Evidence on the Mechanisms of Bariatric Surgery and RCTs with Consistent Results: Proof that Surgery is an Effective Therapy for Patients with Type 2 Diabetes Mellitus

| September 1, 2015

3rd World Congress on Interventional Therapies for Type 2 Diabetes and the 2nd Diabetes Surgery Summit

An Interview with Lee M. Kaplan, MD, and Philip Schauer, MD

Lee M. Kaplan, MD, is the Director, Massachusetts General Hospital Weight Center,
Boston, Massachusetts. Philip Schauer, MD, is the Director of Bariatric and Metabolic Surgery and Director of Minimally Invasive Surgery at The Cleveland Clinic. He is a past president of the American Society for Metabolic and Bariatric Surgery.

Bariatric Times. 2015;12(9):18–22.


On September 28, 2015, London will host two seminal events: The 3rd World Congress on Interventional Therapies for Type 2 Diabetes and the 2nd Diabetes Surgery Summit.

Leading up to this event, Bariatric Times has featured interviews with members of the event’s leadership team—experts in diabetes care and research. This month, we complete the series featuring interviews with Drs. Lee Kaplan and Philip Schauer, members of the organizing committee for the 3rd World Congress on Interventional Therapies for Type 2 Diabetes and the 2nd Diabetes Surgery Summit. Dr. Kaplan discusses the early and current resesarch on mechanisms of bariatric surgery. Dr. Schauer talks about the important progress made in the field of metabolic surgery research—the completion of 15 randomized, controlled trials—and their consistent findings that surgery works to improve T2DM.

Interview #1: Lee Kaplan, MD
Dr. Kaplan, please tell us how you got interested in obesity research.

Dr. Kaplan: By training, I’m an electrobiologist and gastroenterologist. About 18 years ago, I became interested in obesity both from a clinical and scientific perspective. About 10 years ago, I became interested in the effects of bariatric surgery because I was convinced that the mechanisms proposed—that surgery worked by limiting food intake or absorption of ingested food—couldn’t be right. I arrived at this conclusion after hearing what patients were saying after undergoing bariatric surgical procedures. One patient in particular asked if the surgeon operated on her brain because she felt her appetite had changed after gastric bypass surgery. She wasn’t hungry anymore and had a full feeling after meals. Another patient said they developed a new craving for salads. I suspected something else was at work, because if restriction was the mechanism in which the surgery worked, wouldn’t the patient experience increased hunger? Limited food absorption would also cause the patient to be hungrier. The two proposed mechanisms were not consistent with what patients were telling us after weight loss surgery. Everything we do in research is driven by patient observation and response to surgery.

Since those first patients, we have done a lot of research in hopes of better understanding how weight loss procedures, such as Roux-en-Y gastric bypass (RYGB), laparoscopic sleeve gastrectomy (LSG), biliopancreatic diversion (with and without duodenal switch), and vertical banded gastroplasty, work. The goal was to gain a better understanding so we could develop new treatments for obesity and type 2 diabetes mellitus (T2DM).

We developed animal models of all procedures so we could examine how they worked. We knew that surgery clearly worked for treatment of obesity and other complications of obesity. We now know definitely that surgery works by changing the regulation of energy balance, which is a metabolic phenomenon—just as metabolic as changing glucose or lipid regulation. We asked that question and that was our introduction to metabolic research.

Can you give us the main highlights of your early research on the mechanisms of action?

Dr. Kaplan: I have been involved in multiple studies, such as the Metabolic Applied Research Strategy initiative. The idea behind MARS was to understand the physiological mechanisms of surgery better so that perhaps we could develop new, less invasive, effective therapies and reach more people with obesity. Surgery is only used in less than one percent of people with obesity in the United States.[1] Clearly, there was and still is a lot of unmet need.

We learned a lot about the mechanisms of surgery. We’ve also learned how those mechanisms could potentially be exploited. Through mechanistic studies we have demonstrated the following:[2]
•    RYGB, adjustable gastric banding (AGB), LSG, endoluminal duodenal sleeve, and duodenojejunal bypass induce substantial weight loss (generally 10–20% of initial body weight) in animals with diet-induced and genetic obesity.
•    These procedures induce weight loss by different mechanisms.
•    These procedures have variable effects on insulin signaling and diabetes.
•    Gastric procedures primarily affect food intake and body weight.
•    Intestinal procedures have a lesser effect on food intake, but a greater effect on glucose homeostasis.
•    Gastric bypass substantially affects energy expenditure.
•    Intact hormone signaling between the gut and central nervous system (CNS) is required for changes in food intake but not changes in energy expenditure after RYGB.
•    RYGB blocks responsiveness to the food environment in animals that would be otherwise be susceptible to diet-induced obesity.
•    The composition of the gastrointestinal microbiota population is altered by RYGB.
•    The effect of microbiota on weight and adiposity can be transferred from host to recipient.

