We’re back from our week in Sin City with fresh learnings from the final two days of AACE’s Annual Scientific and Clinical Congress. Saturday’s key sessions focused largely on bariatric surgery, while the Sunday agenda featured a unique half-day session titled “Endocrinology for the Non-Endocrinologist” – we were excited to see AACE working to get non-endocrinologist practitioners smarter and more excited about the campaign against diabetes and obesity. Included below are our top five highlights, followed by our complete coverage of days #4-5.
1. In a packed Ethicon product theater, Drs. Philip Schauer (Cleveland Clinic, Cleveland, OH), Arya Sharma (University of Alberta, Edmonton, Canada), and David Cummings (University of Washington, Seattle, WA) teamed up to discuss the unparalleled efficacy bariatric surgery for the treatment of type 2 diabetes.
2. Dr. Alvin Powers (Vanderbilt University, Nashville, TN) busted some myths in the progression of both type 1 and type 2 diabetes in a presentation on stem cells and other cell-based therapies for diabetes.
3. A panel of New Yorkers, including Dr. Jeffrey Mechanick (AACE, Jacksonville, FL & Mt. Sinai Hospital, New York, NY) discussed the remarkable anti-diabetic effect (and the unique safety considerations) associated with biliopancreatic diversion – in a real-world case, the procedure took a patient from an A1c of ~14% down to a medication-free 5.5%.
4. Dr. Carol Cheney (Reno Medical School, Reno, NV) got a room full of non-endocrinologists excited about diabetes therapy by exploring the latest technological advances, including non-invasive glucose monitoring and cutting-edge insulins.
5. Dr. Derek LeRoith (Mt. Sinai Hospital, New York, NY) and Dr. Yehuda Handelsman (Metabolic Institute of America, Tarzana, CA) provided a reassuring perspective on the subject of diabetes, obesity, and cancer.
- Example header
- Product Theater: Identifying the Appropriate Obese/T2DM Patient for Bariatric Surgery (Sponsored by Ethicon)
- The Surgical Option for Treating Type 2 Diabetes
- Effect of Metabolic Surgery on Diabetes and Outcomes
- Bariatric Surgery: Who is the Right Patient?
- Panel Discussion
- Integrative Concepts in Endocrinology and Endocrine Surgery – A Tale of Two Cities
- Plenary Session
- Symposium: Endocrinology for the Non-Endocrinologist
- Workshop Sessions
- Product Theater: Identifying the Appropriate Obese/T2DM Patient for Bariatric Surgery (Sponsored by Ethicon)
Product Theater: Identifying the Appropriate Obese/T2DM Patient for Bariatric Surgery (Sponsored by Ethicon)
The Surgical Option for Treating Type 2 Diabetes
Philip Schauer, MD (Cleveland Clinic, Cleveland, OH)
Speaking before a fairly crowded product theater (n = ~120), Cleveland Clinic’s Dr. Philip Schauer provided an overview of the field of bariatric surgery, especially surgery’s favorable comparison against medical weight therapy with regards to diabetes remission and other outcomes. Although gastric bypass is leading the field in terms of the number of procedures conducted (55%), sleeve gastrectomy is the fastest growing (35%), having leapfrogged gastric banding (8%). Dr. Schauer highlighted the improved safety profile of bariatric surgery, noting that mortality is comparable to other common procedures like C-sections and cholecystectomy. Turning to efficacy in the control of type 2 diabetes, Dr. Schauer provided a high-level overview of the three-year results of the STAMPEDE trial, which found superior rates of diabetes remission with gastric bypass and sleeve gastrectomy relative to intensive medical therapy (read our ACC 2014 Report for full results from that trial). A separate meta-analysis of 11 trials comparing surgery and non-surgical weight loss found that surgery consistently demonstrated superior efficacy across the board, and was relatively safe (no mortality, reoperation rate of 8%). As a result of these findings, Dr. Schauer impressed that bariatric surgery should no longer be seen as a last resort for patients with extreme obesity, and noted that treatment guidelines are including surgery as an option for patients at lower BMIs than was the norm previously.
