Mechanism of Action

The primary mechanism of action of glimepiride in lowering blood glucose appears to be dependent on stimulating the release of insulin from functioning pancreatic beta cells. In addition, extrapancreatic effects may also play a role in the activity of sulfonylureas such as glimepiride. This is supported by both preclinical and clinical studies demonstrating that glimepiride administration can lead to increased sensitivity of peripheral tissues to insulin. These findings are consistent with the results of a long-term, randomized, placebo-controlled trial in which AMARYL therapy improved postprandial insulin/C-peptide responses and overall glycemic control without producing clinically meaningful increases in fasting insulin/C-peptide levels. However, as with other sulfonylureas, the mechanism by which glimepiride lowers blood glucose during long-term administration has not been clearly established.

AMARYL is effective as initial drug therapy. In patients where monotherapy with AMARYL or metformin has not produced adequate glycemic control, the combination of AMARYL and metformin may have a synergistic effect, since both agents act to improve glucose tolerance by different primary mechanisms of action. This complementary effect has been observed with metformin and other sulfonylureas, in multiple studies.

Pharmacodynamics

A mild glucose-lowering effect first appeared following single oral doses as low as 0.5-0.6 mg in healthy subjects. The time required to reach the maximum effect (i.e., minimum blood glucose level [Tmin]) was about 2 to 3 hours. In noninsulin-dependent (Type 2) diabetes mellitus (NIDDM) patients, both fasting and 2-hour postprandial glucose levels were significantly lower with glimepiride (1, 2, 4, and 8 mg once daily) than with placebo after 14 days of oral dosing. The glucose-lowering effect in all active treatment groups was maintained over 24 hours.

In larger dose-ranging studies, blood glucose and HbA_1c were found to respond in a dose-dependent manner over the range of 1 to 4 mg/day of AMARYL. Some patients, particularly those with higher fasting plasma glucose (FPG) levels, may benefit from doses of AMARYL up to 8 mg once daily. No difference in response was found when AMARYL was administered once or twice daily.

In two 14-week, placebo-controlled studies in 720 subjects, the average net reduction in HbA_1c for AMARYL (glimepiride tablets) patients treated with 8 mg once daily was 2.0% in absolute units compared with placebo-treated patients.

In a long-term, randomized, placebo-controlled study of Type 2 diabetic patients unresponsive to dietary management, AMARYL therapy improved postprandial insulin/C-peptide responses, and 75% of patients achieved and maintained control of blood glucose and HbA_1c. Efficacy results were not affected by age, gender, weight, or race.

In long-term extension trials with previously-treated patients, no meaningful deterioration in mean fasting blood glucose (FBG) or HbA_1c levels was seen after 2 ½ years of AMARYL therapy.

Combination therapy with AMARYL and insulin (70% NPH/30% regular) was compared to placebo/insulin in secondary failure patients whose body weight was > 130% of their ideal body weight. Initially, 5-10 units of insulin were administered with the main evening meal and titrated upward weekly to achieve predefined FPG values. Both groups in this double-blind study achieved similar reductions in FPG levels but the AMARYL/insulin therapy group used approximately 38% less insulin.

AMARYL therapy is effective in controlling blood glucose without deleterious changes in the plasma lipoprotein profiles of patients treated forType 2 diabetes.

Pharmacokinetics

Absorption. After oral administration, glimepiride is completely (100%) absorbed from the GI tract. Studies with single oral doses in normal subjects and with multiple oral doses in patients with Type 2 diabetes have shown significant absorption of glimepiride within 1 hour after administration and peak drug levels (Cmax) at 2 to 3 hours. When glimepiride was given with meals, the mean Tmax (time to reach Cmax) was slightly increased (12%) and the mean Cmax and AUC (area under the curve) were slightly decreased (8% and 9%, respectively).

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