Hybrid closed‐loop glucose control with faster insulin aspart (Fiasp) compared with standard insulin aspart in adults with type 1 diabetes: a double‐blind, multicentre, multinational, randomised, crossover study

OBJECTIVE To investigate the pharmacokinetic and pharmacodynamic properties, and safety of a novel formulation of insulin aspart (AT247) versus currently marketed insulin aspart formulations (IAsp and faster IAsp). RESEARCH DESIGN AND METHODS This single-center, randomized, double-blind, three-period, crossover study was conducted in 19 men with type 1 diabetes, receiving single dosing of trial products (0.3 U/kg) in a random order on three visits. Pharmacokinetics and pharmacodynamics were assessed during a euglycemic clamp lasting up to 8 hours. RESULTS Onset of insulin appearance was earlier for AT247 compared with IAsp (−12 minutes [95% CI −14;−8] p=0.0004) and faster IAsp (−2 minutes [−5;−2] p=0.0003). Onset of action was accelerated compared with IAsp (−23 minutes [−37;−15] p=0.0004) and faster IAsp (−9 minutes [−11;−3] p=0.0006). Within the first 60 minutes, a higher exposure was observed for AT247 compared with IAsp (AUCAsp,0-60min: treatment ratio vs IAsp 2.3 [1.9;2.9]; vs faster IAsp 1.5 [1.3;1.8]), which was underpinned by a greater early glucose-lowering effect (AUCGIR,0-60min: treatment ratio vs IAsp 2.8 [2.0;5.5]; vs faster IAsp 1.7 [1.3;2.3]). Furthermore, an earlier offset of exposure was observed for AT247 compared with IAsp (−32 minutes [−58;−15] p=0.0015) and faster IAsp (−27 minutes [−85;−15] p=0.0017), while duration of glucose-lowering effect, measured by tLate50%GIRmax, did not differ significantly. CONCLUSIONS AT247 exhibited an earlier insulin appearance, exposure and offset, with corresponding enhanced early glucose-lowering effect compared with IAsp and faster IAsp. It therefore represents a promising candidate in the pursuit for second generation prandial insulin analogs to improve postprandial glycemic control.

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Pharmacokinetics and Pharmacodynamics of Three Different Formulations of Insulin Aspart: A Randomized, Double-blind, Crossover Study in Men With Type 1 Diabetes

Diabetes Care ◽

10.2337/dc20-1017 ◽

2020 ◽

pp. dc201017

Author(s):

Eva Svehlikova ◽

Ines Mursic ◽

Thomas Augustin ◽

Christoph Magnes ◽

David Gerring ◽

...

Keyword(s):

Type 1 Diabetes ◽

Crossover Study ◽

Insulin Aspart ◽

Pharmacokinetics And Pharmacodynamics ◽

Double Blind ◽

Blind Crossover Study ◽

Double Blind Crossover Study

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Pharmacokinetics and Pharmacodynamics of Three Different Formulations of Insulin Aspart: A Randomized, Double-blind, Crossover Study in Men With Type 1 Diabetes

10.2337/figshare.13236932 ◽

2020 ◽

Author(s):

Eva Svehlikova ◽

Ines Mursic ◽

Thomas Augustin ◽

Christoph Magnes ◽

David Gerring ◽

...

Keyword(s):

