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Aim To evaluate the long-term efficacy, safety and tolerability of dapagliflozin versus placebo added to usual care in patients with type 2 diabetes mellitus ( T2DM) and cardiovascular disease ( CVD). Methods Data were pooled from two phase III studies ( NCT01031680 and NCT01042977) in high-risk patients (N = 1887) with T2DM and CVD treated with dapagliflozin (10 mg/day) or placebo. Patients completing the double-blind treatment studies (24 weeks) entered one or two sequential double-blind, long-term ( LT) extensions of 28 ( LT1; n = 1649) and 52 ( LT2; n = 568) weeks. Results Baseline and CVD characteristics were similar in the two groups. Patients entering LT1 and LT2 on dapagliflozin maintained a greater mean reduction in glycated haemoglobin ( HbA1c) versus placebo at 52 weeks [ LT1, −0.58% (95% confidence interval −0.68, −0.49)] and 104 weeks [ LT2, −0.35% (95% confidence interval −0.59, −0.12)]. Mean body weight and systolic blood pressure ( SBP) reductions versus placebo were maintained in patients entering LT1 (52 weeks; −2.23 kg and −3.25 mmHg, respectively) and LT2 (104 weeks; −3.16 kg and −2.03 mmHg, respectively). Patients on dapagliflozin had a better three-item composite endpoint of clinical benefit (glycaemia, weight and SBP) compared with placebo at week 24 ( LT1, 10.1% vs. 1.1%) and week 104 ( LT2, 6.7% vs. 1.4%). Genital and urinary tract infections were more frequent with dapagliflozin than with placebo. Events of hypoglycaemia, renal impairment/failure and volume depletion were similar between groups. Conclusions The long-term efficacy of dapagliflozin to maintain reductions in HbA1c, SBP and body weight over 2 years, together with its tolerability profile, make dapagliflozin an appropriate option in high-risk patients with T2DM and CVD. [ABSTRACT FROM AUTHOR]

Aims To evaluate the safety and efficacy of dapagliflozin as add-on therapy to metformin plus sulphonylurea over 52 weeks. Methods Patients with type 2 diabetes mellitus ( T2DM) using sulphonylurea and metformin received dapagliflozin 10 mg/day or placebo added to therapy for 52 weeks (24-week randomized, double-blind period plus 28-week double-blind extension). Results A total of 219 patients were randomized 1 : 1 to dapagliflozin or placebo. Over 52 weeks, glycated haemoglobin ( HbA1c) and fasting plasma glucose levels showed greater improvement from baseline with dapagliflozin (−0.8% and −1.5 mmol/l) than with placebo (−0.1% and 0.6 mmol/l). More patients achieved HbA1c <7.0% with dapagliflozin (27.3%) than with placebo (11.3%) at 52 weeks. Dapagliflozin was associated with greater reductions in body weight and systolic blood pressure (−2.9 kg and −1.0 mmHg) compared with placebo (−1.0 kg and 1.1 mmHg). Greater increases in total, LDL and HDL cholesterol and decreases in triglycerides were observed with dapagliflozin (3.4, 4.8, 6.9 and −8.0%, respectively) versus placebo (1.4, 0.9, 0.6 and 2.9%, respectively). Fewer patients were rescued for failing to reach glycaemic targets with dapagliflozin (9.3%) than with placebo (44.4%). Adverse events and serious adverse events were similar between groups (dapagliflozin: 69.7 and 6.4%; placebo: 73.4 and 7.3%). More hypoglycaemic events were observed with dapagliflozin (15.6%) than with placebo (8.3%). Genital infections were reported in more patients in the dapagliflozin (10.1%) than in the placebo group (0.9%) and urinary tract infection frequency was similar in the two groups (10.1 and 11.0%). Conclusion Dapagliflozin as add-on to metformin plus a sulphonylurea was well tolerated and improvement in glycaemic control was maintained over 52 weeks. [ABSTRACT FROM AUTHOR]

