Cardiovascular Outcomes and Safety of Empagliflozin in Patients With Type 2 Diabetes Mellitus and Peripheral Artery Disease: A Subanalysis of EMPA-REG OUTCOME.

Peripheral artery disease (PAD) is one of the most common cardiovascular complications in patients with type 2 diabetes mellitus (T2DM)1 and is a predictor of cardiovascular death.2 Interventions that reduce cardiovascular complications in this patient population are urgently required. In the EMPA-REG OUTCOME trial, the sodium glucose cotransporter 2 inhibitor empagliflozin reduced the risk of cardiovascular death by 38% (hazard ratio [HR], 0.62; 95% confidence interval [CI] 0.49–0.77]) and hospitalization for heart failure (HHF) by 35% (HR, 0.65; 95% CI, 0.50–0.85) versus placebo when given in addition to standard of care.3 We report analyses of the effects of empagliflozin on cardiovascular outcomes, mortality, and renal outcomes in patients with and without PAD at baseline in the EMPA-REG OUTCOME trial. Patients in EMPA-REG OUTCOME had T2DM (hemoglobin A1c, 7%–10%), established cardiovascular disease, and estimated glomerular filtration rate ≥30 mL·min−1·1.73 m−2 at baseline. PAD at inclusion was defined as the presence of any of the following: limb angioplasty, stenting, or bypass surgery; limb or foot amputation resulting from circulatory insufficiency; evidence of significant peripheral artery stenosis (>50% on angiography, or >50% or hemodynamically significant via noninvasive methods) in ≥1 limb; and ankle brachial index <0.9 in ≥1 ankle. Patients were randomized 1:1:1 to empagliflozin 10 mg, empagliflozin 25 mg, or placebo in addition to standard of care. Cardiovascular outcome events and deaths were prospectively adjudicated by Clinical Events committees. An independent ethics committee or institutional review board approved the clinical protocol at each participating center. Patients provided informed consent before study entry. In subgroups by PAD at baseline (yes/no), we assessed the risk of cardiovascular death, 3-point major adverse cardiovascular events (MACE; cardiovascular death, nonfatal myocardial infarction, nonfatal stroke), 4-point MACE (3-point MACE plus hospitalization for unstable angina), all-cause mortality, HHF, the composite of HHF or cardiovascular death, and incident or worsening nephropathy (defined as progression to macroalbuminuria, doubling of serum creatinine, initiation of renal replacement therapy, or death caused by renal disease) with empagliflozin pooled versus placebo using a Cox proportional hazards model. The model included factors for age, sex, baseline body mass index, hemoglobin A 1c, estimated glomerular filtration rate, region, treatment, PAD, and treatment-by-PAD interaction. P values for the treatment-by-subgroup interaction were obtained from tests of homogeneity of treatment group differences among subgroups with no adjustment for multiple testing. Kaplan-Meier estimates are presented for cardiovascular death. Lower limb amputation (LLA) was identified via a systematic search of serious adverse event (AE) narratives, from events reported as AEs, and from those reported as a medical procedure under concomitant therapy in electronic case report forms or in investigator comments describing AEs, and analyzed using a Cox proportional hazards model. Minor LLA was defined as any resection through or distal to the