Type 1 Diabetes ◽

Crossover Study ◽

Insulin Aspart ◽

Pharmacokinetics And Pharmacodynamics ◽

Onset Of Action ◽

Double Blind ◽

Glucose Lowering ◽

Lowering Effect ◽

Glucose Lowering Effect

OBJECTIVE To investigate the pharmacokinetic and pharmacodynamic properties, and safety of a novel formulation of insulin aspart (AT247) versus currently marketed insulin aspart formulations (IAsp and faster IAsp). RESEARCH DESIGN AND METHODS This single-center, randomized, double-blind, three-period, crossover study was conducted in 19 men with type 1 diabetes, receiving single dosing of trial products (0.3 U/kg) in a random order on three visits. Pharmacokinetics and pharmacodynamics were assessed during a euglycemic clamp lasting up to 8 hours. RESULTS Onset of insulin appearance was earlier for AT247 compared with IAsp (−12 minutes [95% CI −14;−8] p=0.0004) and faster IAsp (−2 minutes [−5;−2] p=0.0003). Onset of action was accelerated compared with IAsp (−23 minutes [−37;−15] p=0.0004) and faster IAsp (−9 minutes [−11;−3] p=0.0006). Within the first 60 minutes, a higher exposure was observed for AT247 compared with IAsp (AUCAsp,0-60min: treatment ratio vs IAsp 2.3 [1.9;2.9]; vs faster IAsp 1.5 [1.3;1.8]), which was underpinned by a greater early glucose-lowering effect (AUCGIR,0-60min: treatment ratio vs IAsp 2.8 [2.0;5.5]; vs faster IAsp 1.7 [1.3;2.3]). Furthermore, an earlier offset of exposure was observed for AT247 compared with IAsp (−32 minutes [−58;−15] p=0.0015) and faster IAsp (−27 minutes [−85;−15] p=0.0017), while duration of glucose-lowering effect, measured by tLate50%GIRmax, did not differ significantly. CONCLUSIONS AT247 exhibited an earlier insulin appearance, exposure and offset, with corresponding enhanced early glucose-lowering effect compared with IAsp and faster IAsp. It therefore represents a promising candidate in the pursuit for second generation prandial insulin analogs to improve postprandial glycemic control.

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Home use of closed-loop insulin delivery for overnight glucose control in adults with type 1 diabetes: a 4-week, multicentre, randomised crossover study

The Lancet Diabetes & Endocrinology ◽

10.1016/s2213-8587(14)70114-7 ◽

2014 ◽

Vol 2 (9) ◽

pp. 701-709 ◽

Cited By ~ 113

Author(s):

Hood Thabit ◽

Alexandra Lubina-Solomon ◽

Marietta Stadler ◽

Lalantha Leelarathna ◽

Emma Walkinshaw ◽

...

Keyword(s):

Type 1 Diabetes ◽

Crossover Study ◽

Glucose Control ◽

Closed Loop ◽

Insulin Delivery

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Fast-Acting Insulin Aspart Versus Insulin Aspart Using a Second-Generation Hybrid Closed-Loop System in Adults With Type 1 Diabetes: A Randomized, Open-Label, Crossover Trial

10.2337/figshare.14900547 ◽

2021 ◽

Author(s):

Melissa H. Lee ◽

Barbora Paldus ◽

Sara Vogrin ◽

Dale Morrison ◽

Dessi P. Zaharieva ◽

...

Keyword(s):

Type 1 Diabetes ◽

Insulin Aspart ◽

Glucose Control ◽

Primary Outcome ◽

Closed Loop ◽

Open Label ◽

Modest Improvement ◽

Acting Insulin ◽

Fast Acting

Objective To evaluate glucose control using fast-acting insulin aspart (faster aspart) compared with insulin aspart (IAsp) delivered by the MiniMedä Advanced Hybrid Closed-Loop (AHCL) system in adults with type 1 diabetes. Research Design and Methods In this randomized, open-label, crossover study, participants were assigned to receive faster aspart or IAsp in random-order. Stages 1 and 2 comprised six-weeks in closed-loop; preceded by two-weeks in open-loop. This was followed by Stage 3, whereby participants changed directly back to the insulin formulation used in Stage 1 for one-week in CL. Participants chose their own meals except for two standardized meal tests; a missed and late meal bolus. Primary outcome was % sensor glucose time-in-range (TIR; 70-180mg/dL). Results Twenty-five adults (52% male) were recruited; median (IQR) age was 48 (37, 57) years, and HbA1c 7.0% (6.6, 7.2) (53 [49, 55] mmol/mol). Faster aspart demonstrated greater overall TIR compared with IAsp (82.3% [78.5, 83.7] vs. 79.6% [77.0, 83.4], respectively; mean difference 1.9% [0.5, 3.3]; p=0.007). Four-hour PPG TIR was higher using faster aspart compared with IAsp for all-meals combined (73.6% [69.4, 80.2] vs. 72.1% [64.5, 78.5], respectively; median difference 3.5% [1.0, 7.3]; p=0.003). There was no ketoacidosis or severe hypoglycemia. Conclusions Faster aspart safely improved glucose control compared with IAsp in a well-controlled group of adults with type 1 diabetes using AHCL. The modest improvement mainly related to mealtime glycemia. Whilst the primary outcome demonstrated statistical significance, the clinical impact may be small given an overall difference in TIR of 1.9%.

