risk factor for PAD (defined as intermittent claudication or hospitalization for revascularization) but had no added value over TC:HDL‐C. ³⁴ The Women's Health Study did not show a significant association between LDL‐C (calculated) and incident PAD (defined as intermittent claudication or peripheral artery revascularization, confirmed by physician interview and chart review) after multivariate analysis. ²⁸ Patients in the Cardiovascular Health Study were shown to have declining ABI values with increasing LDL‐C levels but this was likely contaminated by the high prevalence of advanced age in the study (mean age of 74) and therefore likelihood of PAD before study initiation. ²⁵ In those with genetically elevated LDL‐C in the setting of familial hypercholesterolemia, PAD (diagnostic criteria not defined in this study) rates are markedly lower than those for CAD. ⁴⁸ To date, only the FOURIER (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk) trial has shown compelling evidence that there is a correlation between LDL‐C levels and PAD outcomes. ⁴³ Lower LDL‐C down to a level of 10 mg/dL in participants with PAD (ABI <0.85) was associated with lower risk of major adverse limb outcomes (MALE) (P=0.026 for beta coefficient). ⁴³

LDL Subfractions

Small LDL particle (LDL‐P) concentrations derived by nuclear magnetic resonance are higher in women with PAD (either claudication or prior revascularization) compared with those without PAD (particle concentration 953 versus 1208 nmol/L, P≤0.0001 for small LDL‐Ps in those without versus with PAD, respectively). ²⁸ In multivariable models, small LDL‐P association with PAD remained significant. This is opposed to large and medium‐sized LDL‐P, suggesting that the risk of PAD associated with LDL may be specific to small LDL‐P concentration, which is not captured when simply measuring LDL‐C. Rizzo et al. also demonstrated that patients with PAD (defined by intermittent claudication) have decreased LDL‐P size with decreased large subfractions of LDL (including LDL‐I, P<0.001 and LDL‐IIA, P=0.0068) and increased small subfractions of LDL (including LDL‐IIIA P<0.0001, LDL‐IIIB, P=0.0013, LDL‐IVA, P=0.0029, and LDL‐IVB, P<0.0001). ⁴⁹ An elevation in small, dense LDL was independently associated with PAD in the same study (odds ratio [OR], 6.7, P=0.0497). These findings may explain the inconsistencies seen in prior studies suggesting a null association of LDL with PAD (in this case, specifically in women).

Very Low‐Density Lipoprotein Cholesterol

There are few data regarding very LDL‐C (VLDL‐C) levels and risk of PAD. Aday et al. discuss in the Women's Health Study that women developing PAD events (intermittent claudication or peripheral artery revascularization) had on average higher concentrations of total VLDL‐C particles than those remaining free of PAD events. ²⁸ It is also suggested that average VLDL particles size is larger in those developing PAD than in those free of PAD events in both unadjusted and multivariable models (HR, 1.68 [95% CI, 1.06–2.66], P trend=0.02; HR, 1.58 [95% CI, 0.94–2.68], P trend=0.04; HR, 1.98 [95% CI, 1.15–3.41], P trend=0.01 for very large, large, and medium‐sized VLDL particles, respectively). Intermediate density lipoproteins, including VLDL‐C, were seen to be a risk factor in the development and severity of PAD by Senti et al., which is supported by the work of Wang et al. suggesting that both VLDL‐C and chylomicron remnants are significantly increased in those with claudication compared with those without. ⁵⁰ , ⁵¹ Finally, a recent study showed that elevated VLDL‐C was not associated with increased risk of MACE or all‐cause mortality in patients with cardiovascular disease but was associated with increased MALE (HR, 1.49 [95% CI, 1.16–1.93]). ⁴⁵

Triglycerides

Triglycerides levels are on average higher in those who subsequently develop claudication compared with those who do not, and increasing triglycerides levels are incrementally associated with increased risk of intermittent claudication. ³³ Elevated triglycerides may also promote disease progression above and beyond baseline levels. ³⁹ Despite this association, there are conflicting data on whether elevated triglycerides are in fact an independent risk factor for incident PAD. Katsilambros et al. examined 193 patients with noninsulin‐dependent diabetes and PAD (defined by ABI ≤0.89 and claudication). Age, length of diabetes, and waist‐to‐hip ratio were the only factors significantly related to PAD. After multivariate analysis, triglycerides (P=0.02) became significantly and independently associated with PAD. ⁵² Both the Speedwell study and Cheng et al. also found triglycerides as significantly and independently associated with PAD (defined as either intermittent claudication or by noninvasive vascular laboratory investigations, respectively). ³³ , ⁴² In contrast, several other studies including the Women's Health Study, Framingham Offspring Study, Edinburgh Artery Study, and Cardiovascular Health Study did not show associations between triglycerides and PAD (defined either by ABI, prior intervention, or intermittent claudication depending on the study) after multivariate analysis. ⁸ , ²⁸ , ³⁵ , ³⁹ These discrepancies could be partially explained by the known intimate relationship between diabetes and triglycerides, in which higher levels of triglycerides are typically seen with worsening clinical diabetes. Thus, the relationship between triglycerides and PAD may be strongly influenced and dependent on other known independent risk factors for PAD, specifically diabetes in this case.

Lipoprotein(a)

Lp(a) (Lipoprotein(a)) has been associated with progression of PAD in large arteries. ⁴¹ As such it is considered an independent risk factor for PAD. ⁵³ Increased levels have also been associated with presence of PAD defined by ABI <0.9 in people without diabetes as compared with people with diabetes without PAD (Lp(a)level 365 [239–554] versus 184 [17–266] U/I, P<0.01). ⁵⁴ In a prespecified analysis of the ODYSSEY OUTCOMES trial (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome), the risk of PAD events defined as CLTI, limb revascularization, or ischemic amputation after an MI in statin‐treated patients was related to Lp(a) level, with those in the highest Lp(a) quartile (Lp(a) ≥59.6 mg/dL) experiencing more than double the rate of events in the lowest Lp(a) quartile (Lp(a) <6.7 mg/dL). ⁴⁴ Although studies on Lp(a) are recent, this presents an opportunity for future studies to assess the impact on lowering Lp(a) levels on PAD events.

