The sodium glucose co-transporter-2 (SGLT2) is a low-affinity transport system that is specifically expressed in the kidney and plays an important role in renal glucose reabsorption in the proximal tubule. Competitive inhibition of SGLT2 therefore represents an innovative therapeutic strategy for the treatment of hyperglycaemia and/or obesity in patients with type 1 or type 2 diabetes by enhancing glucose and energy loss through the urine. The observation that individuals with familial renal glycosuria maintain normal long-term kidney function provides some reassurance that this mode of action will not adversely affect renal function. Intense research in this therapeutic area has led to the discovery of novel SGLT2 inhibitors, each with different chemical, pharmacodynamic and pharmacokinetic profiles. This review outlines the biology, expression and pleotropic activity of the SGLT system and the pharmacological profile of SGLT2 inhibitors and provides a summary of preclinical and limited clinical data available to characterize the efficacy, safety and potential clinical utility of SGLT2 inhibitors in the management of diabetes.

Chronic hyperglycemia impairs insulin action, resulting in glucotoxicity, which can be ameliorated in animal models by inducing glucosuria with renal glucose transport inhibitors. Here, we examined whether reduction of plasma glucose with a sodium-glucose cotransporter 2 (SGLT2) inhibitor could improve insulin-mediated tissue glucose disposal in patients with type 2 diabetes. Eighteen diabetic men were randomized to receive either dapagliflozin (n = 12) or placebo (n = 6) for 2 weeks. We measured insulin-mediated whole body glucose uptake and endogenous glucose production (EGP) at baseline and 2 weeks after treatment using the euglycemic hyperinsulinemic clamp technique. Dapagliflozin treatment induced glucosuria and markedly lowered fasting plasma glucose. Insulin-mediated tissue glucose disposal increased by approximately 18% after 2 weeks of dapagliflozin treatment, while placebo-treated subjects had no change in insulin sensitivity. Surprisingly, following dapagliflozin treatment, EGP increased substantially and was accompanied by an increase in fasting plasma glucagon concentration. Together, our data indicate that reduction of plasma glucose with an agent that works specifically on the kidney to induce glucosuria improves muscle insulin sensitivity. However, glucosuria induction following SGLT2 inhibition is associated with a paradoxical increase in EGP. These results provide support for the glucotoxicity hypothesis, which suggests that chronic hyperglycemia impairs insulin action in individuals with type 2 diabetes.

Abstract No prospective data exist on the risk of microbiologically confirmed urinary tract infection (UTI) and asymptomatic bacteriuria (AB) in relation to diabetes mellitus and its characteristics. The authors prospectively (1998-2002) followed 218 diabetic and 799 nondiabetic Washington State women aged 55-75 years for UTI and AB. The baseline examination and two annual follow-up examinations included urine culture, measurement of hemoglobin A1c and postvoid residual bladder volume, and a survey of diabetes and other characteristics. Surveillance for UTI included self-reports confirmed by microbiologic culture and medical record review. UTI incidence per 100 person-years was 12.2 for diabetic women and 6.7 for nondiabetic women (relative risk (RR) = 1.8, 95% confidence interval (CI): 1.2, 2.7). AB incidence per 100 person-years was 6.7 for diabetic women and 3.0 for nondiabetic women (RR = 2.3, 95% CI: 1.3, 3.9). In Cox models adjusted for multiple covariates, the increased UTI risk occurred mainly in women taking insulin (RR = 3.7, 95% CI: 1.8, 7.3) and women with a longer diabetes duration (> or =10 years; RR = 2.6, 95% CI: 1.3, 5.1) compared with nondiabetic women. No clear linear trend between hemoglobin A1c and UTI or AB risk was seen. Postmenopausal women with diabetes have higher risks of UTI and AB in relation to diabetes duration and severity but not to recent glucose control.

The influence of glucose metabolism is seen in many infectious diseases, making diabetic patients more vulnerable to sepsis and other serious sequelae of bacterial invasion. Vaginal candidiasis is a common problem if the glycemia is poorly controlled. The level of glucose concentration in the blood after ingestion of sugar seems to explain an increased likelihood of recurrent infection. Specific immune aberrations, such as an elevated T-helper 2 response and a blunted T-helper 1 response, leading to tolerance, may result in chronic recurrent vulvovaginal candidiasis. In such patients, a low-grade infection with frequent exacerbations is seen, and treatment should be based on 24-hour glycemic control and long intermittent treatment with antifungals. Besides candidiasis, there is also evidence of an increased likelihood of cystitis. Upper urinary tract infections (UTIs) are also a frequent result of bladder colonization. Lethal emphysematous nephritis due to Candida albicans or gas-forming bacteria such as Escherichia coli, Klebsiella, Proteus , streptococci, or enterococci are known to occur in diabetic patients. Furthermore, UTIs in diabetic patients are difficult to eradicate and need longer and intense antibiotic therapy. Awareness of the increased likelihood of UTIs, frequent screening, and prolonged treatment in case of cystitis are warranted. For the prevention of UTI and bacterial vaginal infections (bacterial vaginosis, vaginal atrophy with bacterial colonization, aerobic vaginitis) estrogen therapy may be as important as antibiotic therapy. Catheterization should be limited since it promotes infection more in diabetic patients than in nondiabetic patients. In the case of recurrent vaginal candidiasis, tight control of glycemia is crucial, in addition to prolonged, intermittent therapy with antifungals.

