title: Which is the main molecular target responsible for the cardiovascular benefits in the EMPA-REG OUTCOME trial? A journey through the kidney, the heart and other interesting places.
abstract: The results of the EMPA-REG-OUTCOME trial on type 2 diabetic patients at high risk for prior cardiovascular events showed that empagliflozin produces a remarkable reduction in the rates of hospitalization for heart failure (35%), cardiovascular death (38%), and all-cause death (32%). This unexpected cardio-protective action cannot be accounted for by the improvement of "classical" cardiovascular risk factors.
  
  
  
  This review aims at summarizing current knowledge on the cardiovascular action of SGLT2 inhibitors and discuss the different hypotheses formulated to explain the results of the EMPA-REG-OUTCOME-study.
  
  
  
  We discuss in detail the major cardiovascular outcomes of the study in the light of the potential systemic and myocardial mechanisms of action of the drug. In addition, we propose and speculate on a direct effect of empagliflozin on cardiomyocytes.
  
  
  
  The available evidence is insufficient to establish any of the proposed mechanisms of cardiovascular action of empagliflozin. While awaiting for the results of ongoing clinical studies with other SGLT2 inhibitors, the most promising putative mechanisms still deserve to be confirmed with specifically designed, yet unavailable, pre-clinical studies.
authors: Endocrinology Unit, Dept. Clinical and Experimental Biomedical Sciences, University of Florence, Viale G. Pieraccini, 6, Florence, Italy.
authors: M
authors: M
authors: Luconi
authors: Pharmacology Unit, Dept. of Neuroscience, Psychology, Drug Sciences and Child Health, University of Florence, Viale G. Pieraccini, 6, Florence, Italy.
authors: L
authors: L
authors: Raimondi
authors: Endocrinology Unit, Dept. Clinical and Experimental Biomedical Sciences, University of Florence, Viale G. Pieraccini, 6, Florence, Italy.
authors: A
authors: A
authors: Di Franco
authors: Endocrinology Unit, Dept. Clinical and Experimental Biomedical Sciences, University of Florence, Viale G. Pieraccini, 6, Florence, Italy; Diabetology, Careggi Hospital, Florence, Italy. Electronic address: edoardo.mannucci@unifi.it.
authors: E
authors: E
authors: Mannucci
mesh_terms: D000818:Animals; D001559:Benzhydryl Compounds / Q000009:adverse effects / Q000627:therapeutic use*; D002318:Cardiovascular Diseases / Q000401:mortality / Q000503:physiopathology / Q000517:prevention & control*; D002986:Clinical Trials as Topic; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000188:drug therapy* / Q000401:mortality / Q000503:physiopathology; D005960:Glucosides / Q000009:adverse effects / Q000627:therapeutic use*; D006321:Heart / Q000503:physiopathology*; D006801:Humans; D007004:Hypoglycemic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism; D018570:Risk Assessment; D012307:Risk Factors; D051297:Sodium-Glucose Transporter 2 / Q000378:metabolism; D000077203:Sodium-Glucose Transporter 2 Inhibitors; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D001559:Benzhydryl Compounds; D005960:Glucosides; D007004:Hypoglycemic Agents; C089180:SLC5A2 protein, human; D051297:Sodium-Glucose Transporter 2; D000077203:Sodium-Glucose Transporter 2 Inhibitors; C570240:empagliflozin
keywords: Cardio-protection; Empagliflozin; SGLT2 inhibitors; Type 2 diabetes