title: Metabolic consequences of acute and chronic empagliflozin administration in treatment-naive and metformin pretreated patients with type 2 diabetes.
abstract: OBJECTIVE
  Sodium glucose co-transporter 2 (SGLT2) inhibitors lower glycaemia by inducing glycosuria, but raise endogenous glucose production (EGP). Metformin lowers glycaemia mainly by suppressing EGP. We compared the effects of the SGLT2 inhibitor empagliflozin in treatment-naive (TN) and metformin pretreated (Met) patients with type 2 diabetes.
  
  
  METHODS
  A total of 32 TN and 34 patients on a stable dose of metformin, two subgroups of a study that we previously reported, received a mixed meal with double-tracer glucose administration and indirect calorimetry at baseline, after a single 25 mg dose of empagliflozin, and after 4 weeks of treatment with empagliflozin 25 mg/day.
  
  
  RESULTS
  At baseline, compared with the TN group, the Met group had higher fasting glycaemia (9.1 ± 1.7 vs 8.2 ± 1.3 mmol/l), lower fasting and postmeal insulin secretion, lower beta cell glucose sensitivity (37 [18] vs 58 [43] pmol min(-1) m(-2) [mmol/l](-1), median [interquartile range]) and insulin:glucagon ratio, and higher fasting EGP (15.9 [4.3] vs 12.1 [2.7] μmol kgFFM (-1) min(-1)). Change from baseline in fasting EGP after single dose and 4 weeks of treatment with empagliflozin was similar in the Met and TN groups (19.6 [4.2] and 19.0 [2.3] in Met vs 16.2 [3.6] and 15.5 [3.2] μmol kgFFM (-1) min(-1) in TN for acute and chronic dosing, respectively). Beta cell glucose sensitivity increased less in Met than TN patients, whereas substrate utilisation shifted from carbohydrate to fat more in Met than TN patients.
  
  
  CONCLUSIONS
  At baseline, Met patients with type 2 diabetes had more advanced disease than TN patients, featuring worse beta cell function and higher EGP. Empagliflozin induced similar glycosuria and metabolic and hormonal responses in Met and TN patients.
  
  
  BACKGROUND
  ClinicalTrials.gov NCT01248364; European Union Clinical Trials Register 2010-018708-99.
authors.affiliation: Department of Clinical and Experimental Medicine, University of Pisa, Via Roma, 67, 56100, Pisa, Italy.
authors.forename: Elza
authors.initials: E
authors.lastname: Muscelli
authors.affiliation: Department of Clinical and Experimental Medicine, University of Pisa, Via Roma, 67, 56100, Pisa, Italy.
authors.forename: Brenno
authors.initials: B
authors.lastname: Astiarraga
authors.affiliation: Department of Clinical and Experimental Medicine, University of Pisa, Via Roma, 67, 56100, Pisa, Italy.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Barsotti
authors.affiliation: C.N.R. Institute of Neuroscience, Padua, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Mari
authors.affiliation: Profil, Neuss, Germany.
authors.forename: Freimut
authors.initials: F
authors.lastname: Schliess
authors.affiliation: Profil, Neuss, Germany.
authors.forename: Leszek
authors.initials: L
authors.lastname: Nosek
authors.affiliation: Profil, Neuss, Germany.
authors.forename: Tim
authors.initials: T
authors.lastname: Heise
authors.affiliation: Boehringer Ingelheim Pharma GmbH & Co. KG, Ingelheim, Germany.
authors.forename: Uli C
authors.initials: UC
authors.lastname: Broedl
authors.affiliation: Boehringer Ingelheim Pharma GmbH & Co. KG, Ingelheim, Germany.
authors.forename: Hans-Juergen
authors.initials: HJ
authors.lastname: Woerle
authors.affiliation: Department of Clinical and Experimental Medicine, University of Pisa, Via Roma, 67, 56100, Pisa, Italy. ferranni@ifc.cnr.it.|CNR Institute of Clinical Physiology, Pisa, Italy. ferranni@ifc.cnr.it.
authors.forename: Ele
authors.initials: E
authors.lastname: Ferrannini
mesh_terms: D000368:Aged; D001559:Benzhydryl Compounds / Q000627:therapeutic use*; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy*; D005260:Female; D005960:Glucosides / Q000627:therapeutic use*; D006801:Humans; D007004:Hypoglycemic Agents / Q000627:therapeutic use*; D008297:Male; D008687:Metformin / Q000627:therapeutic use*; D008875:Middle Aged
chemical_list: D001559:Benzhydryl Compounds; D005960:Glucosides; D007004:Hypoglycemic Agents; D008687:Metformin; C570240:empagliflozin
keywords: Empagliflozin; Endogenous glucose production; Glycosuria; Metformin; Type 2 diabetes