We now know that all of these mechanisms are very complex, especially energy balance because the body spends an enormous amount of time trying to regulate how it gains energy and uses it. To do that accurately requires a complex system, which is critical to every living organism. About one-quarter of our genes are involved in maintaining this energy balance. So, something like bariatric surgery affects how that one-quarter of our genes works in the body. That is how powerful bariatric surgery is.

Has it been difficult to spread the word and change previous conceptions among the bariatric community, the medical community, and the public?

Dr. Kaplan: At its core, obesity is a physiological problem. The mere understanding that surgery works in a physiological way has enabled us to look at obesity treatment as a more wholesome, effective, and appropriate therapy. Spreading the message that obesity itself is a physiological problem is beneficial because it helps to diminish the stigma and place less responsibility on the individual. It’s more acceptable as a potential fix for the problem in many patients, rather than just painting over it.
Metabolic research has led to all kinds of educational programs that have made the public and medical community more open to consider bariatric surgery as an appropriate therapy for metabolic disease. I just came back from South Asia where I gave talks educating the medical community about the mechanisms of surgery.
The majority of papers in the literature still talk about restriction and malabsorption, even though we know those aren’t the mechanisms. I can tell you that audiences aren’t shocked anymore when they hear about the physiological changes spurred by surgery and they want to understand it better. Most people in the surgical community are now aware of the research and the message that surgery is more complicated than we originally thought. There is a tremendous yearning to understand obesity and surgery.

We have been hearing a lot about the gut microbiome and its role in obesity. Can you discuss that research and other recent studies?
Dr. Kaplan: Much has been learned about surgery’s effect on the gut microbiome. It’s very exciting. Regulation of the gut is very complex. It includes different bugs, hormones, the immune system, and neuronal signals. Dozens of research groups are adding to the literature weekly, so we are still learning about and attempting to understand this mechanism.

We have learned much about how surgery works on obesity and diabetes, but we are also looking at how it works on other diseases, such as fatty liver disease, obstructive sleep apnea, and cognitive dysfunction. There are well over 100 different diseases that are caused or made worse by obesity to the degree that surgery may able to fix things in part by causing weight loss, but in many cases independent of the weight loss. I think surgery can be applied to a whole variety of these other diseases. Obesity, diabetes, and other metabolic diseases are so important that research isn’t going to stop. It’s going to go on forever. It is remarkable to observe the long-term effects of surgery on obesity, diabetes, and other diseases mentioned. Weight loss independent effects of surgery are now evident.

Although there are many mechanisms to surgery, there are still more that might be activated through other channels. For instance, we found that surgery doesn’t seem to be involved in serotonin signaling.[3] Because surgery doesn’t take advantage of that system, you can manipulate it and thus add to the effects of surgery. This gives us the opportunity to use drugs or other approaches to enhance the effects of surgery and address what surgery cannot. There is a lot of evidence that if you give medications, such as weight loss medications, (e.g., phentermine and topiramate, lorcaserin HCl, and naltrexone HCl/bupropion HCl) after surgery, you can enhance surgery’s effects. I have found that combination therapy with both surgical and pharmacological interventions works very well. My center has been employing combination therapy for a long time, working with obesity medicine specialists.

What are your thoughts on the terminology—bariatric surgery, metabolic surgery, diabetes surgery?

Dr. Kaplan: Metabolic disease includes obesity. A lot of times we talk about metabolic surgery as surgery applied to treat T2DM, but surgery works on treating obesity at the same time. It works on T2DM by changing metabolism and on obesity by changing energy balance, so they are all metabolic in the way they cause changes. The terms metabolic surgery and diabetes surgery were coined to emphasize the unique role that these operations play. For instance, the term diabetes surgery is useful in that it makes the point that you can use these operations to treat diabetes in people with a body mass index less than 35kg/m[2]. For that reason, it is valuable to have these different terms. It’s also useful in educating the public.

Please tell us about your involvement in the DSS-1 Summit and  World Congress on Interventional Therapies for Type 2 Diabetes.

