Changes in insulin sensitivity and insulin secretion with the sodium glucose cotransporter 2 inhibitor dapagliflozin.
OBJECTIVE
This randomized, double-blind, placebo-controlled parallel-group study assessed the effects of sodium glucose cotransporter 2 inhibition by dapagliflozin on insulin sensitivity and secretion in subjects with type 2 diabetes mellitus (T2DM), who had inadequate glycemic control with metformin (with or without an insulin secretagogue).


METHODS
Forty-four subjects were randomized to receive dapagliflozin 5 mg or matching placebo once daily for 12 weeks. Subjects continued stable doses of background antidiabetes medication throughout the study. Insulin sensitivity was assessed by measuring the glucose disappearance rate (GDR) during the last 40 min of a 5-h hyperinsulinemic, euglycemic clamp. Insulin secretion was determined as the acute insulin response to glucose (AIRg) during the first 10 min of a frequently sampled intravenous glucose tolerance test. Where noted, data were adjusted for baseline values and background antidiabetes medication.


RESULTS
An adjusted mean increase from baseline in GDR (last observation carried forward), at Week 12, was observed with dapagliflozin (7.98%) versus a decrease with placebo (-9.99%). The 19.97% (95% confidence interval 5.75-36.10) difference in GDR versus placebo was statistically significant (P=0.0059). A change from baseline in adjusted mean AIRg of 15.39 mU/L min was observed with dapagliflozin at Week 12, versus -12.73 mU/L min with placebo (P=0.0598). Over 12 weeks, numerical reductions from baseline in glycosylated hemoglobin (HbA1c), fasting plasma glucose, and body weight were observed with dapagliflozin (-0.38%, -0.39 mmol/L, and -1.58%, respectively) versus slight numerical increases with placebo (0.03%, 0.26 mmol/L, and 0.62%, respectively).


CONCLUSIONS
In patients with T2DM and inadequate glycemic control, dapagliflozin treatment improved insulin sensitivity in the setting of reductions in HbA1c and weight.
1 Center for Metabolic Research, VA San Diego Healthcare System, and University of California , San Diego, San Diego, California.
Sunder
S
Mudaliar
Robert R
RR
Henry
Guenther
G
Boden
Steven
S
Smith
Alexandros-Georgios
AG
Chalamandaris
Dominique
D
Duchesne
Nayyar
N
Iqbal
James
J
List
D000328:Adult; D000368:Aged; D001559:Benzhydryl Compounds; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism*; D002096:C-Peptide / Q000378:metabolism; D003404:Creatinine / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000378:metabolism; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D005260:Female; D005951:Glucose Tolerance Test; D005960:Glucosides / Q000008:administration & dosage*; D006442:Glycated Hemoglobin / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage*; D007328:Insulin / Q000378:metabolism*; D007333:Insulin Resistance; D000078790:Insulin Secretion; D008297:Male; D008687:Metformin / Q000008:administration & dosage*; D008875:Middle Aged; D000077203:Sodium-Glucose Transporter 2 Inhibitors; D016896:Treatment Outcome
D001559:Benzhydryl Compounds; D001786:Blood Glucose; D002096:C-Peptide; D003404:Creatinine; D005960:Glucosides; D006442:Glycated Hemoglobin; D007004:Hypoglycemic Agents; D007328:Insulin; D008687:Metformin; D000077203:Sodium-Glucose Transporter 2 Inhibitors; C517652:hemoglobin A1c protein, human; C529054:dapagliflozin