New insulin glargine 300 U/ml versus glargine 100 U/ml in Japanese adults with type 1 diabetes using basal and mealtime insulin : glucose control and hypoglycaemia in a randomized controlled trial (EDITION JP 1)

Aim: To compare efficacy and safety of new insulin glargine 300 U/ml (Gla‐300) with that of insulin glargine 100 U/ml (Gla‐100) in Japanese adults with type 1 diabetes. Methods: The EDITION JP 1 study (NCT01689129) was a 6‐month, multicentre, open‐label, phase III study. Participants (n = 243) were randomized to Gla‐300 or Gla‐100 while continuing mealtime insulin. Basal insulin was titrated with the aim of achieving a fasting self‐monitored plasma glucose target of 4.4–7.2 mmol/l. The primary endpoint was change in glycated haemoglobin (HbA1c) over 6 months. Safety measures included hypoglycaemia and change in body weight. Results: Gla‐300 was non‐inferior to Gla‐100 for the primary endpoint of HbA1c change over the 6‐month period {least squares [LS] mean difference 0.13 % [95 % confidence interval (CI) −0.03 to 0.29]}. The annualized rate of confirmed (≤3.9 mmol/l) or severe hypoglycaemic events was 34 % lower with Gla‐300 than with Gla‐100 at night [rate ratio 0.66 (95 % CI 0.48–0.92)] and 20 % lower at any time of day [24 h; rate ratio 0.80 (95 % CI 0.65–0.98)]; this difference was most pronounced during the first 8 weeks of treatment. Severe hypoglycaemia was infrequent. The basal insulin dose increased in both groups (month 6 dose: Gla‐300 0.35 U/kg/day, Gla‐100 0.29 U/kg/day). A between‐treatment difference in body weight change over 6 months favouring Gla‐300 was observed [LS mean difference −0.6 kg (95 % CI −1.1 to −0.0); p = 0.035]. Adverse event rates were comparable between the groups. Conclusions: In Japanese adults with type 1 diabetes using basal plus mealtime insulin, less hypoglycaemia was observed with Gla‐300 than with Gla‐100, particularly during the night, while glycaemic control did not differ

Comparative pharmacodynamic and pharmacokinetic characteristics of subcutaneous insulin glulisine and insulin aspart prior to a standard meal in obese subjects with type 2 diabetes

Aims: A multinational, randomized, double-blind, two-way crossover trial to compare the pharmacokinetic and pharmacodynamic properties of bolus, subcutaneously administered insulin glulisine (glulisine) and insulin aspart (aspart) in insulin-naÏve, obese subjects with type 2 diabetes

Patient-level meta-analysis of the EDITION 1, 2 and 3 studies : glycaemic control and hypoglycaemia with new insulin glargine 300 U/ml versus glargine 100 U/ml in people with type 2 diabetes

AimsTo conduct a patient-level meta-analysis of the EDITION 1, 2 and 3 studies, which compared the efficacy and safety of new insulin glargine 300 U/ml (Gla-300) with insulin glargine 100 U/ml (Gla-100) in people with type 2 diabetes (T2DM) on basal and mealtime insulin, basal insulin and oral antihyperglycaemic drugs, or no prior insulin, respectively. MethodsThe EDITION studies were multicentre, randomized, open-label, parallel-group, phase IIIa studies, with similar designs and endpoints. A patient-level meta-analysis of the studies enabled these endpoints to be examined over 6 months in a large population with T2DM (Gla-300, n = 1247; Gla-100, n = 1249). ResultsNo significant study-by-treatment interactions across studies were found, enabling them to be pooled. The mean change in glycated haemoglobin was comparable for Gla-300 and Gla-100 [each -1.02 (standard error 0.03)%; least squares (LS) mean difference 0.00 (95% confidence interval (CI) -0.08 to 0.07)%]. Annualized rates of confirmed (3.9 mmol/l) or severe hypoglycaemia were lower with Gla-300 than with Gla-100 during the night (31% difference in rate ratio over 6 months) and at any time (24 h, 14% difference). Consistent reductions were observed in percentage of participants with 1 hypoglycaemic event. Severe hypoglycaemia at any time (24 h) was rare (Gla-300: 2.3%; Gla-100: 2.6%). Weight gain was low ( ConclusionGla-300 provides comparable glycaemic control to Gla-100 in a large population with a broad clinical spectrum of T2DM, with consistently less hypoglycaemia at any time of day and less nocturnal hypoglycaemia.Peer reviewe

Comparative Effects of Haemodialysis and Haemofiltration on Plasma Atrial Natriuretic Peptide

