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CLINICAL STATEMENTS AND GUIDELINES

Circulation. 2024;149:e1313–e1410. DOI: 10.1161/CIR.0000000000001251 June 11, 2024 e1343

nicotine delivery systems (ie, e-cigarettes, vaping) contain nicotine, particulates, and other toxic chemicals, but at a lower amount than tobacco smoke.19,20,34 The effects of avoiding passive smoke and electronic nicotine delivery system emission exposure on MALE among patients with PAD are unknown.20 Observational studies have shown lower rates of MACE in the general population after enactment of smokefree legislation, although the effect of such interventions on limb-related events remains unknown.35

5.5 Diabetes Management for PAD

Recommendations for Diabetes Management for PAD Referenced studies that support the recommendations are summarized in the Online Data Supplement. COR LOE Recommendations

1 A 1 In patients with PAD and type 2 diabetes, use of

glucagon-like peptide–1 agonists (liraglutide and semaglutide) and sodium-glucose cotransporter-2 (SGLT-2) inhibitors (canagliflozin, dapagliflozin, and empagliflozin) are effective to reduce the risk of MACE.1–12

1 C-EO 2 In patients with PAD, management of diabetes

should be coordinated among members of the health care team.

2b B-NR 3.	 In patients with PAD and diabetes, glycemic control

may be beneficial to improve limb outcomes.13–16

Synopsis Diabetes is an important risk factor for development of PAD and for progression to CLTI. A guideline-based program of pharmacological and nonpharmacological therapies (including weight management) should be implemented for patients with diabetes and underlying PAD. Updated care standards, including recommendations for approach to pharmacological therapy for patients with diabetes, have been published and are beyond the scope of this document.17 Recent RCTs have demonstrated reduction in MACE among patients with PAD and type 2 diabetes treated with glucagonlike peptide-1 agonists or sodium glucose cotransporter-2 inhibitors.1–12 Adequate glycemic control in this patient population has been associated with improved outcomes in observational studies, particularly among patients with CLTI.13–16,18,19 A coordinated effort among clinicians is essential, and a diabetes care plan should be customized to each individual depending on clinical status and risk factors.

Recommendation-Specific Supportive Text

1 Glucagon-like peptide-1 agonists (liraglutide

and semaglutide) and SGLT-2 inhibitors (canagliflozin, dapagliflozin, and empagliflozin) have been demonstrated to reduce MACE in RCTs of patients with type 2 diabetes and CVD, including underlying PAD.1,2,7,8,10 At baseline, 12.5% of patients in the LEADER (Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results) trial and 13.7% of patients in SUSTAIN-6 (Trial to Evaluate Cardiovascular and Other Long-term Outcomes With Semaglutide in Subjects With Type 2 Diabetes) had PAD.1,2 In subgroup analyses, the presence of PAD was associated with increased risk of MACE in both the LEADER trial and SUSTAIN-6, and the use of a glucagon-like peptide-1 agonist was associated with reduced MACE.6 In the LEADER trial, at a median of 3.8 years follow-up, the primary composite MACE outcome occurred in 13.0% of patients in the placebo group compared with 14.9% of patients in the liraglutide group (HR: 0.87; P<0.001).1 In SUSTAIN-6, at a median of 2.1 years of follow-up, the primary composite MACE outcome, which included first occurrence of cardiovascular death, nonfatal MI, or nonfatal stroke, occurred in 6.6% of patients in the semaglutide group and 8.9% of patients in the placebo group (HR: 0.74; P<0.001).2 These benefits do not appear to be related to a class effect given that findings were not replicated in studies dedicated to other glucagon-like peptide-1 agonists, including lixisenatide, exenatide, and dulaglutide.3–5 Study of the glucagon-like peptide-1 agonist tirzepatide in patients with diabetes and CVD is ongoing.20 Multiple RCTs have also demonstrated benefit in terms of reduction of MACE with use of SGLT-2 inhibitors (canagliflozin, dapagliflozin, and empagliflozin) in patients with type 2 diabetes and underlying PAD. In EMPA-REG OUTCOME (Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients), 21% of patients had known PAD.7 Empagliflozin was associated with a reduction in cardiovascular death, nonfatal MI, and nonfatal stroke (10.5% vs 12.1%; P=0.04). Similarly, in CANVAS (CANagliflozin cardiovascular Assessment Study), 21% of patients had known PAD, and canagliflozin was associated with a reduction in cardiovascular death, nonfatal MI, or nonfatal stroke (HR: 0.86; P<0.01).10 In the DECLARE-TIMI 58 (Dapagliflozin Effect on CardiovascuLAR Events- Thrombolysis In Myocardial Infarction 58) study, dapagliflozin was not associated with significant reduction in MACE; however, there was a significant reduction in cardiovascular death or hospitalization for heart failure (4.9% versus 5.8%; P=0.005).8 The reduction in MACE events did not appear to extend to ertugliflozin in the VERTIS CV trial (Cardiovascular Outcomes Following Ertugliflozin Treatment in Type 2 Diabetes Mellitus

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