- Ethicon, part of the J&J family of companies, produces surgical instruments for procedures including bariatric surgery. One of its major products is the Realize adjustable gastric band, which is a competitor to Allergan’s LAP-BAND.
- Dr. Schauer reviewed the three-year results of the STAMPEDE trial, which were presented just a few months ago at this year’s American College of Cardiology meeting (read our coverage). The incidence of diabetes remission (A1c £6%) at year three was much higher for participants with gastric bypass (38%) and with gastric sleeve (25%), compared to the intensive medical therapy (IMT) arm (5%). Additionally, 35% of patients with gastric bypass and 20% of patients with gastric sleeve were able to achieve A1c £6% without any diabetes medication, compared with no patients in the IMT arm. For context, the baseline A1c for each group respectively was 9.0%, 9.3%, and 9.5%, respectively, with gastric bypass, sleeve gastrectomy, and IMT. Patients with gastric bypass and gastric sleeve also had large reductions in FPG (-86 mg/dl and -46 mg/dl, respectively) compared to only -6 mg/dl for patient on medical therapy alone.
- Dr. Schauer also highlighted that even patients with mild obesity and poorly controlled diabetes can achieve significant improvement in A1c that can be sustained after three years. The change in A1c for patients with BMI <35 who had bariatric surgery exhibited very similar A1c benefit to those patients with BMI >35 who had surgery.
- Dr. Schauer presented the Bariatric Surgery Comparison Tool by Ethicon as “an exciting new tool for health care providers.” The tool will help predict the overall benefit, glycemic control, weight loss, and other potential results of different bariatric surgeries (gastric band, gastric bypass, or sleeve) in a specific patient. Assessments will be evaluated based on patient demographics, comorbidities, and past literature. We think that such a comparison tool will help patients weigh their options for bariatric surgery as well as provide realistic expectations and perhaps visual motivation that surgery can yield dramatic benefits.
Effect of Metabolic Surgery on Diabetes and Outcomes
David Cummings, MD (University of Washington, Seattle, WA)
Dr. David Cummings packed his presentation with preclinical and clinical evidence that metabolic surgery influences diabetes remission in large part through mechanisms other than weight loss. In a trial testing gastric bypass in 66 patients with longstanding type 2 diabetes but relatively low baseline BMI (30-35 kg/m2), there was remarkably little correlation between the A1c reductions seen (mean A1c fell from 10% to below 7%) and weight loss (Cohen et al., Diabetes Care 2012). The landmark Swedish Obese Subjects (SOS) trial also found that weight loss was a fairly poor predictor of diabetes remission, among other outcomes. While some theorize that the delivery of food more directly to the distal small intestine (where GLP-1-producing L-cells are located) is the primary driver of gastric bypass’ non-weight-mediated glycemic efficacy, Dr. Cummings presented evidence that the absence of food delivery to the duodenum (the section of the small intestine immediately following the stomach) might be just as important. Delivering food via a gastric tube to the duodenum in patients that had gastric bypass nearly eliminated the increase in insulin sensitivity seen in those patients post-procedure (Cummings & Flum, unpublished data). A recent mechanistic study (Salinari et al., PLOS ONE 2013) suggested that proteins secreted in the intestine in response to food may partially drive increases in muscular insulin resistance. As presenter Dr. Arya Sharma mentioned during the Q&A session, research such as this into the mechanism of bariatric surgery’s efficacy could provide the key to designing better pharmacotherapy for obesity.
- During Q&A, Dr. Cummings expressed optimism that future RCT data on bariatric surgery will show improvements in hard outcomes. He noted that the DCCT and UKPDS showed improvements in outcomes following just a few years of slightly tighter control. Imagine, he proposed, what many years of complete diabetes remission could yield.
- On the subject of the chronic hypoglycemia that is occasionally seen after gastric bypass, Dr. Cummings shared data from his group’s study in a pig model of obesity. As opposed to other forms of bariatric surgery, Roux-en-Y gastric bypass (RYGB) led to a substantial and statistically significant increase in beta cell area per total pancreas area. Such a phenomenon, if conserved in humans, could explain why the procedure occasionally leads to chronic hypoglycemia in a small subset of patients (this point was discussed more during Q&A). However, also during Q&A, Dr. Cummings reminded the audience that the incidence of hypoglycemia that occurs following bariatric surgery is far less than the incidence seen with intensive medical therapy.