Hypertension and type 2 diabetes mellitus (T2DM) are risk factors for cardiovascular disease. Dapagliflozin improves glycemic control and systolic blood pressure (SBP) in T2DM patients. This double-blind phase III study evaluated the effects of dapagliflozin on glycemic control and blood pressure in patients with inadequately controlled T2DM and hypertension, despite ongoing therapy with a renin-angiotensin system blocker. Patients were randomized to receive dapagliflozin 1065mg (n65=65302) or placebo (n65=65311) once daily for 12 weeks. Endpoints were change from baseline to week 12 in seated SBP and glycosylated hemoglobin (HbA1c); longitudinal repeated-measures analysis was performed. Additional endpoints included other hemodynamic measures, serum uric acid, fasting plasma glucose, body weight, blood lipids and heart rate. After 12 weeks, dapagliflozin-treated versus placebo-treated patients showed significant reductions in HbA1c (-0.6% vs -0.1%, p65<650.0001), mean seated SBP (-10.4 vs -7.365mmHg, p65=650.0010) and mean 24 h ambulatory SBP (-9.6 vs -6.765mmHg, p65=650.0043). Dapagliflozin also reduced body weight compared with placebo (-1.0 vs -0.365kg). Dapagliflozin was well tolerated, with adverse events consistent with previous studies. Dapagliflozin improved glycemic control, and reduced SBP as well as body weight in patients with poorly controlled T2DM and hypertension.

Abstract BackgroundDapagliflozin, a highly selective sodium–glucose cotransporter 2 inhibitor, reduces hyperglycemia, body weight, and blood pressure in patients with type 2 diabetes (T2D). MethodsThis randomized double-blind placebo-controlled parallel-group 24-week study assessed the efficacy, safety, and tolerability of dapagliflozin added to metformin in Asian patients with inadequately controlled T2D (HbA1c 7.5%–10.5%). Patients were randomized to receive placebo ( n =65145) or dapagliflozin 5 ( n =65147) or 1065mg ( n =65152). Results<p>Most participants were Chinese (86.0%), with a mean age of 53.865years and mean T2D duration of 4.965years; 92.1% completed the study. Adjusted mean HbA1c changes from baseline at Week 24 (primary endpoint) were 610.23%, 610.82%, and 610.85% in the placebo, dapagliflozin 5 and 1065mg groups, respectively, resulting in dapagliflozin 5 and 1065mg versus placebo differences of 610.59% and 610.62%, respectively (both P ConclusionsDapagliflozin 5 or 1065mg as add-on to metformin was well tolerated in Asian patients with T2D and significantly improved glycemic control with the additional benefit of weight reduction. Abstract 摘要 背景:达格列净是一种高选择性的钠-葡萄糖共转运体2抑制剂,可降低2型糖尿病患者的血糖、体重和血压。 方法:这项为期24周的随机双盲安慰剂对照平行组试验考察了在控制不佳的亚洲2型糖尿病患者(HbA1c 7.5%–10.5%)中,在原有二甲双胍治疗基础上加用达格列净治疗的疗效、安全性和耐受性。患者被随机分为加用安慰剂(n=145)、达格列净5 mg(n=147)或达格列净10 mg 治疗组(n=152)。 结果:<p>大多数参与者为中国患者(86.0%),平均年龄53.8岁,平均2型糖尿病病程为4.9年;92.1%的患者完成了研究。24周时,校正后的平均HbA1c与基线相比的变化值在安慰剂组、达格列净5 mg与达格列净10 mg组分别为-0.23%、-0.82%和-0.85%,达格列净5 mg与10 mg组与安慰剂组的差异分别为-0.59%和-0.62%,差异具有统计学意义( P 均 结论:亚洲2型糖尿病患者在原有二甲双胍治疗基础上加用达格列净5 mg或10 mg治疗的耐受性良好,并可显著改善血糖控制,并可降低体重。

