Effect of Ipragliflozin (ASP1941), a Novel Selective Sodium-Dependent Glucose Co-Transporter 2 Inhibitor, on Urinary Glu
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Clin Drug Investig 2011; 31 (12): 839-851 1173-2563/11/0012-0839/$49.95/0
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Effect of Ipragliflozin (ASP1941), a Novel Selective Sodium-Dependent Glucose Co-Transporter 2 Inhibitor, on Urinary Glucose Excretion in Healthy Subjects Stephan A. Veltkamp,1 Takeshi Kadokura,2 Walter J.J. Krauwinkel1 and Ronald A. Smulders1 1 Astellas Pharma Europe BV, Leiderdorp, the Netherlands 2 Astellas Pharma Inc., Tokyo, Japan
Abstract
Background: Hyperglycaemia is associated with serious complications, significant morbidity and death. Despite the availability of a wide range of therapeutic options, many patients with diabetes mellitus fail to achieve or maintain recommended glycaemic goals. Ipragliflozin (ASP1941) is a novel, selective inhibitor of the sodium-dependent glucose co-transporter 2, which is highly expressed in the proximal tubules of the kidneys. It suppresses renal glucose reabsorption and increases urinary glucose excretion (UGE), potentially providing an insulin-independent treatment option for type 2 diabetes. Methods: This multiple ascending-dose study assessed the safety, tolerability, pharmacokinetics and pharmacodynamics of ipragliflozin in healthy subjects after single doses and multiple once-daily doses for 10 days (dose levels: 5–600 mg). Results: Ipragliflozin was well tolerated following single and multiple oncedaily oral dosing. Ipragliflozin was rapidly absorbed with a median time to reach the maximum plasma concentration of 1.3 hours after the last dose. The area under the plasma concentration-time curve increased proportionally with increasing dose. The mean elimination half-life was 12 hours following the last dose. Ipragliflozin dose dependently increased UGE up to a maximum of approximately 59 g (327 mmol) of glucose excreted over 24 hours following multiple doses, without affecting plasma glucose levels in healthy subjects. Conclusion: Administration of ipragliflozin was well tolerated and resulted in a rapid, dose-dependent increase in glucosuria. Pharmacodynamic and pharmacokinetic data suggest that ipragliflozin is suitable for prolonged once-daily oral treatment. Trial Registration: ClinicalTrials.gov Identifier: NCT01288898.
Veltkamp et al.
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Introduction Type 2 diabetes mellitus is a chronic disease characterized by hyperglycaemia due to insulin resistance and b-cell dysfunction.[1] Hyperglycaemia in patients with type 2 diabetes has been associated with microvascular (nephropathy, retinopathy) and macrovascular (cardiovascular) complications and mortality.[2,3] Important aspects in the treatment of type 2 diabetes are therefore optimizing glucose regulation and reducing the risk of cardiovascular complications. Most patients with type 2 diabetes require a combination of antihyperglycaemic drugs over the course of their disease to maintain glycaemic control.[4] A wide range of therapies are currently available, such as biguanides (metformin), sulfonylurea derivatives (glimepiride), thiazolidinediones (pioglitazone), dipeptidylpept
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