Bariatric Times

FEB 2018

A peer-reviewed, evidence-based journal that promotes clinical development and metabolic insights in total bariatric patient care for the healthcare professional

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18 Review Bariatric Times • February 2018 T2DM, as well as integrated metabolic surgery into the proposed treatment algorithm after extensive evidence appraisal and broad consensus. These guidelines were developed in the second Diabetes Surgery Summit (DSS-II) and were endorsed by numerous medical and scientific societies worldwide. 15 According to these guidelines, bariatric surgery should be recommended to treat T2DM in obese patients with obesity and a BMI of 40kg/m 2 (Grade III obesity) or greater, regardless of glycemic control or complexity of glucose-lowering regimens, and also in patients with a BMI between 35 and 39.9kg/m 2 (Grade II obesity) if hyperglycemia cannot be adequately controlled despite optimal lifestyle and medical treatment. Furthermore, metabolic surgery should be considered as an option to treat T2DM in patients with obesity with a BMI between 30 and 34.9kg/m 2 (Grade I obesity) if adequate glycemic control is not achieved despite maximally intensified treatment with oral or injectable medications. 15 In this joint statement, a critical approach toward the benefits and limitations of metabolic surgery was adopted, and a number of controversial issues were raised, highlighting the complexities in the field. Some of these issues are summarized below: • Long-term (beyond 10 years) efficacy and safety data are lacking. • Factors predicting T2DM remission and relapse after surgery are still incompletely characterized. • There is still insufficient evidence to clearly define cut- off values for T2DM duration or laboratory markers that might be able to quantitatively predict T2DM remission over time. • Available studies include a modest number of patients with a BMI between 30 and 35kg/m 2 . • There are limited comparative (head-to-head) data for distinct surgical interventions in terms of cardiometabolic outcomes. • Data for T2DM-related complications, cancer, and mortality that represent hard and clinically relevant endpoints extrapolated only from non-randomized studies. RCTs for these outcomes are warranted. • There are no studies investigating the role of multimodal therapy with integration of pharmaceutical and surgical treatment strategies to optimize outcomes for patients with T2DM in terms of inducing and maintaining T2DM remission and lowering the risk of complications and comorbidities. • It is necessary to identify more reliable clinical and biological markers that can be applied to define T2DM remission and cure more accurately. • Cost-effectiveness data are pending. • Optimal intervention time for a durable T2DM remission still remains elusive. • The relationship between the duration of T2DM remission and the incidence of micro- and macrovascular complications remains unclear. CONCLUSION The gastrointestinal tract represents a meaningful target to treat T2DM. Surgical operations with intestinal diversion have consistently shown the capacity to improve glucose homeostasis by modulating gut hormones, beyond reducing energy intake and body weight. LAGB, SG, RYGB, and BPD are the four best standardized surgical procedures. The beneficial metabolic effects of surgery are partly mediated by weight loss and severe energy restriction, but there are also weight loss- independent mechanisms. Foremost of these are effects on multi-organ insulin sensitivity, ß-cell function and incretin response, changes in BA composition and flow, modifications of gut microbiota, and intestinal glucose metabolism, and increased metabolic activity of brown adipose tissue. Many studies have tried to explore the best biological and clinical predictors of T2DM remission after surgery. The distinction between responders, those who never respond, and relapsers after initial remission is crucial. A shorter T2DM duration, better preoperative glycemic control, lower baseline HbA1c and waist circumference, and profound postsurgical weight loss all have been associated with higher rates of T2DM remission and lower risk of relapse, but the greatest benefit might actually occur in patients with the largest reduction in HbA1c, even if they stay on medication and do not meet remission criteria. Interestingly, preoperative BMI is of no predictive utility for metabolic outcomes. Many RCTs and high-quality prospective, matched-cohort studies have consistently shown beneficial effects of bariatric surgery in patients with obesity and T2DM. In the short and medium term (up to three years post-surgery), a significant amount of weight loss has been seen, T2DM might