A. Fritsche, M. Schweitzer, Hans-Ulrich Hring
Jun 17, 2003
Citations
10
Influential Citations
358
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Quality indicators
Journal
Annals of Internal Medicine
Abstract
Context Insulin glargine is a long-acting insulin preparation that has recently become available. Its optimal role in the treatment of type 2 diabetes is being defined. Contribution In this randomized, controlled trial of patients who were taking the sulfonylurea glimepiride, those receiving morning glargine had greater improvement in hemoglobin A1c levels and less frequent nocturnal hypoglycemia than did patients receiving either bedtime neutral protamine Hagedorn (NPH) or bedtime glargine. Implications Morning glargine may be a better option for optimizing glycemic control in patients with type 2 diabetes who are also taking sulfonylureas than is either bedtime glargine or bedtime NPH. The Editors Type 2 diabetes is an increasing health problem in all western societies (1); the development of macrovascular complications in patients with type 2 diabetes is a major determinant of morbidity and mortality rates (1, 2). It has also been demonstrated that achieving good glycemic control substantially contributes to the prevention of microvascular complications in patients with type 2 diabetes (3). In addition, epidemiologic association analysis of the data suggests that macrovascular complications can also be prevented (4). However, current therapeutic approaches have not attained the defined targets of good metabolic control in most patients with type 2 diabetes (5). During the natural course of type 2 diabetes, -cell function is progressively lost (6), which limits the period when lifestyle modification, diet, and oral antidiabetic drug therapy are sufficient to meet targets of glycemic control. Thus, the therapeutic regimens for patients with type 2 diabetes have to be continually adapted to allow patients to consistently achieve and maintain good glycemic control. Patients with type 2 diabetes benefit from the addition of insulin to their therapeutic regimen (7-9). However, some patients express reservations regarding the administration and side effects of insulin therapy (10); therefore, effective and convenient regimens must be developed. Combination therapy with oral antidiabetic drugs and bedtime neutral protamine Hagedorn (NPH) insulin has proven to be as effective as other, more complex insulin regimens and is associated with less weight gain (11, 12). Combination therapy with insulin and oral antidiabetic drugs is a regimen that can be managed at outpatient visits and that can be conveniently adapted to the patient's needs by adjusting the insulin dose on the basis of self-measured fasting blood glucose levels (13)a therapeutic target predictive of overall glycemic control (13). There are, however, limitations to achieving optimal results in daily practice with a combination of oral antidiabetic drugs and NPH insulin. Neutral protamine Hagedorn insulin exhibits a peak in its timeaction profile 4 to 6 hours after injection; thus, bedtime NPH insulin is associated with a risk for nocturnal hypoglycemia (14). This risk may limit the feasibility of titrating the NPH insulin dose to reach adequately low fasting blood glucose target values. Furthermore, the activity profile of NPH insulin is too short to provide optimal 24-hour insulin supplementation. Insulin glargine (Lantus, Aventis, Bridgewater, New Jersey) is a recently introduced human insulin analogue that exhibits a 24-hour action profile with no pronounced peak (15-17). One study of patients with type 2 diabetes who were treated with basal and bolus insulin (18) and one study of patients with type 2 diabetes who were receiving oral antidiabetic drugs (14) have suggested that the addition of insulin glargine, injected at bedtime, decreases the risk for nocturnal hypoglycemia compared with NPH insulin. Thus, insulin glargine is an improved basal component for combination regimens with oral antidiabetic drugs in the treatment of type 2 diabetes. It remains unclear whether insulin glargine provides both better metabolic control and decreases the risk for hypoglycemia than compared with NPH insulin when used with sulfonylureas, such as glimepiride. The best timing for insulin glargine administration is also unclear. We investigated the efficacy and safety of a combination therapy of sulfonylurea (3 mg of glimepiride) with either morning insulin glargine, bedtime insulin glargine, or bedtime NPH insulin in patients with type 2 diabetes whose diabetes was poorly controlled with oral antidiabetic drugs alone. Methods Study Design Our study was a 28-week, open-label, randomized, controlled, multinational, multicenter, parallel-group clinical trial. Patients with type 2 diabetes who did not achieve good metabolic control while receiving oral antidiabetic drugs had their oral agents replaced by 3 mg of glimepiride for 4 weeks and were then randomly assigned to receive additional treatment for 24 weeks with insulin glargine in the morning or at bedtime