Surgery or Lifestyle With Intensive Medical Management in the Treatment of Type 2 Diabetes

Study Overview
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Brief Summary
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There is substantial clinical evidence regarding the safety and efficacy of currently practiced bariatric surgical techniques to improve metabolic control and/or resolve type 2 diabetes (T2DM) in clinically severe obese patients (class 3 obesity). Evidence suggests such procedures have greater effects on insulin secretion and insulin action than that expected from weight loss alone, which has led to the recent claim that such procedures may be useful as a primary treatment for T2DM in the moderately obese population. Concurrently, there have also been substantial advances in the non-surgical medical management of T2DM. As a result, the best treatment algorithm for T2DM patients with class 1 & 2 obesity is increasingly controversial. This trial investigates the utility of currently practiced and available bariatric surgical procedures as compared with multidisciplinary intensive medical and weight management for the treatment of T2DM with class 1 and 2 obesity.

Detailed Description
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Primary Specific Aim 1: To evaluate the effectiveness of laparoscopic adjustable gastric band versus intensive medical and weight management in the treatment of T2DM. There has been only one randomized control trial to date comparing surgical to medical management of T2DM in the less obese population, which demonstrated substantial superiority of the laparoscopic adjustable gastric band (LAGB) in the improvement of glycemic and metabolic measures. However, these findings remain controversial as the magnitude of weight loss in this study was far superior to that generally reported following LAGB. Thus, we propose a second prospective randomized trial to evaluate the effectiveness of intensive medical and weight management (IMWM) vs. LAGB in T2DM patients with BMI in the 30-42 kg/m^2 range. This range does extend LAGB surgery to BMI limits below those currently used in medical care, FDA Investigational Device Exemption (IDE) G090163. The primary outcome variable will be attaining glycemic control (as defined by fasting plasma glucose levels <126 mg/dL and HbA1c <6.5%) at one year of follow-up. The study was subsequently extended to 3 years, with the same outcome measures. Primary Specific Aim 2: To evaluate the effectiveness of laparoscopic Roux-en-Y gastric bypass versus intensive medical and weight management in the treatment of T2DM. Although observational studies and meta-analyses suggest rapid and sustained improvement or resolution of diabetes following laparoscopic Roux-en-Y gastric bypass (LRYGB), to date there has been no randomized trial directly comparing these effects to those produced by IMWM. We propose a prospective randomized trial comparing the effectiveness of IMWM vs. LRYGB in T2DM patients with BMI's in the 30-42 kg/m^2 range. This range extends LRYGB surgery to BMI limits below those currently used in medical care to explore the use of this type of surgical procedure in type 2 diabetes with lesser magnitude obesity. The primary outcome variable will be attaining glycemic control (as defined by fasting plasma glucose levels <126 mg/dL and HbA1c <6.5%) at one year of follow-up. The study was subsequently extended to 3 years, with the same outcome measures. The trial is designed to allow for strong patient preference towards specific surgical procedures, and as such is designed as two parallel trials with each of the two surgical procedures judged against intensive medical weight management. Subjects without strong preference will be randomly assigned to one of the four study arms. Secondary Specific Aims: Determination of suitable study design: In addition to testing the effectiveness of current and available surgical techniques as compared to medical management, this trial will also test the utility of this trial design in future multi-institutional comparative effectiveness studies of these therapies, or alternatively, in future trials evaluating new surgical procedures being designed specifically for less obese T2DM patients. Measurement of metabolic factors: Insulin secretion and action will be assessed during provocative mixed meal tolerance tests (MMTT) using the corrected incremental insulin response (CIR) and the composite insulin sensitivity index (CISI). MMTT will be performed in all groups at baseline and repeated at the time point of 10% weight loss (matched for weight loss), and at 12 months following randomization (matched for time). Measurement of cardiovascular risk factors: Each group will be studied for evidence of changes in cardiovascular disease risk factors. Multiple surrogate measures of cardiovascular health will be compared, including blood pressure, fasting lipid profiles, endothelium-dependent vasodilatation and plasma will be collected for circulating markers of endothelial function. The study was subsequently extended to 3 years, with the same outcome measures. Measurement of metabolic rate: Each group will be studied for change in energy expenditure and respiratory quotient using the non-invasive indirect calorimetry technique. Quality of life and cost utility outcomes: Longitudinal measures of patient reported quality of life outcomes, and cost utility measures will also be collected to generate preliminary data for future studies.

Official Title
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Surgery or Lifestyle With Intensive Medical Management in the Treatment of Type 2 Diabetes (SLIMM-T2D)

Conditions
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Type 2 Diabetes Mellitus, Obesity

Intervention / Treatment
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* Device: Allergan Adjustable Gastric Band Surgery
* Other: Intensive Medical Diabetes & Weight Management (Why WAIT) - Band Group
* Procedure: Roux-en-Y Gastric Bypass (RYGB) Surgery
* Other: Intensive Medical Diabetes & Weight Management (Why WAIT) - Bypass Group