Apolipoprotein A‐1

Apolipoprotein A‐1 was shown to be significantly inversely associated with incident PAD (defined as claudication or limb revascularization) in the Women's Health Study (HR, 0.3 [95% CI, 0.18–0.5]) ²⁸ ; however, this association was not statistically significant when measured in the Physicians' Health Study (adjusted RR for development of intermittent claudication or peripheral revascularization 0.6 [95% CI, 0.3–1.1], P=0.09, for highest quartile compared with control). ³⁴ O'Neal et al. examined patients with and without diabetes with PAD (defined by ABI <0.9) and an equal number of controls and found that apolipoprotein A‐1 was significantly decreased in those with PAD (124±3 versus 139±5 mg/dL, P<0.01 and 133±4 versus 147±4 mg/dL, P<0.05 in the groups with and without diabetes, respectively). ⁵⁴ Currently, the Trans‐Atlantic Inter‐Society Consensus II considers apolipoprotein A‐1 protective for the development of PAD. ⁵³

Apolipoprotein B

Similar to apolipoprotein A‐1, the Physicians' Health Study did not show any benefit to testing this lipoprotein measure for assessing future risk of PAD. ³⁴ The Women's Health Study showed that adjusted HRs for association of apolipoprotein B100 and ASCVD were statistically significant only for CAD and CVD, not for PAD. ²⁸ Contrary to this, apolipoprotein B was significantly associated with PAD in a group of people without diabetes when compared with healthy controls without PAD (146+8 versus 117+5 mg/dL, P<0.05). ⁵⁴ These differences in findings are particularly interesting given recent observational research suggests that for risk of MI, measures of cholesterol and triglyceride concentration are not associated with cardiovascular risk beyond the measure of apolipoprotein B‐ containing lipoproteins in both primary and secondary prevention cohorts. ⁵⁵ This study was a prospective cohort analysis of the FOURIER and IMPROVE‐IT (Improved Reduction of Outcomes: Vytorin Efficacy International Trial) trials and included patients with PAD, although observations in this group were not specifically analyzed.

Non‐High‐Density Lipoprotein Cholesterol

Non‐HDL‐C comprises chylomicrons, VLDL‐C, LDL‐C, intermediate‐density lipoprotein cholesterol, Lp(a), and triglycerides and is calculated by subtracting HDL‐C from TC. ⁵⁶ , ⁵⁷ The Women's Health Study did not show a significant relationship between non‐HDL‐C and incident PAD. ²⁸ Conversely, mean non‐HDL‐C was shown to be statistically higher in patients with incident intermittent claudication than those who remained symptom free over a 5‐year period (180.9 mg/dL versus 169.2 mg/dL, respectively, P<0.0001) in an Israeli study of 8343 previously healthy men. ³⁶ Similarly, increases in non‐HDL‐C were shown to correlate with decreases in ABI in the Edinburgh Artery Study (decrease in ABI of 0.02±0.005 units for every 1.3 mmol/L increase in non‐HDL‐C in multivariate analysis). ³⁹ Although a reasonable assumption would suggest a clear association between non‐HDL‐C and incident or worsening PAD, there are currently not enough data to definitively define a causal link.

In summary, lipid risk profiles for PAD are seemingly different from those for CAD or CVD (Figure 2). HDL, TC:HDL, small LDL‐P, and apolipoprotein A‐1 show the closest association with PAD risk, with Ridker et al. suggesting TC:HDL fraction as the best predictor of PAD development overall. ³⁴ In contrast, non‐HDL‐C and apolipoprotein B are likely the strongest predictors of CAD as discussed, but data are lacking in determining their role in PAD. ⁵⁶ , ⁵⁷ Despite current recommendations, a strategy focused on LDL‐C as a target risk factor for PAD may not be sufficient and may exclude patients at risk for future MACE and MALE. Further studies eliciting the role of non‐HDL‐C and apolipoprotein B in incident PAD and secondary events are needed. Additionally, the protective effect of HDL‐C may be more important that the atherogenic effect of LDL‐C and other lipid markers in this population. ⁴⁶

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.

Therapy (Drugs That Affect Cardiovascular and Limb Outcomes in PAD, Mechanisms, and Data Supporting Them)

Individuals with PAD are at an increased risk for MACE (including all‐cause mortality) and MALE regardless of the presence of other cardiovascular disease. ² These 2 major outcomes of interest have been thoroughly evaluated regarding statin use, but a paucity of data exists in terms of potential benefit from many nonstatin therapies. This section breaks down therapy options for outcomes in PAD from both a cardiovascular and specifically a limb outcome standpoint.

Diet and lifestyle changes to reduce cholesterol levels should be considered at baseline for all patients with vascular disease. Regarding pharmacologic lipid‐lowering therapies, the AHA/American College of Cardiology guideline consider PAD equivalent to both CAD and stroke. ⁴ Accordingly, it is recommended by American College of Cardiology/AHA guidelines that all patients with symptomatic PAD be on a high‐intensity statin with a target LDL‐C of <70 mg/dL in those with PAD and another major ASCVD event. ² , ⁴ Despite this, treatment with secondary prevention therapies in patients with PAD is dismal despite many proven therapies known to decrease risk. ⁹ Pande et al. showed that of the roughly 8 million US adults with PAD, only about one third were receiving appropriate prevention therapies amounting to millions of individuals at risk for preventable events. ⁵⁸ The same study showed that among subjects with and without concomitant cardiovascular disease in another vascular bed, treatment with multiple therapies (this included antiplatelet, antihypertensive, and lipid lowering medications) was associated with reduced all‐cause mortality.

As summarized next, lipid‐lowering therapy is associated with improved limb outcomes with lower incidence of revascularization and amputation in this population. ¹¹

Primary Prevention

There are few data on the primary prevention of PAD from a cholesterol reduction standpoint; however, the 4S trial (Scandinavian Simvastatin Survival Study) showed that simvastatin therapy in patients with established CAD reduced new onset intermittent claudication by 38% (RR, 0.62 [95% CI, 0.44–0.88]). ⁵⁹ High‐dose atorvastatin has been shown to be superior to moderate‐dose simvastatin regarding prevention of PAD. ⁶⁰

Secondary Prevention

Statins

Cardiovascular Outcomes

Statins lower cholesterol levels, predominantly LDL‐C, through inhibition of 3‐hydroxyl‐3‐methylclutaryl coenzyme A reductase, a critical step in cholesterol biosynthesis (Table 2, ¹¹ , ⁴³ , ⁴⁴ , ⁶⁰ , ⁶¹ , ⁶² , ⁶³ , ⁶⁴ , ⁶⁵ , ⁶⁶ , ⁶⁷ , ⁶⁸ , ⁶⁹ , ⁷⁰ , ⁷¹ , ⁷² , ⁷³ , ⁷⁴ , ⁷⁵ , ⁷⁶ ). Statin therapy may reduce plaque progression in those with PAD. Specifically, superficial femoral artery plaque volume as measured on lower extremity magnetic resonance imaging numerically decreases with new statin therapy in individuals with PAD. ⁷⁷

Table 2.

