Effect on glycemic control of the addition of 2.5 mg glipizide GITS to metformin in patients with T2DM

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Abstract

Aims:

This study evaluated the effects on glycemic control of the addition of 2.5 mg glipizide GITS to metformin in patients with mild-to-moderate, but suboptimally controlled type 2 diabetes.

Methods:

In this multicenter, double-blind, placebo-controlled study, 122 patients with type 2 diabetes inadequately controlled (A1c 7–8.5%) on metformin (≥1000 mg/day for ≥3 months) were randomized to 16 weeks treatment with 2.5 mg/day glipizide GITS (n = 61) or placebo (n = 61), in addition to their current metformin dose. The primary efficacy variable was the change in A1c from baseline to endpoint. Changes in fasting plasma glucose (FPG), insulin concentrations, lipid profile and safety variables were also measured.

Results:

The addition of glipizide GITS to metformin gave significantly greater improvements in mean A1c and FPG from baseline to endpoint than placebo addition (p < 0.0002). Significantly more patients in the glipizide GITS group than in the placebo group achieved the target A1c level of A1c < 7.0% (p < 0.0001) and an A1c < 6.5% (p < 0.0033). Fasting insulin concentrations were similar in both groups and unchanged by treatment. Addition of glipizide GITS to metformin did not produce any significant or clinically relevant weight gain or changes in BMI. Both treatment regimens were well tolerated.

Conclusions:

This study showed that the addition of 2.5 mg glipizide GITS to metformin significantly improved glucose control in patients with type 2 diabetes inadequately controlled by metformin monotherapy.

Introduction

Obesity is common among patients with type 2 diabetes and weight loss and prevention of weight gain are important in the treatment of patients with type 2 diabetes mellitus. Diet and exercise are the cornerstone of diabetes management; however, the majority of patients are unable to achieve adequate glucose control using non-pharmacologic intervention alone. Metformin is widely used as first-line treatment in obese patients with type 2 diabetes in whom management with diet and exercise is inadequate as it lowers blood glucose effectively, but does not cause weight gain [1], [2], [3], [4], unlike other glucose-lowering medications [1], [5]. For example, the UK Prospective Diabetes Study (UKPDS) revealed that monotherapy with sulphonylureas or insulin resulted in greater weight gain than metformin or placebo [6]. However, monotherapy with oral glucose-lowering agents usually cannot maintain adequate glucose control and a second oral agent, and occasionally a third is added [7]. In the UKPDS, over 50% of people with type 2 diabetes were managed with combination therapy due to insufficient glycemic control with monotherapy [8].

A number of papers have reported the effects of the combination of metformin plus a second oral glucose-lowering agent, including sulphonylureas [4], [9], [10], [11], α-glucosidase inhibitors [12], [13], [14], [15], [16], meglitinides [17] and thiazolidinediones [18], [19]. The most widely used combination therapy for type 2 diabetes is metformin plus a sulphonylurea, which results in a clear additive glucose-lowering effect [10], [20], [21].

Glipizide is a second-generation sulphonylurea that is available in a Gastrointestinal Therapeutic System extended-release formulation that delivers the drug at a controlled rate over a 24-h period (Glipizide GITS; Glucotrol XL®). This once-daily glipizide GITS has been shown to be effective as monotherapy, producing significant decreases in hemoglobin A1c, fasting plasma glucose (FPG) and postprandial glucose in patients with mild to severe type 2 diabetes [22], [23]. In a recent study, following a period of monotherapy with either glipizide GITS or metformin, addition of the second agent resulted in further significant improvements in hemoglobin A1c and FPG [9].

Glipizide GITS is not only effective in achieving glycemic control in many patients, but it also does not appear to produce the weight gain commonly observed with other oral glucose-lowering agents [22]. In addition, it is also associated with a low incidence of hypoglycemia [22], [24], [25], [26]. It is probable that the low rate of hypoglycemic episodes is a reflection of the smooth release of glipizide in the GITS formulation. It is possible that the lack of weight gain with glipizide GITS is due to this low level of hypoglycemia compared with, for example, the higher levels of hypoglycemia and weight gain observed with some sulphonylureas and insulin. Hence, as glipizide GITS and metformin appear to have weight neutral profiles and differing mechanisms of action that are complementary and synergistic, metformin is an insulin sensitizer, predominantly at the liver, and glipizide GITS is primarily an insulin secretagogue, they should provide an effective combination for obese patients with type 2 diabetes.

This 16-week, randomized, double-blind, placebo-controlled study in patients with type 2 diabetes inadequately controlled (A1c 7–8.5%, inclusive) for at least 3 months with metformin monotherapy (≥1000 mg/day) was designed to evaluate the effects on glycemic control of the addition of 2.5 mg glipizide GITS or placebo to their current dosage of metformin. The safety and tolerability of 2.5 mg glipizide GITS in combination with metformin compared with placebo plus metformin were also assessed.

Section snippets

Eligibility criteria

Male and female patients, aged between 30 and 81 years, with type 2 diabetes of at least 6 months duration, moderately (A1c  7.0% and ≤8.5%), but inadequately controlled with metformin monotherapy at a dose ≥1000 mg/day, maintained for at least 3 months prior to screening, and with a body mass index (BMI) of 27–38 kg/m2 were eligible for the study. Main exclusion criteria were: use of any other oral glucose-lowering medication, including thiazolidinediones, α-glucosidase inhibitors, meglitinides,

Demographic and baseline characteristics

Of the 250 patients screened, a total of 122 people with type 2 diabetes were randomized to the two treatment arms. Of these, 56 (91.8%) in each group completed the 16-week treatment period. No patients discontinued due to reasons related to study drug. In the glipizide GITS group, two patients withdrew consent, two discontinued due to protocol violation and one due to not meeting the entrance criteria. In the placebo group, two patients withdrew consent, one discontinued due to an adverse

Discussion

Metformin is the mainstay of pharmacologic treatment in overweight patients with type 2 diabetes; however, a substantial proportion of patients are inadequately controlled by metformin alone. Type 2 diabetes is a progressive disorder, with a steady decline in glycemic control, which is related to continuing deterioration of β-cell function [27]. Patients failing metformin are generally either switched to monotherapy with an alternative agent or a second one is added to the existing metformin

Acknowledgement

Funding for this study was provided through a grant by Pfizer Inc.

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