or NPH insulin at bedtime. Our primary objective was to investigate the effect of the different treatment regimens on glycemic control (hemoglobin A1c [HbA1c]) and on the percentage of patients who experienced hypoglycemia. Secondary objectives were to compare the three different interventions in terms of response rates, blood glucose levels, insulin dose, and body weight, as well as adjustment of insulin dose by the investigator. A total of 111 centers in 13 European countries participated in this study. The institutional ethics committee of each participating center approved the trial, and written informed consent was obtained from all participants before enrollment in the study. Patients We recruited patients from January 2000 to October 2000; treatment took place between February 2000 and June 2001. Criteria for study inclusion were as follows: 1) type 2 diabetes, 2) age younger than 75 years, 3) body mass index less than 35 kg/m2, and 4) previous oral therapy with any sulfonylurea as monotherapy or in combination with metformin or acarbose. Furthermore, the fasting blood glucose level had to be 6.7 mmol/L or greater [ 120 mg/dL], and the HbA1c level had to be between 7.5% and 10.5%. Main exclusion criteria were as follows: 1) pregnancy or breast-feeding, 2) pretreatment with insulin or any investigational drugs within the previous 3 months, or 3) presence of any clinically relevant somatic or mental diseases. Screening Phase The study consisted of a 4-week screening phase and a 24-week treatment phase. Before the start of the study, patients gave informed consent, medical histories were recorded, physical examinations were performed, and inclusion as well as exclusion criteria were satisfied. Blood samples were taken for determination of HbA1c levels, complete hematologic and clinical chemistry analyses, and lipid status. Patients were trained to use the OptiPen Pro (Aventis, Bridgewater, New Jersey) insulin injection device and the One Touch II (LifeScan, Milpitas, California) blood glucose meter. Patients discontinued use of their previous oral antidiabetic drug treatment and received 3 mg of glimepiride in the morning. Patients provided a complete 8-point, 24-hour blood glucose profile on the 2 consecutive days of the screening phase. Randomization A sequence of screening patient numbers was assigned to each study center. All patients who had entered the screening phase received a patient number. With a randomization schedule generated by the sponsor, eligible patients were linked sequentially to treatment codes allocated at random. This schedule was stratified by center on a 1:1:1 basis. Intervention During the treatment phase, patients visited the investigation sites 1, 2, 3, 4, 6, 8, 12, 16, 20, and 24 weeks after randomization. At these visits, patients had to provide daily self-measured fasting blood glucose values, and episodes of hypoglycemia were recorded in a standardized diary. The investigators checked these values, and the insulin dose was adjusted according to a predefined titration regimen. Furthermore, vital signs (including blood pressure and body weight) were recorded at every visit. At baseline, 12 weeks, and 24 weeks after randomization, blood was drawn for measurement of complete hematologic and clinical chemistry analyses. At baseline and 8, 12, and 24 weeks, blood was drawn for measurement of HbA1c levels, and patients had to provide an 8-point daily blood glucose profile on 2 consecutive days. When combination therapy was initiated, insulin glargine or NPH insulin was injected subcutaneously once daily. The insulin glargine and NPH insulin formulation consisted of a cartridge containing 3 mL of either insulin preparation. Neutral protamine Hagedorn insulin had to be mixed thoroughly by rotating the injection device. The insulin dose for the first day of the treatment phase was calculated according to the formula of Holman and Turner (19) by subtracting 2.8 mmol/L (50 mg/dL) from the actual fasting blood glucose value and dividing the result by 0.56 mmol/L (10 mg/dL). During the treatment phase, the insulin dose was titrated every visit by using a predefined regimen: If the fasting blood glucose level was greater than 5.6, 6.7, 7.8, or 8.9 mmol/L (>100, 120, 140, 160 mg/dL) for at least 1 of 2 consecutive days before the visit with no hypoglycemia, the insulin dose was increased by 2, 4, 6, or 8 units, respectively. Doses of glimepiride remained unchanged throughout the study. Analytical Methods Hemoglobin A1c levels were measured by high-performance liquid chromatography (Bio-Rad Diamat, Munich, Germany) in the central laboratory (INTERLAB, Munich, Germany); the reference range was 4.4% to 6.1%. Hematologic and clinical chemistry analyses were measured in local laboratories according to standard laboratory procedures. Statistical Analysis The primary efficacy assessment was the change in HbA1c level from baseline to end point and the frequency of patients who experienced hypoglycemic episodes during the study. Secondary efficacy measurements were HbA1c level ( 7.5%), fasting blood g