- In his conclusion, Dr. Cummings listed other weight-independent mechanisms that could explain RYGB’s effects on diabetes remission: the list included effects on bile acids, changes in the gut microbiome, “reprogramming” of intestinal glucose metabolism, and duodenal factors (among many others). For more on the exciting topic of the gut microbiome, see our AACE 2014 Day #3 Report.
- We were able to sit down for a meaty interview last year with Dr. Cummings – the discussion covered topics many of the topics that Dr. Cummings included in his AACE presentation (read the report and transcript).
Bariatric Surgery: Who is the Right Patient?
Arya Sharma, MD, PhD (University of Alberta, Edmonton, Canada)
Dr. Arya Sharma provided a data-driven presentation on the ways to identify the optimal patients for bariatric surgery. He began by underscoring the importance of bariatric surgery as a part of the endocrinologist’s toolbox, comparing obesity management without bariatric surgery to nephrology without dialysis. He also called attention to the heterogeneity of obesity – using the term “obesities” – and argued that BMI as a diagnostic tool is not nuanced enough to capture this heterogeneity. Complications-based staging systems such as the Edmonton Obesity Staging System (EOSS, which Dr. Sharma helped design) and the brand-new AACE/ACE Advanced Framework (see our Day #3 Report) do a better job of evaluating patients based on how sick they are rather than how big they are. Citing an analysis of the distribution of EOSS staging scores across different BMI categories, Dr. Sharma noted that only using bariatric surgery in patients with class III obesity (BMI>40) will exclude the majority of patients at higher-risk stages (Padwal et al., CMAJ 2011). Additionally, approximately one in six patients with class III obesity are at EOSS stage 0 or 1, and may not really require bariatric surgery. The data Dr. Sharma provided in his presentation hammered home the importance of using a complications-based framework (rather than a purely BMI-based framework) for the diagnosis, staging, and treatment for obesity.
- “By itself,” Dr. Sharma emphasized, “BMI doesn’t mean much, even when looking at it as a surrogate marker for body fat.” He noted that an individual with a BMI of 22 could have 9.1% body fat or 20.2% body fat. Dr. Sharma also acknowledged the term “obesities” in his presentation since obesity encompasses a heterogeneous complex of disorders with multiple etiologies. The size of fat cells, fat distribution in the body, and racial phenotype/genetic predisposition will all determine to what extent excess weight will lead to complications.
- Dr. Sharma stressed that “Having a BMI cut-off for bariatric surgery is an incorrect way of thinking… It’s time to lower the bar for bariatric surgery.” He noted that by providing bariatric surgery to only patients with BMI >40, providers are missing the bulk of patients whose risk is as high as the BMI >40 group.
- In Dr. Sharma’s opinion, metabolic surgery is a far better term than bariatric surgery. Dr. Sharma argued that if patients can focus on metabolic benefits rather than weight loss alone, we would think about metabolic surgery (and perhaps even obesity pharmacotherapy) much differently.
Q: I wonder what the statistics on hypoglycemia post-surgery are. It’s something that we’re all seeing more of in our practice, and I would argue that people who are really morbidly obese have a greater capacity to produce insulin, which enabled their obesity in the first place, since we know that insulin is an anabolic hormone. I wonder if we need to start being more concerned about operating on potentially metabolically healthy obese people who have a high reserve of insulin production to see if they are at greater risk for developing hypoglycemia. The data you presented about GLP-1 constantly being stimulated in some animal models, and causing hyperplasia in the pancreas, is potentially concerning.
Dr. David Cummings (University of Washington, Seattle, WA): I want to emphasize that those cases of severe hypoglycemia are rare. There are eight published studies and from my knowledge there are only a few 100 cases, and that’s divided by a denominator of hundreds of thousands. So your question is much more interesting as a research question: what is the risk of treating hypoglycemia with a lot of medications? I’ve just finished a randomized, controlled trial of gastric bypass vs. aggressive medication therapy and in that study, one difference between groups in terms of safety was much that the medication group had much more hypoglycemia; they were taking a lot more drugs to try to get to A1c to goal at the expense of hypoglycemia. I don’t think this is a big problem for bariatric surgery patients.