Cardiovascular and Limb Outcomes in Patients on Lipid‐Lowering Therapies

Study	Sample size	Study type/duration or follow‐up (if applicable)	Patient population	Study definition of PAD or equivalent	Intervention	MACE end points	MALE end points
HPS HPS Collaborative Group 2007 61	20 536	Prospective, blinded, RCT over mean of 5 y	Patients aged 40–80 y with PAD, CAD, diabetes, or hypertension (if male and >65 y) with cholesterol >135 mg/dL	History of IC (with or without supporting vascular investigation), previous peripheral arterial revascularization, amputation, or aneurysm repair	Simvastatin (10269) vs placebo (10267)	In those with PAD, 22% (15%–29%), P<0.0001, proportional reduction in first occurrence of MACE	16% (5%–25%), P=0.006, reduction in peripheral vascular events
Stoekenbroek et al. 2015 60	8888	Multicenter, open‐label, blinded outcome assessment, RCT over median follow‐up of 4.8 y	Age ≤80 y with a prior confirmed MI	Baseline PAD: a clinical diagnosis documented in patient records Incident PAD: new clinical diagnosis necessitation diagnostic procedures or interventions assessed by a blinded committee	Atorvastatin 80 mg daily vs simvastatin 20–40 mg daily	Cardiovascular events (P=0.046), coronary events (P=0.004), and coronary revascularization (P=0.007) reduced with atorvastatin Major coronary events nonsignificantly lower in atorvastatin group compared with simvastatin group (14.4% vs 20.1%, HR, 0.68 [95% CI, 0.41–1.11], P=0.13)
Aung et al. 2007 62	10 049	Meta‐analysis of 18 RCT	All RCTs involving lipid‐lowering therapy in patients with PAD	Intermittent claudication diagnosed clinically or by questionnaire, CLTI, or asymptomatic disease identified by validated technique such as ABI or angiography	Lipid‐lowering therapies vs placebo	Subgroup analysis with exclusion of Probucol Quantitative Regression Swedish Trial study: reduction in total cardiovascular events (OR, 0.74 [95% CI, 0.55–0.98], and total coronary events (OR, 0.76 [95% CI, 0.67–0.87]
Reduction of Atherothrombosis for Continued Health Registry Kumbhani et al. 2014 11	5861	Registry including only patients with complete 4‐y follow‐up information	Documented PAD symptoms with complete 4‐y follow‐up	Current IC with ABI <0.9 or history of IC with ABI <0.9, or history of IC with previous intervention (angioplasty, stenting, atherectomy, peripheral arterial bypass, amputation)	Statin (62%) vs no statin use (38%)		Reduction in worsening claudication, new CLTI, new LE revascularization, or new ischemic amputation at 4 y in statin (22%) vs nonstatin group (26.2%) (HR, 0.82 [95% CI, 0.72–0.92], P=0.0013)
Arya et al. 2018 63	155 647	Retrospective observational cohort with median follow‐up of 5.9 y	Veterans with diagnosis of PAD from 2003 to 2014	Diagnosis code for PAD in addition to 2 ABIs in 14 mo, 2 vascular clinic visits in 14 mo, or any PAD procedure code	Use of HI statin vs LMI statin vs antiplatelet therapy with no statin	HI statin vs antiplatelet only users: lower mortality (HR, 0.74 [95% CI, 0.70–0.77]) LMI statin vs antiplatelet only users	HI statin vs antiplatelet only users: lower amputation risk (HR, 0.67 [95% CI, 0.61–0.74])
Westin et al. 2014 64	380	Retrospective single‐center cohort with median follow‐up time of 409 days	Presentation with CLTI	Clinical diagnosis with history of angiography or therapeutic endovascular intervention	On statin (65%) vs no statin (35%)	Reduction in composite of stroke, MI, and death at 1 y in statin (18%) vs no statin (23%) (HR, 0.53 [95% CI, 0.28–0.99], P=0.048	Improved amputation‐free survival
Vogel et al. 2013 65	22 954	Medicare claims database review	Age ≥65 y with diagnosis of PAD hospitalized during 2007–2008 for LE revascularization	Chart diagnosis of IC, rest pain, ulceration, or gangrene who underwent LE revascularization (endovascular or open)	On statin at time of revasc (11687) vs no statin		Lower amputations rates at 30 days (P=0.0001), 90 d (P<0.0001), and 1 y, RR, 0.82 [95% CI, 0.78–0.86], P<0.0001) in statin group
Aiello et al. 2012 66	646	Single‐center retrospective review with mean follow‐up 10.4±11 months	Consecutive patients undergoing endovascular treatment for CLTI	CLTI defined as rest pain or tissue loss with documented endovascular revascularization procedure	On statin therapy at time of procedure vs off therapy	Higher rate of overall survival (77% vs 62%, P=0.038) in statin vs nonstatin group	Higher rate of limb salvage (83% vs 62%, P=0.001) in statin vs nonstatin group Statin therapy independently associated with improved limb salvage (HR, 2.55, P<0.001)
DeCarlo et al. 2017 67	811	Single‐center retrospective review	All patients with amputation between November 2009 and November 2014	PAD defined as prior chart diagnosis or prior LE revascularization; all patients had above or below the knee amputation	Low, medium, or high intensity statin use	Medium intensity (HR, 0.64 [95% CI, 0.47–0.87]) and HI statin use (HR, 0.56 [95% CI, 0.33–0.95]) conferred mortality benefit; low‐intensity statins did not
O'Donnell et al. 2017 68	931	Single‐center retrospective review with median follow up of 380 days	All patients with CLTI from 2005 to 2014	CLTI defined by chart diagnosis with documented prior revascularization procedure	Low, medium, high intensity, or no statin use	Discharge on any (HR, 0.71 [95% CI, 0.60–0.90], P<0.01) or recommended intensity statin therapy (HR, 0.73 [95% CI, 0.60–0.99], P<0.05) associated with lower mortality	Discharge on recommended intensity statin therapy associated with lower MALE (HR, 0.71 [95% CI, 0.51–0.97], P<0.05)
Foley et al. 2017 69	909	Retrospective registry study with median follow‐up of 1.4 y	Symptomatic PAD on statin with peripheral angio or intervention 2006–2013 not on other lipid‐lowering med	Chart diagnosis of IC or CLTI with history of lower extremity angiography or endovascular intervention	HI statin vs LMI statin	Improved survival (HR, 0.52 [95% CI, 0.33–0.81], P=0.004) and decreased MACE (HR, 0.58 [95% CI, 0.37–0.92], P=0.02) in HI statin group
Feringa et al. 2007 70	1374	Single center, prospective, observational cohort with mean follow‐up of 6.4±3.6 y	Age ≥18 y with ABI ≤0.90	Typical IC, foot ulceration, hair loss, or reduced capillary refill with ABI ≤0.9	Statin therapy	Lowest all‐cause mortality (18%) and cardiac mortality (13%) observed in those with lowest LDL (<70), P<0.001
Hsu et al. 2017 71	69 332	Nationwide observational cohort with mean follow‐up of 5.7 y	Age ≥20 y with PAD and diabetes	PAD not defined in methods	Statin users (11409) vs nonstatin lipid agents (4430) vs nonusers (53493)	Lower risk of cardiovascular death (aHR 0.78, [95% CI, 0.69–0.87]) and all‐cause mortality (aHR, 0.73 [95% CI, 0.69–0.77]) in statin users vs nousers (secondary outcome)	Lower risk of LE amputation in statin users compared with nonusers (aHR, 0.75 95% CI, [0.62–0.90]) (primary outcome)
Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk Bonaca et al. 2018 43	3642	Subanalysis of double‐blinded RCT with median of 2.2‐y follow‐up	On statin therapy with IC or ABI <0.85 or prior intervention	IC and ABI <0.85, history of peripheral artery revascularization or amputation	Evolocumab vs placebo	Significant decrease in composite of cardiovascular death, MI, stroke, admission for UA, or coronary revascularization (HR, 0.79 [95% CI, 0.66–0.94; P=0.0098]; remained significant when only evaluating cardiovascular death, MI, stroke (P=0.0040)	Significant decrease in major limb events (HR, 0.58 [95% CI, 0.38–0.88], P=0.0093)
Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome Schwartz et al. 2020 44	759	Prespecified analysis of RCT with median follow‐up of 2.8 y	ACS within 12 months, elevated atherogenic lipoproteins on max‐tolerated statin	PAD events defined as CLTI, limb revascularization, or amputation for ischemia	Alirocumab vs placebo		Significant reduction in PAD events with alirocumab (HR, 0.69 [95% CI, 0.54–0.89], P=0.004)
Program on the Surgical Control of the Hyperlipidemias Buchwald et al. 1996 72	838	RCT with mean follow‐up of 9.7 y	Survivors of first myocardial infarction	ABI ≤0.95 or arteriogram with 20% or greater reduction in luminal diameter of peripheral artery	Partial ileal bypass operation vs no operation		Significantly lower rates of claudication or limb threatening ischemia in intervention arm (RR, 0.702 [95% CI, 0.169–1.0000], P=0.049) at trial closure Reduced risk of clinically evident PAD in intervention arm (RR, 0.656 [95% CI, 0.200–0.903]), P=0.009 at 4‐y follow‐up Reduction in new ABI <0.95 significantly lower in surgery arm (RR, 0.577 [95% CI, 0.360–0.863], P<0.01)
Rajamani et al. 2009 73	9795	Double‐blind RCT with median follow‐up of 5 y	Aged 50–75 y with diabetes	PAD not defined; study end point was nontraumatic amputations	Fenofibrate vs placebo over 5 y		Fenofibrate reduced the risk of first amputation (HR, 0.64 [95% CI, 0.44–0.94], P=0.02) and minor amputations in those without known large‐vessel disease (HR, 0.53 [95% CI, 0.30–0.94], P=0.027)
Meade et al. 2002 74	1568	Double‐blind RCT over median follow‐up of 4.6 y	Men with diagnosis of PAD based on Edinburgh claudication questionnaire, diagnostic indices, or on meds used for treatment of PAD	Clinical PAD based on Edinburgh claudication Questionnaire	Bezafibrate vs placebo	No reduction in incident CAD and stroke (composite primary end point) Reduction in nonfatal coronary events (RR, 0.60 [95% CI, 0.36–0.99], hypothesis generating only)
AIM‐HIGH The AIM‐HIGH Investigators 2011 75	3414 (13.6% with PAD)	Multi‐center, open‐label RCT with mean follow‐up of 36 months	Age ≥45 y with established CAD, cerebrovascular disease, carotid disease, or PAD	Documented PAD with ABI <0.85 without or without claudication or prior peripheral arterial intervention	Extended‐release niacin vs placebo (all patients on lipid lowering therapy to maintain LDL‐C 40–80 mg/dL at baseline)	No difference in primary end point (cardiovascular death, nonfatal MI, stroke, admission for ACS, or coronary/cerebral revasc) between groups No PAD subgroup analysis
Pastori et al. 2020 76	138 060	Meta‐analysis (2 RCT, 20 prospective, 29 retrospective studies)	Patients with diagnosis of PAD (definition differed depending on study analyzed)	Variable criteria contingent on individual study	Any statin use	Secondary end points: statin use reduced all‐cause mortality by 39% (HR, 0.608 [95% CI, 0.543–0.680]), cardiovascular death by 41% (HR, 0.594 [95% CI, 0.455–0.777]), composite cardiovascular end points by 34% (HR, 0.662 [95% CI, 0.591–0.741]) and ischemic stroke by 28% (HR, 0.718 [95% CI, 0.620–0.831])	Primary end point: statin use reduced incidence of MALE (amputation, loss of patency/graft occlusion/restenosis, or composite of amputation and repeat revascularization) by 30% (HR, 0.702 [95% CI, 0.605–0.815]) and amputation alone by 35% (HR, 0.654 [95% CI, 0.522–0.819])

