Diet and Medical Therapy Versus Bariatric Surgery in Type 2 Diabetes

Study Overview
=================
Brief Summary
-----------------
It is generally held that ß-cell function is irreversibly lost already at the time the disease manifests itself and thereafter continues to decline linearly with time. Several studies, however, have documented the possibility that ß-cell function may be restored, at least partially, in type 2 diabetes. Of major relevance to the issue of ß-cell recovery in diabetes are the following findings: bariatric surgery in morbidly obese patients with type 2 diabetes can restore euglycaemia, the acute insulin response to glucose and insulin sensitivity; recent studies have reported that diabetic subjects return to euglycaemia and normal insulin levels within days after surgery, long before a significant weight loss has occurred; and whereas gastric bypass (GBP) improves insulin sensitivity in proportion to weight loss, bilio-pancreatic diversion (BPD) improves insulin action out of proportion to weight loss, i.e., it normalizes it at a time when patients are still markedly obese. Because RYGB is a predominantly restrictive procedure involving the foregut, whereas BPD is a predominantly malabsorptive procedure involving the distal gastro-intestinal (GI) tract, these findings suggest that the control of both insulin action and ß-cell function is influenced by signals originating from the GI tract. The principal aim of this study is to verify the effect on type 2 diabetes mellitus (T2DM) of GBP and BPD, the two operations which have shown specific actions on glucose homeostasis control, in type 2 diabetic patients with BMI > 35 kg/m2, and to compare this effect with matched T2DM control patients receiving the standard of medical care.

Detailed Description
-----------------
ß-cell dysfunction and insulin resistance are the main pathophysiological defects responsible for the development of hyperglycaemia [1]. Both these defects predict incident diabetes in high-risk subjects [2]. Insulin resistance per se is not sufficient to cause hyperglycaemia; mild degrees of ß-cell dysfunction, on the other hand, may not result in diabetic hyperglycaemia in insulin sensitive individuals. It is only when impaired ß-cell function occurs in the background of insulin resistance that plasma glucose levels begin to rise (as is the case of individuals with impaired glucose tolerance [3]). The occurrence of postprandial, or day-long, hyperglycaemia further compromises both ß-cell function and insulin action, a phenomenon called glucose toxicity [4-6]. As a consequence, the vast majority of patients with established type 2 diabetes present, in addition to marked insulin resistance, a clear defect in ß-cell function, which is generally proportional to the severity of the hyperglycaemia [7]. Of note is that the extent of ß-cell dysfunction in type 2 patients may be misjudged when ß-cell function is inferred from simple measurements of fasting or postprandial plasma insulin concentrations. In fact, insulin secretion increases (in non-linear manner [8]) in insulin resistant individuals, a compensatory response aimed at maintaining glucose tolerance. As a consequence, the absolute insulin hypersecretion (particularly in the fasting state) commonly found in patients with IGT or diabetes masks the underlying defect in the ability of the ß-cell to cope with nutrient stimulation. It is generally held that ß-cell function is irreversibly lost already at the time the disease manifests itself and thereafter continues to decline linearly with time. Several studies, however, have documented the possibility that ß-cell function may be restored, at least partially, in type 2 diabetes [9-13]. Of major relevance to the issue of ß-cell recovery in diabetes are the following findings: (a) bariatric surgery in morbidly obese patients with type 2 diabetes can restore euglycaemia, the acute insulin response to glucose [14-17] and insulin sensitivity [18,19]; (b) recent studies have reported that diabetic subjects return to euglycaemia and normal insulin levels within days after surgery, long before a significant weight loss has occurred [20]; and (c) whereas RYGB improves insulin sensitivity in proportion to weight loss, BPD improves insulin action out of proportion to weight loss, i.e., it normalises it at a time when patients are still markedly obese [21]. Because RYGB is a predominantly restrictive procedure involving the foregut whereas BPD is a predominantly malabsorptive procedure involving the distal GI tract, these findings suggest that the control of both insulin action and ß-cell function is influenced by signals originating from the GI tract. Some studies have investigated the hormonal changes that follow bariatric surgery. In most cases, however, clinical testing was performed after significant weight reduction, thereby making it difficult to establish whether any observed hormonal effect was the cause or the consequence of weight loss and diabetes resolution. Recently, it has been reported that RYGB induces rapid normalisation of blood glucose and insulin levels in concomitance with significant changes of the levels of hormones involved in the regulation of glucose metabolism (ACTH, leptin and GIP) in the early postoperative period [22]. It has been proposed that the incretins could be one of the key mediators of the anti-diabetic effects of certain types of bariatric surgery. Previous data have shown that the significant weight loss observed after various bariatric procedures was accompanied by improvement of diabetes control and increased GLP-1 levels. However, most studies were cross sectional [23,24], reported fasting [25] rather than post-prandial GLP-1 levels, and compared various types of surgery such as jejuno-ileal bypass (JIB) [26,27] or bilio-pancreatic diversion (BPD) [27], often leading to inconclusive results. Data on fasting GIP levels after bariatric surgery are inconsistent, reporting either a decrease [25,28,29] or an increase [23,24]. GLP-1 levels increase after a meal in patients after RY-GBP [30] or with oral glucose after BPD [30]. Meal-stimulated GIP levels have been reported to increase after JIB [23], or to decrease after GBP, JIB or BPD surgery [26,29,31,32]. None of these studies, however, measured GLP-1 and GIP simultaneously, reported the incretin levels and effect on insulin secretion (with the exception of the last quoted one, which reported both GIP and insulin response to meal markedly reduced after BPD), or was done in diabetic patients. Some authors have suggested that an enhanced release of GLP-1, triggered by the earlier presentation of undigested food to lower segments of the bowel, might be involved in the glycaemic improvement consequent to bypass procedures for obesity surgery. Collectively, these observations clearly suggest that there is a large margin for ß-cell recovery of function in type 2 diabetes and that different segments of the gut participate differentially in such recovery. The primary end-points of the study are the differences in the proportions of patients reaching partial or complete remission of type 2 diabetes between conventional therapy and BPD or conventional therapy and RYGB. In particular, according to Buse et al (Diabetes Care 2009; 32:2133-35) partial remission is defined as fasting glucose values of 100-125 mg/dl [5.6-6.9 mmol/l]) and HbA1c<6.5%, of at least 1 year's duration in the absence of active pharmacologic therapy. Complete remission is referred to fasting glucose <100 mg/dl [5.6 mmol/l]) and HbA1c in the normal range of at least 1 year's duration in the absence of active pharmacologic therapy. Secondary endpoints Secondary endpoints include percentage change of fasting plasma glucose levels, glycated hemoglobin, weight, waist circumference, blood pressure, cholesterol, HDL-cholesterol and triglycerides, and hard cardiovascular risk.