AimsDapagliflozin, 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 48090009weeks 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 104090009weeks are evaluated in this population.MethodsThis was a 24-week, randomized, placebo-controlled, double-blinded, multicentre trial followed by two site- and patient-blinded extension periods of 24 and 56090009weeks (NCT00673231), respectively. A total of 808 patients, whose T2DM was inadequately controlled on insulin 09090630 IU/day, with or without up to two oral antidiabetic drugs, were randomly assigned to receive placebo or 2.5, 5 or 10090009mg/day of dapagliflozin for 104090009weeks. At 48090009weeks, patients on dapagliflozin 5090009mg were switched to 10090009mg. Outcomes over 104090009weeks 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 104090009weeks.ResultsFive hundred and thirteen patients (63.6%) completed the study. Mean HbA1c changes from baseline at 104090009weeks were 0908080.4% in the placebo group and 0908080.6 to 0908080.8% in the dapagliflozin groups. In the placebo group, mean insulin dose increased by 18.3 IU/day and weight increased by 1.8090009kg at 104090009weeks, whereas in the dapagliflozin groups, insulin dose was stable and weight decreased by 0.90900091.4090009kg. 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 7.409000914.3% vs. 3.0%; UTI 8.409000913.8% vs. 5.6%) but most occurred in the first 24090009weeks and most were single episodes that responded to routine management.ConclusionsDapagliflozin improved glycaemic control, stabilized insulin dosing and reduced weight without increasing major hypoglycaemic episodes over 104090009weeks in patients whose T2DM was inadequately controlled on insulin. However, rates of genital infection and of UTI were elevated with dapagliflozin therapy.

Hypertension is a common comorbidity in patients with type 2 diabetes mellitus and a major risk factor for microvascular and macrovascular disease. Although the blood pressure-lowering effects of sodium–glucose cotransporter 2 (SGLT2) inhibitors are already established, guidance is needed on how to use these drugs in patients already receiving antihypertensive therapy. We aimed to compare blood pressure and glycaemic effects of the SGLT2 inhibitor dapagliflozin with placebo in patients with inadequately controlled type 2 diabetes mellitus and hypertension. In this double-blind, placebo-controlled, phase 3 study we enrolled patients from 311 centres in 16 countries across five continents. Patients had uncontrolled type 2 diabetes (HbA1c7·0%–10·5%; 53–91 mmol/mol) and hypertension (systolic 140–165 mm Hg and diastolic 85–105 mm Hg at both enrolment and randomisation, and a mean 24 h blood pressure of ≥130/80 mm Hg by ambulatory monitoring within 1 week of randomisation) and were receiving oral antihyperglycaemic drugs, insulin, or both, plus a renin–angiotensin system blocker and an additional antihypertensive drug. Using an interactive voice-response system, we randomly assigned (1:1) patients to dapagliflozin 10 mg once a day or to placebo, with randomisation stratified by additional antihypertensive drug use and insulin use at baseline, in a block size of two. The co-primary endpoints were changes in seated systolic blood pressure and HbA1cmeasured in the full analysis set, which included all patients who received at least one dose of study drug and had both a baseline and at least one post-baseline measurement of efficacy. This trial is registered withClinicalTrials.gov, numberNCT01195662. Between Oct 29, 2010, and Oct 4, 2012, we randomly assigned 225 patients to dapagliflozin and 224 to placebo. Seated systolic blood pressure was significantly reduced in the group assigned to dapagliflozin (adjusted mean change from baseline 6111·90 mm Hg [95% CI 6113·97 to 619·82]) compared with those assigned to placebo (617·62 mm Hg [–9·72 to 615·51]; placebo-adjusted difference for dapagliflozin 614·28 mm Hg [–6·54 to 612·02]; p=0·0002). Reductions in HbA1cconcentrations were also significantly greater in patients assigned to dapagliflozin (adjusted mean change from baseline 610·63% [95% CI 610·76 to 610·50]) than in those assigned to placebo (610·02% [–0·15 to 0·12]; placebo-adjusted difference 610·61% [–0·76 to 610·46,]; p<0·0001). In a post-hoc analysis, we found difference in blood pressure versus placebo was greater in patients receiving a β blocker (615·76 mm Hg [95% CI 6110·28 to 611·23]) or a calcium-channel blocker (615·13 mm Hg, [619·47 to 610·79]) as their additional antihypertensive drug than in those receiving a thiazide diuretic (612·38 mm Hg [–6·16 to 1·40]). Adverse events were similar in the dapagliflozin and placebo groups (98 [44%] patientsvs93 [42%], respectively, had at least one adverse event), with few adverse events related to renal function (1%vs<1%) or volume depletion (<1%vs0%). Dapagliflozin 10 mg significantly improved blood pressure and HbA1cand was tolerated similarly to placebo. Its blood pressure-lowering properties were particularly favourable in patients already receiving a β blocker or calcium-channel blocker. Dapagliflozin could benefit patients with type 2 diabetes who need a diuretic-like effect to optimise control of blood pressure, adding meaningful efficacy to antihypertensive drug regimens. Bristol-Myers Squibb, AstraZeneca.

