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☆
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.
Section snippets
Patients and methods
Enrolled patients were men or women, 18 years or older, with T2DM (American Diabetes Association, 2000) and a body weight ≤100 kg and BMI ≤40 kg/m2. The patients were naı̈ve to insulin treatment and had inadequate glycemic control (AlC≥7.5%) on a regimen of ≥3 months of metformin as monotherapy or in combination with a sulphonylurea or repaglinide. Subjects were excluded from the study if they had significantly impaired hepatic (alanine aminotransferase or alkaline phosphatase ≥2 times
Subjects
The three treatment groups were similar with regard to demographic and baseline characteristics (Table 1). One hundred and forty (140) patients were enrolled and 131 (94%) patients completed the 12-week insulin treatment period. Of the nine patients who prematurely discontinued during insulin treatment, four were in the biphasic insulin aspart group (two patients due to adverse events, two patients due to noncompliance), four were in the NPH insulin group (all due to noncompliance/other), and
Discussion
Normalization of blood glucose levels and reduction of cardiovascular risk factors are the ultimate treatment goals for patients with type 2 diabetes Kilo, 1985, United Kingdom Prospective Diabetes Study (UKPDS), 1998. An individualized meal plan and exercise program are the cornerstone of effective diabetic treatment. Physicians may elect to add a single oral hypoglycemic agent or a combination of oral agents to help the patient achieve target blood glucose and A1C levels. However, each year,
Conclusion
The long-term benefits of good metabolic control in type 2 diabetes are well recognized. The ability to safely and effectively start patients on insulin therapy when oral agents fail to provide adequate glycemic control can help to assure these benefits are realized. The results of this study indicate that the use of metformin in combination with once-daily injections of biphasic insulin aspart or biphasic human insulin at dinnertime or NPH insulin at bedtime offers patients a safe and
Acknowledgements
The research study was funded by Novo Nordisk Pharmaceuticals (Princeton, NJ). The publication of the results is funded by Novo Nordisk Pharmaceuticals.
Appreciation is expressed to the following members of the NovoLog Mix Study Group and to Dr. Jerzy Kolaczynski for their work with the study. Appreciation is also expressed to Dr. Diane Petrovich for her assistance in preparing the manuscript.
NovoLog Mix Study Group: Andrew Ahmann, MD (Oregon Health Sciences University, Portland, OR), Peter
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An interim analysis of this study was presented at the 2002 American Diabetes Association annual meeting (Kilo, C., et al. (2002). Dinnertime NovoLog Mix 70/30 in combination with metformin—a combination to use? Diabetes, 51(S2), A130, poster 527) and at a breakfast symposium adjacent to the European Association for the Study of Diabetes (EASD) meeting in September 2002.