Shamik Parikh

Effects of dapagliflozin on body weight, total fat mass, and regional adipose tissue distribution in patients with type 2 diabetes mellitus with inadequate glycemic control on metformin.

CONTEXT Dapagliflozin, a selective sodium-glucose cotransporter 2 (SGLT2) inhibitor, reduces hyperglycemia in patients with type 2 diabetes mellitus (T2DM) by increasing urinary glucose excretion, and weight loss is a consistent associated finding. OBJECTIVES Our objectives were to confirm weight loss with dapagliflozin and establish through body composition measurements whether weight loss is accounted for by changes in fat or fluid components. DESIGN AND SETTING This was a 24-wk, international, multicenter, randomized, parallel-group, double-blind, placebo-controlled study with ongoing 78-wk site- and patient-blinded extension period at 40 sites in five countries. PATIENTS Included were 182 patients with T2DM (mean values: women 63.3 and men 58.6 yr of age; hemoglobin A1c 7.17%, body mass index 31.9 kg/m2, and body weight 91.5 kg) inadequately controlled on metformin. INTERVENTION Dapagliflozin 10 mg/d or placebo was added to open-label metformin for 24 wk. MAIN OUTCOME MEASURES Primary endpoint was total body weight (TBW) change from baseline at wk 24. Key secondary endpoints were waist circumference and dual-energy x-ray absorptiometry total-body fat mass (FM) changes from baseline at wk 24, and patient proportion achieving body weight reduction of at least 5% at wk 24. In a subset of patients, magnetic resonance assessment of visceral adipose tissue (VAT) and sc adipose tissue (SAT) volume and hepatic lipid content were also evaluated. RESULTS At wk 24, placebo-corrected changes with dapagliflozin were as follows: TBW, -2.08 kg [95% confidence interval (CI)=-2.84 to -1.31; P<0.0001]; waist circumference, -1.52 cm (95% CI=-2.74 to -0.31; P=0.0143); FM, -1.48 kg (95% CI=-2.22 to -0.74; P=0.0001); proportion of patients achieving weight reduction of at least 5%, +26.2% (95% CI=15.5 to 36.7; P<0.0001); VAT, -258.4 cm3 (95% CI=-448.1 to -68.6; nominal P=0.0084); SAT, -184.9 cm3 (95% CI=-359.7 to -10.1; nominal P=0.0385). In the dapagliflozin vs. placebo groups, respectively, serious adverse events were reported in 6.6 vs. 1.1%; events suggestive of vulvovaginitis, balanitis, and related genital infection in 3.3 vs. 0%; and lower urinary tract infections in 6.6 vs. 2.2%. CONCLUSIONS Dapagliflozin reduces TBW, predominantly by reducing FM, VAT and SAT in T2DM inadequately controlled with metformin.

Dapagliflozin Versus 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

OBJECTIVE Although initially effective, sulfonylureas are associated with poor glycemic durability, weight gain, and hypoglycemia. Dapagliflozin, a selective inhibitor of sodium-glucose cotransporter 2 (SGLT2), reduces hyperglycemia by increasing urinary glucose excretion independent of insulin and may cause fewer of these adverse effects. We compared the efficacy, safety, and tolerability of dapagliflozin with the sulfonylurea glipizide in patients with type 2 diabetes inadequately controlled with metformin monotherapy. RESEARCH DESIGN AND METHODS This 52-week, double-blind, multicenter, active-controlled, noninferiority trial randomized patients with type 2 diabetes (baseline mean HbA1c, 7.7%), who were receiving metformin monotherapy, to add-on dapagliflozin (n = 406) or glipizide (n = 408) up-titrated over 18 weeks, based on glycemic response and tolerability, to ≤10 or ≤20 mg/day, respectively. RESULTS The primary end point, adjusted mean HbA1c reduction with dapagliflozin (−0.52%) compared with glipizide (−0.52%), was statistically noninferior at 52 weeks. Key secondary end points: dapagliflozin produced significant adjusted mean weight loss (−3.2 kg) versus weight gain (1.2 kg; P < 0.0001) with glipizide, significantly increased the proportion of patients achieving ≥5% body weight reduction (33.3%) versus glipizide (2.5%; P < 0.0001), and significantly decreased the proportion experiencing hypoglycemia (3.5%) versus glipizide (40.8%; P < 0.0001). Events suggestive of genital infections and lower urinary tract infections were reported more frequently with dapagliflozin compared with glipizide but responded to standard treatment and rarely led to study discontinuation. CONCLUSIONS Despite similar 52-week glycemic efficacy, dapagliflozin reduced weight and produced less hypoglycemia than glipizide in type 2 diabetes inadequately controlled with metformin. Long-term studies are required to further evaluate genital and urinary tract infections with SGLT2 inhibitors.

