title: COMBINED TREATMENT WITH SAXAGLIPTIN PLUS DAPAGLIFLOZIN REDUCES INSULIN LEVELS BY INCREASED INSULIN CLEARANCE AND IMPROVES β-CELL FUNCTION.
abstract: OBJECTIVE
  To determine if reduction in serum insulin with dapagliflozin plus saxagliptin or dapagliflozin add-on to metformin contributed to increased insulin clearance and to assess the effects of these treatments on β-cell function.
  
  
  METHODS
  Patients (glycated hemoglobin, 8 to 12%; 64 to 108 mmol/mol) were randomized to 24-week, double-blind treatment with saxagliptin 5 mg/day plus dapagliflozin 10 mg/day (n = 179), saxagliptin 5 mg/day plus placebo (n = 176), or dapagliflozin 10 mg/day plus placebo (n = 179) added to metformin. C-peptide to insulin ratio was used as an index of insulin clearance during a meal tolerance test, and β-cell function was evaluated by Homeostasis Model Assessment 2.
  
  
  RESULTS
  At 24 weeks, compared with baseline, saxagliptin + dapagliflozin and saxagliptin + placebo increased mean (95% confidence interval [CI]) C-peptide area under the curve (AUC0-180 min) (40.2 [9.2 to 71.3] ng/mL and 95.4 [63.4 to 127.4] ng/mL, respectively); no change was noted with dapagliflozin + placebo (14.5 [-17.6 to 46.8] ng/mL). Insulin AUC was reduced from baseline with saxagliptin + dapagliflozin (-1,120.4 [-1,633.9 to -606.9] μU/mL) and dapagliflozin + placebo (-1,018.6 [-1550.5 to -486.8] μU/mL) but increased with saxagliptin + placebo (661.2 [131.1 to 1,191.3] μU/mL). C-peptide to insulin ratio did not change versus baseline with saxagliptin + placebo but increased after saxagliptin + dapagliflozin and dapagliflozin + placebo, largely due to decreased insulin AUC with dapagliflozin. All treatments improved β-cell function (mean change [95% CI] from baseline, saxagliptin+dapagliflozin: 20.6% [16.5% to 24.8%]; dapagliflozin + placebo: 17.0% [12.7% to 21.4%]; saxagliptin + placebo: 11.0% [6.6% to 15.5%]).
  
  
  CONCLUSIONS
  Increased C-peptide to insulin ratio with saxagliptin + dapagliflozin and dapagliflozin + placebo add-on to metformin compared with saxagliptin + placebo add-on to metformin suggests that dapagliflozin increases insulin clearance and may contribute to lower circulating insulin. All treatments improved β-cell function, with the greatest improvements with saxagliptin + dapagliflozin and dapagliflozin + placebo.
  
  
  BACKGROUND
  A1c = glycated hemoglobin AUC0-180 min= area under the curve from 0 to 180 minutes HOMA-2β = homeostasis model assessment-2 β-cell function SGLT-2 = sodium-glucose cotransporter-2 T2D = type 2 diabetes.
authors.forename: Ella
authors.initials: E
authors.lastname: Ekholm
authors.forename: Lars
authors.initials: L
authors.lastname: Hansen
authors.forename: Eva
authors.initials: E
authors.lastname: Johnsson
authors.forename: Nayyar
authors.initials: N
authors.lastname: Iqbal
authors.forename: Björn
authors.initials: B
authors.lastname: Carlsson
authors.forename: Hungta
authors.initials: H
authors.lastname: Chen
authors.forename: Boaz
authors.initials: B
authors.lastname: Hirshberg
mesh_terms: D000218:Adamantane / Q000031:analogs & derivatives* / Q000627:therapeutic use; D000368:Aged; D019540:Area Under Curve; D001559:Benzhydryl Compounds / Q000627:therapeutic use*; D001786:Blood Glucose / Q000032:analysis; D002096:C-Peptide / Q000032:analysis; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy; D004151:Dipeptides / Q000627:therapeutic use*; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D005260:Female; D005951:Glucose Tolerance Test; D005960:Glucosides / Q000627:therapeutic use*; D006801:Humans; D007004:Hypoglycemic Agents / Q000627:therapeutic use*; D007328:Insulin / Q000097:blood* / Q000378:metabolism*; D050417:Insulin-Secreting Cells / Q000187:drug effects* / Q000378:metabolism*; D008297:Male; D008687:Metformin / Q000627:therapeutic use; D008875:Middle Aged; D051297:Sodium-Glucose Transporter 2; D000077203:Sodium-Glucose Transporter 2 Inhibitors
chemical_list: D001559:Benzhydryl Compounds; D001786:Blood Glucose; D002096:C-Peptide; D004151:Dipeptides; D005960:Glucosides; D007004:Hypoglycemic Agents; D007328:Insulin; C089180:SLC5A2 protein, human; D051297:Sodium-Glucose Transporter 2; D000077203:Sodium-Glucose Transporter 2 Inhibitors; C529054:dapagliflozin; D008687:Metformin; C502994:saxagliptin; D000218:Adamantane