Introduction Maintenance of drug efficacy and safety over the long term is important to investigate for progressive conditions like type 2 diabetes mellitus (T2DM). This study aimed to evaluate whether efficacy of dapagliflozin added to glimepiride observed at 2402weeks was maintained at 4802weeks, and to provide further safety and tolerability data in patients with T2DM. Methods This 24-week randomized, double-blind, parallel-group, placebo-controlled trial with a 24-week double-blind extension period enrolled adults whose T2DM was inadequately controlled [glycated hemoglobin (HbA 1c ) 7.0–10.0%] on sulfonylurea monotherapy. Patients were randomized to placebo ( n 02=02146) or dapagliflozin 2.502mg ( n 02=02154), 502mg ( n 02=02145), or 1002mg ( n 02=02151) per day added to open-label glimepiride 402mg/day. Results In total, 519 patients (87.1%) completed the study. At 4802weeks, HbA 1c adjusted mean changes from baseline for the placebo versus dapagliflozin 2.5/5/10-mg groups were 610.04% versus 610.41%, 610.56% and 610.73%, respectively. There were no meaningful differences in HbA 1c changes from baseline from 24 to 4802weeks, indicating that glycemic efficacy was maintained. Improvements in fasting plasma glucose and post-challenge plasma glucose were also observed with dapagliflozin over 4802weeks. Dapagliflozin 2.5/5/1002mg produced sustained reductions in weight (611.36/611.54/612.4102kg) versus placebo (610.7702kg). Adjusted mean reductions from baseline in systolic blood pressure were also greater than placebo for all dapagliflozin doses. In the placebo versus dapagliflozin groups, serious adverse events were 8.9% versus 8.6–11.0%, hypoglycemic events were 6.8% versus 9.7–11.3%, and events suggestive of genital infection were 1.4% versus 5.2–8.6%. Conclusion Dapagliflozin added to glimepiride improved glycemic control and body weight, with short-term findings maintained during the study’s extension period. Therapy was generally well tolerated over 4802weeks; hypoglycemic events and events suggestive of genital infection were reported more often in patients receiving dapagliflozin.

Aims To evaluate the efficacy and safety of twice-daily dosing of dapagliflozin and metformin, exploring the feasibility of a fixed-dose combination. Methods In this 16-week, phase III, randomized, double-blind placebo-controlled study, adults who were receiving metformin administered twice daily (≥150065mg/day) and had inadequate glycaemic control were randomized 165:65165:65165:651 to receive dapagliflozin twice daily (2.5 or 565mg), placebo or dapagliflozin 1065mg once daily (which was included as a benchmark). The primary endpoint was change from baseline glycated haemoglobin (HbA1c) level. Secondary endpoints included changes in fasting plasma glucose (FPG) level and body weight. Results <p>Four hundred adults were randomized to dapagliflozin (2.565mg twice daily, 565mg twice daily, 1065mg once daily) or placebo co-administered with metformin twice daily. At 16 weeks, the adjusted mean change in HbA1c from baseline was significantly reduced in the dapagliflozin 2.565mg twice daily and 565mg twice daily groups versus placebo (610.52 vs. 610.30%, p65=650.0106 and 610.65% vs. 610.30%, p65 Conclusions Dapagliflozin 2.5 or 565mg twice daily added to metformin was effective in reducing glycaemic levels in patients with type 2 diabetes inadequately controlled with metformin alone. This study supports the development of a fixed-dose combination regimen.

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 610.42% for placebo versus 610.82 and 610.97% 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.

Abstract OBJECTIVE: To evaluate the efficacy and safety of dapagliflozin in patients with type 2 diabetes inadequately controlled with metformin and sulfonylurea. RESEARCH DESIGN AND METHODS: Patients with HbA1c of 7.0% (53 mmol/mol) to 10.5% (91 mmol/mol) receiving sulfonylurea and metformin were randomized to receive dapagliflozin 10 mg/day (n = 109) or placebo (n = 109) for 24 weeks. RESULTS: HbA1c (baseline: dapagliflozin 8.08% [65 mmol/mol]; placebo 8.24% [67 mmol/mol]) and fasting plasma glucose (baseline: dapagliflozin 167.4 mg/dL [9.29 mmol/L]; placebo 180.5 mg/dL [10.02 mmol/L]) significantly improved from baseline with dapagliflozin (placebo-subtracted change -0.69% [-7.5 mmol/mol], P < 0.0001; -33.5 mg/dL [-1.86 mmol/L], P < 0.0001, respectively). More patients achieved a therapeutic glycemic response (HbA1c <7.0% [53 mmol/mol]) with dapagliflozin (31.8%) versus placebo (11.1%) (P < 0.0001). Body weight and systolic blood pressure were significantly reduced from baseline over 24 and 8 weeks, respectively, with dapagliflozin (placebo-subtracted change -2.1 kg, P < 0.0001; -3.8 mmHg, P = 0.0250). Patients receiving dapagliflozin showed placebo-subtracted increases in total, LDL, and HDL cholesterol (11.4 mg/dL, P = 0.0091; 11.4 mg/dL, P = 0.0030; 2.2 mg/dL, P = 0.0172, respectively) with no change in LDL/HDL cholesterol ratio (0.1; P = 0.2008) or triglycerides (-16.5 mg/dL; P = 0.1755). Adverse events occurred in 48.6% of patients receiving dapagliflozin and 51.4% receiving placebo. Significantly more patients with dapagliflozin compared with placebo experienced hypoglycemia (12.8 vs. 3.7%; P = 0.024) and genital infections (5.5 vs. 0%; P = 0.029). Events of urinary tract infection were reported by 6.4% of patients in both groups. CONCLUSIONS: Dapagliflozin was well tolerated and effective over 24 weeks as add-on to metformin plus sulfonylurea. Adverse effects included hypoglycemia and genital infections. TRIAL REGISTRATION: ClinicalTrials.gov NCT01392677 . 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.