Dr. Kaplan: I was an organizer for the DSS-1 along with Drs. Francesco Rubino, Phil Schauer, and David Cummings. We are resuming our roles as organizers for the DSS-2 and will also be presenting and sitting on panels. We all will get our individual votes in the consensus determining the appropriate use of surgery for the treatment of diabetes.

Do you think research on mechanisms of surgery will be important in the consensus?

Dr. Kaplan: The research used in developing consensus is largely clinical. It is based on clinical data and not so much on mechanistic data, however, the fact that we are beginning to understand the mechanisms in which surgery works on diabetes certainly influences the message that surgery works as a treatment. Once you know that surgery is working to change the physiological abnormalities that occur in patients with obesity and diabetes, and “normalizing” them, you gain more confidence that surgery is a good thing.

What do you hope will be the outcome of the DSS-2? What research do you think we will see come out in 2016?

Dr. Kaplan: I hope that through the DSS-2, more and more of the medical community become knowledgeable about the effects of gastrointestinal surgical manipulation of the gut on diabetes, which will then translate to more sophisticated use of bariatric and metabolic surgery for the treatment of diabetes.

Looking forward in general, I think that the medical community and public recognize not only the effect of bariatric surgery clinically, but also its utility as a model for understanding two important things: 1) how the gut regulates all these metabolic functions, and 2) what the mechanisms are by which they can be regulated to improve obesity, diabetes, and other diseases. I think we are going to be discovering more and more mechanisms, and thus getting a better idea of how surgery improves diabetes. The results of that research will allow us to use our current tools better and also allow us to develop new tools. This will ultimately allow a greater portion of population access to more effective therapies to help the other 99 plus percent of people who could benefit from surgery.

References
1.    Nguyen N. Bariatric Surgery Remains Significantly Underutilized. ASMBS Connec. May 2014. http://connect.asmbs.org/may-2014-president-ninh-blog.html. Accessed 8/24/2015
2.    Massachusetts General Hospital. Obesity, Metabolism and Nutrition Institute (OMNI) http://www.massgeneral.org/omni/research/. Accessed 8/24/15.
3.    Carmody JS, Ahmad NN, Machineni S, Lajoie S, Kaplan LM. Weight loss after RYGB is independent of and complementary to serotonin 2C receptor signaling in male mice. Endocrinology. 2015;156(9):3183–3191. Epub 2015 Jun 11.


Interview #2: Philip Schauer, MD

Dr. Schauer, how did you become involved in bariatric and metabolic surgery research, particularly surgery’s effect on type 2 diabetes mellitus (T2DM)?

Dr. Schauer: I completed a fellowship program in Minimally Invasive Surgery at Duke in 1995. During this time, I became interested in trying to expand the utilization of this great technology. At that time, bariatrics wasn’t being intensely explored as it is today. It was thought that the use of MIS was very beneficial in patients with extreme obesity. What sustained my interest was witnessing the overwhelming impact it has on people’s lives. It was amazing to perform a procedure and see dramatic improvement in many areas, including quality of life and T2DM.

In the late 1990s, I was absolutely marveled by how dramatic and rapid people resolved T2DM after undergoing Roux-en-Y gastric bypass (RYGB). Patients were off insulin within 2 to 3 days after surgery. I was very interested in finding out how this happened so rapidly after surgery, even before weight loss occurred. I learned that weight loss is a contributor to T2DM improvement, but other factors are involved in this phenomenon. I dedicated part of my career to exploring the uses for bariatric surgery, specifically T2DM resolution, and discovering how these operations were actually working.

Please tell us about your involvement in the First Diabetes Surgery Summit in 2007.

Dr. Schauer: The Diabetes Surgery Summit has been a big part of my continued interest in diabetes surgery.

The journey began before the first meeting (DSS-1) in 2007 in Rome, Italy. We planned the Summit with the aim to bring together all of the world experts to discuss the use of surgery to treat T2DM. That meeting in 2007 was a big success. For nonsurgeons, it was a foreign idea. During that meeting, we quickly realized that the guidelines we put forth and our finding was just the beginning of the story.

The DSS-1 resulted in a few milestones for diabetes surgery. In 2009, the American Diabetes Association included bariatric surgery in their guidelines for the treatment of diabetes. It was only one paragraph, but it was a start. After the DSS-1, the International Diabetes Federation (IDF) put forth a document based on the available evidence, recommending where surgery belonged in the treatment of T2DM.

What progress has been made in the field since the DSS-1?

