Feasibility, Efficacy, and Mechanisms of Surgical vs Medical Diabetes Treatment

University Of Washington, Seattle WA

Investigators

Linked publications, trials & patents

Abstract

DESCRIPTION (provided by applicant): Roux-en-Y gastric bypass (RYGB) dramatically ameliorates type 2 diabetes mellitus (T2DM), through poorly understood mechanisms beyond just weight loss. However, due to a paucity of randomized clinical trials (RCTs) the risk-benefit ratio of RYGB compared to non-surgical diabetes care is unknown, especially for patients with less severe obesity. Barriers to appropriate RCTs include challenges in recruiting sufficient numbers of informed patients who are willing to be randomized to surgical or non-surgical approaches, who have a funding source for either intervention, and who are not coerced into an intervention arm, as well as operational issues in longitudinal data gathering and the availability of metrics to delineate mechanisms of T2DM improvement. We propose to address these barriers by pursuing 3 objectives. First, we will determine the feasibility of a novel approach to generating a randomization cohort from among members of an integrated healthcare system that covers RYGB for patients with BMI >35 kg/m2 and is willing to do so among those with BMI 30-35 kg/m2 for this study. We will utilize the databases of this network to identify adults with T2DM and a BMI of 30-40 kg/m2. Sufficient numbers of these patients (4,000-6,000) will be surveyed to identify those without strong preferences regarding medical vs. surgical treatment of diabetes and obesity. This subset will be exposed to a novel, standardized shared-decision-making (SDM) tool that we have developed and validated (the only such instrument in the field), which helps patients explore the risks and benefits of both treatment options, after which their willingness to randomize will be assessed. Second, a cohort of patients who remain in equipoise after the SDM process will be randomized to receive RYGB or a state-of-the-art intensive medical/lifestyle intervention of diet, exercise, and pharmacotherapy for diabetes/obesity that we have helped develop and tested in prior RCTs. The goal of this feasibility RCT will be to demonstrate the utility of our novel cohort generation scheme, to determine the number needed to approach to accomplish appropriate sample sizes, to assess the reliability of passive and active data collection mechanisms, to determine the accuracy of assignment of concurrent healthcare utilization (HCU) measurements, and to determine the resources required for eventual full-scale trial execution and retention. Third, we will assess the usefulness of including a set of novel metrics to elucidate anti-diabetic mechanisms of RYGB in future trials. Among randomized patients, we will test the hypothesis that RYGB alters innate and/or adaptive immunity to improve glucose homeostasis. Chronic inflammation driven by macrophages and T lymphocytes in adipose tissue and islets plays key roles in T2DM pathogenesis, and we hypothesize that RYGB reverses these processes disproportionately to the weight loss it promotes. We will test this hypothesis by quantifying cellular inflammation in adipose-tissue biopsies, systemic inflammation, and anti-islet T-cell reactivity in both randomized groups at baseline, 2 weeks after intervention, and at 7% weight loss, then correlate these findings with changes in glucose homeostasis.