completely regress, and cardiometabolic risk factors are dramatically improved. In the long term (beyond five years), surgery might achieve durable weight loss, prevent T2DM and cancer, improve overall glycemic control (although T2DM might recur in a considerable percentage of patients), and reduce total and cause-specific mortality. The gradient of efficacy for the four established procedures for weight loss and T2DM remission is: BPD > RYGB > SG > LAGB. According to recently released guidelines and recommendations, metabolic surgery should be recommended in appropriate candidates with Grade III obesity, regardless of glycemic control or glucose-lowering regimens, and in patients with Grade II obesity with inadequately controlled T2DM despite optimal therapy. Additionally, patients with Grade I obesity and inadequately controlled hyperglycemia despite optimal medical treatment might benefit from metabolic surgery. In spite of the well-established role of metabolic surgery as an additional therapeutic tool against T2DM, a number of issues still remain to be resolved: the lack of long- term efficacy and safety data, the incomplete characterization of T2DM remission determinants, the paucity of studies investigating multimodal therapies (combined surgical and pharmacological interventions), and the lack of RCTs with diabetes-related hard endpoints, such as diabetic nephropathy and retinopathy, cardiovascular disease, and mortality. For metabolic surgery to become part of standard diabetes care, the surgical and nonsurgical communities will need to objectively look at the data and acknowledge the strengths, weaknesses, and opportunities, because although there is a wealth of new and high-quality science in the field the number of patients receiving surgery as a treatment for diabetes remains disappointingly low. REFERENCES 1. Catoi AF, Pârvu A, Muresan A, Busetto L. Metabolic mechanisms in obesity and type 2 diabetes: insights from bariatric/metabolic surgery. Obes Facts. 2015;8:350– 63. 2. Cefalu WT, Rubino F, Cummings DE. Metabolic surgery for type 2 diabetes: changing the landscape of diabetes care. Diabetes Care. 2016;39:857–60. 3. Rubino F, Schauer PR, Kaplan LM, Cummings DE. Metabolic surgery to treat type 2 diabetes: clinical outcomes and mechanisms of action. Annu Rev Med. 2010;61:393–411. 4. Rubino F, Marescaux J. Effect of duodenal-jejunal exclusion in a non-obese animal model of type 2 diabetes: a new perspective for an old disease. Ann Surg. 2004;239:1–11. 5. Gloy VL, Briel M, Bhatt DL, et al. Bariatric surgery versus non- surgical treatment for obesity: a systematic review and meta- analysis of randomised controlled trials. BMJ. 2013;347:f5934. 6. Mingrone G, Panunzi S, De Gaetano A, et al. Bariatric surgery versus conventional medical therapy for type 2 diabetes. N Engl J Med. 2012;366:1577–85. 7. Schauer PR, Kashyap SR, Wolski K, et al. Bariatric surgery versus intensive medical therapy in obese patients with diabetes. N Engl J Med. 2012;366:1567–76. 8. Mingrone G, Panunzi S, De Gaetano A, et al. Bariatric- metabolic surgery versus conventional medical treatment in obese patients with type 2 diabetes: 5 year follow-up of an open-label, single-centre, randomised controlled trial. Lancet. 2015;386:964–73. 9. Cummings DE, Arterburn DE, Westbrook EO, et al. Gastric bypass surgery vs intensive lifestyle and medical intervention for type 2 diabetes: the CROSSROADS randomised controlled trial. Diabetologia. 2016;59:945–53. 10. Halperin F, Ding SA, Simonson DC, et al. Roux-en-Y gastric bypass surgery or lifestyle with intensive medical management in patients with type 2 diabetes: feasibility and 1-year results of a randomized clinical trial. JAMA Surg. 2014;149:716–26. 11. Ikramuddin S, Korner J, Lee WJ, et al. Roux-en-Y gastric bypass vs intensive medical management for the control of type 2 diabetes, hypertension, and hyperlipidemia: the diabetes surgery study randomized clinical trial. JAMA. 2013;309:2240–9. 12. Courcoulas AP, Goodpaster BH, Eagleton JK, et al. Surgical vs medical treatments for type 2 diabetes mellitus: a randomized clinical trial. JAMA Surg. 2014;149:707–15. 13. Courcoulas AP, Belle SH, Neiberg RH, et al. Three-year outcomes of bariatric surgery vs lifestyle intervention for type 2 diabetes mellitus treatment: a randomized clinical trial. JAMA Surg. 2015;150:931–40. 14. Abdeen G, le Roux CW. Mechanism underlying the weight loss and complications of roux- The gastrointestinal tract represents a meaningful target to treat T2DM. Surgical operations with intestinal diversion have consistently shown the capacity to improve glucose homeostasis by modulating gut hormones, beyond reducing energy intake and body weight.

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