Aims To assess the long-term efficacy and tolerability of dapagliflozin versus glipizide as add-on to metformin in patients with inadequately controlled type 2 diabetes. Methods The present study was an extension of an earlier randomized, double-blind, phase III study of dapagliflozin (n = 406) vs glipizide (n = 408) to 208 weeks (4 years). Patients continued to receive their assigned medication. No statistical treatment-group comparisons were calculated. Results At 208 weeks, dapagliflozin compared with glipizide produced sustained reductions in glycated haemoglogin ( HbA1c): −0.30% [95% confidence interval ( CI), −0.51 to −0.09], in total body weight: −4.38 kg (95% CI −5.31 to −3.46) and in systolic blood pressure ( SBP): −3.67 mmHg (95% CI −5.92 to −1.41). The HbA1c coefficient of failure was significantly lower for dapagliflozin than for glipizide: 0.19 (95% CI 0.12-0.25) versus 0.61 (95% CI 0.49-0.72, difference −0.42; p = 0.0001). Dapagliflozin was not associated with glomerular function deterioration, while this occurred more frequently in patients in the glipizide group. Fewer patients reported hypoglycaemia in the dapagliflozin compared with the glipizide group (5.4 vs 51.5%). Genital and urinary tract infections were more common with dapagliflozin than with glipizide, but their incidence decreased with time and all events responded well to antimicrobial treatment. Conclusions In patients completing 4 years of treatment, dapagliflozin was well tolerated and associated with sustained glycaemic efficacy and greater reductions in body weight and SBP versus glipizide. [ABSTRACT FROM AUTHOR]

Aims To assess the long-term glycaemic durability, safety and tolerability of dapagliflozin versus glipizide as add-on therapies in patients with type 2 diabetes inadequately controlled by metformin alone. Methods This was a 52-week, randomised, double-blind study of dapagliflozin (n = 406) versus glipizide (n = 408), uptitrated over 18 weeks according to tolerability and glycaemic response to a maximum of 10 and 20 mg/day, respectively, as add-on therapies to metformin (≥1500 mg/day) with a 156-week double-blind extension period. Data over 104 weeks are reported here. Results In total, 53.1% of patients completed 104 weeks of treatment. After the greater initial decrease (0-18 weeks) in glycated haemoglobin ( HbA1c) with glipizide, the 18-104-week HbA1c coefficient of failure ( CoF) was lower with dapagliflozin (0.13%/year) than with glipizide (0.59%/year), resulting in significant dapagliflozin versus glipizide differences of −0.46%/year (95% CI −0.60,−0.33; p = 0.0001) for CoF and −0.18%(−2.0 mmol/mol) [95% CI −0.33(−3.6),−0.03(−0.3); p = 0.021] for 104-week HbA1c. Dapagliflozin produced sustained reductions in weight and systolic blood pressure, whereas glipizide increased weight and systolic blood pressure, giving 104-week dapagliflozin versus glipizide differences of −5.1 kg (95% CI: −5.7,−4.4) and −3.9 mmHg (95% CI: −6.1,−1.7), respectively. Over 104 weeks, the hypoglycaemia rate was 10-fold lower with dapagliflozin than with glipizide (4.2 vs. 45.8%), whereas patient proportions with events suggestive of genital infection and of urinary tract infection ( UTI) were greater with dapagliflozin (14.8 and 13.5%, respectively) than with glipizide (2.9 and 9.1%, respectively). Conclusions Over 2 years, compared with glipizide, dapagliflozin demonstrated greater glycaemic durability, sustained reductions in weight and systolic blood pressure and a low hypoglycaemia rate; however, genital infections and UTIs occurred more frequently. [ABSTRACT FROM AUTHOR]

