AimsTo evaluate the pharmacokinetics and pharmacodynamics of faster‐acting insulin aspart and insulin aspart in a randomized, single‐centre, double‐blind study.MethodsFifty‐two patients with type 1 diabetes (mean age 40.3 years) received faster‐acting insulin aspart, insulin aspart, or another faster aspart formulation (not selected for further development), each as a single 0.2 U/kg subcutaneous dose, under glucose‐clamp conditions, in a three‐way crossover design (3–12 days washout between dosing).ResultsFaster‐acting insulin aspart had a faster onset of exposure compared with insulin aspart, shown by a 57% earlier onset of appearance [4.9 vs 11.2 min; ratio 0.43, 95% confidence interval (CI) 0.36; 0.51], a 35% earlier time to reach 50% maximum concentration (20.7 vs 31.6 min; ratio 0.65, 95% CI 0.59; 0.72) and a greater early exposure within 90 min after dosing. The greatest difference occurred during the first 15 min, when area under the serum insulin aspart curve was 4.5‐fold greater with faster‐acting insulin aspart than with insulin aspart. Both treatments had a similar time to maximum concentration, total exposure and maximum concentration. Faster‐acting insulin aspart had a significantly greater glucose‐lowering effect within 90 min after dosing [largest difference: area under the curve for the glucose infusion rate (AUCGIR), 0–30 min ratio 1.48, 95% CI 1.13; 2.02] and 17% earlier time to reach 50% maximum glucose infusion rate (38.3 vs 46.1 min; ratio 0.83, 95% CI 0.73; 0.94). The primary endpoint (AUCGIR , 0–2 h) was 10% greater for faster‐acting insulin aspart, but did not reach statistical significance (ratio 1.10, 95% CI 1.00; 1.22). Both treatments had similar total and maximum glucose‐lowering effects, indicating similar overall potency.ConclusionsFaster‐acting insulin aspart was found to have earlier onset and higher early exposure than insulin aspart, and a greater early glucose‐lowering effect, with similar potency.
OBJECTIVEThis randomized, controlled noninferiority trial aimed to compare the efficacy and safety of insulin detemir (IDet) versus neutral protamine Hagedorn (NPH) (both with prandial insulin aspart) in pregnant women with type 1 diabetes.RESEARCH DESIGN AND METHODSPatients were randomized and exposed to IDet or NPH up to 12 months before pregnancy or at 8–12 weeks gestation. The primary analysis aimed to demonstrate noninferiority of IDet to NPH with respect to A1C at 36 gestational weeks (GWs) (margin of 0.4%). The data were analyzed using linear regression, taking several baseline factors and covariates into account.RESULTSA total of 310 type 1 diabetic women were randomized and exposed to IDet (n = 152) or NPH (n = 158) up to 12 months before pregnancy (48%) or during pregnancy at 8–12 weeks (52%). The estimated A1C at 36 GWs was 6.27% for IDet and 6.33% for NPH in the full analysis set (FAS). IDet was declared noninferior to NPH (FAS, –0.06% [95% CI –0.21 to 0.08]; per protocol, –0.15% [–0.34 to 0.04]). Fasting plasma glucose (FPG) was significantly lower with IDet versus NPH at both 24 GWs (96.8 vs. 113.8 mg/dL, P = 0.012) and 36 GWs (85.7 vs. 97.4 mg/dL, P = 0.017). Major and minor hypoglycemia rates during pregnancy were similar between groups.CONCLUSIONSTreatment with IDet resulted in lower FPG and noninferior A1C in late pregnancy compared with NPH insulin. Rates of hypoglycemia were comparable.
ObjectiveThis randomized controlled trial aimed to compare the efficacy and safety of insulin detemir (IDet) with neutral protamine Hagedorn (NPH), both with insulin aspart, in pregnant women with type 1 diabetes. The perinatal and obstetric pregnancy outcomes are presented.MethodsSubjects were randomized to IDet (n = 152) or NPH (n = 158) ≤12 months before pregnancy or at 8–12 gestational weeks.ResultsFor IDet and NPH, there were 128 and 136 live births, 11 and 9 early fetal losses, and two and one perinatal deaths, respectively. Gestational age at delivery was greater for children from the IDet arm than the NPH arm (treatment difference: 0.49 weeks [95% CI 0.11;0.88], p = 0.012, linear regression). Sixteen children had a malformation (IDet: n = 8/142, 5.6%; NPH: n = 8/145, 5.5%). The incidence of adverse events was similar between treatments.ConclusionIDet is as well tolerated as NPH as regards perinatal outcomes in pregnant women with type 1 diabetes and no safety issues were identified.
Insulin icodec* is a novel basal insulin analog designed for single once-weekly (OW) subcutaneous injection. This randomized, double–blind, double–dummy trial investigated the pharmacokinetics (PK), pharmacodynamics (PD) and safety of insulin icodec. Fifty individuals with type 2 diabetes (insulin treated±metformin; 43 men; mean±SD age 57±5 years, BMI 30.1±2.7 kg/m2, A1C 7.4±0.6%) received OW insulin icodec (12, 20 or 24 nmol/kg) plus once–daily (OD) placebo (N=13, 13, 12) or OD insulin degludec (0.4 U/kg) plus OW placebo (N=12) for 5 weeks in 3 dose level cohorts. PD properties were investigated at close to steady state in 24-h glucose clamps on days 2 and 7 after the last insulin icodec dose. Median tmax,insulin icodec was 16 h and geometric mean t½,insulin icodec was 196 h with no systematic differences between dose levels. The glucose–lowering effect over a weekly dosing interval was derived from the observed PK/PD data using a PK/PD model and showed close to even distribution over the 7 days across all dose levels (Figure). The adverse event (AE) incidence did not increase with increasing insulin icodec dose (100%, 69%, 75%, respectively). There were no serious or severe AEs, severe hypoglycemic episodes or injection site reactions. In conclusion, insulin icodec was safe and well-tolerated and showed PK/PD properties supporting once-weekly administration at clinically relevant dose levels. * Proposed INN. Disclosure U. Hövelmann: None. L. Brøndsted: Employee; Self; Novo Nordisk A/S. Stock/Shareholder; Self; Novo Nordisk A/S. N.R. Kristensen: Employee; Self; Novo Nordisk A/S. Stock/Shareholder; Self; Novo Nordisk A/S. R. Ribel-Madsen: Employee; Self; Novo Nordisk A/S. Stock/Shareholder; Self; Novo Nordisk A/S. J. DeVries: Advisory Panel; Self; Novo Nordisk A/S, Zealand Pharma A/S. Consultant; Self; Metronom Health. Employee; Self; Profil Institute for Clinical Research. T. Heise: Advisory Panel; Self; Mylan, Novo Nordisk A/S. Research Support; Self; ADOCIA, Aerami, Becton, Dickinson and Company, Biocon, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Gan & Lee Pharmaceuticals, MedImmune, Merck KGaA, Mylan, Nordic Bioscience, Novo Nordisk A/S, Poxel SA, Sanofi, Xeris Pharmaceuticals, Inc., Zealand Pharma A/S. Speaker’s Bureau; Self; Eli Lilly and Company, Novo Nordisk A/S. H. Haahr: Employee; Self; Novo Nordisk A/S. Stock/Shareholder; Self; Novo Nordisk A/S. Funding Novo Nordisk
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