http://care.diabetesjournals.org/lookup/doi/10.2337/dc15-0779

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.

To assess the efficacy of dapagliflozin, a sodium-glucose cotransporter 2 inhibitor, for the treatment of individuals with type 2 diabetes mellitus (T2DM) and preexisting cardiovascular disease (CVD).Randomized, double-blind, age-stratified (<65 and ≥ 65), 24-week clinical trial with a 28-week extension.One hundred seventy-three centers in 10 countries.Individuals (N = 964) with T2DM, glycosylated hemoglobin (HbA1c) of 7.0% to 10.0%, and documented CVD.Dapagliflozin 10 mg/d or placebo was added to usual care. Participants receiving insulin had their total daily insulin dose reduced by 25% at randomization.Two equal primary end points: change from baseline in HbA1c and proportion of participants achieving a three-item end point (reduction of ≥ 0.5% in HbA1c, ≥ 3% in body weight, and ≥ 3 mmHg in systolic blood pressure) at 24 weeks.Forty-seven percent were aged 65 and older, 7.7% were aged 75 and older, mean duration of T2DM was 13 years, mean baseline HbA1c was 8.1%, and approximately 60% were taking insulin. The placebo-corrected change in HbA1c with dapagliflozin was -0.4% at 24 weeks. Significantly more participants achieved the three-item end point with dapagliflozin (10.0%) than with placebo (1.9%). The placebo-corrected percentage change in body weight for dapagliflozin was -1.9% (-1.8 kg). Similar results were observed in both age strata, and changes were maintained over 52 weeks. More than one-quarter (28.2%) of participants receiving dapagliflozin and 25.3% of those receiving placebo experienced hypoglycemia. More participants receiving dapagliflozin had vulvovaginitis, balanitis, or urinary tract infection.When added to a usual background regimen in an older population with advanced T2DM and preexisting comorbid CVD, dapagliflozin improved glycemic control without an increase in hypoglycemic risk, promoted weight loss, and was well tolerated.

AimsSodium090009glucose 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).MethodsIn this randomized, placebo-controlled, double-blind trial, 75 subjects with type 2 diabetes were assigned placebo, dapagliflozin 10090009mg/day, or HCTZ 25090009mg/day. Changes from baseline BP, body weight, plasma volume and GFR were assessed after 12090009weeks of treatment.ResultsSubjects' mean age was 56090009years, type 2 diabetes mellitus (T2DM) duration 6.3090009years, 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 0908080.9 (95%CI 0908084.2, +2.4), 0908083.3 (95%CI 0908086.8, +0.2), and 0908086.6 (95%CI 0908089.9, 0908083.2) 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 (09080810.8%; 95%CI 09080814.6, 0908086.7) relative to placebo (0908082.9%; 95% CI 0908086.9, +1.2) or HCTZ (0908083.4%; 95%CI 0908087.3, +0.6).ConclusionsDapagliflozin-induced SGLT2 inhibition for 12090009weeks 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.

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 -1.8902kg for the 5- and 10-mg doses, respectively, and +0.2102kg 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 502mg (+0.1302mg/dl) and 1002mg (+0.1802mg/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.

http://doi.wiley.com/10.1111/dom.12325

AimDapagliflozin 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.MethodsPatients (n090009=090009279) were randomized to receive dapagliflozin (1, 2.5, 5 or 10090009mg/day) or placebo once daily for 12090009weeks. 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.ResultsSignificant reductions in HbA1c were seen with all dapagliflozin doses (0908080.11 to 0908080.44%) versus placebo (+0.37%). Reductions were also observed in FPG with dapagliflozin (0908080.87 to 0908081.77090009mmol/l [09080815.61 to 09080831.94090009mg/dl]) versus placebo (+0.62090009mmol/l [+11.17090009mg/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 (40.709000953.8%) versus placebo (38.9%) and were mostly mild/moderate in intensity. Three hypoglycaemic events were reported (1 each with placebo, dapagliflozin 2.5090009mg and 10090009mg). The frequency of signs and symptoms suggestive of urinary tract or genital infections was 00900093.8 and 00900091.8% respectively with dapagliflozin and 1.9 and 0% with placebo. No AEs of pyelonephritis were observed.ConclusionsCompared with placebo, dapagliflozin significantly reduced hyperglycaemia over 12090009weeks with a low risk of hypoglycaemia in Japanese T2DM patients with inadequate glycaemic control.