Aims This study evaluated change in health-related quality of life ( HRQOL) associated with ongoing weight change among patients with type 2 diabetes mellitus ( T2DM) treated with dapagliflozin, a highly selective sodium-glucose cotransporter 2 ( SGLT2) inhibitor that lowers blood glucose by increasing urinary glucose excretion and is associated with body weight reductions. Methods Patients with T2DM who had inadequate glycaemic control on metformin ( MET) alone were enrolled in a 24-week, double-blind, randomized, placebo-controlled study with a 78-week extension to evaluate the effect of dapagliflozin + MET on body weight. Patients also completed the Study to Help Improve Early evaluation and management of risk factors Leading to Diabetes Weight Questionnaire-9 ( SHIELD-WQ-9), a weight change-related HRQOL survey. Difference in proportions of patients treated with dapagliflozin 10 mg + MET (n = 89) or placebo + MET (n = 91) who reported improvement in HRQOL was analysed with Fisher's exact test. Results Dapagliflozin patients had significantly greater weight loss than placebo patients over 102 weeks (p < 0.05). This corresponded to a numerically greater proportion of dapagliflozin-treated patients reporting ongoing weight loss and associated improvements in most HRQOL domains at three different evaluation points (weeks 24, 50 and 102) than placebo-treated patients. In a post-hoc analysis among patients who reported ongoing weight loss regardless of treatment arm, a significantly greater proportion of patients reporting weight loss versus weight gain reported improvements in physical health, self-esteem and overall HRQOL at weeks 24, 50 and 102. Conclusions Dapagliflozin-induced weight loss was associated with improvement in overall HRQOL. Overall, ongoing weight loss was associated with improvements in several HRQOL domains compared with weight gain. [ABSTRACT FROM AUTHOR]

Aims Dapagliflozin, a selective inhibitor of sodium-glucose cotransporter 2 ( SGLT2), has been shown to improve glycaemic control, stabilize insulin dosing and mitigate insulin-associated weight gain over 48 weeks in patients whose type 2 diabetes mellitus ( T2DM) was inadequately controlled despite high doses of insulin. Here the efficacy and safety of dapagliflozin therapy after a total of 104 weeks are evaluated in this population. Methods This was a 24-week, randomized, placebo-controlled, double-blinded, multicentre trial followed by two site- and patient-blinded extension periods of 24 and 56 weeks (NCT00673231), respectively. A total of 808 patients, whose T2DM was inadequately controlled on insulin ≥30 IU/day, with or without up to two oral antidiabetic drugs, were randomly assigned to receive placebo or 2.5, 5 or 10 mg/day of dapagliflozin for 104 weeks. At 48 weeks, patients on dapagliflozin 5 mg were switched to 10 mg. Outcomes over 104 weeks included change from baseline in HbA1c, insulin dose and body weight; analyses used observed cases and included data after insulin up-titration. Adverse events ( AEs) were evaluated throughout 104 weeks. Results Five hundred and thirteen patients (63.6%) completed the study. Mean HbA1c changes from baseline at 104 weeks were −0.4% in the placebo group and −0.6 to −0.8% in the dapagliflozin groups. In the placebo group, mean insulin dose increased by 18.3 IU/day and weight increased by 1.8 kg at 104 weeks, whereas in the dapagliflozin groups, insulin dose was stable and weight decreased by 0.9-1.4 kg. AEs, including hypoglycaemia, were balanced across groups. Proportions of patients with events suggestive of genital infection and of urinary tract infection ( UTI) were higher with dapagliflozin versus placebo (genital infection 7.4-14.3% vs. 3.0%; UTI 8.4-13.8% vs. 5.6%) but most occurred in the first 24 weeks and most were single episodes that responded to routine management. Conclusions Dapagliflozin improved glycaemic control, stabilized insulin dosing and reduced weight without increasing major hypoglycaemic episodes over 104 weeks in patients whose T2DM was inadequately controlled on insulin. However, rates of genital infection and of UTI were elevated with dapagliflozin therapy. [ABSTRACT FROM AUTHOR]

