Over Two Decades of Progress: The Need for Updated Guidelines Governing Usage of Bariatric and Metabolic Surgery

| July 1, 2015

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

An Interview with David E. Cummings, MD, Professor of Medicine, Senior Investigator, Diabetes and Obesity Center of Excellence, University of Washington, Seattle, Washington

Bariatric Times. 2015;12(7):19–21.


 

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 will feature interviews with members of the event’s leadership team—experts in diabetes care and research. This month, we feature an interview with Dr. David E. Cummings, Co-Director of the 2nd Diabetes Surgery Summit. Here, he discusses his work in diabetes research and participation in the first Diabetes Surgery Summit in 2007. He provides his perspective on the need for new guidelines governing the use of bariatric and metabolic surgery.

Dr. Cummings, can you please provide background on your interest and involvement in diabetes research?

Dr. Cummings: When I was an endocrinology fellow, I thought that I wanted to work on male reproductive endocrinology with an eye toward developing a long-acting male contraceptive that would be used in the developing world to help curb population growth. My original interest was in international health and tropical diseases. After developing a new gene-knockout mouse strain for male reproductive research, I began to notice that the mice were exceptionally lean. I observed a 50-percent reduction in their body fat and, as a consequence, they were much healthier, lived longer, and were resistant to diabetes.

This became the first genetically engineered lean animal model, and it was a big stride in my career. It got me a first-author paper in Nature[1] and was featured on the front cover of the journal that month. This generated a National Institutes of Health (NIH) Research Project Grant Program (RO1), which then diverged me away from male reproductive endocrinology and into body weight regulation research.

When I started working in this area of investigation, my earliest major field of study was on a new hormone that had just been discovered, ghrelin, which is the only known appetite-stimulating hormone. One of my first findings was that ghrelin levels in the blood of humans naturally rose before every meal and were rapidly suppressed when people ate.[2] This implicated ghrelin as the potential agent that causes ordinary day-to-day mealtime hunger, something that prior to that time had been completely mysterious. Mealtime hunger is a very powerful experience. Our work on ghrelin helped identify ghrelin as the agent that causes that sensation.

How did these studies lead you to research bariatric and metabolic surgery?

Dr. Cummings: Shortly after the study on ghrelin and mealtimes was published, I wrote a paper that got me into bariatric surgery research—another ghrelin paper that looked at ghrelin levels after diet-induced weight loss versus gastric bypass surgery.[3]

We made the nonsurgical subjects lose weight with a very low-calorie diet. Over three months, they lost about 15 percent of their body weight. To make sure they were at a new stable, steady state, we fixed them at the new lower body weight for another three months. At the end of that six-month period, we re-did the 24-hour ghrelin profiles. We found that the entire curve was elevated after weight loss compared to what it had been prior to weight loss. Every time point throughout 24 hours was higher after weight loss. So, this implicated ghrelin as one of the agents that the body uses to resist weight loss and promote weight regain—making it hard to diet.

In contrast to the weight loss achieved with a low-calorie diet, if we looked at people who achieved even greater weight loss with Roux-en-Y gastric bypass (RYGB), they had very low ghrelin levels throughout the day and did not show mealtime spikes. This was especially surprising because we knew that weight loss achieved by other methods—diet, exercise, getting sick—triggers a compensatory rise in ghrelin. However, when weight loss was achieved with RYGB, levels paradoxically fell. That suggested that maybe ghrelin levels are contributing to the weight loss that is achieved by gastric bypass.

Prior to that time, bariatric surgeons had long noticed that individuals who undergo RYGB lose a lot of weight and yet tell them that they feel less hungry. The previous thinking behind the reason for this enhanced weight loss included two mechanisms: 1) gastric restriction (i.e., reducing the volume of the stomach) and 2) malabsorption.
I came to question these two hypotheses because there were several flaws in the logic. First, clinically significant overall calorie malabsorption is not observed after the standard proximal RYGB.

Second, if gastric restriction were a major driver of weight loss, why wouldn’t people with a total gastrectomy lose a great deal of weight (which they don’t), because they have zero gastric capacity? Also, if gastric restriction were a major component, why wouldn’t people just eat multiple small meals and choose calorie-dense foods? Studies have shown that if you look at the eating patterns of people after a gastric bypass, it is true that they eat small meals, but instead of eating more meals per day, they chose to eat fewer of them and have fewer snacks between them. If you look at the types of foods that they eat after RYGB compared to what they used to eat, they tend to eat less calorie-dense food after RYGB, which is contrary to what you might think.

