Lipid Management in Peripheral Artery Disease: A Focus on Recent and Evolving Data

Aug 19, 2024   |  Sivan Naveh, MD; Mario Enrico Canonico, MD, PHD; Robert Kevin Rogers, MD; Christopher Jennings Regan, MD, FACC; Marc P. Bonaca, MD, FACC

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  • Combination therapy with low-density lipoprotein cholesterol (LDL-C)–lowering therapies with proven outcome benefit is increasingly needed for patients with peripheral artery disease (PAD) to achieve lower LDL-C levels that meet current guideline recommendations.
  • Although statins remain foundational, proprotein convertase subtilisin/kexin type 9 inhibitors, ezetimibe, and bempedoic acid have reduced major adverse cardiac events in randomized controlled trials with emerging data on limb outcomes and can be used in combination with statin therapy to lower LDL-C levels and improve outcomes in patients with PAD.

Peripheral artery disease (PAD) is a prevalent and severe form of atherosclerotic vascular disease, affecting >230 million people worldwide. PAD reduces patients' walking capacity and increases the risk of major adverse limb events (MALE) such as acute limb ischemia (ALI), amputation, or peripheral revascularization. Coexisting coronary or cerebrovascular disease is prevalent in this population, with increased risk of major adverse cardiovascular events (MACE).1 Lipid lowering is a vital component of risk reduction in patients with PAD,2 and evidence regarding the benefits of different lipid-lowering therapies and low-density lipoprotein cholesterol (LDL-C) goals in the setting of PAD continues to evolve.

Statins competitively inhibit hydroxy-methyl-glutaryl coenzyme A reductase, the rate-limiting enzyme in cholesterol synthesis. The HPS (Heart Protection Study) results showed a 24% reduction in MACE, which aligned with the observed absolute lowering of LDL-C levels. Results were consistent in the 6,748 participants with PAD, and a subsequent paper reported a reduction in vascular events including aortic, carotid, and lower extremity procedures.3 A large body of evidence has consistently demonstrated benefits of statins for MACE outcomes, and statins are considered foundational therapy in current guidelines.2 However, improvements in limb outcomes with statins have not been shown in randomized controlled trials (RCTs). Data from several observational studies have shown associations between statin use and limb outcomes, and data from a single small trial showed functional outcome benefit.4

Although LDL-C goals for patients with PAD remain a topic of discussion, trial data and guideline recommendations continue to support increasingly lower levels. Recent RCT data have shown a consistent association between LDL-C level reduction and decrease in both MACE and MALE outcomes with evidence of better risk reduction with lower LDL-C thresholds.5,6 Whereas European Society of Cardiology (ESC) guidelines and American College of Cardiology (ACC) consensus statements recommend levels <55 mg/dL,7 current ACC/American Heart Association (AHA) guidelines still describe 70 mg/dL.2 Despite this debate, achieving LDL-C goal <70 mg/dL with statins alone can be challenging for many patients.2 Thus, the development of novel low-density lipoprotein (LDL)–lowering mechanisms that have proven outcome benefits and can be used in combination with statins has enabled strategies that help more patients achieve very low LDL-C levels more rapidly and that accommodate patient preferences regarding statin use and dosing.

Ezetimibe inhibits intestinal cholesterol absorption, lowering LDL-C levels. In the IMPROVE-IT (Improved Reduction of Outcomes: Vytorin Efficacy International Trial) data, ezetimibe added to a statin (simvastatin) demonstrated a decrease in MACE in 18,144 patients following acute coronary syndrome (ACS). Consistent results, with numerically higher absolute risk reduction (ARR), were found in patients with polyvascular disease, including 1,005 with PAD.8 Emerging data suggest potential benefits for chronic limb-threatening ischemia and progressive disease leading to revascularization.8,9

Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors target a protein that promotes LDL receptor degradation in the liver, leading to significant LDL level reduction. Recent trial data have shown that PCSK9 inhibitors can reduce the risk of MACE in patients with established atherosclerosis or with ACS,5,6 and have yielded promising results for patients with PAD. In the FOURIER (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk) trial, 27,564 patients with cardiovascular disease (CVD) and LDL-C levels of approximately 90 mg/dL were randomized to evolocumab or placebo. Evolocumab decreased LDL-C levels by approximately 60% and reduced the risk of the primary composite endpoint of cardiovascular (CV) death, myocardial infarction (MI), stroke, and hospitalization for unstable angina (UA) or coronary revascularization by 15%. Among the 3,642 patients with PAD, evolocumab reduced the risk of CV death, MI, or stroke by 27%.5 The risk of MALE, defined as a composite of ALI, major amputation, or urgent revascularization, was reduced by 37%.10 In the ODYSSEY OUTCOMES (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab) trial data, alirocumab reduced the risk of MACE, defined as death from coronary heart disease, MI, fatal or nonfatal ischemic stroke, or UA requiring hospitalization, by 15% in 18,924 patients with recent ACS and LDL-C levels ≥70 mg/dL. Numerically higher ARR in MACE was found in patients with polyvascular disease, including PAD.11 PAD events, defined as critical limb ischemia, limb revascularization, or unplanned amputation for ischemia, were reduced by 31%.6,12 Notably, PCSK9 inhibitors were shown to decrease levels of lipoprotein(a) (Lp[a]), an independent risk factor for CVD.4

RCT data also show MACE reduction for bempedoic acid and icosapent ethyl (IPE) in PAD subgroups. IPE, a highly purified eicosapentaenoic acid ethyl ester that lowers triglyceride levels, showed 25% reduction in CV events in the results of an RCT of 8,179 patients, with consistent results in the PAD subgroup.13 Bempedoic acid is an adenosine triphosphate citrate lyase inhibitor that reduces LDL-C levels. In the CLEAR Outcomes (Cholesterol Lowering via Bempedoic Acid, an ACL-Inhibiting Regimen) trial data, compared with placebo, bempedoic acid significantly reduced a four-component MACE outcome in 13,970 patients, including 1,624 patients with PAD, who had or were at high risk of CVD and who were unable or unwilling to take statins.14 Whether there are benefits for reducing adverse limb events has not been demonstrated for these therapies.

The benefits of other available lipid-lowering therapies such as niacin and fibrates have been examined in the PAD population.4 In an RCT, niacin failed to show significant benefit for CV events in patients with PAD already taking statins. In a subanalysis of an RCT's data that looked at fibrates versus placebo in patients with diabetes mellitus, a lower risk of minor but not major amputations was seen with fibrate treatment. Additional studies are needed to further assess the role of fibrates in PAD lipid management.

Novel lipid-lowering therapies are actively being studied. Inclisiran, a small interfering RNA targeting PCSK9, was associated with a lower risk of MACE in a pooled analysis of data from three RCTs, including patients with CVD or risk equivalent on statin therapy.15 Large outcomes trials in both primary and secondary prevention are ongoing. Ongoing trials of oral PCSK9 inhibitors (CORALreef [Cardiovascular Outcomes in Renal Atherosclerotic Lesions]) are studying this therapy in patients at high risk and include limb outcomes in their primary endpoint. Ongoing studies are evaluating the impact of Lp(a) level reduction on CV outcomes. Data regarding PAD populations and limb outcomes would be of interest for these emerging therapies.

In conclusion, for patients with PAD, achieving very low LDL-C levels has become the main goal in reducing their risk of MACE and MALE.2 To accomplish this reduction, combination lipid-lowering therapy using multiple agents with proven outcome benefits will facilitate rapid achievement of LDL goals, particularly because there appears to be no lower limit for safety. When selecting the components of this combination approach, prioritizing agents that have demonstrated favorable effects on limb outcomes, in addition to MACE, is a consideration. Currently, the evidence supporting limb outcome benefits is strongest for PCSK9 inhibitors and is emerging for ezetimibe, both showing benefit in RCT data (Tables 1, 2).9,10,12 Ongoing research continues to refine the role of lipid-lowering strategies in the comprehensive management plan for patients with PAD.

