The first dose-ranging study of linagliptin in male patients with Type 2 diabetes demonstrates significant improvement in glucose parameters and good tolerability, report researchers.

Linagliptin is one of the latest agents in the dipeptidyl peptidase (DPP)-4 inhibitor class to enter phase III trials for the treatment of Type 2 diabetes. Klaus Dugi (Boehringer Ingelheim GmbH, Ingelheim, Germany) and colleagues report the first results with this agent in patients with Type 2 diabetes in a placebo-controlled, dose-ranging study.

To explore the safety, tolerability, pharmacokinetics, and pharmacodynamics of linagliptin, 47 men with Type 2 diabetes were randomly assigned to receive linagliptin 1.0, 2.5, 5.0, or 10.0 mg, or placebo, once daily for 12 days.

The patients, most of whom were on metformin, entered a washout period prior to participating in the study for a period of 3??”12 days.

Presenting the results in the journal Diabetes, Obesity and Metabolism, the authors write: “Linagliptin had a long-lasting effect on DPP-4 inhibition with almost complete DPP-4 inhibition at the 5.0- and 10.0-mg dose levels (92.3 and 93.7% inhibition at steady state, respectively, and more than 80% inhibition over a 24-hour interval after drug intake).”

Linagliptin resulted in a significant reduction in blood glucose levels following an oral glucose tolerance test, 24 hours after the last dose, at doses of 2.5 mg or higher, when compared with placebo.

The agent was rapidly absorbed in all patients with a median t_max of approximately 1.5 hours after drug intake. Linagliptin exposure (AUC and C_max) increased dose dependently, but less than dose proportionally.

Accumulation half-life was short and decreased with dose from about 24 hours for the 1.0-mg dose to about 9 hours for the 10.0-mg dose. As a result there was rapid attainment of steady state (2??”5 days) and little accumulation (range 1.18??”2.03).

The long terminal half-life (113??”131 hours) led to the sustained inhibition of DPP-4 activity.

Renal excretion was only a minor route of linagliptin elimination (less than 7%), in contrast to other DPP-4 inhibitors.

The frequency of adverse events was 54% for linagliptin and 75% for placebo. No serious adverse events were reported and there were no episodes of hypoglycemia.

The authors note that these properties compare favorably with those reported for other DPP-4 inhibitors, but indicate that linagliptin may have an even longer-lasting effect making it particularly suitable for once-daily dosing.

“Further investigations are needed to confirm that these unique pharmacological properties of linagliptin, together with the predominantly non-renal elimination route, lead to clinical improvements beyond those already observed with other compounds of the DPP-4 inhibitor class,” they conclude.

MedWire (www.medwire-news.md) is an independent clinical news service provided by Current Medicine Group, a part of Springer Science+Business Media. © Current Medicine Group Ltd; 2009

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