After gastric bypass, patients can tell you that if they take a bite of ice cream, it still tastes good and the experience of deliciousness hasn’t changed, but their ability to turn the other cheek and pass it by has changed. It’s much easier for them to do so. This suggests an alteration in their appetite system. When we discovered the potential role of ghrelin in gastric bypass mechanisms, the bariatric surgeons said, “Okay, finally we understand why their appetite is destroyed—ghrelin levels are compromised.”

Although it has since turned out that ghrelin plays at most a minor role in RYGB mechanisms, I believe our findings played an important, historic role, because they turned people on to the notion that bariatric surgery is an endocrine intervention and may make metabolic and physiologic changes that contribute to its effects.
Through the ghrelin studies, we learned that there were more interesting things to be found.

Your research is fascinating. What have you been working on in recent years? Can you discuss other findings from studies of RYGB patients, particularly weight-independent mechanisms for improvement or remission of type 2 diabetes mellitus?

Dr. Cummings: Several large independent bodies of evidence indicate that RYGB improves type 2 diabetes mellitus (TD2M) through mechanisms additional to weight loss. There are several theories to explain this. One hypothesizes that there is enhanced nutrient stimulation of L-cell peptides (e.g., glucagon-like peptide-1 [GLP-1]) from the lower intestine after an individual undergoes an operation that expedites delivery of nutrients to the distal intestine. L-cell secretion stimulation is higher after a meal and five times higher after RYGB. This is associated with stimulating insulin secretion.

However, the physical shortcut as reason for hyperstimulated L-cells is over-simplified. For example, after laparoscopic sleeve gastrectomy (LSG), a weight loss operation that doesn’t create a shortcut and leaves the pylorus intact, the GLP-1 enhancement is similar to RYGB. Moreover, evidence indicates that enhanced GLP-1 secretion is only a relatively small part of the whole story.

We have been hearing a lot more about research on the gut microbiome and how it affects insulin sensitivity. Have you been involved in this research as well?

Dr. Cummings: We are finding that the gastrointestinal system does play a role in insulin sensitivity. The gut has neural and hormonal mechanisms that we think are changed by bypass operations. There is a big story building around the gut microbiome, as there are changes in the array of bugs. Dr. Lee Kaplan and colleagues have done much work on this field of study.[4,5] They present convincing evidence that gut microbiome changes contribute to body weight loss.

They performed a fascinating study[4,5] where mice were placed in two groups. One group underwent RYGB and the other group underwent a sham operation. Researchers then transplanted the feces from each of these groups of mice into new germ-free recipient mice. They found that mice who received feces from the RYGB group weighed less compared to those that received feces from the sham-operated group.

The same experiment was done comparing RYGB with restrictive diet/behavior modifications. Again, the RYGB group lost more weight.

Tell us more about your role in the first DSS-1. What was accomplished from that first summit?

Dr. Cummings: I was an organizer for the DSS-1 as part of what some people call “the four amigos,” made up of Drs. Rubino, Schauer, Kaplan, and myself.

The DSS-1 had 50 voting delegates, who were weighted toward nonsurgeons and academicians. Members of industry were not included, and proceedings were done in public. This format was different from that used in crafting the 1991 NIH guidelines. We felt this was a more transparent and honest way to do it.

DSS-1 was an important conceptual step forward because it got people thinking of surgery as an intervention for T2DM, which has led to thinking of it as an intervention for patients with lower body mass indices (BMIs).
Within about a year after DSS-1, the American Society for Bariatric Surgery (ASBS) changed its name to add the word “Metabolic.” Other societies followed in changing their names; The International Federation for the Surgery of Obesity and Metabolic Disorders (IFSO) along with many other societies worldwide.

The DSS-1 also concluded with policy recommendations for clinical usage, advocating use of surgery, RYGB in particular, to treat diabetes. Our guidelines stated that RYGB should be considered to treat poorly controlled T2DM in appropriate surgical candidates among patients with a BMI of 30kg/m2 or greater. This was a big accomplishment as it differed from the 1991 NIH Guidelines,[6] which stated surgery for BMI 40kg/m2 and above or 35kg/m2 and above with comorbidities. Recommending to bring BMI criteria down from 35 to 30kg/m2 was important because even though it was a small numerical change, it grabbed a lot of potential patients, more than one-quarter of all Americans with diabetes. In the rest of the world, the vast majority of people with T2DM have BMIs under 35kg/m2. Just that drop to 30kg/m2 has a big impact on the world because it allows a lot more people to be surgical candidates.