Dapagliflozin is a highly selective, orally active inhibitor of renal sodium-glucose cotransporter 2 that reduces hyperglycemia by increasing urinary glucose excretion. The goal of this study was to evaluate dapagliflozin as monotherapy in drug-naive Asian patients with type 2 diabetes whose disease was inadequately controlled with diet and exercise. In this Phase III, multicenter, parallel-group, double-blind study, drug-naive patients with glycosylated hemoglobin (HbA1c) levels ≥7.0% to ≤10.5% (≥53–≤91 mmol/mol) were randomized (by using an interactive voice response system) to receive placebo (n = 132), dapagliflozin 5 mg (n = 128), or dapagliflozin 10 mg (n = 133). The primary end point was mean change from baseline in HbA1c level at week 24 (last-observation-carried-forward). Secondary end points included changes in fasting plasma glucose, 2-hour postprandial glucose, body weight, and other glycemic parameters. Baseline characteristics were balanced across groups. Most patients (89%) were Chinese, median disease duration was 0.2 year, and mean HbA1c level was 8.26%. Most patients (87%) completed the study. At week 24, mean reductions in HbA1c were 610.29% for placebo versus 611.04% and 611.11% for dapagliflozin 5 and 10 mg, respectively (P < 0.0001 for both doses). Changes in fasting plasma glucose were 2.5, 6125.1, and –31.6 mg/dL (0.14, 611.39, and 611.75 mmol/L) for placebo, dapagliflozin 5 mg, and dapagliflozin 10 mg. Changes in 2-hour postprandial glucose were 1.1, 6146.8, and 6154.9 mg/dL (0.06, 612.60, and 613.05 mmol/L). Reductions in body weight were 610.27, 611.64, and 612.25 kg. Proportions of patients achieving HbA1c levels <7.0% (53 mmol/mol) were 21.3%, 42.6%, and 49.8%. Adverse events (AEs) occurred in 63.6%, 61.7%, and 60.9% of patients, and serious AEs occurred in 1.5%, 3.9%, and 3.0% of patients. No deaths occurred. Hypoglycemia was uncommon (1.5%, 0.8%, and 0.8%); no hypoglycemic event led to discontinuation. Genital infections occurred in 0.8%, 3.1%, and 4.5% of patients and urinary tract infections in 3.0%, 3.9%, and 5.3% of patients. No AEs of renal infection or pyelonephritis were reported. No changes in renal function or AEs of renal failure occurred. Compared with placebo, dapagliflozin 5 and 10 mg demonstrated clinically and statistically significant improvements in HbA1c levels after 24 weeks of treatment. Dose-dependent, statistically significant reductions in fasting plasma glucose, postprandial glucose, and weight were also observed for both doses compared with placebo. AEs and serious AEs were balanced across groups, with low rates of hypoglycemia and no increase in renal events. Genital infections and urinary tract infections were more common with dapagliflozin. Dapagliflozin as monotherapy in these drug-naive Asian patients was well tolerated, significantly improving glycemic control with the additional benefit of weight loss.

To assess the efficacy and safety of dapagliflozin as add-on therapy in patients with type 2 diabetes who were inadequately controlled with a dipeptidyl peptidase-4 inhibitor with or without metformin. In this 24-week, multicenter, randomized, double-blind, placebo-controlled, parallel-group, phase 3 study with a 24-week blinded extension period, 432 patients were randomized to receive dapagliflozin 10 mg/day or placebo added to sitagliptin (100 mg/day) metformin ( 1,500 mg/day). Baseline HbA1c and FPG levels were 7.9% (63.0 mmol/mol) and 162.2 mg/dL (9.0 mmol/L) for the dapagliflozin group and 8.0% (64.0 mmol/mol) and 163 mg/dL (9.0 mmol/L) for placebo. At week 24, dapagliflozin significantly reduced mean HbA1c levels (-0.5% [-4.9 mmol/mol]) versus placebo (0.0% [+0.4 mmol/mol]). Dapagliflozin reduced body weight versus placebo (-2.1 and -0.3 kg) and reduced HbA1c levels in patients with baseline values 8.0% (-0.8% [8.7 mmol/mol] and 0.0% [0.3 mmol/mol]) and fasting plasma glucose levels (-24.1 mg/dL [-1.3 mmol/L] and 3.8 mg/dL [0.2 mmol/L]). Similar results were observed when data were stratified by background therapy. Glycemic and weight benefits observed at week 24 were maintained through week 48. Changes from baseline in systolic blood pressure at week 8 were not significantly different between treatment groups. Over 48 weeks, fewer patients receiving dapagliflozin were discontinued or rescued for failing to achieve glycemic targets compared with placebo. Adverse events were balanced between groups, and discontinuation rates were low. At week 48, signs and symptoms suggestive of genital infection were more frequent with dapagliflozin (9.8%) than with placebo (0.4%). Signs and symptoms suggestive of urinary tract infection were balanced between dapagliflozin (6.7%) and placebo (6.2%). These results suggest that in patients with type 2 diabetes, inadequately controlled on sitagliptin with or without metformin, add-on treatment with dapagliflozin provides additional clinical benefit and is well tolerated.