Long-Term Efficacy of Dapagliflozin in Patients With Type 2 Diabetes Mellitus Receiving High Doses of Insulin: A Randomized Trial

BACKGROUND Dapagliflozin, a selective inhibitor of sodium-glucose cotransporter 2, may improve glycemic control with a lower dose of insulin and attenuate the associated weight gain in patients with inadequate control despite high doses of insulin. OBJECTIVE To evaluate the efficacy and safety of adding dapagliflozin therapy in patients whose type 2 diabetes mellitus is inadequately controlled with insulin with or without oral antidiabetic drugs. DESIGN A 24-week, randomized, placebo-controlled, multicenter trial followed by a 24-week extension period. An additional 56-week extension period is ongoing. (ClinicalTrials.gov registration number: NCT00673231) SETTING 126 centers in Europe and North America from 30 April 2008 to 19 November 2009. PATIENTS 808 patients with inadequately controlled type 2 diabetes mellitus receiving at least 30 U of insulin daily, with or without up to 2 oral antidiabetic drugs. INTERVENTION Patients were randomly assigned in a 1:1:1:1 ratio and allocated with a computer-generated scheme to receive placebo or 2.5, 5, or 10 mg of dapagliflozin, once daily, for 48 weeks. MEASUREMENTS The primary outcome was change in hemoglobin A(1c) from baseline to 24 weeks. Secondary outcomes included changes in body weight, insulin dose, and fasting plasma glucose level at 24 weeks and during the 24-week extension period. Adverse events were evaluated throughout both 24-week periods. RESULTS 800 patients were analyzed. After 24 weeks, mean hemoglobin A(1c) decreased by 0.79% to 0.96% with dapagliflozin compared with 0.39% with placebo (mean difference, -0.40% [95% CI, -0.54% to -0.25%] in the 2.5-mg group, -0.49% [CI, -0.65% to -0.34%] in the 5-mg group, and -0.57% [CI, -0.72% to -0.42%] in the 10-mg group). Daily insulin dose decreased by 0.63 to 1.95 U with dapagliflozin and increased by 5.65 U with placebo (mean difference, -7.60 U [CI, -10.32 to -4.87 U] in the 2.5-mg group, -6.28 U [CI, -8.99 to -3.58 U] in the 5-mg group, and -6.82 U [CI, -9.56 to -4.09 U] in the 10-mg group). Body weight decreased by 0.92 to 1.61 kg with dapagliflozin and increased by 0.43 kg with placebo (mean differences, -1.35 kg [CI, -1.90 to -0.80 kg] in the 2.5-mg group, -1.42 kg [CI, -1.97 to -0.88 kg] in the 5-mg group, and -2.04 kg [CI, -2.59 to -1.48 kg] in the 10-mg group). These effects were maintained at 48 weeks. Compared with the placebo group, patients in the pooled dapagliflozin groups had a higher rate of hypoglycemic episodes (56.6% vs. 51.8%), events suggesting genital infection (9.0% vs. 2.5%), and events suggesting urinary tract infection (9.7% vs. 5.1%). LIMITATION Insulin doses were not titrated to target, and the study was not designed to evaluate long-term safety. CONCLUSION Dapagliflozin improves glycemic control, stabilizes insulin dosing, and reduces weight without increasing major hypoglycemic episodes in patients with inadequately controlled type 2 diabetes mellitus. PRIMARY FUNDING SOURCE AstraZeneca and Bristol-Myers Squibb.

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

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.

Dapagliflozin maintains glycaemic control while reducing weight and body fat mass over 2 years in patients with type 2 diabetes mellitus inadequately controlled on metformin

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.

Dapagliflozin is effective as add-on therapy to sitagliptin with or without metformin: a 24-week, multicenter, randomized, double-blind, placebo-controlled study.

OBJECTIVE 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. RESEARCH DESIGN AND METHODS 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). RESULTS 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%). CONCLUSIONS 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.