The effects of 4 h haemodialysis (15 patients) or 4 h haemofiltration (five patients) on plasma concentrations of atrial natriuretic peptide (ANP) were compared by means of a sensitive radioreceptor binding assay, and related to accompanying changes in body weight, blood pressure and plasma renin activity. Before dialysis, plasma ANP concentrations were considerably elevated: haemodialysis group 10-484 pmol/l (mean 156 pmol/l); haemofiltration group 72-320 pmol/l (mean 170 pmol/l). Although plasma concentrations of ANP fell markedly with treatment in both groups: post-haemodialysis 2-187 pmol/l (mean 67 pmol/l); post-haemofiltration 47-135 pmol/l (mean 79 pmol/l), after treatment it remained above the normal range in 14 of the 20 patients. Pretreatment plasma ANP was related to systolic blood pressure (r=0.459; P<0.05) but bore no relationship to mean or diastolic blood pressure, or plasma renin activity. The fall in plasma ANP concentration during treatment correlated with the postural blood pressure drop after dialysis (r=0.505; P<0.05), but was unrelated to changes in weight or plasma renin activity with haemodialysis or haemofiltration. Plasma ANP concentrations rose rapidly again in the 60 min after dialysis treatment, without change in body weight. These results show that high levels of biologically active ANP circulate in end-stage renal disease. The fact that these are not reduced to normal by haemodialysis or haemofiltration, despite restoration to normovolaemic or hypovolaemic state, suggests that the increased levels of ANP in end-stage renal failure are due to both hypervolaemia and other factors, which may include occult cardiac dysfunction and loss of renal clearanc

New insulin glargine 300 U/ml compared with glargine 100 U/ml in insulin-naïve people with type 2 diabetes on oral glucose-lowering drugs:a randomized controlled trial (EDITION 3)

AIMS: To compare the efficacy and safety of new insulin glargine 300 U/ml (Gla-300) with that of glargine 100 U/ml (Gla-100) in insulin-naïve people with type 2 diabetes using oral glucose-lowering drugs. METHODS: The EDITION 3 study was a multicentre, open-label, parallel-group study. Participants were randomized to Gla-300 or Gla-100 once daily for 6 months, discontinuing sulphonylureas and glinides, with a dose titration aimed at achieving pre-breakfast plasma glucose concentrations of 4.4–5.6 mmol/l (80–100 mg/dl). The primary endpoint was change in glycated haemoglobin (HbA1c) from baseline to month 6. The main secondary endpoint was percentage of participants with ≥1 nocturnal confirmed [≤3.9 mmol/l (≤70 mg/dl)] or severe hypoglycaemia from week 9 to month 6. Other measures of glycaemia and hypoglycaemia, weight change and insulin dose were assessed. RESULTS: Randomized participants (n = 878) had a mean (standard deviation) age of 57.7 (10.1) years, diabetes duration 9.8 (6.4) years, body mass index 33.0 (6.7) kg/m(2) and HbA1c 8.54 (1.06) % [69.8 (11.6) mmol/mol]. HbA1c levels decreased by equivalent amounts with the two treatments; the least squares mean difference in change from baseline was 0.04 [95% confidence interval (CI) −0.09 to 0.17] % or 0.4 (−1.0 to 1.9) mmol/mol. Numerically fewer participants reported ≥1 nocturnal confirmed (≤3.9 mmol/l) or severe hypoglycaemia from week 9 to month 6 [relative risk (RR) 0.89 (95% CI 0.66 to 1.20)] with Gla-300 versus Gla-100; a significantly lower risk of hypoglycaemia with this definition was found over the 6-month treatment period [RR 0.76 (95% CI 0.59 to 0.99)]. No between-treatment differences in adverse events were identified. CONCLUSIONS: Gla-300 is as effective as Gla-100 in reducing HbA1c in insulin-naïve people with type 2 diabetes, with lower hypoglycaemia risk

One-year sustained glycaemic control and less hypoglycaemia with new insulin glargine 300 U/ml compared with 100 U/ml in people with type 2 diabetes using basal plus meal-time insulin : the EDITION 1 12-month randomized trial, including 6-month extension

