Peripheral Artery Disease: Emerging Advances in Medical Therapy to Reduce Cardiovascular and Limb Risks

Highlight

• Peripheral artery disease (PAD) remains underdiagnosed and undertreated despite its association with high cardiovascular and limb event risks.
• Multifaceted management strategies involving lifestyle modification, risk factor control, and advanced pharmacotherapy improve outcomes in PAD patients.
• Dual pathway antithrombotic therapy with low-dose rivaroxaban plus aspirin significantly reduces both major adverse cardiovascular and limb events compared to single antiplatelet therapy.
• Adjunctive lipid-lowering agents beyond statins, including ezetimibe, bempedoic acid, and PCSK9 inhibitors, help achieve LDL-C targets in PAD patients.
• Novel antidiabetic medications, especially GLP-1 receptor agonists and SGLT2 inhibitors, provide cardiovascular and renal protection; GLP-1 RAs like semaglutide also exhibit potential limb event reduction.

Study Background

Peripheral artery disease is a common yet frequently under-recognized manifestation of systemic atherosclerosis affecting the lower extremities. Characterized by arterial stenosis or occlusion, PAD leads to compromised blood flow and manifests clinically as intermittent claudication, critical limb ischemia, or asymptomatic disease. The global burden of PAD is substantial and increasing with aging populations and rising prevalence of diabetes and other risk factors. Critically, PAD is strongly linked to elevated risks of major adverse cardiovascular events (MACE) such as myocardial infarction and stroke, as well as major adverse limb events (MALE) including limb ischemia and amputation. Despite guideline recommendations, PAD patients are often underdiagnosed and undertreated, with suboptimal implementation of risk factor modification and pharmacotherapy, resulting in preventable cardiovascular morbidity and limb loss. This scenario underscores the urgent need for improved and individualized medical management strategies.

Medical Management Strategies and Pharmacologic Advances

Management of PAD requires a comprehensive approach targeting the metabolic, lipid, immuno-inflammatory, and thrombotic contributors to disease progression. Crucial to this approach is optimizing lifestyle factors through smoking cessation, adopting a heart-healthy diet, and promoting regular physical activity—all foundational to ameliorating both cardiovascular and limb risks.

Antithrombotic Therapy

Antithrombotic treatment plays a pivotal role in reducing ischemic events in PAD. Current evidence supports the superiority of dual pathway inhibition combining low-dose rivaroxaban (2.5 mg twice daily) and aspirin over aspirin monotherapy in patients with high ischemic risk without elevated bleeding risk. This regimen reduces the incidence of MACE and MALE significantly and is now endorsed by contemporary guidelines. Balancing bleeding risk is critical, necessitating individualized patient assessment.

Lipid-Lowering Therapy

Statins remain first-line lipid-lowering agents for all PAD patients due to their proven efficacy in reducing cardiovascular events. Achieving stringent low-density lipoprotein cholesterol (LDL-C) targets is essential. When maximal tolerated statin therapy fails to meet LDL-C goals, adjunctive agents such as ezetimibe, bempedoic acid, and proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) should be incorporated. These agents provide incremental LDL-C reduction and have shown cardiovascular benefit in diverse atherosclerotic populations, including PAD.

Metabolic and Antidiabetic Agents

Given the strong association of PAD with diabetes and metabolic syndrome, antidiabetic medications with cardiovascular and renal benefits independent of glycemic control have transformed management paradigms. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and sodium-glucose cotransporter-2 inhibitors (SGLT2is) have demonstrated reductions in cardiovascular mortality and events. Emerging data suggest GLP-1 RAs may also reduce limb events, potentially through anti-inflammatory and metabolic effects beyond glycemic lowering. Among GLP-1 RAs, semaglutide stands out as the only anti-obesity pharmacotherapy proven to reduce cardiovascular events in high-risk overweight or obese patients without diabetes, highlighting its potential broader applicability in PAD management.

Risk Stratification and Phenotype-Driven Approaches

PAD exhibits heterogeneity in clinical presentation and risk profiles. A phenotype-driven approach stratifying patients according to ischemic risk, bleeding risk, metabolic phenotype, and limb threat can guide individualized intensity and selection of therapeutic strategies. Such personalized management maximizes benefit and minimizes harms, aligning with the principles of precision medicine. Reflection of patient constitution, comorbidities, and response to therapy should inform dynamic treatment adjustments.

Expert Commentary

The evolving landscape of PAD medical therapy represents significant progress but is challenged by underdiagnosis and insufficient treatment implementation globally. The dual pathway antithrombotic regimen marks a paradigm shift by effectively addressing both cardiovascular and limb ischemic events. However, it necessitates careful bleeding risk evaluation. Adjunct lipid-lowering agents complement statins, allowing attainment of LDL-C targets critical to vascular event reduction. The cardiovascular and potential limb benefits of novel antidiabetic drugs herald a new dimension of integrated metabolic-vascular care in PAD. Nevertheless, larger randomized studies specifically focusing on PAD populations are warranted to consolidate these data and explore optimal combinations. The incorporation of risk phenotyping and individualized strategies is essential for translating these advances into routine clinical practice, aiming to reduce the high residual risk in PAD despite current standards.

Conclusion

Peripheral artery disease remains a serious yet underrecognized global health challenge closely tied to major cardiovascular and limb complications. Advances in medical therapy—including dual pathway antithrombotic therapy, intensified lipid lowering, and novel metabolic interventions—offer promising avenues to improve outcomes. Multifaceted management integrating lifestyle changes, pharmacologic optimization, and personalized risk stratification is fundamental to achieving sustained cardiovascular and limb event reduction. Future research should focus on refining phenotype-driven approaches and generating PAD-specific evidence to guide best practice towards reducing the global burden of this debilitating disease.

Funding and Clinical Trials

The reviewed studies and trials were funded by various academic institutions, industry sponsors, and governmental research grants dedicated to improving cardiovascular health. Relevant ongoing clinical trials exploring dual pathway inhibition, novel lipid-lowering agents, and antidiabetic therapies in PAD populations are registered at ClinicalTrials.gov but require further confirmation in pragmatic clinical settings.

References

• Garagoli F, Slipczuk L, Shapiro MD, Bonaca MP, Bhatt DL. Peripheral artery disease: advances in medical therapy. European Heart Journal. 2026 Jul 17. PMID: 42466921.
• Bonaca MP, et al. Low-Dose Rivaroxaban and Aspirin in Patients with Stable Peripheral or Carotid Artery Disease: The COMPASS Trial. N Engl J Med. 2017 Oct 26;377(14):1319-1330.
• Baigent C, et al. Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomised trials. Lancet. 2005 Oct 8;366(9493):1267-78.
• Marso SP, et al. Semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med. 2016 Nov 10;375(19):1834-44.
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