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CLINICAL STATEMENTS AND GUIDELINES June 11, 2024 Circulation. 2024;149:e1313–e1410. DOI: 10.1161/CIR.0000000000001251 e1344 Participants With Vascular Disease).9 Notably, the safety of canagliflozin in patients with PAD has been evaluated by the FDA, given an increased rate of associated lower extremity amputations in the CANVAS trial (6.3 versus 3.4 placebo per 1000 patient years; P<0.001).10 Most amputations were minor and occurred at the toe or metatarsal level (71%).10 However, these findings were not reproduced in the CREDENCE (Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation) trial or a more recently published systematic review and metaanalysis of 30 trials.11,12 A subgroup analysis of patients with PAD at baseline (n=1462; 20.8%) in EMPA-REG OUTCOME showed superior limb survival in patients treated with empagliflozin versus placebo.7 Because of the conflicting subsequent data, the black box warning associated with canagliflozin was removed by the FDA in August 2020.21 For patients with PAD who have heart failure, RCT data and clinical practice guidelines further support the use of SGLT2 inhibitors to prevent MACE.22 Overall, these data provide robust support for use of these agents to reduce MACE among patients with PAD and type 2 diabetes. 2. Diabetes is associated with an increased risk of PAD, with an odds ratio ranging from 1.89 to 4.05.23 In the EUCLID trial, of the 13 885 patients enrolled, 5345 patients (38.5%) had diabetes.18 It has been estimated that approximately 50% of patients with CLTI have diabetes.24 In patients with known PAD, the presence of diabetes confers increased risk for MACE and MALE outcomes, including progression to CLTI, amputation, and death.25 In a subgroup analysis of patients with diabetes in the EUCLID trial, a 14.2% increased relative risk of MACE (95% CI: 1.09-1.2; P<0.0001) was observed with every 1% increase in hemoglobin A1c, suggesting an opportunity for improved glycemic control to improve outcomes in this patient population.18 Management of diabetes should include a coordinated care plan among clinicians to address diet, exercise, weight management, pharmacotherapy for glycemic control, management of other cardiovascular risk factors, and foot care and ulcer prevention. 3. Poor glycemic control is a known risk factor for diabetic neuropathy, which is associated with diabetic foot ulcer development, a cardinal manifestation of CLTI.26,27 Multiple population-based and clinical observational studies have demonstrated an association between incrementally higher hemoglobin A1c values and MALE, particularly amputation, among patients with PAD and diabetes. In the Strong Heart study, in a cohort of 1974 patients who had diabetes, patients with PAD and a hemoglobin A1c level of <6.5% had a lower age-adjusted odds ratio of major amputation during longitudinal followup compared with those with a hemoglobin A1c level of 6.5% to 9.5% and hemoglobin A1c level of >9.5%.19 Lane et al performed a meta-analysis of patients with diabetic foot ulcers and found a lower risk of amputation associated with a hemoglobin A1c level of <8%.13 Preprocedural glycemic control has also been associated with outcomes after revascularization for PAD. In a large observational study from the US Department of Veterans Affairs database (N=26 799), poor glycemic control, as measured by preprocedural hemoglobin A1c levels, was associated with increased risk of MALE during longitudinal follow-up, including amputation, among individuals with PAD undergoing endovascular or surgical revascularization.16 In an observational study of 278 patients with CLTI undergoing endovascular revascularization, diabetes with poor glycemic control (defined as hemoglobin A1c level ≥6.8%) was associated with risk of major amputation.14 Similarly, in a registry-based series of 309 infrapopliteal endovascular procedures performed in patients with PAD and either CLTI or ALI, a preprocedural median fasting blood glucose ≥144 mg/dL was associated with a higher rate of major amputation and lower primary patency at the interventional site.15 Although further study of the impact of glycemic control on limb outcomes is warranted, these data support diabetes management as a component of GDMT for patients with PAD. 5.6 Other Medical Therapies for Cardiovascular Risk Reduction in PAD Recommendations for Other Medical Therapies for Cardiovascular Risk Reduction in PAD Referenced studies that support the recommendations are summarized in the Online Data Supplement. COR LOE Recommendations 1 C-LD 1. Patients with PAD should receive an annual influenza vaccination.1–5 1 C-EO 2 Patients with PAD should receive the severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) vaccination sequence, including the booster(s). 2a B-R 3 In patients at high cardiovascular risk, a diet emphasizing intake of vegetables, fruits, legumes, nuts, whole grains, and fish can be beneficial for reducing the risk of developing PAD and the risk of MACE.6–15 3: No Benefit B-R 4 In patients with PAD, B-complex vitamin supple- mentation to lower homocysteine levels is not beneficial for prevention of MACE.16–18 3: No Benefit B-R 5. In patients with PAD, chelation therapy (eg, EDTA) is not beneficial for prevention of MACE.19,20 3: No Benefit B-R 6. In patients with PAD, vitamin D supplementation is not beneficial for prevention of MACE.21–25 Downloaded from http://ahajournals.org by on October 7, 2026