Abstract Aims To assess initial pharmacotherapy of Type 2 diabetes with the sodium-glucose cotransporter-2 inhibitor dapagliflozin. Methods This double-blind, placebo-controlled trial, randomly allocated people with Type 2 diabetes aged 18–7702years and inadequate glycaemic control on diet and exercise [HbA1c 53–8602mmol/mol (7.0–10.0%)] to receive placebo ( n 02=0275) or dapagliflozin monotherapy 2.502mg ( n 02=0265), 502mg ( n 02=0264) or 1002mg ( n 02=0270) once daily in the morning. After 2402weeks, low-dose double-blind metformin 50002mg/day was added to the placebo group regimen (placebo+low-dose metformin group). Changes in HbA1c level, fasting plasma glucose and body weight, as well as adverse events, were assessed over 10202weeks. Results Of the 274 participants randomized, 167 completed the study (60.9%). At 102 weeks, significant differences vs placebo+low-dose metformin with dapagliflozin 5 and 10 mg were observed for HbA1c (615.8 mmol/mol [610.53%], P = 0.018; and 614.8 mmol/mol [610.44%], P = 0.048), respectively); and for FPG (610.69 mmol/L, P = 0.044; and 611.12 mmol/l, P = 0.001, respectively). For body weight, the difference between the dapagliflozin 10-mg group and the placebo+low-dose metformin group was significant (612.6002kg; P 02=020.016). Hypoglycaemic events were uncommon, with rates of 5.3% for placebo+low-dose metformin group and 0–4.6% for the dapagliflozin groups. Genital infections and urinary tract infections were more common in the dapagliflozin groups than in the placebo+low-dose metformin group. Conclusions Dapagliflozin as monotherapy in treatment-na07ve people with early Type 2 diabetes improved glycaemic control and reduced weight without increasing hypoglycaemia over 10202weeks. Dapagliflozin may provide an alternative initial pharmacotherapy in such people.

Background Management of type 2 diabetes with metformin often does not provide adequate glycemic control, thereby necessitating add-on treatment. In a 24-week clinical trial, dapagliflozin, an investigational sodium glucose cotransporter 2 inhibitor, improved glycemic control in patients inadequately controlled with metformin. The present study is an extension that was undertaken to evaluate dapagliflozin as long-term therapy in this population. Methods This was a long-term extension (total 102 weeks) of a 24-week phase 3, multicenter, randomized, placebo-controlled, double-blind, parallel-group trial. Patients were randomly assigned (1:1:1:1) to blinded daily treatment (placebo, or dapagliflozin 2.5 to 5, or 10 mg) plus open-label metformin (???1,500 mg). The previously published primary endpoint was change from baseline in glycated hemoglobin (HbA1c) at 24 weeks. This paper reports the follow-up to week 102, with analysis of covariance model performed at 24 weeks with last observation carried forward; a repeated measures analysis was utilized to evaluate changes from baseline in HbA1c, fasting plasma glucose (FPG), and weight. Results A total of 546 patients were randomized to 1 of the 4 treatments. The completion rate for the 78-week double-blind extension period was lower for the placebo group (63.5%) than for the dapagliflozin groups (68.3% to 79.8%). At week 102, mean changes from baseline HbA1c (8.06%) were +0.02% for placebo compared with -0.48% (P = 0.0008), -0.58% (P <0.0001), and -0.78% (P <0.0001) for dapagliflozin 2.5 to 5, and 10 mg, respectively. In addition, all dapagliflozin groups had sustained reductions from baseline in FPG (-1.07 to -1.47 mmol/l) and body weight (-1.10 to -1.74 kg) at 102 weeks, whereas increases were noted in placebo-treated patients for both of these outcomes. Events of hypoglycemia were rare and were not severe. Evidence suggestive of genital infection was reported in 11.7% to 14.6% of dapagliflozin patients and 5.1% of placebo patients, with one related discontinuation (dapagliflozin 5 mg). Evidence suggestive of urinary tract infection was reported in 8.0% to 13.3% of dapagliflozin patients and 8.0% of placebo patients, with one related discontinuation (dapagliflozin 2.5 mg). Conclusions Dapagliflozin added to metformin for 102 weeks enabled sustained reductions in HbA1c, FPG, and weight without increased risk of hypoglycemia in patients with type 2 diabetes who were inadequately controlled on metformin alone. Trial registration ClinicalTrials.gov: NCT00528879