ABI indicates ankle brachial index; ACS, acute coronary syndrome; aHR, adjusted hazard ratio; AIM‐HIGH, Atherothrombosis Intervention in Metabolic Syndrome With Low HDL/High Triglycerides: Impact on Global Health Outcomes; CAD, coronary artery disease; CLTI, chronic limb threatening ischemia; HI, high‐intensity; HPS, Heart Protection Study; HR, hazard ratio; IC, intermittent claudication; LDL‐C, low‐density lipoprotein cholesterol; LE, lower extremity; LMI, low or moderate‐intensity; MACE, major adverse cardiovascular event; MALE, major adverse limb event; MI, myocardial infarction; OR, odds ratio; PAD, peripheral artery disease; RCT, randomized, controlled trial; RR, relative risk; and UA, unstable angina.

Among patients with PAD, statin use reduces both MACE and MALE as well as cardiac and all‐cause mortality. ² , ⁷⁸ In a prespecified subgroup analysis of the HPS (Heart Protection Study) in patients with known PAD, simvastatin use was associated with a 20% to 25% reduction in MACEs as compared with placebo. ⁶¹ Even in low‐risk individuals with asymptomatic PAD but without clinically recognized cardiovascular disease, statin therapy is associated with a significant reduction in MACE and all‐cause mortality. ⁷⁹ Current guidelines for secondary prevention and risk reduction in patients with PAD strongly recommend lipid‐lowering therapy with a statin to decrease LDL‐C by ≥50%. ² , ⁴ Several nonrandomized trials and observational studies have shown similar outcomes with statin use. An outcome of composite MACE (death, MI, stroke) in patients with CLTI either on or not on a statin at time of presentation showed a significantly lower rate in patients on a statin compared with those not (18% versus 23%, respectively, HR, 0.53 [95% CI, 0.28–0.99], P=0.048). ⁶⁴

The benefit of statin therapy in reduction of cardiac and all‐cause mortality is related to both the statin dose and the degree to which LDL‐C is lowered. ⁷⁰ From a statin dose standpoint, higher does seem to be “better.” Among 909 patients on either high‐intensity (13.6%) statin therapy or low/moderate‐intensity statin therapy who underwent peripheral angiogram or endovascular intervention, there was improved survival (HR, 0.52 [95% CI, 0.33–0.81], P=0.004) and decreased MACE (HR, 0.58 [95% CI, 0.37–0.92], P=0.02) in the high‐intensity statin group despite similar LDL‐C levels between the groups. ⁶⁹ Statin use in the perioperative/periprocedural period has also shown improvements in MACE. Statin use was associated with improved overall survival in patients with CLTI undergoing endovascular intervention in several studies. ⁶⁶ , ⁶⁸ Postoperatively, statin use following lower extremity amputation results in improved mortality for patients on both moderate and high‐intensity statins ⁶⁷ (see Table 1, ³ , ⁸ , ²⁵ , ²⁸ , ²⁹ , ³⁰ , ³¹ , ³² , ³³ , ³⁴ , ³⁵ , ³⁶ , ³⁷ , ³⁸ , ³⁹ , ⁴⁰ , ⁴¹ , ⁴² , ⁴³ , ⁴⁴ , ⁴⁵ ).