AimsTo evaluate the maintenance of efficacy and safety of insulin glargine 300 U/ml (Gla-300) versus glargine 100 U/ml (Gla-100) in people with type 2 diabetes mellitus (T2DM) using basal plus meal-time insulin for 12 months in the EDITION 1 trial. MethodsEDITION 1 was a multicentre, randomized, open-label, two-arm, phase IIIa study. Participants completing the initial 6-month treatment period continued to receive Gla-300 or Gla-100, as previously randomized, once daily for a further 6-month open-label extension phase. Changes in glycated haemoglobin (HbA1c) and fasting plasma glucose concentrations, insulin dose, hypoglycaemic events and body weight were assessed. ResultsOf 807 participants enrolled in the initial phase, 89% (359/404) assigned to Gla-300 and 88% (355/403) assigned to Gla-100 completed 12 months. Glycaemic control was sustained in both groups (mean HbA1c: Gla-300, 7.24%; Gla-100, 7.42%), with more sustained HbA1c reduction for Gla-300 at 12 months: least squares mean difference Gla-300 vs Gla-100: HbA1c -0.17 [95% confidence interval (CI) -0.30 to -0.05]%. The mean daily basal insulin dose at 12 months was 1.03 U/kg for Gla-300 and 0.90 U/kg for Gla-100. Lower percentages of participants had 1 confirmed [3.9 mmol/l (70 mg/dl)] or severe hypoglycaemic event with Gla-300 than Gla-100 at any time of day [24 h; 86 vs 92%; relative risk 0.94 (95% CI 0.89-0.99)] and during the night [54 vs 65%; relative risk 0.84 (95% CI 0.75-0.94)], while the annualized rates of such hypoglycaemic events were similar. No between-treatment differences in adverse events were apparent. ConclusionDuring 12 months of treatment of T2DM requiring basal and meal-time insulin, glycaemic control was better sustained and fewer individuals reported hypoglycaemia with Gla-300 than with Gla-100. The mean basal insulin dose was higher with Gla-300 compared with Gla-100, but total numbers of hypoglycaemic events and overall tolerability did not differ between treatments.Peer reviewe

Similar glycaemic control and risk of hypoglycaemia with patient- versus physician-managed titration of insulin glargine 300 U/mL across subgroups of patients with T2DM: a post hoc analysis of ITAS

Aims: The Italian Titration Approach Study (ITAS) demonstrated comparable HbA1c reductions and similarly low hypoglycaemia risk at 6&nbsp;months in poorly controlled, insulin-naïve adults with T2DM who initiated self- or physician-titrated insulin glargine 300 U/mL (Gla-300) in the absence of sulphonylurea/glinide. The association of patient characteristics with glycaemic and hypoglycaemic outcomes was assessed. Methods: This post hoc analysis investigated whether baseline patient characteristics and previous antihyperglycaemic drugs were associated with HbA1c change and hypoglycaemia risk in patient- versus physician-managed Gla-300 titration. Results: HbA1c change, incidence of hypoglycaemia (any type) and nocturnal rates were comparable between patient- and physician-managed arms in all subgroups. Hypoglycaemia rates across subgroups (0.03 to 3.52 events per patient-year) were generally as low as observed in the full ITAS population. Small increases in rates of 00:00–pre-breakfast and anytime hypoglycaemia were observed in the ≤ 10-year diabetes duration subgroup in the patient- versus physician-managed arm (heterogeneity of effect; p &lt; 0.05). Conclusions: Comparably fair glycaemic control and similarly low hypoglycaemia risk were achieved in almost all patient subgroups with patient- versus physician-led Gla-300 titration. These results reinforce efficacy and safety of Gla-300 self-titration across a range of phenotypes of insulin-naïve people with T2DM. Clinical trial registration: EudraCT 2015-001167-3

Glycaemic control and hypoglycaemia with new insulin glargine 300 U/ml versus insulin glargine 100 U/ml in people with type 2 diabetes using basal insulin and oral antihyperglycaemic drugs: the EDITION 2 randomized 12-month trial including 6-month extension

Peer reviewe

Pharmacokinetics and Pharmacodynamics of Therapeutic Doses of Basal Insulins NPH, Glargine, and Detemir After 1 Week of Daily Administration at Bedtime in Type 2 Diabetic Subjects: A randomized cross-over study

OBJECTIVE-To compare the pharmacokinetics and pharmacodynamics of NPH, glargine, and detemir insulins in type 2 diabetic subjects. RESEARCH DESIGN AND METHODS-This study used a single-blind, three-way, cross-over design. A total of 18 type 2 diabetic subjects underwent a euglycemic clamp for 32 h after a subcutaneous injection of 0.4 units/kg at 2200 h of either NPH, glargine, or detemir after 1 week of bedtime treatment with each insulin. RESULTS-The glucose infusion rate area under the curve(0-32 h) was greater for glargine than for detemir and NPH (1,538 +/- 688; 1,081 +/- 785; and 1,170 +/- 703 mg/kg, respectively; P 150 mg/dL. CONCLUSIONS-Compared with NPH and detemir, glargine provided greater metabolic activity and superior glucose control for up to 32 h.Lucidi, P.; Porcellati, F.; Rossetti ., P.; Candeloro, P.; Cioli, P.; Marzotti, S.; Andreoli, AM.... (2011). Pharmacokinetics and pharmacodynamics of therapeutic doses of basal insulins NPH, glargine, and detemir after 1 week of daily administration at bedtime in type 2 diabetic subjects: a randomized cross-over study. Diabetes Care. 34(6):1312-1314. doi:10.2337/dc10-1911S1312131434