Glipizide and Metformin Hydrochloride (Page 3 of 10)

Pediatrics:

No data from pharmacokinetic studies in pediatric subjects are available for glipizide. After administration of a single oral metformin hydrochloride 500 mg tablet with food, geometric mean metformin C _max and AUC differed less than 5% between pediatric type 2 diabetic patients (12 to 16 years of age) and gender- and weight-matched healthy adults (20 to 45 years of age), all with normal renal function.

Gender:

There is no information on the effect of gender on the pharmacokinetics of glipizide.

Metformin pharmacokinetic parameters did not differ significantly in subjects with or without type 2 diabetes when analyzed according to gender (males=19, females=16). Similarly, in controlled clinical studies in patients with type 2 diabetes, the antihyperglycemic effect of metformin was comparable in males and females.

Race:

No information is available on race differences in the pharmacokinetics of glipizide.

No studies of metformin pharmacokinetic parameters according to race have been performed. In controlled clinical studies of metformin in patients with type 2 diabetes, the antihyperglycemic effect was comparable in whites (n=249), blacks (n=51), and Hispanics (n=24).

Clinical Studies:

Patients with Inadequate Glycemic Control on Diet and Exercise Alone:

In a 24-week, double-blind, active-controlled, multicenter international clinical trial, patients with type 2 diabetes, whose hyperglycemia was not adequately controlled with diet and exercise alone (hemoglobin A _1c [HbA _1c ]>7.5% and ≤12% and fasting plasma glucose [FPG]<300 mg/dL) were randomized to receive initial therapy with glipizide 5 mg, metformin 500 mg, glipizide and metformin hydrochloride tablets 2.5 mg/250 mg, or glipizide and metformin hydrochloride tablets 2.5 mg/500 mg. After two weeks, the dose was progressively increased (up to the 12-week visit) to a maximum of four tablets daily in divided doses as needed to reach a target mean daily glucose (MDG) of ≤130 mg/dL. Trial data at 24 weeks are summarized in Table 2.

Table 2 Active-Controlled Trial of Glipizide and Metformin Hydrochloride Tablets as Initial Therapy: Summary of Trial Data at 24 Weeks

	Glipizide Tablets 5 mg	Metformin Tablets 500 mg	Glipizide and Metformin Hydrochloride Tablets 2 . 5 mg / 250 mg	Glipizide and Metformin Hydrochloride Tablets 2 . 5 mg / 500 mg
* p <0.001
Mean Final Dose	16.7 mg	1749 mg	7.9 mg/791 mg	7.4 mg/1477 mg
Hemoglobin A 1 c (%)	N = 168	N = 171	N = 166	N = 163
Baseline Mean	9.17	9.15	9.06	9.10
Final Mean	7.36	7.47	6.93	6.95
Adjusted Mean Change from Baseline	-1.77	-1.46	-2.15	-2.14
Different from Glipizide			-0.38 *	-0.37 *
Different from Metformin			-0.70 *	-0.69 *
% Patients with Final HbA 1 c <7%	43.5%	35.1%	59.6%	57.1%
Fasting Plasma Glucose ( mg / dL )	N = 169	N = 176	N = 170	N = 169
Baseline Mean	210.7	207.4	206.8	203.1
Final Mean	162.1	163.8	152.1	148.7
Adjusted Mean Change from Baseline	-46.2	-42.9	-54.2	-56.5
Different from Glipizide			-8.0	-10.4
Different from Metformin			-11.3	-13.6

After 24 weeks, treatment with glipizide and metformin hydrochloride tablets 2.5 mg/250 mg and 2.5 mg/500 mg resulted in significantly greater reduction in HbA _1c compared to glipizide and to metformin therapy. Also, glipizide and metformin hydrochloride tablets 2.5 mg/250 mg therapy resulted in significant reductions in FPG versus metformin therapy.

Increases above fasting glucose and insulin levels were determined at baseline and final study visits by measurement of plasma glucose and insulin for three hours following a standard mixed liquid meal. Treatment with glipizide and metformin hydrochloride tablets lowered the three-hour postprandial glucose AUC, compared to baseline, to a significantly greater extent than did the glipizide and the metformin therapies. Compared to baseline, glipizide and metformin hydrochloride tablets enhanced the postprandial insulin response, but did not significantly affect fasting insulin levels.

There were no clinically meaningful differences in changes from baseline for all lipid parameters between glipizide and metformin hydrochloride tablets therapy and either metformin therapy or glipizide therapy. The adjusted mean changes from baseline in body weight were: glipizide and metformin hydrochloride tablets 2.5 mg/250 mg, -0.4 kg; glipizide and metformin hydrochloride tablets 2.5 mg/500 mg, -0.5 kg; glipizide, -0.2 kg; and metformin, -1.9 kg. Weight loss was greater with metformin than with glipizide and metformin hydrochloride tablets.