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

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 -1.89kg for the 5- and 10-mg doses, respectively, and +0.21kg 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 5mg (+0.13mg/dl) and 10mg (+0.18mg/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. 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 -1.89kg for the 5- and 10-mg doses, respectively, and +0.21kg 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 5mg (+0.13mg/dl) and 10mg (+0.18mg/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. Current medications for treating type 2 diabetes mellitus (T2DM) target the pancreas, liver, intestines, muscle, or adipose tissue and act by increasing insulin secretion or action, or by improving insulin sensitivity.1.Tahrani A.A. Bailey C.J. Del Prato S. et al.Management of type 2 diabetes: new and future developments in treatment.Lancet. 2011; 378: 182-197Abstract Full Text Full Text PDF PubMed Scopus (431) Google Scholar The sodium-glucose cotransporter-2 (SGLT2), located in the renal proximal tubule, reabsorbs the majority of filtered glucose.2.Wood I.S. Trayhurn P. Glucose transporters (GLUT and SGLT): expanded families of sugar transport proteins.Br J Nutr. 2003; 89: 3-9Crossref PubMed Scopus (684) Google Scholar,3.Kanai Y. Lee W.S. You G. et al.The human kidney low affinity Na+/glucose cotransporter SGLT2. Delineation of the major renal reabsorptive mechanism for D-glucose.J Clin Invest. 1994; 93: 397-404Crossref PubMed Scopus (538) Google Scholar Inhibition of renal glucose reabsorption via inhibition of SGLT2, an insulin-independent process, represents a novel approach to treating T2DM. Several clinical trials with dapagliflozin, a potent and selective SGLT2 inhibitor, showed that it reduces hyperglycemia and improves glycemic control in patients with T2DM. These trials examined dapagliflozin as monotherapy4.Ferrannini E. Ramos S.J. Salsali A. et al.Dapagliflozin monotherapy in type 2 diabetic patients with inadequate glycemic control by diet and exercise: a randomized, double-blind, placebo-controlled, phase 3 trial.Diabetes Care. 2010; 33: 2217-2224Crossref PubMed Scopus (590) Google Scholar or in combination with metformin,5.Bailey C.J. Gross J.L. Pieters A. et al.Effect of dapagliflozin in patients with type 2 diabetes who have inadequate glycaemic control with metformin: a randomised, double-blind, placebo-controlled trial.Lancet. 2010; 375: 2223-2233Abstract Full Text Full Text PDF PubMed Scopus (712) Google Scholar sulfonylureas,6.Strojek K. Yoon K.H. Hruba V. et al.Effect of dapagliflozin in patients with type 2 diabetes who have inadequate glycaemic control with glimepiride: a randomized, 24-week, double-blind, placebo-controlled trial.Diabetes Obes Metab. 2011; 13: 928-938Crossref PubMed Scopus (335) Google Scholar,7.Nauck M.A. Del Prato S. Meier J.J. et al.Dapagliflozin vs. glipizide as add-on therapy in patients with type 2 diabetes who have inadequate glycemic control with metformin: a randomized, 52-week, double-blind, active-controlled noninferiority trial.Diabetes Care. 2011; 34: 2015-2022Crossref PubMed Scopus (452) Google Scholar thiazolidinediones,8.Rosenstock J. Vico M. Wei L. et al.Effects of dapagliflozin, an SGLT2 inhibitor, on HbA(1c), body weight, and hypoglycemia risk in patients with type 2 diabetes inadequately controlled on pioglitazone monotherapy.Diabetes Care. 2012; 35: 1473-1478Crossref PubMed Scopus (319) Google Scholar or insulin.9.Wilding J.P. Norwood P. T'Joen C. et al.A study of dapagliflozin in patients with type 2 diabetes receiving high doses of insulin plus insulin sensitizers: applicability of a novel insulin-independent treatment.Diabetes Care. 2009; 32: 1656-1662Crossref PubMed Scopus (331) Google Scholar,10.Wilding J.P. Woo V. Soler N.G. et al.Long-term efficacy of dapagliflozin in patients with type 2 diabetes mellitus receiving high doses of insulin: a randomized trial.Ann Intern Med. 2012; 156: 405-415Crossref PubMed Scopus (389) Google Scholar Treatment with dapagliflozin induces glucosuria, resulting in caloric elimination and weight loss.4.Ferrannini E. Ramos S.J. Salsali A. et al.Dapagliflozin monotherapy in type 2 diabetic patients with inadequate glycemic control by diet and exercise: a randomized, double-blind, placebo-controlled, phase 3 trial.Diabetes Care. 2010; 33: 2217-2224Crossref PubMed Scopus (590) Google Scholar, 5.Bailey C.J. Gross J.L. Pieters A. et al.Effect of dapagliflozin in patients with type 2 diabetes who have inadequate glycaemic control with metformin: a randomised, double-blind, placebo-controlled trial.Lancet. 