Dr. Philip Schauer (Cleveland Clinic, Cleveland, OH): In our center in Cleveland, we do about 800 procedures each year, mostly gastric bypass. About one percent, or eight out of 800, have clinically significant hypoglycemia after the operation. Out of those, four are able to resolve the problem with extensive counseling from dietitians, and so we only send four to endos. Usually, with medications, they have been able to get those folks clinically improved. It is extremely rare, in my career, that we have had to intervene with surgery to correct any of this chronic hypoglycemia.
Q: Are there any age limitations at the younger end for bariatric surgery?
Dr. Schauer: No. Teens do require additional help though; it’s important that the pediatricians, psychiatrists, and family get involved. Also, we’re less likely to intervene so quickly in kids since we want to make sure they’re physically and psychologically mature. The youngest patient that I operated on was 12 years old, but he weighed 400 lbs.
Dr. Cummings: From my clinical experience, diet and exercise is not going to cut it for a child who is 12 and weighs 400 pounds. Any procedure that could cause malabsorption, even a tiny bit of malabsorption, prior to the time that epiphyseal plates have closed is something to be very concerned about. These procedures can cause vitamin D deficiency, and patients will need supplements for that.
Q: With all this impressive data for gastric bypass, why are bariatric surgeons still sticking with gastric banding and sleeve gastrectomy?
Dr. Schauer: The use of the banding procedure has decreased. Five to eight years ago, gastric banding was very common, but not in the US and around the world, its utilization has dropped quite dramatically. Nowadays only about 10% of procedures are banding, and that continues to drop, due to relatively modest weight loss seen with banding. About 50% of folks getting banding would require another subsequent surgery. Sleeve gastrectomy is closer to gastric bypass, although there are some metabolic benefits of bypass over the sleeve – the sleeve is less invasive and involves fewer GI complications, which is important to consider.
Dr. Cummings: Sleeve gastrectomy is the most interesting procedure in the field because it works as well as it does and yet its mechanism is completely unintuitive because full gastrectomy has weight loss in one year but this is later completely reverted. However, sleeve gastrectomy works really well.
Q: Dr. Sharma indicated that maybe you should consider surgery in overweight patients with BMIs between 25-30. Is there research or data on potential beneficial effects of surgery in patients that do not have diabetes, but only have another complication like sleep apnea and NASH? Are there really beneficial effects in those patients?
Dr. Sharma: There are a number of ongoing studies looking at surgery in the lower BMI group; it’s a very interesting group. There are some within that group that appear to be more genetically prone to the complications of obesity. I would think that someone who has a BMI of 40 but that is metabolically healthy, as our data shows, has a low risk in the long term of getting complications. With people with a BMI of 27 who already have diabetes and liver problems, these are the people that, with conventional treatment, would probably go on and gain more weight and move on to phase 3 of the Edmonton staging system. We’re talking about 50 million people here, and I don’t see surgeons operating on 50 million people. Dr. Cumming’s work is important, as we need to understand the biology of how surgery works. By better understanding the actual physiology that is being corrected by surgery, it may open the field to new pharmacological agents by finding new modes of action. We’re not going to be treating 50-100 million people worldwide with surgery, although there is no question that it has great efficacy in individually selected patients. But I’m not a surgeon – what I want to know is why surgery works, and how to turn that mechanism into pharmacological agents, because I don’t see this epidemic going anywhere any time soon.
Dr. Schauer: In a side answer to the question about sleep apnea and NASH, bariatric surgery is clearly associated with significant improvement in sleep apnea. Fifty percent of patients with sleep apnea can be weaned off CPAP with bariatric surgery. NASH is interesting; in a systematic review of pre- and post-op biopsy, we saw significant improvement in historical improvements. Even frank cirrhosis has been improved or resolved.