Official Title
-----------------
Prospective Randomized Controlled Trial on the Effect of Gastric Bypass and Biliopancreatic Diversion on Type 2 Diabetes Mellitus in Patients With BMI > 35 vs. Medical Therapy

Conditions
-----------------
Type 2 Diabetes

Intervention / Treatment
-----------------
* Procedure: Bariatric surgery: Gastric bypass
* Procedure: Bariatric surgery: Bilio-pancreatic diversion
* Behavioral: anti-diabetic drugs and behavioral suggestions


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: patients with type 2 diabetes and BMI ≥35 kg.m-2 age between 30 and 60 years duration of diabetes ≥ 5 years poor glycemic control (i.e., HbA1c ≥ 7.0%) in spite a medical antidiabetic therapy in accordance with good clinical practice (GCP) Exclusion Criteria: pregnancy medical conditions requiring acute hospitalisation severe diabetes complications or associated medical conditions (such as blindness, end-stage renal failure, liver cirrhosis, malignancy, chronic congestive heart failure) recent (within preceding 12 months) myocardial infarction, stroke or TIA unstable angina pectoris psychological conditions which may hamper patient's cooperation geographic inaccessibility any condition which, in the judgement of the Investigator, may make risky the participation in the study or bias the results

Ages Eligible for Study
-----------------
Minimum Age: 30 Years
Maximum Age: 60 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

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: GBP<br>Type 2 diabetic subjects with BMI ≥ 35, poor glycemic control (HbA1c ≥ 7.0%) and diabetes duration ≥ 5 years undergo gastric bypass | Procedure: Bariatric surgery: Gastric bypass<br>* Gastric bypass (GBP): A subcardial gastric pouch with a 30±10 ml capacity will be created on a naso-gastric 36F calibrating tube by sectioning the stomach with a linear stapler 3-4 cm horizontally on the lesser curve, 4 cm distal to the e-g junction, and then vertically until attainment of the angle of Hiss. After identification of the Treitz ligament, the jejunum will be transected at 100 cm from the ligament of Treitz and the two stumps will be closed. The distal stump will be anastomosed to the distal end of the gastric pouch. The preferred gastro-jejunal anastomosis is the totally hand-sewn one, but it can be performed using any other the technique the surgeon is more familiar with. Finally, the proximal stump of the transacted bowel will be joined end-to-side to the jejunum 150 cm distal to the gastroenterostomy.<br>|
| Active Comparator: BPD 2<br>Type 2 diabetic subjects with BMI ≥ 35, poor glycemic control (HbA1c ≥ 7.0%) and diabetes duration ≥ 5 years undergo bilio-pancreatic diversion | Procedure: Bariatric surgery: Bilio-pancreatic diversion<br>* Biliopancreatic diversion (BPD): A distal two-third gastrectomy will be carried out aiming at leaving an about 400 ml gastric remnant. The gastrointestinal continuity will be re-established by sectioning the small bowel 300 cm proximal to the ileocecal valve, closing the intestinal stumps, and joining the proximal one end-to-side to the distal ileum at 50 cm from the ligament of Treitz. The distal stump of the transacted bowel will be anastomosed to the left corner of the gastric stump, preferably in a totally hand-sewn fashion.<br>|
| Active Comparator: Med Ter3<br>Type 2 diabetic subjects with BMI ≥ 35, poor glycemic control (HbA1c ≥ 7.0%) and diabetes duration ≥ 5 yearsundergo medical therapy | Behavioral: anti-diabetic drugs and behavioral suggestions<br>* Medical therapies (oral hypoglycemic agents and insulin) are optimized on an individual basis. Lifestyle modification programs, including reduced energy and fat (<30% total fat and <10% saturated fat, high fibre content) intake and increased physical exercise (suggested at least 30 minutes of brisk walking every day possibly associated with a moderate intensity aerobic activity twice a week), are tailor made by an experienced diabetologist assisted by a dietitian. After the two years, the patients in control group will be offered the choice to undergo one of the two surgical procedures.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To assess the efficacy of bariatric surgery in inducing partial or total remission of type 2 diabetes mellitus, as compared to standard medical anti-diabetic care (STC). |  | 10 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Secondary endpoints include percentage change of fasting plasma glucose levels, glycated hemoglobin, weight, waist circumference, blood pressure, cholesterol, HDL-cholesterol and triglycerides, hard cardiovascular risk and quality of life. |  | 10 years | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
bariatric surgery, GBP, BPD, type 2 diabetes