In last month’s interview, Dr. Cohen explained why he thought there was a need for new guidelines on surgery for T2DM and referred us to a paper that you co-wrote with him titled, “Beyond BMI: the need for new guidelines governing the use of bariatric and metabolic surgery.”[7] Can you tell us why you think we need new guidelines?

Dr. Cummings: There is a very important need for new guidelines for many different reasons. To understand this, one first must understand how the 1991 NIH guidelines were crafted.

The NIH guidelines largely dictate who should get surgery. In 1991, bariatric surgery was still relatively new. The NIH guidelines state that surgery can be considered for anyone with a BMI greater than 40kg/m2 or greater than 35kg/m2 with serious comordbities, such as severe T2DM.

Despite the fact the NIH guidelines were put together by a small group of people with no transparency or opportunity for the public to weigh in, they have been enormously impactful on the world. Other consensus statements adopted after that time by various organizations reiterate the very same information from the NIH. Even though the NIH may not have meant to dictate policy outside American borders, it definitely had that impact and became the global standard ever since.

Despite their importance, there were serious shortcomings in the NIH guidelines. One consideration is the fact that they only had data from open operations. Another is that they paid too little attention to T2DM. There was still much we had yet to learn about the disease and the anti-diabetes mechanisms of metabolic surgery.
These guidelines also include only two operations: gastric bypass and gastroplasty or “stomach stapling.” Gastroplasty basically disappeared within a few years after the guidelines, so that means that only one of the operations approved in these guidelines is still around. RYGB has been refined to be a safer, more effective, and ultimately better operation than it used to be. In the interim, think of all that has happened in the field: gastric banding, sleeve gastrectomy, biliopancreatic diversion (BPD) with and without duodenal switch, gastric plication, gastric balloons, and other experimental devices and procedures like endoluminal sleeves, ileal interposition, and duodenojejunal bypass have all been invented since 1991.

The guidelines are woefully outdated and the NIH admits this. The website containing the guidelines contains the following disclaimer: “This statement is more than five years old and is provided solely for historical purposes. Due to the cumulative nature of medical research, new knowledge has inevitably accumulated in this subject area in the time since the statement was initially prepared. Thus some of the material is likely to be out of date, and at worst simply wrong. For reliable, current information on this and other health topics, we recommend consulting the National Institutes of Health’s MedlinePlus http://www.nlm.nih.gov/medlineplus/.”[8]

Also, the guidelines were based on too few studies with Level 1 evidence, that of which comes from randomized, controlled trials (RCTs). It took us many years to get our first surgical versus nonsurgical RCT. What we have now that we didn’t have then is a large body of RCT data comparing various approaches—surgical, medical, dietary, lifestyle modification—and their effects on diabetes and body weight. They have all arrived at the same conclusion: surgery is superior at getting rid of T2DM.[9–14]

I’m not a critic of the 1991 guidelines because they served a valuable world purpose of unifying practice patterns of diverse peoples across many cultures and nations. Now that we’ve gathered the data, we can ask how well surgery works in the real world when practiced according to these old standards.

A big question we are seeking to answer is “Is it appropriate to consider surgery for people outside of those boundaries?” For example, is it appropriate to perform surgery on patients with different BMIs and in different age groups? Also, how do you select an operation for a patient?

These are all topics we will discuss and vote on during DSS-2.

What do you hope to achieve during DSS-2?

Dr. Cummings: I think that if we were to come down strongly again and put forth guidelines that say it is reasonable to do metabolic surgery on people with a BMI down to 30kg/m2 with poorly controlled T2DM, which is what we said in the DSS-1, and had them approved by the American Diabetes Association (ADA), European Association for the Study of Diabetes (EASD), and International Diabetes Federation (IDF), maybe that would finally move the needle on the procedures for which insurance companies in the United States are willing to pay. Ultimately, these policies don’t make much difference unless the insurance companies begin to dictate payment plans using them. Insurance coverage is still largely pinned on the 1991 NIH guidelines.