There are also several known pleiotropic effects of statins on the vascular bed including plaque stabilization, decreased inflammation, and improved endothelial function. ⁸⁰ In a prospective study of 515 patients with severe PAD, those who received statin therapy had lower levels of inflammation (hs‐CRP [high‐sensitivity C‐reactive protein]) P<0.001) and improved survival (adjusted HR, 0.52, P=0.022) and event‐free survival (adjusted HR, 0.48, P=0.004) compared with those not receiving statin therapy. ⁸¹ Interestingly, patients with baseline low inflammatory states (hs‐CRP ≤0.42 mg/dL) did not show statin‐related improvement in outcomes (P=0.74 for survival; P=0.83 for event‐free survival). Coronary endothelial vasomotor function and release of vascular nitric oxide also seem to be mediated by statin therapy leading to improved microcirculatory blood flow. This is presumed to hold true for peripheral arteries as well, although has not been assessed in large studies. ⁸²

Interestingly, statin initiation rather than statin intensification seems to have a greater effect on change in vessel characteristics. In individuals newly started on statins versus statin intensification in long‐term users, 1‐year differences in carotid artery intimal medial thickness (CIMT) and common femoral artery intimal medial thickness were striking, with those newly initiated on therapy showing a significant reduction (−8 and +11%, −11 and +22%, respectively) compared with those who intensified therapy. ⁸³ This again suggests that effects other than lipid‐lowering may be at play regarding vascular changes with statin therapy.

Limb Outcomes

The HPS showed a relative reduction of 16% in incidence of first peripheral vascular event driven by a 20% relative reduction in noncoronary revascularization procedures in those treated with statin therapy. ⁶¹ Additionally, statin use has been associated with an 18% lower rate of MALE in patients with PAD. This analysis of the REACH registry assessed the impact of statin used on primary adverse limb outcomes and found a 22% event rate with statin use compared with a 26.2% event rate in no statin use (HR, 0.82 [95% CI, 0.72–0.92], P=0.0013). ¹¹ This included worsening lower extremity symptoms, rates of peripheral revascularization, and ischemic amputations. ¹¹ Limb salvage rates were similarly improved at 1 year in Medicare patients undergoing lower extremity revascularization in those receiving a statin preoperatively (RR, 0.82 [95% CI 0.78–0.86], P<0.0001). ⁶⁵ In a registry study by Westin et al., a secondary outcome of amputation‐free survival in a group of patients with CLTI on a statin versus not on a statin at time of presentation showed benefit in those on statins (HR, 0.59 [95% CI 0.35–0.98], P=0.04). ⁶⁴ Several other observational studies have shown improved outcomes in MALE as a primary or secondary end point in those on statins as compared with statin nonusers with suggestion that the benefit is dose dependent. ⁶³ , ⁶⁶ , ⁶⁸ , ⁷¹ Perhaps most strikingly in meta‐analysis, statins were seen to reduce MALE incidence by 30% (pooled HR, 0.702 [95% CI 0.605–0.815]) and amputations by 35% (HR, 0.654 [95% CI 0.522–0.819]) in patients with PAD (variable defining criteria based on study). ⁷⁶

There are conflicting data regarding symptom improvement with statins in patients with PAD. A randomized, double‐blinded study comparing atorvastatin (high or low dose) with placebo in patients with symptomatic PAD revealed improved pain‐free walking distance without improvement in maximal walking time (the primary outcome of the study) after 12 months of therapy with high‐dose atorvastatin compared with placebo. ⁷⁸ Subjective improvement in ambulatory ability has been observed in some other studies as well. ⁸⁴

There are several proposed theories for justification of symptom improvement with statin therapy in patients with PAD. One is microcirculation vasomotor regulation of blood flow through known local vasoactive factors such as nitric oxide, prostacyclin, and adenosine may be improved with statin therapy. ⁷⁸ Cholesterol, specifically elevated LDL, low HDL, and elevated triglycerides promote endothelial dysfunction and reduce release of vasoactive factors that disrupt vasomotor tone. ⁸⁵ Treatment with statins increases endothelium‐dependent vasodilation and theoretically should improve blood flow through microcirculation. ⁸² Second, statins have been shown to have proangiogenic properties independent of cholesterol reduction. As hypercholesterolemia is known to inhibit angiogenesis, cholesterol reduction could have a secondary effect of removing this inhibition thus promoting new blood vessel formation. ⁸⁶ These mechanisms collectively may improve claudication symptoms.

However, several studies have failed to reproduce an improvement in functional status in patients with PAD treated with statins. ⁸⁷ , ⁸⁸ In a subgroup analysis of the 4S, statin use was associated with a reduction in risk of new or worsening claudication by 38% but did not improve established symptoms. ⁵⁹ In a magnetic resonance imaging based study of patients with PAD treated with statins, despite significant decreases in LDL, there were no changes seen in calf muscle perfusion or metabolism as measured by magnetic resonance imaging, nor in treadmill exercise parameters. ⁸⁸ There was, however, a significant improvement in rest ABI seen in the statin group.

Ezetimibe

Ezetimibe is a nonstatin lipid‐lowering drug that predominantly modifies LDL‐C alone or when combined with statin therapy however its effects on atherosclerotic plaque regression are controversial. ⁷⁷ , ⁸⁹ When added to statin therapy, ezetimibe lowers LDL‐C by an additional 23% to 24%. ⁹⁰ The addition of ezetimibe to statin therapy in high‐risk patients significantly reduces risk of cardiovascular death, MI, and stroke. ⁹⁰ West et al. suggest that ezetimibe given concurrently with a statin halts progression of atherosclerotic plaque formation in the superficial femoral artery, but when given to those previously initiated on a statin, atherosclerotic plaque formation progresses. This was despite a 22% decrease in LDL‐C in this intervention arm. ⁷⁷ Moreover, in other peripheral vascular beds, namely the carotid arteries, data show that addition of ezetimibe to statin therapy does not significantly reduce CIMT over 2 years when compared with placebo, despite a significant reduction in LDL‐C in the statin + ezetimibe arm. ⁹¹ However, in a secondary analysis of IMPROVE‐IT, individuals with coronary artery disease and polyvascular disease had additive long‐term cardiovascular risk of the primary end point of cardiovascular death, major coronary event (nonfatal MI, documented unstable angina requiring hospital admission, or coronary revascularization occurring at least 30 days after randomization), or stroke (ischemic or hemorrhagic) at 7 years (39.8% compared with 29.6% without polyvascular disease). Ezetimibe has consistent benefit in those with and without polyvascular disease. The addition of diabetes and polyvascular disease further increased cardiovascular risk to 60%. ⁹²

In patients with familial hypercholesterolemia, adding ezetimibe to statin therapy did not result in a significant decrease in common femoral artery intimal medial thickness or CIMT. ⁹¹ The extended‐release niacin or ezetimibe and carotid intima‐media thickness (ARBITER‐6 HALTS [Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol 6‐HDL and LDL Treatment Strategies in Atherosclerosis]) trial showed that greater degrees of LDL lowering with ezetimibe added to statin therapy paradoxically increased CIMT. ⁹³ Although these data were not encouraging for reduction in limb events, these populations were not selected with baseline significant CIMT and therefore did not have significant CIMT to improve.