2010; 375: 2223-2233Abstract Full Text Full Text PDF PubMed Scopus (712) Google Scholar, 6.Strojek K. Yoon K.H. Hruba V. et al.Effect of dapagliflozin in patients with type 2 diabetes who have inadequate glycaemic control with glimepiride: a randomized, 24-week, double-blind, placebo-controlled trial.Diabetes Obes Metab. 2011; 13: 928-938Crossref PubMed Scopus (335) Google Scholar, 7.Nauck M.A. Del Prato S. Meier J.J. et al.Dapagliflozin vs. glipizide as add-on therapy in patients with type 2 diabetes who have inadequate glycemic control with metformin: a randomized, 52-week, double-blind, active-controlled noninferiority trial.Diabetes Care. 2011; 34: 2015-2022Crossref PubMed Scopus (452) Google Scholar, 8.Rosenstock J. Vico M. Wei L. et al.Effects of dapagliflozin, an SGLT2 inhibitor, on HbA(1c), body weight, and hypoglycemia risk in patients with type 2 diabetes inadequately controlled on pioglitazone monotherapy.Diabetes Care. 2012; 35: 1473-1478Crossref PubMed Scopus (319) Google Scholar, 9.Wilding J.P. Norwood P. T'Joen C. et al.A study of dapagliflozin in patients with type 2 diabetes receiving high doses of insulin plus insulin sensitizers: applicability of a novel insulin-independent treatment.Diabetes Care. 2009; 32: 1656-1662Crossref PubMed Scopus (331) Google Scholar, 10.Wilding J.P. Woo V. Soler N.G. et al.Long-term efficacy of dapagliflozin in patients with type 2 diabetes mellitus receiving high doses of insulin: a randomized trial.Ann Intern Med. 2012; 156: 405-415Crossref PubMed Scopus (389) Google Scholar, 11.List J.F. Woo V. Morales E. et al.Sodium-glucose cotransport inhibition with dapagliflozin in type 2 diabetes.Diabetes Care. 2009; 32: 650-657Crossref PubMed Scopus (572) Google Scholar A decrease in blood pressure has also been observed4.Ferrannini E. Ramos S.J. Salsali A. et al.Dapagliflozin monotherapy in type 2 diabetic patients with inadequate glycemic control by diet and exercise: a randomized, double-blind, placebo-controlled, phase 3 trial.Diabetes Care. 2010; 33: 2217-2224Crossref PubMed Scopus (590) Google Scholar, 5.Bailey C.J. Gross J.L. Pieters A. et al.Effect of dapagliflozin in patients with type 2 diabetes who have inadequate glycaemic control with metformin: a randomised, double-blind, placebo-controlled trial.Lancet. 2010; 375: 2223-2233Abstract Full Text Full Text PDF PubMed Scopus (712) Google Scholar, 6.Strojek K. Yoon K.H. Hruba V. et al.Effect of dapagliflozin in patients with type 2 diabetes who have inadequate glycaemic control with glimepiride: a randomized, 24-week, double-blind, placebo-controlled trial.Diabetes Obes Metab. 2011; 13: 928-938Crossref PubMed Scopus (335) Google Scholar, 7.Nauck M.A. Del Prato S. Meier J.J. et al.Dapagliflozin vs. glipizide as add-on therapy in patients with type 2 diabetes who have inadequate glycemic control with metformin: a randomized, 52-week, double-blind, active-controlled noninferiority trial.Diabetes Care. 2011; 34: 2015-2022Crossref PubMed Scopus (452) Google Scholar, 8.Rosenstock J. Vico M. Wei L. et al.Effects of dapagliflozin, an SGLT2 inhibitor, on HbA(1c), body weight, and hypoglycemia risk in patients with type 2 diabetes inadequately controlled on pioglitazone monotherapy.Diabetes Care. 2012; 35: 1473-1478Crossref PubMed Scopus (319) Google Scholar, 9.Wilding J.P. Norwood P. T'Joen C. et al.A study of dapagliflozin in patients with type 2 diabetes receiving high doses of insulin plus insulin sensitizers: applicability of a novel insulin-independent treatment.Diabetes Care. 2009; 32: 1656-1662Crossref PubMed Scopus (331) Google Scholar, 10.Wilding J.P. Woo V. Soler N.G. et al.Long-term efficacy of dapagliflozin in patients with type 2 diabetes mellitus receiving high doses of insulin: a randomized trial.Ann Intern Med. 2012; 156: 405-415Crossref PubMed Scopus (389) Google Scholar, 11.List J.F. Woo V. Morales E. et al.Sodium-glucose cotransport inhibition with dapagliflozin in type 2 diabetes.Diabetes Care. 2009; 32: 