Sodium-glucose cotransport inhibition with dapagliflozin in type 2 diabetes

James F List, Vincent Woo, Enrique Morales, Weihua Tang, Fred T Fiedorek, James F List, Vincent Woo, Enrique Morales, Weihua Tang, Fred T Fiedorek

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 (DeltaA1C -0.55 to -0.90% and DeltaFPG -16 to -31 mg/dl). Weight loss change versus placebo was -1.3 to -2.0 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 approximately 200-300 kcal/day. Dapagliflozin treatment demonstrated no persistent, clinically significant osmolarity, volume, or renal status changes.

Trial registration: ClinicalTrials.gov NCT00263276.

Figures

Figure 1
Figure 1
Patient disposition and study design. T2DM, type 2 diabetic.
Figure 2
Figure 2
Changes in glycemic parameters. A: Adjusted mean change from baseline in A1C at week 12 (LOCF). B: Mean change in FPG over time (observed values). C: Adjusted mean change from baseline in postprandial glucose area under the curve (AUC) during a 75-g oral glucose tolerance test at week 12 (LOCF). D: Change from baseline in 24-h urinary glucose (grams) normalized for urinary creatinine (grams) at week 12 (LOCF). Displayed are means and 95% CIs (A, B, and D). When statistical significance was achieved with dapagliflozin groups compared with placebo, Dunnett's multiplicity adjustment was used. P values versus placebo at week 12.
Figure 3
Figure 3
Percent changes in weight. A: Percent change from baseline in weight over the 12-week treatment period and 4-week follow-up period (observed values). B: Adjusted mean percent change from baseline in weight after 12 weeks of treatment (LOCF). Displayed are means and 95% CIs.

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