Keith Bowering

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.

A study comparing insulin lispro mix 25 with glargine plus lispro therapy in patients with Type 2 diabetes who have inadequate glycaemic control on oral anti-hyperglycaemic medication: results of the PARADIGM study.

Diabet. Med. 29, e263‐e272 (2012)

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.

Faster Aspart Versus Insulin Aspart As Part of a Basal-Bolus Regimen in Inadequately Controlled Type 2 Diabetes: The onset 2 Trial

OBJECTIVE This multicenter, double-blind, treat-to-target, phase 3 trial evaluated the efficacy and safety of fast-acting insulin aspart (faster aspart) versus insulin aspart (IAsp) in adults with type 2 diabetes receiving basal insulin and oral antidiabetic agents. RESEARCH DESIGN AND METHODS The primary end point was HbA1c change from baseline after 26 weeks’ treatment. After an 8-week run-in to optimize basal insulin, subjects were randomized (1:1) to mealtime faster aspart (n = 345) or IAsp (n = 344), titrated using a simple daily patient-driven algorithm, plus insulin glargine U100 and metformin. RESULTS HbA1c change was –1.38% (faster aspart) and –1.36% (IAsp); mean HbA1c was 6.6% for both groups. Faster aspart demonstrated noninferiority versus IAsp in reducing HbA1c (estimated treatment difference [ETD] [95% CI] –0.02% [–0.15; 0.10]). Both treatments improved postprandial plasma glucose (PPG) control; the PPG increment (liquid meal test) was statistically significant in favor of faster aspart after 1 h (ETD [95% CI] −0.59 mmol/L [−1.09; −0.09]; −10.63 mg/dL [−19.56; −1.69]; P = 0.0198), but not after 2–4 h. Change from baseline in fasting plasma glucose, body weight, and overall severe/blood glucose–confirmed hypoglycemia rates (rate ratio [RR] [95% CI] 1.09 [0.88; 1.36]) were similar between treatments. Postmeal hypoglycemia (0−2 h) rates were 2.27 (faster aspart) and 1.49 (IAsp) per patient-year of exposure (RR [95% CI] 1.60 [1.13; 2.27]). CONCLUSIONS Faster aspart and IAsp were confirmed noninferior in a basal-bolus regimen regarding change from baseline in HbA1c. Faster aspart improved 1-h PPG with no differences in 2−4-h PPG versus IAsp. Overall hypoglycemia rates were similar except for an increase in 0−2-h postmeal hypoglycemia with faster aspart.

The effect of basal-bolus therapy varies with baseline 1,5-anhydroglucitol level in people with Type 2 diabetes: a post hoc analysis

To investigate the impact of baseline 1,5‐anhydroglucitol on the treatment effect of basal–bolus therapy in people with Type 2 diabetes.

Response to Comment on Russell-Jones et al. Diabetes Care 2017;40:943–950. Comment on Bowering et al. Diabetes Care 2017;40:951–957

We appreciate the relevant comments raised by Wu et al. (1) regarding the challenges faced by clinicians in safely achieving postprandial, and overall, glycemic control for patients with diabetes in the face of individual needs and physiological variation (including varying rates of gastric emptying/gastroparesis). Increasing awareness and understanding of factors affecting the complex physiology of postprandial glucose regulation, together with an understanding of the clinical pharmacological profile, are key in guiding appropriate dosing and timing of any mealtime insulin therapy. In the onset 1 and 2 trials, both mealtime (0–2 min before the meal) and postmeal dosing (20 min after the start of a meal investigated in onset 1) of fast-acting insulin aspart (faster aspart) demonstrated noninferior overall glycemic control compared with mealtime conventional insulin aspart. Importantly, no statistically significant differences in the overall rates of hypoglycemia were found in these trials …