Dr. Cummings: The top of the list is diabetes, as well as weight loss. Other things surgery helps well are sleep apnea, HDL, triglycerides, and the overall use of diabetes medications. It is less effective at lowering LDL and controlling blood pressure.
Dr. Schauer: I’d add one other thing that is very important to doctors: quality of life. Every quality of life study shows improvement in quality of life after bariatric surgery. Even though it’s more invasive, patients with gastric bypass were happier. At end of day, that quality of life improvement is the most important thing that we can do for our patients.
Dr. Cummings: To counterbalance this, there is probably a true finding that people predisposed to alcohol abuse might see that condition worse with gastric bypass, which would allow more rapid delivery of alcohol to the absorptive surfaces and higher peak alcohol levels.
Q: I have patients who meet those categories and still regain the weight after surgery. How do you know which patients will fail?
Dr. Schauer: Failure, meaning either regaining most of weight or having a poor result out of the gate, is realistically around 10-15%. This procedure isn’t perfect and it will fail sometimes. We think this might be biologically driven, and it does seem to correlate with higher BMI. Patients weighing 600-800 lbs may lose 100 lbs, but in the end they are still 700 lbs. For that reason, we are doing more aggressive weight loss with patients a very high BMI because it’s more effective.
Dr. Sharma: One of the things we don’t have are good predictors of outcomes. There are a couple of obvious red flags, such as severe uncontrolled mental health issues, addiction problems, and recent suicidal ideations. When you go beyond those obvious factors, we don’t do a good job of predicting who will do well and who doesn’t. There are some patients that you think are the perfect candidates, and then after surgery things turn messy. There are other patients where you are not so sure if the outcome will be great initially, but then they get the surgery and end up being the perfect patient. It’s very hard to predict.
Dr. Cummings: There are some ongoing studies that are identifying genetic marker outcomes for those who don’t succeed on bariatric surgery.
Dr. Schauer: Of the 15% or so who had a bad outcome during the initial procedure, there are some potential revisional surgery options. Some will fail because staple lines open up and cause a fistula, which can be fairly easily corrected with a surgery. Some will need a more aggressive procedure done. Perhaps if a patient starts with a sleeve and doesn’t do well, they could do better with gastric bypass. However, that decision needs to be made carefully, as revisional surgery comes with higher risk relative to initial procedures.
Q: Are there any long-term issues with nutritional deficiencies?
Dr. Schauer: Yes definitely, but most of these are preventable. Compliance can be difficult. Anemia is the most common, occurring ~15% of the time, but that is fairly mild anemia, which can be corrected. Also common is metabolic bone disease, but calcium and vitamin D supplements over the long-term can help. You can get into rare vitamin deficiencies if patients are not taking vitamins regularly.
Dr. Cummings: Most of what he said applies to gastric bypass as well. Vitamin B12 deficiency is expected universally, and that would apply with gastric bypass and sleeve.
Q: I have a dedicated bariatric surgeon who requires that a psychological screen be done before surgery. To be honest, I’ve ignored that and let him make sure that’s done. Is there some standard procedure to determine who would be qualified for a psychiatric screening?
Dr. Sharma: We don’t have any solid randomized control trials testing a good psychiatric assessment pre-operation. From personal experience, I can tell you that if the psychiatrist that is doing the screening does not understand what bariatric surgery is all about, and the challenges that patients will have to face to make it work, then the screening is not very meaningful. You need psychiatrists that are familiar with the procedures to get meaningful consults.
Q: Most of this data is performed at academic medical centers. What do you think the data is in the real world, i.e. in community centers where we don’t have an extensive team approach? What advice can you offer to practitioners in community clinics?
Dr. Schauer: Bariatric surgery, particularly ten years ago, went through a dramatic growth period. As a result of that, there were clearly some quality issues in centers that were not well established and trained. Out of that problem came the American College of Surgeons and American Society for Metabolic and Bariatric Surgeons’ Centers of Excellence program, that has a pretty high threshold of quality required. These COE centers need to have well-trained surgeons, large volumes of procedures, psychologists, MDs, and dietitians available. Certain insurance companies require this accreditation before covering procedures. I think that you are pretty safe if you send a patient to one of those designated centers.
