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OBJECTIVEDapagliflozin, a highly selective inhibitor of the renal sodium-glucose cotransporter-2, increases urinary excretion of glucose and lowers plasma glucose levels in an insulin-independent manner. We evaluated the efficacy and safety of dapagliflozin in treatment-naive patients with type 2 diabetes.RESEARCH DESIGN AND METHODSThis was a 24-week parallel-group, double-blind, placebo-controlled phase 3 trial. Patients with A1C 7.0–10% (n = 485) were randomly assigned to one of seven arms to receive once-daily placebo or 2.5, 5, or 10 mg dapagliflozin once daily in the morning (main cohort) or evening (exploratory cohort). Patients with A1C 10.1–12% (high-A1C exploratory cohort; n = 73) were randomly assigned 1:1 to receive blinded treatment with a morning dose of 5 or 10 mg/day dapagliflozin. The primary end point was change from baseline in A1C in the main cohort, statistically tested using an ANCOVA.RESULTSIn the main cohort, mean A1C changes from baseline at week 24 were −0.23% with placebo and −0.58, −0.77 (P = 0.0005 vs. placebo), and −0.89% (P < 0.0001 vs. placebo) with 2.5, 5, and 10 mg dapagliflozin, respectively. Signs, symptoms, and other reports suggestive of urinary tract infections and genital infection were more frequently noted in the dapagliflozin arms. There were no major episodes of hypoglycemia. Data from exploratory cohorts were consistent with these results.CONCLUSIONSDapagliflozin lowered hyperglycemia in treatment-naive patients with newly diagnosed type 2 diabetes. The near absence of hypoglycemia and an insulin-independent mechanism of action make dapagliflozin a unique addition to existing treatment options for type 2 diabetes.

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

In patients with diabetes, glycemic improvement by sodium-glucose cotransporter-2 inhibition depends on the kidney's ability to filter glucose. Dapagliflozin, a sodium-glucose cotransporter-2 inhibitor, reduces hyperglycemia in patients with diabetes and normal or mildly impaired renal function. In this randomized, double-blind, placebo-controlled study we assessed daily treatment with dapagliflozin in 252 patients with inadequately controlled type 2 diabetes and moderate renal impairment. The primary endpoint, the mean change in HbA1c, was not statistically different from placebo after 24 weeks (−0.41% and −0.44% for 5- and 10-mg doses, respectively, and −0.32% for placebo). The mean weight change from baseline was −1.54 and −1.89 kg for the 5- and 10-mg doses, respectively, and +0.21 kg for placebo. The mean systolic and diastolic blood pressure decreased in the dapagliflozin groups compared to placebo. Through 104 weeks, 13 patients receiving dapagliflozin and no patients receiving placebo experienced bone fracture. At 1 week, the mean serum creatinine increased with dapagliflozin 5 mg (+0.13 mg/dl) and 10 mg (+0.18 mg/dl) and did not change further after 104 weeks. Mean serum electrolytes did not change in any group, and there were fewer episodes of hyperkalemia with dapagliflozin than placebo. Thus, in patients with moderate renal impairment, dapagliflozin did not improve glycemic control, but reduced weight and blood pressure.

Aims: Sodium-glucose co-transporter 2 (SGLT2) reabsorbs glucose and sodium in the renal proximal tubule. Dapagliflozin, an SGLT2 inhibitor, targets hyperglycaemia in type 2 diabetes by increasing renal glucose excretion. To investigate whether the parallel occurring sodium loss would have diuretic-like physiologic effects, we compared dapagliflozin and hydrochlorothiazide (HCTZ) effects on 24-h blood pressure (BP), body weight, plasma volume and glomerular filtration rate (GFR). Methods:In this randomized, placebo-controlled, double-blind trial, 75 subjects with type 2 diabetes were assigned placebo, dapagliflozin 10 mg/day, or HCTZ 25 mg/day. Changes from baseline BP, body weight, plasma volume and GFR were assessed after 12 weeks of treatment.Results: Subjects' mean age was 56 years, type 2 diabetes mellitus (T2DM) duration 6.3 years, and haemoglobin A1c (HbA1c) 7.5%. Treatment with placebo, dapagliflozin or HCTZ resulted in changes from baseline in 24-h ambulatory mean systolic blood pressure (SBP) of −0.9 (95%CI −4.2, +2.4), −3.3 (95%CI −6.8, +0.2), and −6.6 (95%CI −9.9, −3.2) mmHg, respectively at week 12, adjusted for baseline SBP. Body weight decreased with dapagliflozin and HCTZ. In a sub-study plasma volume appeared to decrease with dapagliflozin but did not change with placebo or HCTZ treatment. Dapagliflozin induced a greater reduction in GFR (−10.8%; 95%CI −14.6, −6.7) relative to placebo (−2.9%; 95% CI −6.9, +1.2) or HCTZ (−3.4%; 95%CI −7.3, +0.6).Conclusions: Dapagliflozin-induced SGLT2 inhibition for 12 weeks is associated with reductions in 24-h BP, body weight, GFR and possibly plasma volume. Cumulatively, these effects suggest that dapagliflozin may have a diuretic-like capacity to lower BP in addition to beneficial effects on glycaemic control.

