Faster Onset and Greater Early Exposure and Glucose-Lowering Effect with Faster-Acting Insulin Aspart vs. Insulin Aspart: A Pooled Analysis in Subjects with Type 1 Diabetes

2016 ◽  
Vol 40 (5) ◽  
pp. S57 ◽  
Author(s):  
Tim Heise ◽  
Thomas R. Pieber ◽  
Thomas Danne ◽  
Lars Erichsen ◽  
Arash Pakseresht ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Insulin Aspart ◽  
Pooled Analysis ◽  
Early Exposure ◽  
Glucose Lowering ◽  
Lowering Effect ◽  
Acting Insulin ◽  
Glucose Lowering Effect

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

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 <p>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).</p> <p> </p> <p>RESEARCH DESIGN AND METHODS</p> <p>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. </p> <p> </p> <p>RESULTS</p> <p>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 (AUC<sub>Asp,0-60min</sub>: 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 (AUC<sub>GIR,0-60min</sub>: 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 t<sub>Late50%GIRmax</sub>, did not differ significantly.</p> <p> </p> <p>CONCLUSIONS</p> <p>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.</p>

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

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 <p>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).</p> <p> </p> <p>RESEARCH DESIGN AND METHODS</p> <p>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. </p> <p> </p> <p>RESULTS</p> <p>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 (AUC<sub>Asp,0-60min</sub>: 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 (AUC<sub>GIR,0-60min</sub>: 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 t<sub>Late50%GIRmax</sub>, did not differ significantly.</p> <p> </p> <p>CONCLUSIONS</p> <p>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.</p>

scholarly journals UCP1-independent glucose-lowering effect of leptin in type 1 diabetes: only in conditions of hypoleptinemia

2020 ◽  
Vol 318 (1) ◽  
pp. E72-E86
Author(s):  
Petr Zouhar ◽  
Günaj Rakipovski ◽  
Muhammad Hamza Bokhari ◽  
Oliver Busby ◽  
Johan F. Paulsson ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Therapeutic Potential ◽  
Uncoupling Protein ◽  
Leptin Resistance ◽  
Diabetic Mice ◽  
High Fat ◽  
Glucose Lowering ◽  
Lowering Effect ◽  
Glucose Lowering Effect

The possibility to use leptin therapeutically for lowering glucose levels in patients with type 1 diabetes has attracted interest. However, earlier animal models of type 1 diabetes are severely catabolic with very low endogenous leptin levels, unlike most patients with diabetes. Here, we aim to test glucose-lowering effects of leptin in novel, more human-like murine models. We examined the glucose-lowering potential of leptin in diabetic models of two types: streptozotocin-treated mice and mice treated with the insulin receptor antagonist S961. To prevent hypoleptinemia, we used combinations of thermoneutral temperature and high-fat feeding. Leptin fully normalized hyperglycemia in standard chow-fed streptozotocin-treated diabetic mice. However, more humanized physiological conditions (high-fat diets or thermoneutral temperatures) that increased adiposity — and thus also leptin levels — in the diabetic mice abrogated the effects of leptin, i.e., the mice developed leptin resistance also in this respect. The glucose-lowering effect of leptin was not dependent on the presence of the uncoupling protein-1 and was not associated with alterations in plasma insulin, insulin-like growth factor 1, food intake or corticosterone but fully correlated with decreased plasma glucagon levels and gluconeogenesis. An important implication of these observations is that the therapeutic potential of leptin as an additional treatment in patients with type 1 diabetes is probably limited. This is because such patients are treated with insulin and do not display low leptin levels. Thus, the potential for a glucose-lowering effect of leptin would already have been attained with standard insulin therapy, and further effects on blood glucose level through additional leptin cannot be anticipated.

scholarly journals Fast‐acting insulin aspart in people with type 2 diabetes: Earlier onset and greater initial exposure and glucose‐lowering effect compared with insulin aspart

2019 ◽  
Vol 21 (9) ◽  
pp. 2068-2075 ◽  
Author(s):  
Thomas R. Pieber ◽  
Eva Svehlikova ◽  
Martina Brunner ◽  
Inge B. Halberg ◽  
Karen Margrete Due Thomsen ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Insulin Aspart ◽  
Initial Exposure ◽  
Glucose Lowering ◽  
Lowering Effect ◽  
Acting Insulin ◽  
Glucose Lowering Effect ◽  
Fast Acting

scholarly journals Fast-acting insulin aspart: a review of its pharmacokinetic and pharmacodynamic properties and the clinical consequences

2020 ◽  
Vol 23 (2) ◽  
pp. 140-160
Author(s):  
Hanne Haahr ◽  
Tim Heise
Keyword(s):  
Clinical Pharmacology ◽  
Insulin Aspart ◽  
Postprandial Glucose ◽  
Phase Iii ◽  
Initial Exposure ◽  
Glucose Lowering ◽  
Lowering Effect ◽  
Acting Insulin ◽  
Glucose Lowering Effect ◽  
Fast Acting

Fast-acting insulin aspart (faster aspart) is insulin aspart (IAsp) with two added excipients, L-arginine and niacinamide, to ensure formulation stability with accelerated initial absorption after subcutaneous administration compared with previously developed rapid-acting insulins. The pharmacokinetic/pharmacodynamic properties of faster aspart have been characterised in clinical pharmacology trials with comparable overall methodology. In subjects with type 1 (T1D) or type 2 (T2D) diabetes, the serum IAsp concentration-time and glucose-lowering effect profiles are left-shifted for faster aspart compared with IAsp. In addition, faster aspart provides earlier onset, doubling of initial exposure, and an up to 2.5-fold increase in initial glucose-lowering effect within 30 min of subcutaneous injection, as well as earlier offset of exposure and effect. Similar results have been shown using continuous subcutaneous insulin infusion (CSII). The improved pharmacological properties of faster aspart versus IAsp are consistent across populations, i.e. in the elderly, children, adolescents and the Japanese. Thus, the faster aspart pharmacological characteristics more closely resemble the mealtime insulin secretion in healthy individuals, giving faster aspart the potential to further improve postprandial glucose control in subjects with diabetes. Indeed, change from baseline in 1-h postprandial glucose increment is in favour of faster aspart versus IAsp when used as basal-bolus or CSII treatment in phase III trials in subjects with T1D or T2D. This review summarises the currently published results from clinical pharmacology trials with faster aspart and discusses the potential clinical benefits of faster aspart compared with previous rapid-acting insulin products.

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