OBJECTIVE: To study the prevalence of and risk factors for asymptomatic bacteriuria (ASB) in women with and without diabetes. RESEARCH DESIGN AND METHODS: A total of 636 nonpregnant women with diabetes (type 1 and type 2) who were 18-75 years of age and had no abnormalities of the urinary tract, and 153 women without diabetes who were visiting the eye and trauma outpatient clinic (control subjects) were included. We defined ASB as the presence of at least 10(5) colony-forming units/ml of 1 or 2 bacterial species in a culture of clean-voided midstream urine from an individual without symptoms of a urinary tract infection (UTI). RESULTS: The prevalence of ASB was 26% in the diabetic women and 6% in the control subjects (P < 0.001). The prevalence of ASB in women with type 1 diabetes was 21%. Risk factors for ASB in type 1 diabetic women included a longer duration of diabetes, peripheral neuropathy, and macroalbuminuria. The prevalence of ASB was 29% in women with type 2 diabetes. Risk factors for ASB in type 2 diabetic women included age, macroalbuminuria, a lower BMI, and a UTI during the previous year. No association was evident between current HbA1c level and the presence of ASB. CONCLUSIONS: The prevalence of ASB is increased in women with diabetes and might be added to the list of diabetic complications in these women.

http://linkinghub.elsevier.com/retrieve/pii/S0924857907004864

The incidence of type 2 diabetes mellitus is increasing worldwide. The existing therapeutic classes of antidiabetic drugs are not adequately effective in maintaining long-term glycemic control in most patients, even when used in combination. One emerging novel therapeutic class of antidiabetic drugs is sodium glucose cotransporter 2 (SGLT2) inhibitors. SGLT2 accounts for 90% of the glucose reabsorption in the kidney. The SGLT2 inhibitors increase urinary excretion of glucose and lower plasma glucose levels in an insulin-independent manner. Dapagliflozin, the most prominent molecule in this class, is currently in a phase III clinical trial. Other members of this class (eg, sergliflozin, remogliflozin) are also in different phases of clinical trials. This class of novel agents can effectively control blood sugar level without producing weight gain or hypoglycemia. Results of ongoing phase III clinical trials are crucial to determine whether the risk-benefit ratio will allow approval of this new class of drugs for the management of type 2 diabetes mellitus.

Urinary tract infections (UTIs) are considered to be the most common bacterial infection. According to the 1997 National Ambulatory Medical Care Survey and National Hospital Ambulatory Medical Care Survey, UTI accounted for nearly 7 million office visits and 1 million emergency department visits, resulting in 100,000 hospitalizations. Nevertheless, it is difficult to accurately assess the incidence of UTIs, because they are not reportable diseases in the United States. This situation is further complicated by the fact that accurate diagnosis depends on both the presence of symptoms and a positive urine culture, although in most outpatient settings this diagnosis is made without the benefit of culture. Women are significantly more likely to experience UTI than men. Nearly 1 in 3 women will have had at least 1 episode of UTI requiring antimicrobial therapy by the age of 24 years. Almost half of all women will experience 1 UTI during their lifetime. Specific subpopulations at increased risk of UTI include infants, pregnant women, the elderly, patients with spinal cord injuries and/or catheters, patients with diabetes or multiple sclerosis, patients with acquired immunodeficiency disease syndrome/human immunodeficiency virus, and patients with underlying urologic abnormalities. Catheter-associated UTI is the most common nosocomial infection, accounting for > 1 million cases in hospitals and nursing homes. The risk of UTI increases with increasing duration of catheterization. In noninstitutionalized elderly populations, UTIs are the second most common form of infection, accounting for nearly 25% of all infections. There are important medical and financial implications associated with UTIs. In the nonobstructed, nonpregnant female adult, acute uncomplicated UTI is believed to be a benign illness with no long-term medical consequences. However, UTI elevates the risk of pyelonephritis, premature delivery, and fetal mortality among pregnant women, and is associated with impaired renal function and end-stage renal disease among pediatric patients. Financially, the estimated annual cost of community-acquired UTI is significant, at approximately $1.6 billion.

The clinical significance and management of asymptomatic bacteriuria (ASB) differs according to different groups of patients. ASB requires antibiotic treatment in pregnant women, children aged 5–6 years and prior to invasive genitourinary procedures. However, there is a consensus that ASB in the elderly, healthy school girls and young women, diabetic women and patients with indwelling catheters or intermittent catheterization has no clinical significance and antibiotic prescription is not indicated.