K. Rohwedder

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.

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.

Long-term glycaemic response and tolerability of dapagliflozin versus a sulphonylurea as add-on therapy to metformin in patients with type 2 diabetes: 4-year data.

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.

Dapagliflozin Improves Glycemic Control and Reduces Body Weight as Add-on Therapy to Metformin Plus Sulfonylurea: A 24-Week Randomized, Double-Blind Clinical Trial

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.

Durability of glycaemic efficacy over 2 years with dapagliflozin versus glipizide as add‐on therapies in patients whose type 2 diabetes mellitus is inadequately controlled with metformin

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.

Durability and tolerability of dapagliflozin over 52 weeks as add-on to metformin and sulphonylurea in type 2 diabetes

To evaluate the safety and efficacy of dapagliflozin as add‐on therapy to metformin plus sulphonylurea over 52 weeks.

Dapagliflozin Versus Glipizide as Add-on Therapy in Patients With Type 2 Diabetes Who Have Inadequate Glycemic Control With Metformin

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.

Patient-reported outcomes among patients with type 2 diabetes mellitus treated with dapagliflozin in a triple-therapy regimen for 52 weeks.

Patients with type 2 diabetes (T2DM) and inadequate glycaemic control on combination metformin (MET) and sulphonylurea (SU) were enrolled in a 24‐week, double‐blind, randomized, placebo‐controlled study with a 28‐week extension. The five‐dimension EuroQol questionnaire (EQ‐5D), SHIELD Weight Questionnaire‐9 (WQ‐9), Impact of Weight on Quality of Life‐Lite (IWQOL‐Lite) questionnaire and the Diabetes Treatment Satisfaction Questionnaire (DTSQ) were used to evaluate health status and health‐related quality of life (HRQoL) at baseline and week 52. Patients with dapagliflozin 10 mg + MET + SU (n = 108) were compared with patients treated with placebo + MET + SU (n = 108), using a repeated‐measures mixed model. EQ‐5D visual analogue scale scores, IWQOL‐Lite and DTSQ scores improved in the dapagliflozin and placebo groups from baseline to week 52; however, there was no significant difference between groups (p > 0.20). EQ‐5D index scores remained the same from baseline to week 52 for dapagliflozin and placebo (p = 0.54). A numerically greater proportion of the dapagliflozin group reported improvement in all nine SHIELD WQ‐9 items compared with placebo, and the difference was statistically significant for physical health (p = 0.017). Over 52 weeks of therapy, patients maintained their health status and HRQoL when dapagliflozin was added to the treatment.

Changes in patient characteristics, glucose lowering treatment, glycemic control and complications in type 2 diabetes in general practices (Disease Analyzer, Germany: 2008-2016)

ABSTRACT Objectives: The objectives were to examine long-term changes in type 2 diabetes patient characteristics, diabetes treatment, control and complications in general practices. Methods: All type 2 diabetes patients were identified in a representative general practice database (Disease Analyser, Germany) in three periods (01/2008–12/2008: n = 90.866, 818 practices, mean age (SD): 67.6 (12.1) years, 51% males; 01/2012–12/2012: n = 179.923, 1.158 practices, 68.3 (12.6) years, 51% males; 10/2015–09/2016: n = 201.667, 1.184 practices, 68.2 (12.9) years, 52% males). Chi-square and Wilcoxon rank-sum tests were used for testing differences (2008 vs. 2015/16). Results: The mean number of type 2 patients per practice increased (2008: 111; 2015/16: 170). The proportion of retirees declined (74% vs. 61%) and patients in the working population increased (18% vs. 28%) (all p < 0.001). There were no relevant changes in mean HbA1c (7.1% vs. 7.2%), fasting blood glucose (141 mg/dl vs. 144 mg/dl) and BMI (31 kg/m2 vs. 32 kg/m2), whereas total cholesterol (204 mg/dl vs. 196 mg/dl) and triglycerides (159 mg/dl vs. 153 mg/dl) slightly declined (all p < 0.001). Prescription use of metformin, dipeptidyl peptidase-4 (DPP-4) and sodium dependent glucose transporter-2 (SGLT-2) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists enlarged (dual or triple combinations) while sulfonylurea use decreased. Prevalence of polyneuropathy (6.2% vs. 8.6%), nephropathy (1.9% vs. 3.2%) and depression (7.6% vs. 10.0%) rised (all p < 0.001). Conclusions: General practitioners play a key role in diabetes care, increasingly treating type 2 diabetes patients in the working population. There was no change in glycemic control over the study period (2008–2016). The use of glucose-lowering drug combinations increased and microvascular complications were more often recorded.