Proprotein Convertase Subtilisin‐Kexin Type 9 Monoclonal Antibodies

PCSK9 (proprotein convertase subtilisin‐kexin type 9) monoclonal antibodies have been shown to significantly lower LDL‐C and lipoprotein(a). Since their emergence in the past decade, they have been used primarily in patients who have not met LDL goal based on comorbid conditions despite statin use and in those intolerant to statins. ⁹⁴ PCSK9 inhibitors reduce LDL by approximately 50% regardless of concomitant statin use, and have been shown to significantly reduce all‐cause mortality, CV death, and rate of MI in a large meta‐analysis. ⁹⁴ In an extension of the FOURIER trial, evolocumab significantly reduced the composite primary end point of CV death, MI, stroke, or hospital admission for unstable angina or coronary revascularization in patients with and without a diagnosis of PAD (HR, 0.79 [95% CI, 0.66–0.94], P=0.0098, and HR, 0.86 [95% CI, 0.80–0.93], P=0.0003, respectively). ⁴³ This remained significant for both patients with and without PAD when removing hospital admissions from the composite end point (HR, 0.73 [95% CI, 0.59–0.91], P=0.0040 for those with PAD; HR, 0.81 [95% CI, 0.73–0.90], P<0.0001 for those without PAD), and amounted to an absolute risk reduction of 3.5% in patients with PAD and 1.6% in those without PAD.

The FOURIER and ODYSSEY OUTCOMES trials are among the first to show significant improvement in hard peripheral outcomes, especially in patients without concomitant CAD/MI or CVD/stroke. Major limb events (including acute limb ischemia, major amputation, and urgent peripheral revascularization for ischemia) were significantly reduced in those receiving evolocumab (HR, 0.58 [95% CI, 0.38–0.88], P=0.0093) in the FOURIER trial, amounting to a relative risk reduction of 42%. The authors further note an absolute risk reduction of 6.3% at 2.5 years for composite MACE/MALE in patients with symptomatic PAD and no prior MI or stroke with a number needed to treat of 16 at 2.5 years and of only 8 at 5 years. ⁴³ Studies using alirocumab have shown similar results. A prespecified analysis of the ODYSSEY OUTCOMES trial showed that PAD events (including CLTI, limb revascularization, and amputation for ischemia) in statin‐treated patients with recent MI were reduced by alirocumab use (HR, 0.69 [95% CI, 0.54–0.89], P=0.004) ⁴⁴ (Figure 3, ¹¹ , ⁴³ , ⁴⁴ , ⁶⁰ , ⁶² , ⁶³ , ⁶⁴ , ⁶⁵ , ⁶⁶ , ⁶⁷ , ⁶⁸ , ⁶⁹ , ⁷⁰ , ⁷¹ , ⁷² , ⁷³ , ⁷⁴ , ⁷⁵ , ⁷⁶ ).

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.

The underlying cause of this benefit, especially given the poor association of LDL‐C with PAD risk, is not totally clear. Perhaps intensive lipid lowering (down to an LDL‐C nadir of 10 mg/dL in the FOURIER trial) is the key mechanism for improvement in MALE, as previous trials have not achieved such a low level of LDL‐C reduction. For example, simvastatin use compared with placebo in the Heart Protection Study reduced noncoronary revascularization in those with and without PAD (however, was an exploratory outcome and included carotid interventions) but did not reduce risk of amputation. ⁶¹ Baseline LDL of participants in this study was ~135 mg/dL and simvastatin 40 mg daily decreased this by ~60 mg/dL on average in this population. The ODYSSEY OUTCOMES trial suggests that the benefit of reduced MALE with PCSK9 inhibitors may be from reduction in Lp(a) as opposed to LDL‐C as the reduction in PAD events was associated with baseline quartile of Lp(a) but not LDL‐C (P‐trend=0.03 and P‐trend=0.50, respectively). ⁴⁴ Additionally, absolute reductions in Lp(a) were contingent on baseline levels of Lp(a) such that those with high baseline levels had substantial absolute reductions, and those with low baseline levels accordingly had minimal absolute reductions whereas similar absolute reductions in LDL‐C were seen across all baseline levels of LDL‐C; risk of PAD events was reduced only in those with high baseline levels of Lp(a). Finally, as opposed to statins in which anti‐inflammatory effects have been well studied and may contribute to improvements in limb outcomes, this mechanism has been suggested only with PCSK9 inhibitors and no direct anti‐inflammatory effect has been identified to date.

Niacin

Niacin is a predominantly HDL‐C increasing drug with some effect on LDL‐C and triglyceride lowering. Its efficacy in PAD has been studied in combination with statins but has not been tested individually on a large scale. The AIM‐HIGH (Atherothrombosis Intervention in Metabolic Syndrome With Low HDL/High Triglycerides: Impact on Global Health Outcomes) trial evaluated use of niacin 1500 to 2000 mg daily in patients with controlled LDL levels (<70 mg/dL) and known vascular disease including history of MI, stroke, PAD, or symptomatic CAD. In this study, 13.6% of patients in both the intervention arm and the control arm had a history of PAD. Participants received a high‐intensity statin during a run‐in period and additionally ezetimibe if TC was >135 mg/dL after statin. There was no significant effect on major vascular events including coronary events, stroke, cardiovascular mortality, or all‐cause mortality at 36‐month follow‐up. ⁷⁵ Limb events were not addressed in the study outcomes, and there was no subgroup analysis of outcomes stratified by patients with PAD.

Role of Triglyceride‐Lowering Agents

Bezafibrate, a fibrate drug that lowers triglycerides and more modestly lowers LDL and increases HDL, has not shown significant clinical benefits in patients with PAD. Although the fibrate lowered triglyceride levels by 23.3% in patients with PAD, there was no reduction in incident CAD, stroke, or all‐cause mortality in the trial population studied and only a modest decrease in incidence of nonfatal coronary events in those receiving the drug, particularly in those <65 years of age. ⁷⁴ The trial did, however, show that bezafibrate was associated with early improvement of claudication severity compared with placebo at 1, 2, and 3 years post randomization (P value 0.001, 0.01, and 0.02, respectively) but not beyond 3 years (P value 0.49 for years 4–6). Limb outcomes were not assessed.

A prespecified analysis of the FIELD study (Effect of Fenofibrate on Amputation Events in People With Type 2 Diabetes Mellitus) assessed use of fenofibrate versus placebo in 9795 patients with diabetes over a 5‐year period. ⁷³ Fenofibrate reduced the risk of first amputation (HR, 0.64 [95% CI, 0.44–0.94], P=0.02) and minor amputations in those without known large‐vessel disease (HR, 0.53 [95% CI, 0.30–0.94], P=0.027). There was no difference in risk of major amputations.