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Faster Compared With Standard Insulin Aspart During Day-and-Night Fully Closed-Loop Insulin Therapy in Type 1 Diabetes: A Double-Blind Randomized Crossover Trial

Diabetes Care ◽

10.2337/dc19-0895 ◽

2019 ◽

Vol 43 (1) ◽

pp. 29-36 ◽

Cited By ~ 14

Author(s):

Klemen Dovc ◽

Claudia Piona ◽

Gül Yeşiltepe Mutlu ◽

Natasa Bratina ◽

Barbara Jenko Bizjan ◽

...

Keyword(s):

Type 1 Diabetes ◽

Insulin Therapy ◽

Insulin Aspart ◽

Closed Loop ◽

Crossover Trial ◽

Double Blind ◽

Randomized Crossover Trial

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Fast-Acting Insulin Aspart Versus Insulin Aspart Using a Second-Generation Hybrid Closed-Loop System in Adults With Type 1 Diabetes: A Randomized, Open-Label, Crossover Trial

10.2337/figshare.14900547.v1 ◽

2021 ◽

Author(s):

Melissa H. Lee ◽

Barbora Paldus ◽

Sara Vogrin ◽

Dale Morrison ◽

Dessi P. Zaharieva ◽

...

Keyword(s):

Type 1 Diabetes ◽

Insulin Aspart ◽

Glucose Control ◽

Primary Outcome ◽

Closed Loop ◽

Open Label ◽

Modest Improvement ◽

Acting Insulin ◽

Fast Acting

Objective To evaluate glucose control using fast-acting insulin aspart (faster aspart) compared with insulin aspart (IAsp) delivered by the MiniMedä Advanced Hybrid Closed-Loop (AHCL) system in adults with type 1 diabetes. Research Design and Methods In this randomized, open-label, crossover study, participants were assigned to receive faster aspart or IAsp in random-order. Stages 1 and 2 comprised six-weeks in closed-loop; preceded by two-weeks in open-loop. This was followed by Stage 3, whereby participants changed directly back to the insulin formulation used in Stage 1 for one-week in CL. Participants chose their own meals except for two standardized meal tests; a missed and late meal bolus. Primary outcome was % sensor glucose time-in-range (TIR; 70-180mg/dL). Results Twenty-five adults (52% male) were recruited; median (IQR) age was 48 (37, 57) years, and HbA1c 7.0% (6.6, 7.2) (53 [49, 55] mmol/mol). Faster aspart demonstrated greater overall TIR compared with IAsp (82.3% [78.5, 83.7] vs. 79.6% [77.0, 83.4], respectively; mean difference 1.9% [0.5, 3.3]; p=0.007). Four-hour PPG TIR was higher using faster aspart compared with IAsp for all-meals combined (73.6% [69.4, 80.2] vs. 72.1% [64.5, 78.5], respectively; median difference 3.5% [1.0, 7.3]; p=0.003). There was no ketoacidosis or severe hypoglycemia. Conclusions Faster aspart safely improved glucose control compared with IAsp in a well-controlled group of adults with type 1 diabetes using AHCL. The modest improvement mainly related to mealtime glycemia. Whilst the primary outcome demonstrated statistical significance, the clinical impact may be small given an overall difference in TIR of 1.9%.

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