Dr. Schauer: There has been much progress made since the DSS-1. During the time of the DSS-1, there was only one randomized, controlled trial (RCT).[1] Although there were observational studies, the medical community at large did not accept them and demanded RCTs. Back in 2007, many thought it would be difficult to do RCTs in this patient population in terms of recruiting and randomizing. Now that I have been involved in RCTs,[2,3] I can appreciate how challenging they are to conduct. Since 2007, there have been about 15 RCTs, all of which have consistent findings: surgery works in improving T2DM. I think that these studies have awakened many thought leaders and referring physicians, but feel there are still referring physicians who do not understand them and could benefit from clear ADA guidelines on surgery for T2DM.

This year’s summit is going to bring all of this new information together. Proceedings are scheduled to publish in Diabetes Care.

What do you hope to gain during the DSS-2?

Dr. Schauer: What we hope to gain through the DSS-2 is a more universal and broad recognition of and agreement on the role of surgery for T2DM treatment based on the current evidence. We also hope that the ADA adopts our guidelines for multiple reasons. First, insurance payers give the ADA a lot of respect and look to their guidelines when developing coverage policies. The payer community hasn’t been pressured enough, and if/when they are faced with the ADA endorsing and recommending surgery for T2DM treatment, they will need to consider it more seriously. Second, referring physicians also consult the ADA guidelines. We really believe we will get the endorsement of the ADA this time.

Why hasn’t gaining coverage for diabetes surgery moved more quickly?

Dr. Schauer: Coverage for diabetes surgery has lagged for a couple of reasons. First, in the minds of people, the notion of surgery is very radical, and it takes time for people to adjust their thinking. Second, we are just getting a grip on diminishing the stigma of obesity and T2DM. Some people still believe that obesity and T2DM are due to poor lifestyle choices. We now know that that is a myth. Before, our critics said we didn’t have enough RCTs. Now, we have the RCTs, but our trials are small and short term. Next, they say five-year data isn’t sufficient because it doesn’t show mortality rates. Despite our critics, I think the real thinkers are beginning to change and let go of these “obstacles” and ideas of surgery. We think the time is right.

Partner diabetes organizations are supporting the DSS-2. Do you think that this is evidence that endocrinologists and surgeons are now aligned toward the common goal of fighting T2DM through integration of combination therapies?

Dr. Schauer: Yes, I believe they have found common ground. For example, the ADA does mention surgery in their guidelines as I’ve mentioned previously. Another big step forward occurred in 2011 when the IDF met and formed consensus, endorsing surgery for T2DM. It didn’t carry as much weight as an ADA endorsement, but it represented progress.

Endocrinologists and surgeons are different, but hopefully we all believe that evidence and science should drive treatment. At DSS-1, we had to work really hard to get diabetes partner organizations on board as they were skeptical. Now, for DSS-2, they have actually asked to be a part of the meeting. Also, it took three years for the information from the DSS-1 to be published. For DSS-2, we already have an agreement for publication. I believe these are real testaments to our tremendous progress.

Dr. Schauer, are you working on any other RCTs or projects that you’d like to share with us?

Dr. Schauer: Yes, I am currently involved in a very exciting project titled Alliance of Randomized Trials of Medicine vs Metabolic Surgery in Type 2 Diabetes (ARMMS-T2D). Through this project, we will examine data from four sites—Pittsburgh, Washington, Seattle, and Harvard. This project is valuable because it will give us a larger sample size—around 300 patients. You can learn more about ARMMS-T2D at https://clinicaltrials.gov/ct2/show/NCT02328599.

References
1.    Dixon JB, O’Brien PE, Playfair J, et al. Adjustable gastric banding and conventional therapy for type 2 diabetes: a randomized controlled trial. JAMA. 2008;299(3):316–323.
2.    Kashyap SR, Bhatt DL, Schauer PR; STAMPEDE Investigators. Bariatric surgery vs. advanced practice medical management in the treatment of type 2 diabetes mellitus: rationale and design of the Surgical Therapy And Medications Potentially Eradicate Diabetes Efficiently trial (STAMPEDE). Diabetes Obes Metab. 2010;12(5):452–454.
3.    Schauer PR, Bhatt DL, Kirwan JP, et al. Bariatric surgery versus intensive medical therapy for diabetes–3-year outcomes. N Engl J Med. 2014;370(21):2002-13.

For more information on the World Congress, visit http://www.wcitt2d.org/. For group registration (10 participants and more), please contact the registration department at reg_wcidt15@kenes.com.

Funding: No funding was provided in the preparation of this manuscript.

Financial disclosures: The authors report  no conflicts of interest relevant to the content of this article.

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