Table 1: MACE Outcomes in RCTs of Lipid-Lowering Therapy in the Setting of PAD

Study, Author, Year No. of Pts. (Pts. With PAD) Patient Population Intervention Median Follow-Up Time Outcome Results
HPS, Heart Protection Study Collaborative Group, 20073 20,536 (6,748) Coronary disease, other occlusive arterial disease, or DM Simvastatin vs. placebo 5 years Major vascular event (MI, coronary death, stroke, or revascularization) Simvastatin treatment reduced major vascular events

HR, 0.78 (95% CI, 0.71-0.85; p < 0.0001)
FOURIER, Bonaca, 201810 27,564 (3,642) Previous MI, nonhemorrhagic stroke, or symptomatic PAD, with LDL-C level ≥70 mg/dL on statin ± ezetimibe Evolocumab vs. placebo 2.2 years MACE composite: CV death, MI, stroke, hospital admission for UA, or coronary revascularization Evolocumab reduced MACE in patients with PAD

HR, 0.79 (95% CI, 0.66-0.94; p = 0.0098)
REDUCE-IT PAD subanalysis, Bhatt, 202113 8,179 (688) Established CVD or DM and other risk factors, taking statin therapy, with fasting TG level 135-499 mg /dL and LDL-C level 41-100 mg/dL IPE 2 g twice daily vs. placebo 4.9 years Composite of CV death, nonfatal MI, nonfatal stroke, coronary revascularization, or UA IPE showed consistent risk reduction in the first primary outcome in patients with established CVD with or without PAD

HR, 0.78 (95% CI, 0.59-1.03; p = 0.08)

pinteraction = 0.58
ODYSSEY OUTCOMES, Jukema, 201911 18,924 (1,405) polyvascular disease Recent (12 months) history of ACS, LDL-C level ≥70 mg/dL on statin Alirocumab vs. placebo 2.8 years Composite MACE: coronary heart disease death, MI, stroke, UA requiring hospitalization Alirocumab showed improvement in overall CV outcomes

HR, 0.84 (95% CI, 0.78-0.93; p < 0.0001)

Numerically higher ARR in MACE was seen in patients with polyvascular disease, including PAD

ARR: Coronary disease: 1.4% (0.6-2.3%)

Polyvascular disease:
  • 2 vascular beds: 1.9% (-2.4% to 6.2%)
  • 3 vascular beds: 13% (-2% to 28%)
pinteraction = 0.0006
IMPROVE-IT secondary analysis, Bonaca, 20188 18,144 (1,005) polyvascular disease Recent (10 days) ACS, taking statin, LDL-C level 50-125 mg/dL Ezetimibe vs. placebo 6.6 years MACE composite of CV death, major coronary event, or stroke Ezetimibe reduced MACE in patients following ACS

HR, 0.94 (95% CI, 0.89-0.99; p = 0.016)

Numerically higher ARR was found in patients with polyvascular disease including PAD

ARR:
  • No polyvascular disease 1.7% (95% CI, 0.33-3.04)
  • With polyvascular disease 4.2 (95% CI, -1.06 to 9.53)
pinteraction = 0.75
CLEAR Outcomes, Nissen, 202314 13,970 (1,564) Previous CV event or high risk of a CV event, statin intolerant Bempedoic acid vs. placebo 3.4 years MACE composite: CV death, MI, stroke, or coronary revascularization Bempedoic acid treatment was associated with a lower risk of MACE

