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Cardiovascular Outcomes and Safety of Empagliflozin in Patients With Type 2 Diabetes Mellitus and Peripheral Artery Disease

2017; Lippincott Williams & Wilkins; Volume: 137; Issue: 4 Linguagem: Inglês

10.1161/circulationaha.117.032031

1524-4539

Subodh Verma, C. David Mazer, Mohammed Al‐Omran, Silvio E. Inzucchi, David Fitchett, Uwe Hehnke, Jyothis T. George, Bernard Zinman,

Pharmacology and Obesity Treatment

HomeCirculationVol. 137, No. 4Cardiovascular Outcomes and Safety of Empagliflozin in Patients With Type 2 Diabetes Mellitus and Peripheral Artery Disease Free AccessLetterPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessLetterPDF/EPUBCardiovascular Outcomes and Safety of Empagliflozin in Patients With Type 2 Diabetes Mellitus and Peripheral Artery DiseaseA Subanalysis of EMPA-REG OUTCOME Subodh Verma, MD, C. David Mazer, MD, Mohammed Al-Omran, MD, Silvio E. Inzucchi, MD, David Fitchett, MD, Uwe Hehnke, Dipl Stat, Jyothis T. George, MD and Bernard Zinman, MD Subodh VermaSubodh Verma St. Michael's Hospital, Division of Cardiac Surgery (S.V.) , C. David MazerC. David Mazer Department of Anesthesia (C.D.M.) , Mohammed Al-OmranMohammed Al-Omran Division of Vascular Surgery (M.A.-O.) Department of Surgery, King Saud University, Riyadh, Saudi Arabia (M.A.-O.) , Silvio E. InzucchiSilvio E. Inzucchi Section of Endocrinology, Yale University School of Medicine, New Haven, CT (S.E.I.) , David FitchettDavid Fitchett Division of Cardiology (D.F.), University of Toronto, Ontario, Canada , Uwe HehnkeUwe Hehnke Boehringer Ingelheim Pharma GmbH & Co KG, Ingelheim, Germany (U.H., J.T.G.) , Jyothis T. GeorgeJyothis T. George Boehringer Ingelheim Pharma GmbH & Co KG, Ingelheim, Germany (U.H., J.T.G.) and Bernard ZinmanBernard Zinman Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada (B.Z.) Division of Endocrinology, University of Toronto, Ontario, Canada (B.Z.). Originally published13 Nov 2017https://doi.org/10.1161/CIRCULATIONAHA.117.032031Circulation. 2018;137:405–407Other version(s) of this articleYou are viewing the most recent version of this article. Previous versions: January 1, 2017: Previous Version 1 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 A1c, 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 articulation of the ankle.4 Minor LLA, major LLA, and other AEs were assessed descriptively.Of 7020 patients treated, 1461 (20.8%) had PAD at baseline (982 treated with empagliflozin, 479 treated with placebo). In this group, baseline mean±SD age was 64.0±8.5 years, body mass index was 30.7±5.3 kg/m2, hemoglobin A1c was 8.12±0.86%, 69% were male, 10% had a history of HF, 67% were current or ex-smokers, 30% had estimated glomerular filtration rate <60 mL·min−1·1.73 m−2, 92% were on antihypertensive therapy, 75% were on lipid-lowering therapy, and 85% were on antiplatelet/anticoagulant therapy. 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