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Pharmacodynamics: Sitagliptin Phosphate: General: In patients with type 2 diabetes, administration of single oral doses of sitagliptin leads to inhibition of DPP-4 enzyme activity for a 24-hr period, resulting in a 2- to 3-fold increase in circulating levels of active GLP-1 and GIP, increased plasma levels of insulin and C-peptide, decreased glucagon concentrations, reduced fasting glucose, and reduced glucose excursion following an oral glucose load or a meal.

In Phase III clinical studies of 18- and 24-week duration, treatment with sitagliptin 100 mg daily in patients with type 2 diabetes significantly improved β cell function, as assessed by several markers, including HOMA-β (Homeostasis Model Assessment-β), proinsulin to insulin ratio, and measures of β cell responsiveness from the frequently-sampled meal tolerance test. In Phase II studies, sitagliptin 50 mg twice daily provided similar glycemic efficacy compared to sitagliptin 100 mg once daily. In a randomized, placebo-controlled, double-blind, double-dummy, 4-period crossover 2-day study in healthy adult subjects, the effects on post-meal plasma concentrations of active and total GLP-1 and glucose after co-administration of sitagliptin and metformin were compared with those after administration of sitagliptin alone, metformin alone or placebo, each administered for 2 days. The incremental 4-hr post-meal weighted mean active GLP-1 concentrations were increased approximately 2-fold after either administration of sitagliptin alone or metformin alone compared with placebo. The effect on active GLP-1 concentrations after co-administration of sitagliptin and metformin were additive, with active GLP-1 concentrations increased by approximately 4-fold compared with placebo. Sitagliptin alone increased only active GLP-1 concentrations, reflecting inhibition of DPP-4, whereas metformin alone increased active and total GLP-1 concentrations to a similar extent. These data are consistent with different mechanisms for the increase in active GLP-1 concentrations. Results from the study also demonstrated that sitagliptin, but not metformin, enhances active GIP concentrations.

In studies with healthy subjects, sitagliptin did not lower blood glucose or cause hypoglycemia, suggesting that the insulinotropic and glucagon suppressive actions of the drug are glucose dependent.

Effects on Blood Pressure: In a randomized, placebo-controlled crossover study in hypertensive patients on one or more anti hypertensive drugs (including angiotensin-converting enzyme inhibitors, angiotensin-II antagonists, calcium-channel blockers, β-blockers and diuretics), co-administration with sitagliptin was generally well tolerated. In these patients, sitagliptin had a modest blood pressure-lowering effect; 100 mg/day of sitagliptin reduced 24-hr mean ambulatory systolic blood pressure by approximately 2 mm Hg, as compared to placebo. Reductions have not been observed in subjects with normal blood pressure.

Cardiac Electrophysiology: In a randomized, placebo-controlled crossover study, 79 healthy subjects were administered a single oral dose of sitagliptin 100 mg, sitagliptin 800 mg (8 times the recommended dose), and placebo. At the recommended dose of 100 mg, there was no effect on the QTc interval obtained at the peak plasma concentration, or at any other time during the study. Following the 800-mg dose, the maximum increase in the placebo-corrected mean change in QTc from baseline at 3 hrs postdose was 8 msec. This small increase was not considered to be clinically significant. At the 800-mg dose, peak sitagliptin plasma concentrations were approximately 11 times higher than the peak concentrations following a 100-mg dose.

In patients with type 2 diabetes administered with sitagliptin 100 mg (N=81) or sitagliptin 200 mg (N=63) daily, there were no meaningful changes in QTc interval based on ECG data obtained at the time of expected peak plasma concentration.

Clinical Studies: Clinical studies of the co-administration of sitagliptin and metformin demonstrated significant improvements in glycemic control in patients with type 2 diabetes. There have been no clinical efficacy studies conducted with Janumet tablets; however, bioequivalence of Janumet tablets with co-administered sitagliptin and metformin HCI tablets was demonstrated. Sitagliptin and Metformin as Initial Therapy in Patients with Type 2 Diabetes: A total of 1091 patients with type 2 diabetes and inadequate glycemic control on diet and exercise participated in a 24-week, randomized, double-blind, placebo-controlled factorial study designed to assess the safety and efficacy of initial therapy with the combination of sitagliptin and metformin. Approximately equal numbers of patients were randomized to receive initial therapy with placebo; 100 mg of sitagliptin once daily; 500 or 1000 mg of metformin twice daily; or 50 mg of sitagliptin twice daily in combination with 500 or 1000 mg of metformin twice daily.

Initial therapy with the combination of sitagliptin and metformin provided significant improvements in HbA_1c, FPG, and 2-hr PPG compared to placebo, to metformin alone, and to sitagliptin alone (p<0.001; Table 1, Figure 1). An improvement in FPG, with near maximal FPG reduction, was achieved by the 3-week time point (the first time point assessed after initiation of therapy) and sustained throughout the 24-week study. Measures of β cell function, HOMA-β and the proinsulin to insulin ratio also showed greater improvement with the co-administration of sitagliptin and metformin compared with either monotherapy alone. Lipid effects were generally neutral. The decrease in body weight in the groups given sitagliptin in combination with metformin was similar to that in the groups given metformin alone or placebo. Mean reductions from baseline in HbA_1c compared with placebo were generally greater for patients with higher baseline HbA_1c values. The improvement in HbA_1c was generally consistent across subgroups defined by gender, age, race or baseline BMI. Mean reductions from baseline in HbA_1c for patients not on an antihyperglycemic agent at study entry were: Sitagliptin 100 mg once daily, -1.06%; metformin 500 mg twice daily, -1.09%; metformin 1000 mg twice daily, -1.24%; sitagliptin 50 mg twice daily with metformin 500 mg twice daily, -1.59%; and sitagliptin 50 mg twice daily with metformin 1000 mg twice daily, -1.94%; and for patients receiving placebo, -0.17%.

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