Aims Dapagliflozin, a highly selective inhibitor of sodium-glucose cotransporter 2 ( SGLT2), reduces hyperglycaemia and weight in patients with type 2 diabetes mellitus ( T2DM) by increasing urinary glucose excretion. Long-term glycaemic control, body composition and bone safety were evaluated in patients with T2DM after 102 weeks of dapagliflozin treatment. Methods This randomized, double-blind, placebo-controlled study ( NCT00855166) enrolled patients with T2DM [mean: age 60.7 years; HbA1c 7.2%; body mass index ( BMI) 31.9 kg/m2; body weight 91.5 kg] inadequately controlled on metformin. Patients (N = 182) were randomly assigned 1 : 1 to receive dapagliflozin 10 mg/day or placebo added to open-label metformin for a 24-week double-blind treatment period followed by a 78-week site- and patient-blinded extension period. At week 102, changes from baseline in HbA1c, weight, waist circumference, total body fat mass as measured by dual-energy X-ray absorptiometry ( DXA), serum markers of bone turnover, bone mineral density ( BMD) as measured by DXA, and adverse events were evaluated. Results A total of 140 patients (76.9%) completed the study. Over 102 weeks, dapagliflozin-treated patients showed reductions in HbA1c by −0.3%, weight by −4.54 kg, waist circumference by −5.0 cm and fat mass by −2.80 kg without increase in rate of hypoglycaemia. Compared with placebo, no meaningful changes from baseline in markers of bone turnover or BMD were identified over 102 weeks. One fracture occurred in each treatment group. The frequency of urinary tract infection ( UTI) and genital infection was similar in both treatment groups. Conclusions Over 102 weeks, dapagliflozin improved glycaemic control, and reduced weight and fat mass, without affecting markers of bone turnover or BMD in patients with T2DM inadequately controlled on metformin. [ABSTRACT FROM AUTHOR]

Aim Dapagliflozin is a selective sodium-glucose co-transporter 2 ( SGLT2) inhibitor under development as a treatment for type 2 diabetes mellitus ( T2DM). This study assessed the efficacy and safety of dapagliflozin monotherapy in Japanese T2DM patients with inadequate glycaemic control. Methods Patients (n = 279) were randomized to receive dapagliflozin (1, 2.5, 5 or 10 mg/day) or placebo once daily for 12 weeks. The primary endpoint was change from baseline in haemoglobin A1c ( HbA1c) at week 12. Secondary endpoints included change from baseline in fasting plasma glucose ( FPG) and proportion of patients achieving HbA1c <7.0% at week 12. Results Significant reductions in HbA1c were seen with all dapagliflozin doses (−0.11 to −0.44%) versus placebo (+0.37%). Reductions were also observed in FPG with dapagliflozin (−0.87 to −1.77 mmol/l [−15.61 to −31.94 mg/ dl]) versus placebo (+0.62 mmol/l [+11.17 mg/dl]). No significant difference in the proportion of patients achieving HbA1c levels <7.0% was noted with dapagliflozin versus placebo. Adverse events ( AEs) were more frequent with dapagliflozin (40.7-53.8%) versus placebo (38.9%) and were mostly mild/moderate in intensity. Three hypoglycaemic events were reported (1 each with placebo, dapagliflozin 2.5 mg and 10 mg). The frequency of signs and symptoms suggestive of urinary tract or genital infections was 0-3.8 and 0-1.8% respectively with dapagliflozin and 1.9 and 0% with placebo. No AEs of pyelonephritis were observed. Conclusions Compared with placebo, dapagliflozin significantly reduced hyperglycaemia over 12 weeks with a low risk of hypoglycaemia in Japanese T2DM patients with inadequate glycaemic control. [ABSTRACT FROM AUTHOR]

Aims Dapagliflozin, a selective sodium-glucose cotransporter 2 ( SGLT2) inhibitor, reduces hyperglycaemia in patients with type 2 diabetes ( T2DM) by increasing urinary glucose excretion. Owing to its mechanism of action, dapagliflozin could potentially affect the renal tubular transportation of bone minerals. Therefore, markers of bone formation and resorption and bone mineral density ( BMD) were evaluated in patients with T2DM after 50 weeks of dapagliflozin treatment. Methods This international, multi-centre, randomized, parallel-group, double-blind, placebo-controlled study (ClinicalTrials.gov NCT00855166) enrolled patients with T2DM (women 55-75 years and men 30-75 years; HbA1c 6.5-8.5%; BMI ≥ 25 kg/m2; body weight ≤ 120 kg) whose T2DM was inadequately controlled on metformin. One hundred and eighty-two patients were randomly assigned 1:1 to receive dapagliflozin 10 mg/day or placebo added to open-label metformin for a 24-week double-blind treatment period followed by a 78-week site- and patient-blinded extension period. At week 50, serum markers of bone formation (procollagen type 1 N-terminal propeptide; P1NP) and resorption (C-terminal cross-linking telopeptides of type I collagen; CTX), bone mineral density ( BMD) as assessed by standardized Dual-Energy X-ray Absorptiometry ( DXA) measurements and adverse events of fracture were evaluated as safety objectives. Results One hundred and sixty-five patients (90.7%) completed the first 50 weeks. Compared with placebo, no significant changes from baseline in P1NP, CTX or BMD were identified over 50 weeks of dapagliflozin treatment, with no significant treatment-by-gender interactions. No fractures were reported. Conclusions Dapagliflozin had no effect on markers of bone formation and resorption or BMD after 50 weeks of treatment in both male and post-menopausal female patients whose T2DM was inadequately controlled on metformin. [ABSTRACT FROM AUTHOR]