Since Dr. Cohen and I wrote “Beyond BMI,”[7] I have learned that the NIH is never going to come up with new guidelines in this arena. So, we are now looking to come out with new guidelines that the insurance companies will use in place of the NIH.

What will be the method for developing new guidelines during DSS-2? Will members of prominent diabetes societies or members of industry be involved in voting?

Dr. Cummings: In DSS-1, societies, such as ADA, had policies that stated they would not endorse guidelines unless they were developed by and belonged to them. In DSS-2, the voting panel will include representatives from those societies who will be involved throughout the process.

Other stakeholders include the EASD, IDF, Indian Diabetes Society, and Chinese Diabetes Society. The current panel could be seen as more objective because it isn’t just the academic people who are working in the field and are already sold on metabolic surgery.

We have tried to really balance the voting panel. In addition to society representatives, we’ve invited diabetologists and professional academics. It is weighted against surgeons, as they have a potential bias toward surgery.

We will be using the Delphi method to reach consensus and draft guidelines. The Delphi technique is a widely used and accepted method for gathering data from respondents within their domain of expertise. The technique is designed as a several-month-long group communication process that aims to achieve a convergence of opinion on a specific real-world issue. This means that the meeting itself will be the culminating stage where results will be revealed to the group. After hearing results and audience discussion, the 54 voting delegates will retire and cast their final votes.

One large part of the process is the audience discussion, which all attendees are encouraged to join. As Dr. Rubino has already told you, it is a very unique opportunity to be a part of and witness history.
For more information, visit http://www.wcitt2d.org/. For group registration (10 participants and more), please contact the registration department at reg_wcidt15@kenes.com.

What would be the best possible outcome for the DSS-2?

Dr. Cummings: One best outcome would be that whatever we recommend changes payment policies globally because that will in turn change practice patterns. I think a necessary step to that is developing new guidelines and having the societies endorse them. Big insurance companies are going to start paying if they see endorsed guidelines that come with the stamp of approval from the ADA, The Endocrine Society, and others.

References
1.    Cummings DE, Brandon EP, Planas JV, et al. Genetically lean mice result from targeted disruption of the RII beta subunit of protein kinase A. Nature. 1996;382(6592):622–626.
2.    Cummings DE, Purnell JQ, Frayo RS, et al. A preprandial rise in plasma ghrelin levels suggests a role in meal initiation in humans. Diabetes. 2001;50(8):1714–1719.
3.    Cummings DE, Weigle DS, Frayo RS, et al. Plasma ghrelin levels after diet-induced weight loss or gastric bypass surgery. N Engl J Med. 2002;346(21):1623–1630.
4.    Liou AP, Paziuk M, Luevano JM Jr, et al. Conserved shifts in the gut microbiota due to gastric bypass reduce host weight and adiposity. Sci Transl Med. 2013;5(178):178ra41
5.    Nieuwdorp M, Gilijamse PW, Pai N, Kaplan LM. Role of the microbiome in energy regulation and metabolism. Gastroenterology. 2014;146(6):1525–1533.
6.    Consensus Development Conference Panel. NIH conference. Gastrointestinal surgery for severe obesity. Ann Intern Med. 1991;115:956–961.
7.    Cummings DE, Cohen RV. Beyond BMI: the need for new guidelines governing the use of bariatric and metabolic surgery. Lancet Diabetes Endocrinol. 2014;2(2):175–181.
8.    National Institutes of Health. Consensus Development Conference Statement. Gastrointestinal Surgery for Severe Obesity. March 25–27, 1991. http://consensus.nih.gov/1991/1991gisurgeryobesity084html.htm. Accessed July 1, 2015.
9.    Schauer P, Kashyap S, Wolski K, et al. Bariatric surgery versus intensive medical therapy in obese patients with diabetes. N Engl J Med. 2014;370(21):2002–2013.
10.    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(17):1577–1585.
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(21):2240–2249.
12.    Dixon JB, Hur KY, Lee WJ, et al. Gastric bypass in Type 2 diabetes with BMI < 30: weight and weight loss have a major influence on outcomes. Diabet Med. 2013;30(4):e127–134.
13.    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(7):716–726.
14.    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 Jul 1. [Epub ahead of print]

Funding: No funding was provided in the preparation of this manuscript.
Financial disclosures: The author reports no conflicts of interest relevant to the content of this article.

 

 

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