650-657Crossref PubMed Scopus (572) Google Scholar and may occur as a consequence of osmotic diuresis and weight loss. The mechanism of dapagliflozin depends on filtration of glucose at the glomerulus. Thus, with reduced renal function, dapagliflozin is expected to be less efficacious. Previous studies have shown efficacy of dapagliflozin in populations consisting primarily of patients with normal renal function or mild renal impairment. This study examines the efficacy and safety of dapagliflozin in patients with T2DM and moderate renal impairment. Of the 631 enrolled patients, 252 were randomized (Figure 1). A total of 203 patients completed the first 24 weeks (short-term period), 202 entered the additional 28-week period (long-term period) with 182 completing it, and 171 entered the second year (extension period), with 139 completing it (Figure 1). The short-term completion rate was lower for placebo (73.8%) than for dapagliflozin 5-mg (86.7%) and 10-mg (81.2%) groups, the main difference being higher rate of discontinuations for adverse events for placebo during the first 24 weeks than for dapagliflozin. Groups generally appeared to be balanced with respect to key demographic and baseline characteristics (Table 1).Table 1Demographics and baseline characteristicsPlaceboDapagliflozin 5mgDapagliflozin 10mgn848385Age (years)67±8.666±8.968±7.7Men53 (63.1)55 (66.3)56 (65.9)Women31 (36.9)28 (33.7)29 (34.1)Geographic region North America41 (48.8)51 (61.4)48 (56.5) Latin America23 (27.4)15 (18.1)17 (20.0) Europe11 (13.1)9 (10.8)9 (10.6) Asia/Pacific9 (10.7)8 (9.6)11 (12.9)Race White69 (82.1)65 (78.3)77 (90.6) African American1 (1.2)7 (8.4)4 (4.7) Asian6 (7.1)4 (4.8)3 (3.5) Other8 (9.5)7 (8.4)1 (1.2)HbA1c (%)8.53±1.288.30±1.048.22±0.98FPG (mg/dl)149±48161±56164±66Weight (kg)89.6±20.095.2±20.993.2±17.3BMI, ≥30kg/m250 (59.5)59 (71.1)54 (63.5)Duration of diabetes (years)15.7±9.516.9±9.018.2±10.1Pre-enrollment antihyperglycemic therapy Insulin based55 (65.5)54 (65.1)55 (64.7) Sulfonylurea based21 (25.0)21 (25.3)21 (24.7) Thiazolidinedione based1 (1.2)1 (1.2)2 (2.4) Other7 (8.3)7 (8.4)7 (8.2)Chronic kidney disease stage: eGFR (ml/min per 1.73m2) Stage 4: <304 (4.8)4 (4.8)2 (2.4) Stage 3B: ≥30 and <4534 (40.5)41 (49.4)47 (55.3) Stage 3A: ≥45 and Stage by and is by and is with diabetic body filtration HbA1c, or by and is in a new body filtration HbA1c, or In this moderate renal the primary mean change in after glycemic was not statistically different from placebo at 24 and for and 10-mg dapagliflozin, respectively, and and for dapagliflozin and 10mg vs. in at and at 104 weeks shown in glucose showed mean for dapagliflozin and 10mg compared with placebo at 24 weeks (Table and 104 weeks (Table for and were in that after glycemic at 24 with after 5mg 10mg is the of randomized patients with baseline and 24 mean Mean change from baseline from placebo vs. was at and was a at is the of randomized patients with baseline and 24 mean Mean change from baseline from placebo of HbA1c, with after is the of randomized patients with baseline and 24 was at and was a at in a new from baseline in efficacy and renal mean or mean 5mg 10mg after at at at after at at at after at at at after at at at (ml/min per 1.73m2) (10.6) at at at at at at creatinine filtration HbA1c, mean or mean after after after in a new of HbA1c, creatinine filtration HbA1c, was an in the with dapagliflozin compared with placebo (Table The dapagliflozin groups experienced mean weight there was an in the placebo (Figure 2 and by baseline kidney disease (Table showed a in mean change in and from baseline to 24 for dapagliflozin vs. placebo for filtration rate ≥45 and per 1.73m2) than for ≥30 and per The mean from baseline in at 24 for dapagliflozin treatment groups in patients in and there is no change in patients in difference was for change in body weight at 24 and (Table by baseline and at 24 difference in mean change from baseline of dapagliflozin vs. placebo after on an with treatment and as main and baseline as a from from from 3B: eGFR ≥30 and per 3A: eGFR ≥45 and per of kidney HbA1c, difference in mean change from baseline of dapagliflozin vs. placebo after on an with treatment and as main and baseline as a in a new of kidney HbA1c, The of patients an adverse were for dapagliflozin and placebo (Table patients in the placebo adverse events to (Table than in dapagliflozin were during the 104 weeks of in placebo and renal and 2 in dapagliflozin 5mg with and and 3 in dapagliflozin 10mg and The of patients with adverse events the treatment period were for dapagliflozin and placebo. A higher of was with dapagliflozin than and a of patients experienced with dapagliflozin and placebo (Table and events 5mgDapagliflozin adverse to adverse events of of of or creatinine (1.2)2 (2.4) (1.2)1 (9.6)11 (2.4) of hypoglycemia patients with of hypoglycemia as a to in or with a or glucose and after glucose or or and after as a to in or with a or glucose and after glucose or in a new or and after Through 104 weeks, 13 patients experienced in the dapagliflozin groups at 5mg and at vs. on placebo (Table after and were of low of 13 were assessed as adverse events and 1 with dapagliflozin of events to of study of 13 patients who a of diabetic or Of the 13 patients and of renal or renal were during the period (Table of events were in the dapagliflozin groups than in the placebo (Table patients on dapagliflozin 10mg and on experienced major episodes of hypoglycemia the 104 weeks (Table At there were mean from baseline in systolic and diastolic blood pressure and for dapagliflozin The of the mean was generally for the first weeks for this treatment and These after (Table the of patients with at any during the 104 weeks was higher for the dapagliflozin groups to than for the placebo to this difference to a higher rate of in dapagliflozin at baseline and for the dapagliflozin 5- and 10-mg groups, respectively, vs. for of at 104 5mgDapagliflozin creatinine at 104 at 104 at 104 at 104 at 104 at 104 at 104 at 104 blood pressure at 104 blood pressure at 104 mean at baseline or mean change or for blood from baseline and after in a new mean at baseline or mean change or for blood from baseline and after A mean from baseline in serum creatinine was at 1 in dapagliflozin 5mg and 10mg The of this mean the of the study for dapagliflozin (Table A was for eGFR and creatinine with mean at 1 by (Table 3 and Mean in eGFR 104 did not to for or The of patients with a in serum creatinine as a or from 104 weeks of treatment was the treatment mean and in of during the treatment period were in a higher of patients in placebo than in dapagliflozin or 10mg and In was as to of to to or and showed that for patients, to patients to a lower at 104 patients from to from to and 1 from to compared with patients who to a higher patients from to and from to In the placebo group, the of patients who to a lower patients, from to and from to was to the of patients who to a higher patients, 3 from to and from to in the dapagliflozin groups and the placebo group, the was not and the patients did not a from baseline at change from baseline was in mean serum or with dapagliflozin or placebo. of or was of were in the placebo than in dapagliflozin 5-mg or 10-mg groups during the patients experienced of for patients to of or for patients of on treatment with dapagliflozin 5mg or 10mg than placebo receiving dapagliflozin a mean decrease in serum than receiving placebo (Table The mean of serum the of normal at baseline in treatment groups, and there were mean in in dapagliflozin compared with placebo during the period (Table ability to renal glucose reabsorption with glucose is lower in patients with T2DM with dapagliflozin as compared with patients with normal or mildly impaired renal J.F. Woo V. Morales E. et al.Sodium-glucose cotransport inhibition with dapagliflozin in type 2 diabetes.Diabetes Care. 2009; 32: 650-657Crossref PubMed Scopus (572) Google Scholar is expected the in filtered glucose with with the lower dapagliflozin did not have a on glycemic control in patients with there was a decrease in and in patients with a of showed in weight glycemic receiving dapagliflozin weight in to receiving who weight The weight to studies in patients with normal to mildly impaired renal E. Ramos S.J. Salsali A. et al.Dapagliflozin monotherapy in type 2 diabetic patients with inadequate glycemic control by diet and exercise: a randomized, double-blind, placebo-controlled, phase 3 trial.Diabetes Care. 2010; 33: 2217-2224Crossref PubMed Scopus (590) Google Scholar, 5.Bailey C.J. Gross J.L. Pieters A. et al.Effect of dapagliflozin in patients with type 2 diabetes who have inadequate glycaemic control with metformin: a randomised, double-blind, placebo-controlled trial.Lancet. 