HR, 0.87 (95% CI, 0.79-0.96; p = 0.004)
Table 1: MACE Outcomes in RCTs of Lipid-Lowering Therapy in the Setting of PAD. Courtesy of Naveh S, Canonico ME, Rogers KR, Regan C, Bonaca MP.
ACS = acute coronary syndrome; ARR = absolute risk reduction; CI = confidence interval; CLEAR Outcomes = Cholesterol Lowering via Bempedoic Acid, an ACL-Inhibiting Regimen; CLI = critical limb ischemia; CLTI = chronic limb-threatening ischemia; CV = cardiovascular; CVD = cardiovascular disease; DM = diabetes mellitus; FOURIER = Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk; HPS = Heart Protection Study; HR = hazard ratio; IMPROVE-IT = Improved Reduction of Outcomes: Vytorin Efficacy International Trial; IPE = icosapent ethyl; LDL-C = low-densitity lipoprotein cholesterol; MACE = major adverse cardiovascular disease; MI = myocardial infarction; No. = number; ODYESSY OUTCOMES = Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab; PAD = peripheral artery disease; Pts. = patients; RCT = randomized controlled trial; REDUCE-IT = Reduction of Cardiovascular Events With Icosapent Ethyl–Intervention Trial; RR = relative risk; TG = triglyceride; UA = unstable angina.

Table 2: Limb Outcomes in RCTs of Lipid-Lowering Therapy in the Setting of PAD

Study, Author, Year No. of Pts. (Pts. With PAD) Patient Population Intervention Median Follow-Up Time Outcome Results
FOURIER, Bonaca, 201810 27,564 (3,642) Previous MI, nonhemorrhagic stroke, or symptomatic PAD, with LDL-C level ≥70 mg/dL on statin ± ezetimibe Evolocumab vs. placebo 2.2 years MALE (ALI, major amputation, or urgent peripheral revascularization) Evolocumab reduced MALE

All cohorts: HR, 0.58 (95% CI, 0.38-0.88; p = 0.0093)

No PAD: HR, 0.37 (95% CI, 0.16-0.88)

PAD: HR, 0.63 (95% CI, 0.39-1.03)

pinteraction = 0.29
ODYSSEY OUTCOMES, Schwartz, 202012 18,924 (1,405) polyvascular disease Recent (12 months) history of ACS, LDL-C level ≥70 mg/dL on statin Alirocumab vs. placebo 2.8 years PAD events (CLI, limb revascularization, or amputation for ischemia) Alirocumab reduced risk of PAD events

HR, 0.69 (95% CI, 0.54-0.89; p = 0.004)
IMPROVE-IT, Bonaca, 20239 18,144 (1,005) Recent (10 days) ACS, taking statin, LDL-C level 50-125 mg/dL Ezetimibe vs. placebo 6.6 years PAD events (CLI or worsening symptoms) Ezetimibe reduced risk of CLTI and progressive disease leading to revascularization

RR, 0.77 (95% CI, 0.62-0.96; p = 0.018)
Table 2: Limb Outcomes in RCTs of Lipid-Lowering Therapy in the Setting of PAD. Courtesy of Naveh S, Canonico ME, Rogers KR, Regan C, Bonaca MP.
ACS = acute coronary syndrome; ALI = acute limb ischemia; CI = confidence interval; CLI = critical limb ischemia; CLTI = chronic limb-threatening ischemia; CV = cardiovascular; FOURIER = Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk; HR = hazard ratio; IMPROVE-IT = Improved Reduction of Outcomes: Vytorin Efficacy International Trial; LDL-C = low-densitity lipoprotein cholesterol; MACE = major adverse cardiovascular disease; MALE = major adverse limb event; MI = myocardial infarction; No. = number; ODYESSY OUTCOMES = Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab; PAD = peripheral artery disease; Pts. = patients; RCT = randomized controlled trial; RR = relative risk.