OBJECTIVETo determine whether dapagliflozin, which selectively inhibits renal glucose reabsorption, lowers hyperglycemia in patients with type 2 diabetes that is poorly controlled with high insulin doses plus oral antidiabetic agents (OADs).RESEARCH DESIGN AND METHODSThis was a randomized, double-blind, three-arm parallel-group, placebo-controlled, 26-center trial (U.S. and Canada). Based on data from an insulin dose-adjustment setting cohort (n = 4), patients in the treatment cohort (n = 71) were randomly assigned 1:1:1 to placebo, 10 mg dapagliflozin, or 20 mg dapagliflozin, plus OAD(s) and 50% of their daily insulin dose. The primary outcome was change from baseline in A1C at week 12 (dapagliflozin vs. placebo, last observation carried forward [LOCF]).RESULTSAt week 12 (LOCF), the 10- and 20-mg dapagliflozin groups demonstrated −0.70 and −0.78% mean differences in A1C change from baseline versus placebo. In both dapagliflozin groups, 65.2% of patients achieved a decrease from baseline in A1C ≥0.5% versus 15.8% in the placebo group. Mean changes from baseline in fasting plasma glucose (FPG) were +17.8, +2.4, and −9.6 mg/dl (placebo, 10 mg dapagliflozin, and 20 mg dapagliflozin, respectively). Postprandial glucose (PPG) reductions with dapagliflozin also showed dose dependence. Mean changes in total body weight were −1.9, −4.5, and −4.3 kg (placebo, 10 mg dapagliflozin, and 20 mg dapagliflozin). Overall, adverse events were balanced across all groups, although more genital infections occurred in the 20-mg dapagliflozin group than in the placebo group.CONCLUSIONSIn patients receiving high insulin doses plus insulin sensitizers who had their baseline insulin reduced by 50%, dapagliflozin decreased A1C, produced better FPG and PPG levels, and lowered weight more than placebo.

OBJECTIVETo examine the safety and efficacy of dapagliflozin, a sodium-glucose cotransporter-2 inhibitor, added on to pioglitazone in type 2 diabetes inadequately controlled on pioglitazone.RESEARCH DESIGN AND METHODSTreatment-naive patients or those receiving metformin, sulfonylurea, or thiazolidinedione entered a 10-week pioglitazone dose-optimization period with only pioglitazone. They were then randomized, along with patients previously receiving pioglitazone ≥30 mg, to 48 weeks of double-blind dapagliflozin 5 (n = 141) or 10 mg (n = 140) or placebo (n = 139) every day plus open-label pioglitazone. The primary objective compared HbA1c change from baseline with dapagliflozin plus pioglitazone versus placebo plus pioglitazone at week 24. Primary analysis was based on ANCOVA model using last observation carried forward; all remaining analyses used repeated-measures analysis.RESULTSAt week 24, the mean reduction from baseline in HbA1c was −0.42% for placebo versus −0.82 and −0.97% for dapagliflozin 5 and 10 mg groups, respectively (P = 0.0007 and P < 0.0001 versus placebo). Patients receiving pioglitazone alone had greater weight gain (3 kg) than those receiving dapagliflozin plus pioglitazone (0.7–1.4 kg) at week 48. Through 48 weeks: hypoglycemia was rare; more events suggestive of genital infection were reported with dapagliflozin (8.6–9.2%) than placebo (2.9%); events suggestive of urinary tract infection showed no clear drug effect (5.0–8.5% for dapagliflozin and 7.9% for placebo); dapagliflozin plus pioglitazone groups had less edema (2.1–4.3%) compared with placebo plus pioglitazone (6.5%); and congestive heart failure and fractures were rare.CONCLUSIONSIn patients with type 2 diabetes inadequately controlled on pioglitazone, the addition of dapagliflozin further reduced HbA1c levels and mitigated the pioglitazone-related weight gain without increasing hypoglycemia risk.

In treatment-naïve patients with T2D, dapagliflozin plus metformin was generally well tolerated and effective in reducing HbA1c, FPG and weight. Dapagliflozin-induced glucosuria led to an increase in events suggestive of urinary tract and genital infections.