Dapagliflozin in patients with type 2 diabetes receiving high doses of insulin: efficacy and safety over 2 years.

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.

Vulvovaginitis and balanitis in patients with diabetes treated with dapagliflozin

BACKGROUND Vulvovaginitis, balanitis, and related genital infections are common in patients with type 2 diabetes. Glucosuria, which is an outcome of treatment with sodium glucose cotransporter 2 (SGLT2) inhibitors, is among the possible causes. Dapagliflozin, an SGLT2 inhibitor with demonstrated glycemic benefits in patients with diabetes, has been studied across a broad spectrum of patients. Analysis of multi-trial safety data may better define the relationship between glucosuria and genital infection. METHODS Safety data were pooled from 12 randomized, placebo-controlled Phase 2b/3 trials to analyze the association of glucosuria with genital infection in patients with suboptimally controlled diabetes (HbA1c >6.5%-12%). Patients were randomized to receive dapagliflozin (2.5mg, 5mg, or 10mg) or placebo once daily, either as monotherapy or add-on to metformin, insulin, sulfonylurea, or thiazolidinedione for 12-24weeks. The incidence of clinical diagnoses and of events suggestive of genital infection was evaluated. RESULTS The pooled safety data included 4545 patients: 3152 who received once-daily dapagliflozin (2.5mg [n=814], 5mg [n=1145], or 10mg [n=1193]) as monotherapy or add-on treatment, and 1393 placebo-treated patients. For dapagliflozin 2.5mg, 5mg, 10mg, and placebo, diagnosed infections were reported in 4.1%, 5.7%, 4.8%, and 0.9%, respectively. Most infections were mild or moderate and responded to standard antimicrobial treatment. Discontinuation due to these events was rare. No clear dose-response relationship between dapagliflozin and genital infection was demonstrated. CONCLUSIONS Treatment with dapagliflozin 2.5mg, 5mg, or 10mg once daily is accompanied by an increased risk of vulvovaginitis or balanitis, related to the induction of glucosuria. Events were generally mild to moderate, clinically manageable, and rarely led to discontinuation of treatment.

Dapagliflozin has no effect on markers of bone formation and resorption or bone mineral density in patients with inadequately controlled type 2 diabetes mellitus on metformin

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.

Urinary tract infections in patients with diabetes treated with dapagliflozin

AIMS Urinary tract infection is common in patients with type 2 diabetes. Possible causative factors include glucosuria, which is a result of treatment with sodium glucose cotransporter 2 (SGLT2) inhibitors. Dapagliflozin is an investigative SGLT2 inhibitor with demonstrated glycemic benefits in patients with diabetes. Data from dapagliflozin multi-trial safety data were analyzed to clarify the association between glucosuria and urinary tract infection. METHODS Safety data from 12 randomized, placebo-controlled trials were pooled to evaluate the relationship between glucosuria and urinary tract infection in patients with inadequately controlled diabetes (HbA1c >6.5%-12%). Patients were treated with dapagliflozin (2.5, 5, or 10mg) or placebo once daily, either as monotherapy or add-on to metformin, insulin, sulfonylurea, or thiazolidinedione for 12-24weeks. The incidence of clinical diagnoses and events suggestive of urinary tract infection were quantified. RESULTS This analysis included 3152 patients who received once-daily dapagliflozin (2.5mg [n=814], 5mg [n=1145], or 10mg [n=1193]) as monotherapy or add-on treatment, and 1393 placebo-treated patients. For dapagliflozin 2.5mg, 5mg, 10mg, and placebo, diagnosed infections were reported in 3.6%, 5.7%, 4.3%, and 3.7%, respectively. Urinary glucose levels, but not the incidence of urinary tract infection, increased progressively with dapagliflozin dosage. Most identified infections were those considered typical for patients with diabetes. Discontinuations due to urinary tract infection were rare: 8 (0.3%) dapagliflozin-treated patients and 1 (0.1%) placebo-treated patient. Most diagnosed infections were mild to moderate and responded to standard antimicrobial treatment. CONCLUSIONS Treatment of type 2 diabetes with once-daily dapagliflozin 5 or 10mg is accompanied by a slightly increased risk of urinary tract infection. Infections were generally mild to moderate and clinically manageable. This analysis did not demonstrate a definitive dose relationship between glucosuria and urinary tract infection.