Starting patients with type 2 diabetes on insulin therapy using once-daily injections of biphasic insulin aspart 70/30, biphasic human insulin 70/30, or NPH insulin in combination with metformin

Abstract

Transitioning safely to insulin therapy when oral antidiabetic agents fail to provide adequate glycemic control is a critical aspect of care for the patient with type 2 diabetes mellitus (T2DM). We evaluated the clinical effectiveness of starting patients on a relatively simple regimen of once-daily injections of either biphasic insulin aspart 70/30 (10 min before dinner), NPH insulin (at 10 p.m.), or biphasic human insulin 70/30 (30 min before dinner) in combination with metformin. Enrolled patients had T2DM and inadequate glycemic control (AlC≥7.5%) on a previous regimen of metformin as monotherapy or in combination with a sulphonylurea. One hundred and forty (140) patients received metformin monotherapy for 4 weeks followed by 12 weeks of combination treatment with metformin and once-daily insulin injections. AlC levels decreased from baseline by 1.1–1.3% for patients in each of the three treatment groups. Overall, FPG values decreased from baseline by 31% (biphasic insulin aspart), 37% (NPH insulin), and 28% (biphasic human insulin). Subjects whose final FPG level was <126 mg/dl experienced the largest decreases in AlC values (−2.3%, −1.9%, −1.8%, respectively). All three treatment regimens were well tolerated. The results indicate that patients with T2DM can safely and effectively begin insulin therapy using once-daily injections of biphasic insulin aspart 70/30, biphasic human insulin 70/30, or NPH insulin in combination with metformin.

Introduction

The use of a single dinnertime or bedtime insulin injection in combination with an oral hypoglycemic agent is a common approach to starting patients with type 2 diabetes mellitus (T2DM) on insulin therapy. The combination of a single daily insulin injection with continuation of metformin or sulfonylurea treatment has been demonstrated to provide more effective glycemic control than single insulin injections alone Riddle et al., 1992, Riddle et al., 1989, Shank et al., 1995, Yki-Järvinen et al., 1992. Intermediate-acting insulin, such as NPH, is commonly used in these regimens to reduce endogenous glucose output during the nighttime hours. However, many patients with T2DM eat a substantial portion of their daily calories at dinnertime and snack before bedtime. Therefore, the use of a biphasic insulin formulation at dinnertime would provide control of the prandial glucose load (soluble component) while the protaminated component would cover nighttime insulin needs.

Premixed insulin offers patients the convenience of not having to self-mix their insulin preparations and therefore may reduce dosing errors. Although the most commonly used premixed preparation, biphasic human insulin 70/30 (70% NPH insulin, 30% regular human insulin), is usually used in a twice-daily regimen, clinical studies have shown that a single injection of biphasic human insulin, used in combination with an oral agent, may also be effective Riddle et al., 1992, Yki-Järvinen et al., 1992. A limitation associated with biphasic human insulin, however, is the potential for nocturnal hypoglycemia resulting from the overlapping actions of regular human insulin and NPH insulin.

The availability of biphasic preparations of rapid-acting insulin analogs, such as NovoLog Mix 70/30 (70% protaminated insulin aspart, 30% soluble insulin aspart), has provided patients and physicians with an alternative to biphasic human insulin. In clinical trials, NovoLog Mix 70/30 has demonstrated improved postprandial glycemic control with higher peak insulin levels and lower peak postprandial glucose levels after subcutaneous injection as compared to biphasic human insulin 70/30, resulting in improved postprandial glycemic control and reduced risk of delayed postprandial hypoglycemia Boehm et al., 2002, Hermansen et al., 2002, McSorley et al., 2002.

Because it does not stimulate insulin secretion, metformin use as monotherapy is not associated with hypoglycemia. The mechanism of action of metformin is not completely understood but may involve a reduction in hepatic glucose production, a reduction in insulin resistance, and an increased muscular uptake of glucose Cusi & DeFronzo, 1998, Dunn & Peters, 1995. Metformin use is not associated with weight gain unless caloric intake is excessive. The clinical properties of metformin have prompted its widespread use in the management of T2DM. Clinical studies have shown that metformin improves glycemic control when used in combination with insulin in many patients with T2DM Aviles-Santa et al., 1999, DeFronzo et al., 1991, Kilo, 1997, Wulffele et al., 2002.

This clinical study was conducted to evaluate the effectiveness and safety of starting patients with T2DM on insulin therapy with once-daily injections of biphasic insulin aspart 70/30, NPH insulin, or biphasic human insulin 70/30 in combination with metformin.