2010; 375: 2223-2233Abstract Full Text Full Text PDF PubMed Scopus (712) Google Scholar, 6.Strojek K. Yoon K.H. Hruba V. et al.Effect of dapagliflozin in patients with type 2 diabetes who have inadequate glycaemic control with glimepiride: a randomized, 24-week, double-blind, placebo-controlled trial.Diabetes Obes Metab. 2011; 13: 928-938Crossref PubMed Scopus (335) Google Scholar, 7.Nauck M.A. Del Prato S. Meier J.J. et al.Dapagliflozin vs. glipizide as add-on therapy in patients with type 2 diabetes who have inadequate glycemic control with metformin: a randomized, 52-week, double-blind, active-controlled noninferiority trial.Diabetes Care. 2011; 34: 2015-2022Crossref PubMed Scopus (452) Google Scholar, 8.Rosenstock J. Vico M. Wei L. et al.Effects of dapagliflozin, an SGLT2 inhibitor, on HbA(1c), body weight, and hypoglycemia risk in patients with type 2 diabetes inadequately controlled on pioglitazone monotherapy.Diabetes Care. 2012; 35: 1473-1478Crossref PubMed Scopus (319) Google Scholar, 9.Wilding J.P. Norwood P. T'Joen C. et al.A study of dapagliflozin in patients with type 2 diabetes receiving high doses of insulin plus insulin sensitizers: applicability of a novel insulin-independent treatment.Diabetes Care. 2009; 32: 1656-1662Crossref PubMed Scopus (331) Google Scholar and the weight in this study was patients in and The in glycemic and weight may be to a of in this study may have a of glucosuria, further weight was not of to caloric or this may be to weight from glucosuria, less to weight blood glucose and different from weight and to different for is to the of glycemic efficacy from weight efficacy in this The to the that there is glycemic efficacy in this group, this study is not to The blood pressure is the of weight and osmotic is not expected to be on glycemic control, it is on weight events were balanced treatment and placebo groups 104 weeks, the and and was with dapagliflozin than with as has been in E. Ramos S.J. Salsali A. et al.Dapagliflozin monotherapy in type 2 diabetic patients with inadequate glycemic control by diet and exercise: a randomized, double-blind, placebo-controlled, phase 3 trial.Diabetes Care. 2010; 33: 2217-2224Crossref PubMed Scopus (590) Google Scholar, 5.Bailey C.J. Gross J.L. Pieters A. et al.Effect of dapagliflozin in patients with type 2 diabetes who have inadequate glycaemic control with metformin: a randomised, double-blind, placebo-controlled trial.Lancet. 2010; 375: 2223-2233Abstract Full Text Full Text PDF PubMed Scopus (712) Google Scholar, 6.Strojek K. Yoon K.H. Hruba V. et al.Effect of dapagliflozin in patients with type 2 diabetes who have inadequate glycaemic control with glimepiride: a randomized, 24-week, double-blind, placebo-controlled trial.Diabetes Obes Metab. 2011; 13: 928-938Crossref PubMed Scopus (335) Google Scholar, 7.Nauck M.A. Del Prato S. Meier J.J. et al.Dapagliflozin vs. glipizide as add-on therapy in patients with type 2 diabetes who have inadequate glycemic control with metformin: a randomized, 52-week, double-blind, active-controlled noninferiority trial.Diabetes Care. 2011; 34: 2015-2022Crossref PubMed Scopus (452) Google Scholar, 8.Rosenstock J. Vico M. Wei L. et al.Effects of dapagliflozin, an SGLT2 inhibitor, on HbA(1c), body weight, and hypoglycemia risk in patients with type 2 diabetes inadequately controlled on pioglitazone monotherapy.Diabetes Care. 2012; 35: 1473-1478Crossref PubMed Scopus (319) Google Scholar, 9.Wilding J.P. Norwood P. T'Joen C. et al.A study of dapagliflozin in patients with type 2 diabetes receiving high doses of insulin plus insulin sensitizers: applicability of a novel insulin-independent treatment.Diabetes Care. 2009; 32: 1656-1662Crossref PubMed Scopus (331) Google Scholar glucose is to this in as a for The of the in with dapagliflozin in this study is of the were in not of bone and The dapagliflozin groups higher of and at to the the increased be a in was in from patients the dapagliflozin clinical studies with or in patients with normal to mildly impaired renal and and Scholar In dapagliflozin has been shown to have no on bone or on of bone in patients with normal to mildly impaired renal J. L. et al.Dapagliflozin has no on of bone and or bone in patients with inadequately controlled type 2 diabetes mellitus on Obes Metab. 