Aims: Progressive deterioration of glycaemic control in type 2 diabetes mellitus (T2DM) often requires treatment intensification. Dapagliflozin increases urinary glucose excretion by selective inhibition of renal sodium-glucose cotransporter 2 (SGLT2). We assessed the efficacy, safety and tolerability of dapagliflozin added to glimepiride in patients with uncontrolled T2DM. Methods: This 24-week, randomized, double-blind, placebo-controlled, parallel-group, international, multicentre trial (ClinicalTrials.gov NCT00680745) enrolled patients with uncontrolled T2DM [haemoglobin A1c (HbA1c) 7-10%] receiving sulphonylurea monotherapy. Adult patients (n = 597) were randomly assigned to placebo or dapagliflozin (2.5, 5 or 10 mg/day) added to open-label glimepiride 4 mg/day for 24 weeks. Primary endpoint was HbA1c mean change from baseline at 24 weeks. Secondary endpoints included change in body weight and other glycaemic parameters. Results: At 24 weeks, HbA1c adjusted mean changes from baseline for placebo versus dapagliflozin 2.5/5/10 mg groups were −0.13 versus −0.58, −0.63, −0.82%, respectively (all p < 0.0001 vs. placebo by Dunnett's procedure). Corresponding body weight and fasting plasma glucose values were −0.72, −1.18, −1.56, −2.26 kg and −0.11, −0.93, −1.18, −1.58 mmol/l, respectively. In placebo versus dapagliflozin groups, serious adverse events were 4.8 versus 6.0-7.1%; hypoglycaemic events 4.8 versus 7.1-7.9%; events suggestive of genital infection 0.7 versus 3.9-6.6%; and events suggestive of urinary tract infection 6.2 versus 3.9-6.9%. No kidney infections were reported. Conclusions: Dapagliflozin added to glimepiride in patients with T2DM uncontrolled on sulphonylurea monotherapy significantly improved HbA1c, reduced weight and was generally well tolerated, although events suggestive of genital infections were reported more often in patients receiving dapagliflozin. [ABSTRACT FROM AUTHOR]

The primary objective of this single-centre, open-label crossover study ( NCT01072578) was to assess the effect of dapagliflozin on the amount of glucose in the blood and urine in healthy volunteers when dapagliflozin was administered once a day (10 mg) versus twice a day (5 mg every 12 h) after 5 days of dosing. At steady state, the AUCss (0-24) (area under the dapagliflozin curve (0-24 hours) at steady state), Css, av (average concentration at steady state) between dapagliflozin 5 mg twice daily and 10 mg once daily were similar AUCss(0-24) [5 mg bid, (458.0 (28.7)) and 10 mg qd, (470.0 (28.5))] and Css, av [5 mg bid 18.8 (28.9)) and 10 mg qd, (19.6(28.5))], but minimum and maximum plasma levels of dapagliflozin differed significantly. Percent inhibition of renal glucose reabsorption (% IRGRA) and total urinary glucose excretion over 24 h were similar for both doses. The relationship between the mean dapagliflozin concentration and % IRGRA and the total urinary glucose excreted was well described by a maximum effect model. The results indicate that dapagliflozin may be used for either once daily or twice daily administration. [ABSTRACT FROM AUTHOR]