Dataset Information

Fast-acting insulin aspart versus insulin aspart in the setting of insulin degludec-treated type 1 diabetes: Efficacy and safety from a randomized double-blind trial.

ABSTRACT:

Aim

To evaluate the efficacy and safety of mealtime or post-meal fast-acting insulin aspart (faster aspart) vs mealtime insulin aspart (IAsp), both in combination with insulin degludec, in participants with type 1 diabetes (T1D).

Methods

This multicentre, treat-to-target trial (Clinical trial registry: NCT02500706, ClinicalTrials.gov) randomized participants to double-blind mealtime faster aspart (n = 342) or IAsp (n = 342) or open-label post-meal faster aspart (n = 341). The primary endpoint was change from baseline in HbA1c 26 weeks post randomization. All available information, regardless of treatment discontinuation, was used for evaluation of the effect.

Results

Non-inferiority for the change from baseline in HbA1c was confirmed for mealtime and post-meal faster aspart vs IAsp (estimated treatment difference [ETD]: 95%CI, -0.02% [-0.11; 0.07] and 0.10% [0.004; 0.19], respectively). Mealtime faster aspart was superior to IAsp for 1-hour PPG increment using a meal test (ETD, -0.90 mmol/L [-1.36; -0.45]; P < 0.001). Self-monitored 1-hour PPG increment favoured faster aspart at breakfast (ETD, -0.58 mmol/L [-0.99; -0.17]; P = 0.006) and across all meals (-0.48 mmol/L [-0.74; -0.21]; P < 0.001). Safety profiles and overall rate of severe or blood glucose-confirmed hypoglycaemia were similar between treatments, but significantly less hypoglycaemia was seen 3 to 4 hours after meals with mealtime faster aspart.

Conclusion

Mealtime and post-meal faster aspart in conjunction with insulin degludec provided effective glycaemic control compared with IAsp, with no increased safety risk. Mealtime faster aspart provided PPG control superior to that of IAsp.

SUBMITTER: Buse JB

PROVIDER: S-EPMC6231963 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BACKGROUND:Fast-acting insulin aspart (faster aspart) is an ultra-fast-acting formulation of insulin aspart (IAsp). This post hoc analysis investigated the pharmacokinetics of faster aspart versus IAsp, measured as free or total IAsp, and the relationship between anti-IAsp antibodies and the pharmacokinetics/pharmacodynamics of faster aspart and IAsp. METHODS:Free and total IAsp concentrations and anti-IAsp antibodies were determined in adults with type 1 diabetes mellitus receiving subcutaneous faster aspart and/or IAsp in four single-dose clinical pharmacology trials (n = 175) and a 26-week phase IIIa trial (n = 1040). Pharmacodynamics were assessed by euglycaemic clamp or meal test, respectively. RESULTS:The pharmacokinetic profile was left-shifted and early exposure was greater with faster aspart versus IAsp independent of free or total IAsp assay. The faster aspart-IAsp difference in the time to 50% of maximum IAsp concentration in the early part of the pharmacokinetic profile (tEarly 50 % Cmax) [95% confidence interval (CI)] was - 8.8 [- 10.0 to - 7.5] and - 7.6 [- 8.8 to - 6.4] min for free and total IAsp, respectively. The faster aspart/IAsp ratio for the area under the concentration-time curve (AUC) for IAsp from time zero to 30 min (AUCIAsp,0-30 min) [95% CI] was 1.88 [1.74-2.04] and 1.77 [1.64-1.90] for free and total IAsp. Higher anti-IAsp antibody levels were associated with a lower ratio of free/total IAsp for the total AUC for IAsp (AUCIAsp,0-t). Early glucose-lowering effect (AUC for the glucose infusion rate [GIR] from time zero to 60 min [AUCGIR,0-60 min]) was greater by 25-44% for faster aspart versus IAsp independent of anti-IAsp antibody levels. Total glucose-lowering effect (total AUC for GIR [AUCGIR,0-t]) in a clamp and 1-h postprandial glucose increment in a meal test appeared essentially unaffected by anti-IAsp antibodies. CONCLUSIONS:Faster aspart provides accelerated pharmacokinetics versus IAsp regardless if based on free or total IAsp assay. Higher anti-IAsp antibodies increase total IAsp concentrations but do not influence faster aspart nor IAsp pharmacodynamics. CLINICALTRIALS. GOV IDENTIFIERS:NCT01618188, NCT02003677, NCT01934712, NCT02568280, NCT01831765.