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The Effect of Rosiglitazone on Overweight Subjects with Type 1 Diabetes

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The Effect of Rosiglitazone on Overweight Subjects with Type 1 Diabetes Clinical Care/Education/Nutrition ORIGINAL ARTICLE The Effect of Rosiglitazone on Overweight Subjects With Type 1 Diabetes SUZANNE M. STROWIG, MSN, RN the potentially serious consequences of PHILIP RASKIN, MD excessive weight gain and insulin- induced hypoglycemia, investigators con- tinue to search for treatments that address both the treatment of insulin deficiency as well as other metabolic abnormalities that OBJECTIVE — To evaluate the safety and effectiveness of rosiglitazone in the treatment of are associated with diabetes (5). overweight subjects with type 1 diabetes. Insulin resistance, a metabolic abnor- mality common in type 2 diabetes, ap- RESEARCH DESIGN AND METHODS — A total of 50 adult type 1 diabetic subjects 2 pears to be present in individuals with with a baseline BMI Ն27 kg/m were randomly assigned in a double-blind fashion to take insulin and placebo (n ϭ 25) or insulin and rosiglitazone 4 mg twice daily (n ϭ 25) for a period of 8 type 1 diabetes, as well. Although insulin months. Insulin regimen and dosage were modified in all subjects to achieve near-normal resistance in type 2 diabetes is generally glycemic control. associated with obesity, hypertension, dyslipidemia, and other metabolic disor- RESULTS — Both groups experienced a significant reduction in HbA1c (A1C) level (rosigli- ders, studies have shown that overweight tazone: 7.9 Ϯ 1.3 to 6.9 Ϯ 0.7%, P Ͻ 0.0001; placebo: 7.7 Ϯ 0.8 to 7.0 Ϯ 0.9%, P ϭ 0.002) and as well as normal-weight adults with type a significant increase in weight (rosiglitazone: 97.2 Ϯ 11.8 to 100.6 Ϯ 16.0 kg, P ϭ 0.008; 1 diabetes can have peripheral and he- Ϯ Ϯ ϭ ϭ placebo: 96.4 12.2 to 99.1 15.0, P 0.016). Baseline measures of BMI (P 0.001), total patic insulin resistance. Insulin clamp daily insulin dose (P ϭ 0.002), total cholesterol (P ϭ 0.005), HDL cholesterol (P ϭ 0.00l), and ϭ procedures performed on nonobese type LDL cholesterol (P 0.02) were predictors of improvement in A1C level only in the group 1 diabetic subjects under a variety of gly- treated with rosiglitazone. Total daily insulin dose increased in subjects taking placebo (74.0 Ϯ 33.8 to 82.0 Ϯ 48.9 units, P Ͻ 0.05 baseline vs. week 32), but it decreased slightly in subjects cemic conditions demonstrated increased taking rosiglitazone (77.5 Ϯ 28.6 to 75.3 Ϯ 33.1 units). Both systolic blood pressure (137.4 Ϯ hepatic glucose production and reduced 15.6 vs. 128.8 Ϯ 14.8 mmHg, baseline vs. week 32, P Ͻ 0.02) and diastolic blood pressure insulin clearance compared with nondia- (87.2 Ϯ 9.4 vs. 79.4 Ϯ 7.2 mmHg, P Ͻ 0.0001) improved in the group treated with rosiglita- betic subjects (6–10). Others have shown zone. The total incidence of hypoglycemia did not differ between groups. that type 1 diabetic subjects with a family history of type 2 diabetes who have un- CONCLUSIONS — Rosiglitazone in combination with insulin resulted in improved glyce- dergone intensive insulin therapy have a mic control and blood pressure without an increase in insulin requirements, compared with greater tendency toward expressing the insulin- and placebo-treated subjects, whose improved glycemic control required an 11% in- markers of insulin resistance, such as crease in insulin dose. Weight gain and hypoglycemia were similar in both groups at the end of the study. The greatest effect of rosiglitazone occurred in subjects with more pronounced mark- weight gain, increased insulin require- ers of insulin resistance. ments, and dyslipidemia (11). Insulin sensitizers such as biguanide, Diabetes Care 28:1562–1567, 2005 metformin, and the thiazolidinedione compounds troglitazone, rosiglitazone, and pioglitazone have significantly im- esearch in the past decade has con- proving glycemic control, these treat- proved blood glucose levels in type 2 di- clusively demonstrated that im- ments involve considerable effort and abetic individuals by suppressing hepatic proved blood glucose control is of cost (3) and can result in weight gain and glucose output and enhancing insulin- R mediated glucose disposal (12,13). Be- benefit in preventing the microvascular increased risk for severe and asymptom- complications of diabetes (1,2). Although atic hypoglycemia (4). Faced with the cause insulin sensitizers have been new insulin analogs and intensive insulin challenge of balancing aggressive insulin effective in improving blood glucose con- treatment regimens are effective in im- replacement therapy against the risk for trol in type 2 diabetic individuals, for ●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●● whom insulin resistance is a prevailing feature, it seems reasonable to consider From the University of Texas Southwestern Medical Center at Dallas, Dallas, Texas. the possibility that these agents would be Address correspondence and reprint requests to Suzanne M. Strowig, University of Texas Southwestern Medical Center at Dallas, 5323 Harry Hines Blvd., Dallas, TX 75390-8858. E-mail: suzanne.strowig@ of benefit in overweight subjects with utsouthwestern.edu. type 1 diabetes, who are more likely to Received for publication 15 February 2005 and accepted in revised form 14 April 2005. have a degree of insulin resistance. Stud- A table elsewhere in this issue shows conventional and Syste`me International (SI) units and conversion ies have shown that the insulin sensitizer factors for many substances. metformin significantly reduces the © 2005 by the American Diabetes Association. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby amount of insulin required to improve marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. blood glucose levels in both adult and ad- 1562 DIABETES CARE, VOLUME 28, NUMBER 7, JULY 2005 Strowig and Raskin olescent subjects with type 1 diabetes ical activity throughout the study. In- one-way ANOVA assessed between- (14–17). No study, however, has investi- formed consent was obtained from all group differences, and a paired t test de- gated the potential benefit of a thiazo- subjects after approval by the university’s termined within-group differences. The lidinedione in the management of type 1 institutional review board. Mann-Whitney U test was used to analyze diabetes. Thus, this study was designed to categorical variables. A regression analy- examine the safety and efficacy of the thia- Intervention sis was performed to identify predictors zolidinedione rosiglitazone in the treat- At the randomization visit, subjects were for change in A1C level and incidence of ment of overweight adults with type 1 given either placebo or rosiglitazone 4 mg adverse events within each group. Pear- diabetes. twice daily. The insulin dose was modi- son correlations were performed for all fied as needed in all subjects in an attempt variables. RESEARCH DESIGN AND to achieve normal glycemic control. At Two-tailed tests were performed for METHODS — Subjects entered the each clinic visit, plasma glucose levels the analyses. A P value Ͻ0.05 was consid- study based on the following criteria: age were downloaded from the patient’s ered statistically significant. All analyses Ն19 years, medical history consistent meter to the computer; all patients used a were conducted using SPSS software, ver- with type 1 diabetes, HbAlc (A1C) level glucose meter that stored plasma glucose sion 12.0. Results are reported as the Ն6.5%, BMI Ն27 kg/m2, insulin dose readings as well as the date and time the means Ϯ SD, unless otherwise indicated. Ͼ35 units per day, and normal hepatic, readings were obtained. renal, and cardiac function. Subjects who The frequency of hypoglycemia was RESULTS — A total of 52 subjects met met the inclusion criteria were randomly determined by the number of plasma glu- the baseline criteria and were randomized assigned in a double-blind fashion to ros- cose readings stored in the patient’s meter to treatment. Two female subjects chose iglitazone 4 mg twice daily or placebo one that were Ͻ65 mg/dl. Mild hypoglycemia not to continue study participation after tablet twice daily. Tablets of rosiglitazone was defined as a reading between 45 and Ͻ4 weeks of treatment. One of these sub- and placebo, identical in appearance, 65 mg/dl. Moderate hypoglycemia was jects had been assigned to rosiglitazone, were dispensed by the pharmacist in the defined as the number of plasma glucose and one had been assigned to placebo. Clinical Trials Office at the University of readings Յ45 mg/dl. Severe hypoglyce- The remaining 50 subjects completed the Texas Southwestern Medical Center. The mia, as in the DCCT (Diabetes Control study. At baseline, the two groups were randomization codes were held in the and Complications Trial), was defined as comparable in age, sex, ethnicity, dura- Clinical Trials Office until the conclusion any low plasma glucose level that patients tion of diabetes, weight, BMI, waist-to- of the study. The insulin dose and/or reg- were unable to treat themselves, and the hip ratio, total daily insulin dose, imen were changed as needed in all sub- patient’s symptoms were reversed with C-peptide, and A1C level. The group ran- jects in an attempt to achieve normal oral carbohydrate, glucagon, or intrave- domized to treatment with rosiglitazone plasma glucose and A1C levels and to nous glucose. Edema was determined to had a higher baseline systolic blood pres- minimize episodes of hypoglycemia. be absent or present based on the patient’s sure (P ϭ 0.003) and total cholesterol Subjects were seen biweekly the first report of swelling combined with a phys- level (P ϭ 0.02) than the group random- month of treatment, once the second ical examination. ized to placebo (Tables 1 and 2).
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