Sodium-Glucose Cotransport Inhibition With Dapagliflozin in Type 2 Diabetes

Abstract

OBJECTIVE -Dapagliflozin, a novel inhibitor of renal sodium-glucose cotransporter 2, allows an insulin-independent approach to improve type 2 diabetes hyperglycemia. In this multiple-dose study we evaluated the safety and efficacy of dapagliflozin in type 2 diabetic patients.RESEARCH DESIGN AND METHODS -Type 2 diabetic patients were randomly assigned to one of five dapagliflozin doses, metformin XR, or placebo for 12 weeks. The primary objective was to compare mean change from baseline in A1C. Other objectives included comparison of changes in fasting plasma glucose (FPG), weight, adverse events, and laboratory measurements.RESULTS -After 12 weeks, dapagliflozin induced moderate glucosuria (52-85 g urinary glucose/day) and demonstrated significant glycemic improvements versus placebo (⌬A1C Ϫ0.55 to Ϫ0.90% and ⌬FPG Ϫ16 to Ϫ31 mg/dl). Weight loss change versus placebo was Ϫ1.3 to Ϫ2.0 kg. There was no change in renal function. Serum uric acid decreased, serum magnesium increased, serum phosphate increased at higher doses, and dose-related 24-h urine volume and hematocrit increased, all of small magnitude. Treatment-emergent adverse events were similar across all groups.CONCLUSIONS -Dapagliflozin improved hyperglycemia and facilitates weight loss in type 2 diabetic patients by inducing controlled glucosuria with urinary loss of ϳ200 -300 kcal/day. Dapagliflozin treatment demonstrated no persistent, clinically significant osmolarity, volume, or renal status changes. Diabetes Care 32:650-657, 2009

Familial Renal Glucosuria and SGLT2

“…In the short-duration treatment trial with dapagliflozin previously reported, an increase in urinary sodium was initially observed, returning to baseline by day 13 (70). In the pilot study that enrolled 348 patients with type 2 diabetes, it was shown that dapagliflozin displayed a dosage-dependent mild diuretic effect as assessed by daily urine output (71). Unfortunately, urinary sodium was not reported, so we can only speculate whether this diuretic effect was a consequence of glucosuric osmosis or, alternatively, dependent of true natriuresis reflecting the failure of the distal nephron to compensate for the Na ϩ proximal losses.…”

“…When administered for 14 d to drug-naive or metformin-treated patients with type 2 diabetes, dapagliflozin induced a dosage-dependent increase in urinary glucose excretion, reaching a maximum of 70 g/d, and improved fasting blood glucose and glucose tolerance (70). In a more prolonged study, a total of 348 drug-naive patients with type 2 diabetes were randomly assigned to receive 2.5, 5.0, 10.0, 20.0, or 50.0 mg of dapagliflozin; 1.5 g of metformin; or placebo (71). Significant reduction of glycosylated hemoglobin, fasting plasma glucose, and body weight had occurred by the end of the study.…”

Effect of Sodium‐Glucose Cotransport‐2 Inhibitors on Blood Pressure in People With Type 2 Diabetes Mellitus: A Systematic Review and Meta‐Analysis of 43 Randomized Control Trials With 22 528 Patients

“…Data were sorted by first author, year of publication, country of the study, design, age range of the participants, total sample size, SGLT2 inhibitor, comparator, number of patients, dosage, and follow‐up duration (Table 1). 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55 …”

Use of SGLT-2 inhibitors in the treatment of type 2 diabetes mellitus

“…[16][17][18] A study with dapagliflozin showed a significant reduction in waist circumference, which is consistent with a reduction in fat mass. 19 Studies evaluating body composition suggested that most of the weight loss associated with SGLTi-2 was due to a reduction in visceral or subcutaneous fat.…”