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Potential participants will be those with T2DM, with a diagnosis of diabetes of at least one year in duration, BMI 30-45 kg/m^2 for the LAGB compared to intensive medical weight and diabetes management and BMI 30-42 kg/m^2 for LRYGB compared to intensive medical weight and diabetes management, Age 21-65 years, With a strong desire for substantial weight loss, who are free from active cardiovascular or other diseases that would render them unable to partake in a structured exercise program or to undergo a bariatric surgical procedure, and who are committed to life long medical and nutritional follow up. Exclusion Criteria: Detectable levels of glutamic acid decarboxylase (GAD) antibody or a history of diabetic ketoacidosis or uncontrolled T2DM (consistent fasting blood glucose >200 mg/dl or HbA1c above twice normal); Previous gastrointestinal surgery, inflammatory bowel disease, esophageal diseases including severe intractable esophagitis, Barrett's Disease, esophageal dysmotility or other impaired gastric motility (gastroparesis), or hiatal hernia >3 cm in size, chronic or acute bleeding conditions including peptic ulcer disease, portal hypertension (gastric or esophageal varices), chronic pancreatitis, or cirrhosis of the liver; Malignant or debilitating medical conditions, severe cardiopulmonary disease including uncontrolled hypertension (repeated systolic measures >160 or diastolic > 95 mm Hg on more than one day), unstable angina pectoris, recent myocardial infarction within 6 months, history of coronary artery bypass surgery or angioplasty, congestive heart failure, arrhythmia, stroke or transient ischemic attacks, urinary albumin excretion >300 mcg/mg creatinine and/or serum creatinine >1.5 mg/dL (permitting safety of increased dietary protein intake), Any endocrine disorder other than T2DM or thyroid disease which is stable on replacement therapy, including Cushing's syndrome; Any previous history of eating disorders, history of drug and/or alcohol abuse within 2 years of the screening visit, history of impaired mental status as defined by Diagnostic and Statistical Manual, 4th Edition (DSM-4) criteria and including, but not limited to active substance abuse, a history of schizophrenia, borderline personality disorder, uncontrolled depression, suicidal attempts within the past two years or current suicidal tendencies or ideations. Subjects will be excluded if there is a history of significant weight loss (>3%) within the previous 3 months or participation in alternate medically supervised exercise or weight reduction program within the previous 3 months, or with use of prescription or over the counter weight reduction medications or supplements within one month of the Screening Visit and for the duration of study participation. Women who are lactating, planning pregnancy, or unwilling to use contraception during the course of the trial.

Ages Eligible for Study
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Minimum Age: 21 Years
Maximum Age: 65 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: Gastric Band vs Intensive Diabetes & Weight Management<br>Patients will be randomized to receive either 1) laparoscopic placement of an adjustable gastric band (LAGB) or 2) treatment with an intensive medical and weight management (IMWM) program. LAGB will be placed using the pars flaccida technique. The Allergan laparoscopic band LAP BAND system will be utilized. LAGB ports will be placed in subcutaneous pockets in the right upper abdomen. The IMWM group will participate in the Weight Achievement and Intensive Treatment (Why WAIT) program, which is a multidisciplinary program for weight control and intensive diabetes management designed by Joslin Diabetes Center. Key aspects include: 1) Intensive and interactive medication adjustments, 2) Structured modified dietary intervention, 3) Graded, balanced, and individualized exercise intervention, 4) Cognitive behavioral intervention and 5) Group education. | Device: Allergan Adjustable Gastric Band Surgery<br> <br> Other: Intensive Medical Diabetes & Weight Management (Why WAIT) - Band Group<br>* Intensive Medical Diabetes & Weight Management (Why WAIT) - Band Group<br>|
| Active Comparator: RYGB vs Intensive Diabetes & Weight Management<br>Patients will be randomized to receive either 1) Roux-en-Y gastric bypass (RYGB) surgery or 2) treatment with an intensive medical and weight management (IMWM) program. RYGB will be performed using a 75 cm antecolic, ante-gastric Roux limb created with a 50 cm pancreaticobiliary limb. A 15-20 cc gastric pouch will be created lying along the lesser curve of the stomach, with division of the vagal trunks at the lower border of the pouch. The IMWM group will participate in the Weight Achievement and Intensive Treatment (Why WAIT) program, which is a multidisciplinary program for weight control and intensive diabetes management designed by Joslin Diabetes Center. Key aspects include: 1) Intensive and interactive medication adjustments, 2) Structured modified dietary intervention, 3) Graded, balanced, and individualized exercise intervention, 4) Cognitive behavioral intervention and 5) Group education. | Procedure: Roux-en-Y Gastric Bypass (RYGB) Surgery<br> <br> Other: Intensive Medical Diabetes & Weight Management (Why WAIT) - Bypass Group<br>* Intensive Medical Diabetes & Weight Management (Why WAIT) - Bypass Group<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Fasting Plasma Glucose <126 mg/dL and HbA1c < 6.5% at Three Years of Follow-up. | The primary outcome variable of both parallel trials will be the percent of patients attaining glycemic control (defined as fasting plasma glucose < 126 mg/dL and HbA1c < 6.5%) at three years of follow-up. | 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Glycemic Control, as Measured by Hemoglobin A1c | All participants had type 2 diabetes. Long-term diabetes control is typically evaluated in both clinical and research settings using the measurement of Hemoglobin A1c (a measure of glycated hemoglobin, proportional to average glucose levels over approximately 3 months). This endpoint (hemoglobin A1c) was measured at 3 years after intervention. Reported values are changes from baseline derived from the mixed effects model analysis, adjusted for baseline. | 3 years | 
| Body Mass Index | Change in body mass index 3 years after intervention | 3 years | 
| Cardiovascular Risk | UKPDS risk of coronary heart disease, reported as change from baseline | 3 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Type 2 Diabetes Mellitus, Obesity, Lifestyle, Bariatric Surgery, Laparoscopic Adjustable Gastric Band, Laparoscopic Roux-en-Y Gastric Bypass