Eicosapentaenoic acid and its high‐purity prescription‐only ethyl ester, icosapent ethyl, are omega‐3 fatty acids that have shown reductions in several MACE end points in REDUCE‐IT (Cardiovascular Risk Reduction With Icosapent Ethyl for Hypertriglyceridemia). ⁹⁵ Patients with elevated triglyceride levels despite statin use had lower cardiovascular death and ischemic events compared with those receiving placebo. ⁹⁵ Patients selected with PAD (688 patients) had statistically similar risk reduction in first (P=0.58) and total primary end points (P=0.78) and higher first (26.2% compared with 24.5% without PAD) and total event rates (112.8 per 1000 patient years compared with 101.7 per 1000 patient years). ⁹⁶

NOVEL LIPID‐LOWERING THERAPIES

Plasma Apheresis

In a study of statin therapy versus plasma apheresis plus statin therapy to reduce levels of serum Lp(a) in patients with CAD, combination therapy led to a 19% decrease in Lp(a) concentration compared with a 15% increase in Lp(a) levels in those receiving statin therapy alone. ⁹⁷ Assessment of the femoral and tibial arteries with duplex ultrasound in these same patients showed that those in the statin only arm had an increase in hemodynamically significant new stenoses whereas there was a significant decrease in new stenoses in the combination therapy arm.

Ileal Bypass Surgery

A novel means of cholesterol reduction, ileal bypass surgery, was previously studied by Buchwald et al. The POSCH (Program on the Surgical Control of the Hyperlipidemias) trial randomized 838 patients with prior MI to either partial ileal bypass or control (no surgery). ⁷² There was a significant decrease seen in TC and LDL levels in the surgery group compared with control. A substudy showed significantly less claudication or limb‐threatening ischemia in the intervention arm at time of trial close (72/417 control group versus 54/421 intervention group, RR, 0.702 [95% CI, 0.169–1.000], P=0.049) and a reduction in development of clinically evident PAD (ABI <0.95 and ≥20% reduction in arterial luminal diameter on angiogram) at 5‐year follow‐up (41/120 control group versus 24/126 intervention group, RR, 0.557 [95% CI, 0.360–0.863], P<0.01). Notably there was no significant change in plaque burden on peripheral arteriogram in this study.

Small Interfering RNAs

Inclisiran is a new small interfering RNA therapy, the mechanism of which prevents PCSK9 production thus resulting in reduced LDL levels. This novel therapy is dosed only twice yearly thus having the potential to significantly improve adherence long term. The ORION‐10 (Inclisiran for Participants With Atherosclerotic Cardiovascular Disease and Elevated Low‐Density Lipoprotein Cholesterol) trial demonstrated an LDL reduction of 56% with twice yearly dosing of inclisiran in patients with ASCVD on maximum tolerated statin therapy with LDL ≥70 mg/dL. ⁹⁸ Similar results were shown in ORION‐11 (Inclisiran for Subjects With ASCVD or ASCVD‐Risk Equivalents and Elevated Low‐Density Lipoprotein Cholesterol) including patients with ASCVD risk‐equivalents (including PAD). ⁹⁸ The prespecified exploratory composite end point of cardiovascular death, cardiac arrest, nonfatal MI, and stroke in ORION‐11 was 7.8% with inclisiran versus 10.3% with placebo. Further studies assessing cardiovascular and limb outcomes with inclisiran are needed for this emerging and promising therapy.

Bempedoic Acid

A first‐in‐class adenosine triphosphate‐citrate lyase inhibitor, bempedoic acid has been shown to significantly decrease total cholesterol (mean difference [MD] –10.9% [−13.3% to −8.5%]), LDL (MD –17.5% [−22.9% to −12.0%]), non‐HDL (MD –12.3% [−15.3% to −9.2%]), apolipoprotein B (MD –10.6% [−13.2% to −8.02%]), and hs‐CRP (MD –13.2% [−16.7% to −9.79%]) compared with standard treatment. ⁹⁹ Its mechanism of action is novel and distinct from other lipid‐lowering therapies and ultimately leads to suppressed cholesterol synthesis, upregulation of LDL receptors on the liver, and therefore increased clearance of LDL. It has been suggested as a possible treatment for patients with statin intolerance and for those not able to achieve their suggested LDL target despite therapy with both a statin and ezetimibe. The CLEAR (Evaluation of Major Cardiovascular Events in Participants With, or at High Risk for, Cardiovascular Disease Who Are Statin Intolerant Treated With Bempedoic Acid or Placebo) outcomes study reported bempedoic acid compared with placebo had significant reduction 4 four‐component MACEs (nonfatal MI, nonfatal stroke, coronary revascularization, or cardiovascular death) 11.7% versus 13.3%, HR, 0.87 [95% CI, 0.79–0.96]; P=0.004). ¹⁰⁰ Several trials including patients with PAD have demonstrated safety of the drug and significantly LDL lowering capabilities; however, use in a specific population with PAD are still needed.

UNANSWERED QUESTIONS AND FUTURE PERSPECTIVES

While there is evidence that LDL reduction may not ultimately be the best treatment target in PAD, it is currently the guideline recommended treatment standard across the world. Despite this, there is significant lack of uniformity among recommendations by different societies on lipid management in these patients. Differences between recommendations by the American College of Cardiology Foundation/American Heart Association and the European Society of Cardiology has created significant heterogeneity in the treatment of PAD. American College of Cardiology FoundationAHA guidelines from 2011 have a Class I recommendation to achieve LDL <100 mg/dL in PAD and a Class IIA recommendation for LDL <70 mg/dL in those with high ischemic risk. ¹⁰¹ The 2016 American College of Cardiology Foundation/AHA guidelines have a Class IA recommendation for statin therapy in PAD without an LDL target, which differs from the society stance presented in the blood cholesterol guidelines (aim for 50% reduction in LDL). ² , ⁴ Finally, the 2017 European Society of Cardiology guidelines recommend statin therapy in all patients with PAD to reduce LDL <70 mg/dL or decrease by >50% if LDL is 70 to 135 mg/dL. ¹⁰² The updated 2019 European Society of Cardiology guidelines for management of dyslipidemias recommend an LDL <55 mg/dL in PAD ¹⁸ (see Table 3, ² , ⁴ , ¹⁸ , ¹⁰¹ , ¹⁰² , ¹⁰³ , ¹⁰⁴ ).

Table 3.