2012; PubMed Scopus Google Scholar there was no of for bone for this the in a safety to patients with or and for further study of the this is to be with the Mean eGFR and creatinine after 1 of dapagliflozin but 104 weeks of in the placebo The in eGFR with dapagliflozin may be to a and as as increased C. et and of SGLT2 on and function in the diabetic J 2012; PubMed Scopus Google Scholar the change in from baseline at 104 was in the dapagliflozin and placebo receiving dapagliflozin were to to a lower than patients receiving placebo. Thus, it be of to dapagliflozin reduces renal and of was with fewer episodes and fewer discontinuations hyperkalemia compared with placebo. This is to osmotic diuresis by dapagliflozin in patients with ability to The study has The of in of patients, with of insulin with respect to and of insulin placebo and dapagliflozin the efficacy of dapagliflozin. A second is the of the was for a change in and in ability to glycemic were at the this was we from the study of patients with normal kidney C.J. Gross J.L. Pieters A. et al.Effect of dapagliflozin in patients with type 2 diabetes who have inadequate glycaemic control with metformin: a randomised, double-blind, placebo-controlled trial.Lancet. 2010; 375: 2223-2233Abstract Full Text Full Text PDF PubMed Scopus (712) Google Scholar and the in patients with decreased renal S. et al.The of kidney function on dapagliflozin and efficacy in and in patients with type 2 diabetes J Clin 2012; Scopus Google Scholar this study may be and to type 2 of in this study of glycemic with dapagliflozin in this was not statistically of the inadequate renal function in The reduced glucose in this to for the weight and blood pressure in patients with diabetes and from the in the safety of dapagliflozin was to that in studies patients with T2DM and normal renal function to mild renal impairment. This randomized, double-blind, placebo-controlled, phase study in in and or this This study was in with the of and and patients with T2DM and inadequate glycemic control as and were enrolled from to eGFR of to per and body was as diet and therapy or in combination with a of any in doses of or not during weeks or doses of insulin or insulin not by during weeks or the of serum total of diabetes or diabetic or as systolic blood pressure diastolic blood pressure or of the for or renal of renal renal or renal renal or and were at the of the treating as no were A period diet and the patients were randomized in a to dapagliflozin or dapagliflozin 10-mg in to was on antihyperglycemic therapy or the first 24 weeks (short-term period), patients or completing the first 24 weeks were to an additional 28-week period and were to completing the first weeks short-term plus were to the period additional and and or after glycemic as The primary efficacy compared the change from baseline in with of dapagliflozin vs. placebo at 24 weeks. The compared the change from baseline in and weight for of dapagliflozin vs. placebo at 24 and change from baseline in eGFR of in and creatinine and for dapagliflozin vs. placebo at weeks. safety after glycemic and adverse discontinuations to adverse and blood pressure and rate were in at study and and blood pressure were at and at weeks and and were on were the for clinical and of and with by the at A the for the efficacy and safety for and for creatinine and The primary efficacy was on an of with treatment and antihyperglycemic therapy as and the baseline as a patients with no 24 or the and 24 was for diabetes and for treatment and Scholar and were at the of and no was Several with or after were 104 weeks, was to the change in HbA1c, and total body weight from the of on therapy week, and as as of baseline and baseline patients per treatment group, there was at to a difference of in mean change from baseline in dapagliflozin treatment and placebo at a of and an of that of the patients not have a a total of 252 patients patients per treatment to be The study the patients for and during the also the and from study to for and in this This and study is also as and is with at and was by and of from this study were at the of