References

  1. Aday AW, Matsushita K. Epidemiology of peripheral artery disease and polyvascular disease. Circ Res 2021;128:1818-32.
  2. Gornik HL, Aronow HD, Goodney PP, et al.; Writing Committee Members. 2024 ACC/AHA/AACVPR/APMA/ABC/SCAI/SVM/SVN/SVS/SIR/VESS guideline for the management of lower extremity peripheral artery disease: a report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. J Am Coll Cardiol 2024;83:2497-2604.
  3. Heart Protection Study Collaborative Group. Randomized trial of the effects of cholesterol-lowering with simvastatin on peripheral vascular and other major vascular outcomes in 20,536 people with peripheral arterial disease and other high-risk conditions. J Vasc Surg 2007;45:645-54; discussion 653-4.
  4. Bonaca MP, Hamburg NM, Creager MA. Contemporary medical management of peripheral artery disease. Circ Res 2021;128:1868-84.
  5. Sabatine MS, Giugliano RP, Keech AC, et al.; FOURIER Steering Committee and Investigators. Evolocumab and clinical outcomes in patients with cardiovascular disease. N Engl J Med 2017;376:1713-22.
  6. Schwartz GG, Steg PG, Szarek M, et al. Alirocumab and cardiovascular outcomes after acute coronary syndrome. N Engl J Med 2018;379:2097-107.
  7. Lloyd-Jones DM, Morris PB, Ballantyne CM, et al.; Writing Committee. 2022 ACC expert consensus decision pathway on the role of nonstatin therapies for LDL-cholesterol lowering in the management of atherosclerotic cardiovascular disease risk: a report of the American College of Cardiology Solution Set Oversight Committee. J Am Coll Cardiol 2022;80:1366-1418.
  8. Bonaca MP, Gutierrez JA, Cannon C, et al. Polyvascular disease, type 2 diabetes, and long-term vascular risk: a secondary analysis of the IMPROVE-IT trial. Lancet Diabetes Endocrinol 2018;6:934-943.
  9. Bonaca MP, Giugliano RP, Cannon CP, et al. Reduction in the risk of major adverse limb events with ezetimibe versus placebo in addition to statin therapy: insights from the IMPROVE IT trial. Eur Heart J 2023;44:[ePub ahead of print].
  10. Bonaca MP, Nault P, Giugliano RP, et al. Low-density lipoprotein cholesterol lowering with evolocumab and outcomes in patients with peripheral artery disease: insights from the FOURIER trial (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk). Circulation 2018;137:338-50.
  11. Jukema JW, Szarek M, Zijlstra LE, et al. Alirocumab in patients with polyvascular disease and recent acute coronary syndrome: ODYSSEY OUTCOMES trial. J Am Coll Cardiol 2019;74:1167-76.
  12. Schwartz GG, Steg PG, Szarek, et al. Peripheral artery disease and venous thromboembolic events after acute coronary syndrome: role of lipoprotein(a) and modification by alirocumab: prespecified analysis of the ODYSSEY OUTCOMES randomized clinical trial. Circulation 2020;141:1608-17.
  13. Bhatt DL, Steg PG, Miller M, et al. Abstract 10627: benefits of icosapent ethyl in patients with prior peripheral artery disease: REDUCE-IT PAD. Circulation 2021;144:[ePub ahead of print].
  14. Nissen SE, Lincoff AM, Brennan D, et al. Bempedoic acid and cardiovascular outcomes in statin-intolerant patients. N Engl J Med 2023;388:1353-64.
  15. Ray KK, Raal FJ, Kallend DG, et al. Inclisiran and cardiovascular events: a patient-level analysis of phase III trials. Eur Heart J 2023;44:129-38.

Resources

Clinical Topics: Dyslipidemia, Vascular Medicine, Atherosclerotic Disease (CAD/PAD), Lipid Metabolism, Nonstatins, Statins, Prevention

Keywords: Peripheral Arterial Disease, Lipids, PCSK9 Inhibitors, Ezetimibe, Cholesterol, LDL