Baseline nocturnal glucose change: A predictor of the treatment effect of bolus intensification in insulin-treated type 2 diabetes.

This post hoc analysis of an 18-week randomized trial explored the utility of calculating baseline glycated haemoglobin (HbA1c), postprandial glucose (PPG) increments and nocturnal glucose change in predicting efficacy and safety outcomes in response to bolus insulin intensification in people with type 2 diabetes (T2D). Analyses were conducted on 236 participants with T2D receiving metformin: 116 received fast-acting insulin aspart (faster aspart) basal-bolus therapy and 120 received basal-only insulin. Participants were grouped according to baseline HbA1c, PPG increments and nocturnal glucose change variables; analyses were performed on the end-of-trial treatment differences between "high" and "low" baseline values. The change from baseline in end-of-trial mean HbA1c and mean PPG increments was in favour of faster aspart across all subgroups. Significantly greater treatment differences were observed in participants with high (vs. low) baseline nocturnal glucose change and PPG increments. For baseline HbA1c, significantly greater treatment differences were observed for change in end-of-trial PPG increments, but not end-of-trial HbA1c. In conclusion, both nocturnal glucose change and PPG increments may be more useful than HbA1c for identifying subgroups of people with T2D who would most benefit from bolus intensification.

Investigating the Association Between Baseline Characteristics (HbA1c and Body Mass Index) and Clinical Outcomes of Fast-Acting Insulin Aspart in People with Diabetes: A Post Hoc Analysis.

INTRODUCTION: The aim of this study was to investigate the association between baseline characteristics [HbA1c and body mass index (BMI)] and the effect of mealtime fast-acting insulin aspart (faster aspart) relative to insulin aspart (IAsp) or basal-only insulin therapy on several efficacy and safety outcomes in people with diabetes. METHODS: Post hoc analysis of three randomised phase 3a trials in people with type 1 diabetes (T1D; onset 1) and type 2 diabetes (T2D; onset 2 and 3). Participants (N = 1686) were stratified according to baseline BMI (< 25 kg/m2, 25-< 30 kg/m2, ≥ 30 kg/m2) or HbA1c (≤ 58 mmol/mol, > 58-< 64 mmol/mol, ≥ 64 mmol/mol; ≤ 7.5%, > 7.5-< 8.0%, ≥ 8.0%). RESULTS: In participants with T2D, the estimated treatment difference for change in HbA1c was similar for all BMI and HbA1c subgroups. No major differences between treatments were observed in risk of overall hypoglycaemia or insulin dose across subgroups. In participants with T1D, change in HbA1c was similar across BMI and HbA1c subgroups, and no major differences between treatments were observed for severe or blood glucose-confirmed hypoglycaemia across subgroups. Total daily insulin dose (U/kg) was similar across all baseline HbA1c groups and the BMI < 25 kg/m2 and 25-30 kg/m2 groups, but was significantly lower with mealtime faster aspart compared with IAsp in the BMI > 30 kg/m2 subgroup. CONCLUSIONS: In participants with T1D and T2D, treatment differences (for change in HbA1c and overall hypoglycaemia) between mealtime faster aspart and insulin comparators were similar to the corresponding overall analysis across baseline HbA1c and BMI subgroups. The finding of a lower total daily insulin dose in participants with obesity (BMI > 30 kg/m2) and T1D treated with faster aspart, versus those treated with IAsp, may warrant further investigation. TRIAL REGISTRATION: ClinicalTrials.gov NCT01831765 (onset 1); NCT01819129 (onset 2); NCT01850615 (onset 3). FUNDING: Novo Nordisk A/S, Søborg, Denmark.

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.

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.