bts-67582 and Diabetes-Mellitus--Type-2

The loss of early insulin secretion appears to be a critical event in the deterioration in glucose tolerance during the development of type 2 diabetes. There is therefore a strong rationale for developing new antidiabetic agents aimed at restoring or replacing early prandial insulin secretion and thereby curbing mealtime glucose excursions in patients with type 2 diabetes. Four such new agents are either now available (repaglinide and nateglinide) or in clinical development (KAD-1229 and BTS 67 582). Preclinical studies suggest that each of these new insulinotropic agents share a common receptor/effector mechanism with the sulfonylureas (SUs) but that each may have distinct characteristics that differentiate them from the SUs and from each other. Nateglinide and KAD-1229 clearly stimulate biphasic insulin secretion in vitro and in vivo and their effects are rapidly reversible, whereas the effects of repaglinide and BTS 67 582 are prolonged well beyond their removal from perfusion media in vitro or their clearance in vivo. Available data from human studies indicate that the pharmacokinetics of repaglinide and nateglinide are similar, i.e., they are both rapidly absorbed and eliminated, but consistent with findings from animal studies, the insulinotropic and glucose-lowering effects of repaglinide are slower in onset and more prolonged than those of nateglinide. Repaglinide and nateglinide have been shown to be safe and well-tolerated in patients with type 2 diabetes and to produce clinically-meaningful reductions of HbA1c, both alone and in combination with agents with complementary modes of action (e.g., metformin and thiazolidinediones). Because these new agents can potentially bring patients to near normoglycemia without an undue risk of hypoglycemia, they are important additions to the therapeutic armamentarium.

Topics: Animals; Carbamates; Cyclohexanes; Diabetes Mellitus, Type 2; Glucose; Guanidines; Humans; Hypoglycemic Agents; Indoles; Insulin; Insulin Secretion; Isoindoles; Nateglinide; Phenylalanine; Piperidines

To determine the effect over a 4-week period of varying doses of BTS 67,582, a novel nonsulfonylurea insulinotropic agent, on fasting plasma glucose (FPG) levels in sulfonylurea-responsive NIDDM patients.. This was a 12-week multicenter, double-masked, placebo-controlled trial. Patients entered a 4-week stabilization period during which they received their previously prescribed sulfonylurea. Qualified patients (FPG < or = 10 mmol/l) then entered a 4-week sulfonylurea withdrawal single-masked placebo run-in period. Qualified patients (FPG 8.9-16.7 mmol/l) were randomized to either placebo (n = 14), 50 mg b.i.d. BTS 67,582 (n = 18), 250 mg b.i.d. BTS 67,582 (n = 18), 500 mg b.i.d. BTS 67,582 (n = 15), 100 mg q.d. BTS 67,582 (n = 17), or 500 mg q.d. BTS 67,582 (n = 16). The primary efficacy variables were mean changes from baseline in FPG and fructosamine (FRUC). Additional variables included mean changes from baseline in HbA1c, fasting serum insulin (FSI), and fasting serum C-peptide.. After 4 weeks of treatment, all BTS 67,582 dose groups showed a decrease from baseline in FPG and FRUC compared with the placebo group. The treatment groups of 250 mg b.i.d. (-3.1 +/- 0.7 mmol/l), 500 mg b.i.d. (-2.3 +/- 0.6 mmol/l), and 500 mg q.d. (-1.2 +/- 0.7 mmol/l) had statistically significant (P < 0.05) decreases in FPG compared with placebo (0.7 +/- 0.6 mmol/l). Similarly, there were statistically significant (P < 0.05) decreases from baseline in FRUC for the 250 mg b.i.d (-55 +/- 10 mumol/l), 500 mg b.i.d. (-40 +/- 12 mumol/l), and 500 mg q.d. (-13 +/- 9 mumol/l) treatment groups compared with placebo (15 +/- 11 mumol/l). Although the treatment period was only 4 weeks in duration, there were also significant differences (P < 0.05) in the HbA1c changes from baseline for the 250 mg b.i.d. (0.0 +/- 0.1%) and 500 mg b.i.d. (-0.2 +/- 0.1%) treatment groups compared with placebo (0.6 +/- 0.2%). There were no significant differences among the treatment groups in the changes from baseline for FSI or C-peptide levels. The most frequently reported side effects were headache, asthenia, infection, and thirst, and the incidence of these events as well as the incidence of study drug discontinuation was comparable in all treatment groups including placebo.. Four weeks of treatment with BTS 67,582 at doses of 250 mg b.i.d. and 500 mg b.i.d. in NIDDM patients was effective in reducing FPG and FRUC, with significant results also seen for HbA1c. The drug was well tolerated with an incidence of discontinuations and laboratory side-effect safety profiles comparable to placebo. BTS 67,582 is a safe and effective oral treatment for NIDDM patients.

Topics: Adult; Aged; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Double-Blind Method; Drug Administration Schedule; Fasting; Female; Fructosamine; Glycated Hemoglobin; Guanidines; Humans; Hyperglycemia; Hypoglycemic Agents; Insulin; Male; Middle Aged; Patient Selection; Placebos; Postmenopause

Topics: Area Under Curve; Blood Glucose; Clinical Trials as Topic; Diabetes Mellitus, Type 2; Guanidines; Humans; Hypoglycemic Agents; Insulin