Differences in Guideline Recommendations for Treatment of Lipids in PAD

Guideline	Class I (or Grade 1 where appropriate)	Class IIa	Class IIb
ACC Foundation/AHA 2005 and 2011 Compilation Guideline on Management of PAD 101	Treatment with a statin is indicated for all patients with PAD to achieve target LDL‐C of <100 mg/dL (LOE B)	Treatment with a statin to achieve target LDL‐C of <70 mg/dL is reasonable for patients with PAD at very high risk of ischemic events (LOE B) Treatment with a fibric acid derivative can be useful for patients with PAD and low HDL‐C, normal LDL‐C, and elevated triglycerides (LOE C)
AHA/ACC 2016 Guideline on Management of PAD 2	Treatment with a statin medication is indicated for all patients with PAD (no specified LDL‐C target) (LOE A)
AHA/ACC 2018 Guideline on Management of Blood Cholesterol 4	ASCVD not at very high risk: high‐intensity statin with goal LDL‐C decreased of ≥50% if age ≤75 y (LOE A); ASCVD at very high risk 1 : High‐intensity or maximal statin; if PCSK9i considered, add ezetimibe first (LOE B)	ASCVD not at very high risk: initiation or continuation of a moderate or high‐intensity statin is reasonable if age >75 y (LOE C); ASCVD at very high risk: If on max statin therapy and LDL‐C ≥70, adding ezetimibe is reasonable (LOE B); if LDL‐C remains ≥70 or non‐HDL‐C ≥100, it is reasonable to add PCSK9i (LOE A)	ASCVD not at very high risk: if on max statin therapy and LDL‐C ≥70 mg/dL, addition of ezetimibe is reasonable (LOE B)
2017 ESC Guidelines on Diagnosis and Treatment of PAD 102	Statins are recommended in all patients with PAD (LOE A); Patients with PAD should have LDL‐C reduced to ≤70 mg/dL or decrease by ≥50% if baseline values are 70–135 mg/dL (LOE C)
2019 ESC/EAS Guidelines for Management of Dyslipidemias	In patients with PAD, a max tolerated dose of statin plus ezetimibe or a combination with PCSK9iI is recommended to reduce ASCVD events (LOE A); In secondary prevention for patients at very high risk, 2 reduce LDL‐C by ≥50% and to a goal of <55 mg/dL (LOE A); In primary prevention for patients at very high risk without FH, reduce LDL‐C by ≥50% and to a goal of <55 mg/dL (LOE C)		Patients with ASCVD who experience a second vascular event within 2 y on max tolerated statin therapy, consider an LDL‐C goal of <40 mg/dL (LOE B)
2015 Society for Vascular Surgery Guidelines for Atherosclerotic Occlusive Disease of the Lower Extremities 103	Statin therapy is recommended for all patients with symptomatic PAD (LOE A)
2019 Global Vascular Guidelines of the Management of Chronic Limb‐Threatening Ischemia 104	Use moderate or high‐intensity statin therapy to reduce all‐cause and cardiovascular mortality in patients with chronic limb‐threatening ischemia (LOE A)

According to the AHA/ACC, very high‐risk patients include those with a history of multiple major ASCVD events (recent acute coronary syndrome, history of myocardial infarction, history of ischemic stroke, symptomatic PAD) or 1 major ASCVD event and multiple high‐risk conditions (age ≥65, familial hypercholesterolemia, history of prior surgical or percutaneous coronary intervention, diabetes, hypertension, chronic kidney disease, current smoking, history of heart failure, or LDL‐C ≥100 mg/dL despite max tolerated therapy).

Among other categories, all patients with PAD are considered very high risk per ESC/EAS guidelines.

ACC indicates American College of Cardiology; ACCF, American College of Cardiology; AHA, American Heart Association; ASCVD, atherosclerotic cardiovascular disease; EAS, European Atherosclerosis Society; ESC, European Society of Cardiology; FH, familial hypercholesterolemia; HDL‐C, high‐density lipoprotein cholesterol; LDL‐C, low‐density lipoprotein cholesterol; LOE, level of evidence; PCSK9i, proprotein convertase subtilisin kexin type 9 inhibitor; and PAD, peripheral artery disease.

It has been postulated that a trial comparing low LDL (<70 mg/dL) versus higher LDL in patients with diagnosed PAD is needed to compare both MACE and MALE outcomes in these patients to help streamline lipid‐lowering therapy. What is not discussed, and of utmost importance, is the need for randomized, controlled trials comparing not only nonstatin therapies such as PCSK9 monoclonal antibodies, triglyceride‐lowering agents, and novel lipid‐lowering therapies in patients with PAD but also randomized trials comparing lipid‐lowering therapy to nonlipid modifying therapy in patients with PAD (ie, immune modulators).

There are several ongoing studies addressing novel treatment for patients with PAD. Rheopheresis is an apheresis technique used to address microcirculatory disorders. It has shown to be effective in treatment of dry macular degeneration and may be a promising therapy for patients with PAD. RHEO‐PAD (Efficacy and Tolerance of Rheopheresis in the Treatment of Peripheral Artery Disease in Hemodialysis Patients) is an ongoing French trial randomizing patients with PAD and end‐stage renal disease on hemodialysis in a prospective, controlled, parallel, single‐blinded trial to either rheopheresis or control over 12 sessions with primary end points of major amputation rates at 8 months and percentage of complete wound healing of ischemic lesions at 8 months (NCT03975946). Patients undergoing hemodialysis will have a secondary double cascade plasma filter in tandem with a hemodialysis monitor that reduces plasma viscosity and eliminates inflammatory mediators.

CONCLUSIONS

Patients with PAD have a very high risk of cardiovascular events, which includes both MACE and MALE. The global prevalence and cost associated with PAD continue to rise while mortality rate remains stagnant. PAD remains ubiquitously underdiagnosed and undertreated across the world. The lipid hypothesis for PAD is not as well understood as it is for CAD, but there is little doubt that arterial disease in the lower extremities is a separate entity from arterial disease in the coronary and cerebral arteries. Despite differences in plaque morphology and characteristics between these entities, lipid‐lowering therapy has proven to reduce hard events in both. As such lipid reduction in patients with PAD remains a central tenant of PAD management, with reductions in MACE and MALE by one fourth when achieving guideline‐recommended LDL goals. Addition of medications such as PCSK9 monoclonal antibodies can even further lower these risks. Lipid‐lowering therapies, specifically statins, have also demonstrated improvement in walking performance in these patients. Whether this is more closely related to direct modification of atheroma or to pleiotropic effects of these medications (namely statins) is yet to be discovered.

It is currently unclear if targeting non‐LDL targets has a less, equal, or greater impact on PAD outcomes than targeting LDL‐C. As discussed, HDL, TC:HDL, small LDL‐P, and apolipoprotein A‐1 are more closely associated with PAD risk than LDL, with PAD development best modeled by TC:HDL fraction. Moreover, data show that the protective association of HDL in these patients likely outweighs the atherogenic association of LDL. Although lipids play a critical role in several aspects of PAD pathophysiology, diagnosis, and treatment, focus should not be drawn away from improving other risk factors such as smoking and diabetes. Additionally, thrombosis, calcification, and stable plaque characteristics seem to be the driving factors in development and progression of PAD as opposed to vulnerable plaque types in CAD/CVD. Given these underlying thrombotic and fibrocalcific mechanisms of PAD development and progression, nonlipid modifying therapies may categorically prove to be instrumental in prevention and treatment of PAD. Although the current data are overly sparse to suggest a paradigm shift in the treatment of PAD, they have been sufficient to warrant further research into novel approaches to PAD management.

Sources of Funding

None.

Disclosures

None.