Preferred Treatment of Type 1.5 Diabetes

Study Overview
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Brief Summary
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The purpose of this research was to test whether one treatment was superior over another in the management of type 1.5 diabetes. Specifically we tested recently diagnosed antibody positive type 2 diabetic patients to determine whether treatment with rosiglitazone results in greater preservation of beta cell function compared to treatment with glyburide.

Detailed Description
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Type 1 diabetes and Type 2 diabetes have different underlying pathophysiologic processes. The disease process in classical Type 1 diabetes is an autoimmune destruction of the pancreatic beta cells. In contrast, the disease process in classical Type 2 diabetes is not autoimmune in nature, a decreased sensitivity to insulin action is central to the disease process, and a poorly understood but non-inflammatory beta cell lesion occurs which diminishes insulin secretion. In clinical practice, the diagnosis of Type 1 versus Type 2 diabetes is made phenotypically using variables such as age at onset, apparent abruptness of onset of hyperglycemia, presence of ketosis, degree of obesity (especially central and intra abdominal), prevalence of other autoimmune diseases, and apparent need for insulin replacement. This clinical distinction of Type 1 versus Type 2 diabetes is recognized to be imperfect. There is also a third group of individuals, who phenotypically are usually like classic Type 2 diabetics but who are positive for one or more of the autoantibodies commonly seen in the Type 1 disease process, namely islet cell antibodies (ICA) and/or insulin autoantibodies (IAA) and/or autoantibodies to glutamic acid decarboxylase (GAD Ab) and/or autoantibodies to the tyrosine phosphatase islet cell autoantibody 512 (IA 2 Ab). These patients, autoantibody positive [Ab(+)] Type 2 or Type 1.5 diabetes, were the focus of our study. Compared to antibody negative Type 2 diabetics, patients with Type 1.5 diabetes have a more rapid decline in beta cell function, fail sulfonylurea therapy and require insulin therapy earlier (4-13). Hypothesis: Rosiglitazone treatment will ameliorate or slow the underlying disease process in antibody positive Type 2 diabetes. Patients meeting the inclusion criteria came in for a baseline visit. The nature of the study was explained and informed consent obtained. A fasting blood sample was obtained for autoantibodies, glucose, C peptide of proinsulin molecule (C-peptide), glycosylated hemoglobin (HbA1c), genetic typing, and T lymphocyte (T cell) responses to islet antigens. The beta cell function test was performed. Patients were then randomized to either rosiglitazone or glyburide. All patients were encouraged to perform self blood glucose monitoring twice per day, before breakfast and before dinner. The treatment goals for all patients was the same: before breakfast and before dinner blood sugar levels between 90-130 milligrams per deciliter (mg/dI) and HbA1c of less then 7% without severe hypoglycemia. Patients unable to reach goal with monotherapy had metformin (initially) or acarbose (secondarily) added, as there is no evidence to suggest that either affect beta-cell function. The rosiglitazone treatment group commenced therapy with 4 milligram (mg) once per day and increased to twice per day if adequate glycemic control was not achieved. For glyburide, therapy was initiated with 2.5 mg in the morning or the patient was maintained on the dose they had been receiving prior to starting the study. The starting dose was raised by 2.5 mg in the evening and further up to a maximum of 10 mg twice a day if necessary to achieve desired glycemic control. If adequate control, HbA1c less than 7%, was not achieved on glyburide or rosiglitazone monotherapy, metformin was added and the dose gradually increased as needed and tolerated to a maximum of 1000 mg twice daily. If necessary, acarbose was also used up to a maximum dose of 100 mg thrice daily as needed and tolerated. After initiation of the study, patients were seen at 1 month and then every 3 months for up to 3 years. Those patients randomized to rosiglitazone had the liver enzyme alanine transaminase (ALT) monitored every 2 months. In addition, telephone contact was utilized to achieve and maintain glycemic goals. Each participant was followed for up to 3 years. Drs. Chiu and Palmer coordinated the study. If the patient and his/her private physician prefer, the treatment protocol was implemented by the patient's private physician.

Official Title
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Rosiglitazone Intervention Study in Patients With Type 1.5 Diabetes

Conditions
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Type 2 Diabetes Mellitus

Intervention / Treatment
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* Drug: rosiglitazone
* Drug: glyburide


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age at onset of diabetes - 35-69 years old. No history of ketonuria or ketoacidosis. Not requiring insulin to achieve glycemic control. Not receiving more than two oral hypoglycemic agents. Not taking a thiazolidinedione agent. HbA1c in established patients (on an oral hypoglycemia agent for over 4 months) of greater than 6% and under 10%. Fasting c-peptide greater than or equal to 0.8 ng/ml. Women must be either post-menopausal or on adequate birth control (i.e. oral contraceptives, tubal ligation, hysterectomy, condoms, or diaphragm) or use abstinence. Exclusion Criteria: Patients with history of chronic pancreatitis or other secondary causes of diabetes. Patients receiving systemic corticosteroids. Patients with severe systemic illness (e.g. recent MI, CHF or cerebral vascular disease). Creatinine greater than 1.4 or liver enzymes greater than 2 times the upper limits of normal. Not able to adhere to the protocol.

Ages Eligible for Study
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Minimum Age: 35 Years
Maximum Age: 69 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: rosiglitazone<br>Rosiglitazone is an oral antidiabetic agent which acts primarily by increasing insulin sensitivity. The rosiglitazone treatment group commenced therapy with 4 mg once per day and increase to twice per day if adequate glycemic control was not achieved. | Drug: rosiglitazone<br>* Tablet taken orally at a dosage of 4 mg once per day and increase to twice per day if adequate glycemic control was not achieved. Study drug was taken up to 3 years.<br>* Other names: Avandia;|
| Active Comparator: glyburide<br>Glyburide is a sulfonylurea. Glyburide therapy was initiated with 2.5 mg in the morning or the patient was maintained on the dose they had been receiving prior to starting the study. This starting dose was raised by 2.5 in the evening and further up to a maximum of 10 mg twice a day if necessary to achieve desired glycemic control. | Drug: glyburide<br>* Tablet taken orally, initially 2.5 mg in the morning or dose subject received prior to starting the study. Dosage was increased by 2.5 mg in the evening up to a maximum of 10 mg twice a day if necessary to achieve desired glycemic control. Study drug was taken up to 3 years.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes in Beta Cell Function Assessed by Fasting and Stimulated C-peptide Measured at 36 Months. | Changes in beta cell function assessed by fasting and stimulated C-peptide measured at 36 months. | 36 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Patients Positive for T Cell Responses to Islet Proteins at 36 Months. | Number of participants positive for T cell reactivity to islet proteins at 36 months. | 36 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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type 2 diabetes mellitus, autoantibodies, islet proteins, rosiglitazone, glyburide, c-peptide