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Randomized Controlled Trial
. 2014 Apr;85(4):962-71.
doi: 10.1038/ki.2013.356. Epub 2013 Sep 25.

Long-term study of patients with type 2 diabetes and moderate renal impairment shows that dapagliflozin reduces weight and blood pressure but does not improve glycemic control

Donald E Kohan  1 , Paola Fioretto  2 , Weihua Tang  3 , James F List  3
Affiliations
Free PMC article
Randomized Controlled Trial

Long-term study of patients with type 2 diabetes and moderate renal impairment shows that dapagliflozin reduces weight and blood pressure but does not improve glycemic control

Donald E Kohan et al. Kidney Int. 2014 Apr.
Free PMC article

Abstract

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.

Trial registration: ClinicalTrials.gov NCT00663260.

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Figures

Figure 1
Figure 1
Trial profile through 104 weeks. A total of five patients left the trial because they ‘no longer met study criteria.' For the three patients in the placebo group, (1) the patient had insulin regimen altered, which is against the protocol guidance, (2) the patient met discontinuation criteria for sustained elevated serum creatinine, and (3) the patient was inappropriately randomized with a high screening potassium and removed a few days after starting treatment. The patient in the 5-mg group had myasthenia gravis, was administered prednisone for treatment and was asked to be discontinued by the medical monitor. The patient in the 10-mg group was discontinued owing to serum creatinine greater than two times the baseline at day 78.
Figure 2
Figure 2
Mean change from baseline in HbA1c, urinary glucose:creatinine ratio, and body weight for placebo (circles, solid line), dapagliflozin 5-mg (squares, dashed line), and dapagliflozin 10-mg (triangles, dotted line) groups, all plus original pre-enrollment antidiabetic regimen up to 104 weeks. Data are means (95% confidence interval (CI)). Mean change from baseline in HbA1c after adjustment for baseline value (a), mean change from baseline in urinary glucose:creatinine ratio (g/g) after adjustment for baseline value (b), and mean change from baseline in body weight after adjustment for baseline value (c). HbA1c and weight obtained from longitudinal repeated-measure analysis; HbA1c excludes data after rescue; urinary glucose:creatinine ratio and weight include data after rescue. Treatment symbols shifted horizontally to prevent error bar overlapping. DAPA, dapagliflozin; HbA1c, hemoglobin A1c; PBO, placebo.
Figure 3
Figure 3
Mean change from baseline after adjustment for baseline value in eGFR for placebo (circles, solid line), dapagliflozin 5-mg (squares, dashed line), and dapagliflozin 10-mg (triangles, dotted line) groups, all plus original pre-enrollment antidiabetic regimen up to 104 weeks including data after rescue. DAPA, dapagliflozin; eGFR, estimated glomerular filtration rate; PBO, placebo.
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