Dr. Cummings: It’s a complicated question. The paper I mentioned showed that in contrast to extremely safe profiles by database, when you go into real world with physicians in smaller clinics, you see much higher rates of morbidity and mortality. Looking at these in terms of cost, these are absolutely cost effective for cost per effect on life. It’s about ten times lower than cost per QALY for dialysis. We often hear that surgery should pay for itself as business model. When you ask question, what is the number of years to get your money back, this question is hugely influenced by how many train wrecks are in the ICU since those cost an incredible amount. You can limit to Centers of Excellence (COEs), but for context, the non-COE penetrance is currently 1%. This is incredibly low, and if you limit bariatric surgery to COEs, you may hamper this even more and you effectively restrict people in rural areas from this procedure. So there is value in a COE debate for sure.
Q: Could you talk about the use of bariatric surgery in very obese type 1 diabetes patients?
Dr. Schauer: There is not a whole lot of data there. We, in fact, one or two months ago published some data in Diabetes Care. We had a dozen patients that had clear evidence of being type 1 diabetes patients, which is important because in obese patients it can be hard to differentiate. We didn’t cure anybody, of course, but these obese type 1 diabetes patients had significant weight loss, an average BMI drop of 10 from an average baseline of 45, and had significant reductions in insulin requirement greater than 50%. Some of them had metabolic comorbidities, such as dyslipidemia and sleep apnea, and those typically got better. It is an option for type 1 diabetes that should improve quality of life and comorbidities, although don’t expect it to cure the diabetes. Perioperative management is much more difficult, however. One patient we saw had a bit of subclinical ketoacidosis. Type 1 diabetes patients would need to be watched carefully after the procedure, which is where an endocrinologist on staff would be very helpful.
Dr. Cummings: I would say though that there is no conception that this will reverse the autoimmune attack. If you had a skinny, childhood-onset, classic type 1 patient, I don’t think surgery is the right option. There is huge population of type 1.5 and everyone in between. Due to insulin growth hormone, you get increased body weight and so we often see lots of type 1 patients that become very obese.
Dr. Schauer: Some of these folks who have been on insulin for many, many years have gained significant weight because insulin is a growth hormone. There are more obese type 1 patients nowadays.
Q: I have a few patients that have type 1 with a gastric sleeve or Roux-en-Y, and most have done well, but some with the sleeve have postprandial insulinemia. I have to have them bolus 20-30 min before they eat still and they have such a quick first-phase response. A lot of our type 2 patients, most have been obese and have had diabetes for 20-30 years. Do you ever check C-peptide prior to surgery? Most need insulin again. It depends on where they are in stage of dm.
Dr. Cummings: There is not question that after bypass, when you have food dropping right into the intestine, you get a big spike in glucose. In type 2 diabetes you get a resulting spike in insulin, but this makes management in type 1 diabetes more challenging.
Dr. Schauer: We did measure C-peptide in our STAMPEDE trial as a surrogate marker. We didn’t see C-peptide as a very good predictor of remission or glycemic control in patients. We did however see that duration of diabetes was good predictor. Individuals with diabetes eight years or less were more likely to reach A1c of 6% threshold than those who had diabetes for longer duration. Beta cell activity with time intervention is probably important, and there is probably a threshold where we’ll be able to achieve remission or not.
Dr. Cummings: On predictors of diabetes remission, taking the landmark studies into account, the most consistent predictor of failure to achieve diabetes remission are diabetes duration of over ten years and patients that require insulin. These factors are a proxy for beta cell burnout. There are other things, such as high baseline A1c, low C-peptide, but those are less powerful.
Q: How does age and coronary artery disease factor into your decision to choose patients for bariatric surgery?
Dr. Schauer: Both of those correlate with disease severity to some extent. Older people with more CAD do have higher risk of surgery. However lots of them can be managed pre-operatively. Patients at our group who have CAD have extensive cardiac evaluation, and many get a heart stent before gastric bypass. So CAD is not a contraindication, but they should be evaluated more carefully up-front.
Dr. Cummings: We don’t have a lot of level 1 evidence of the benefit of surgery over nonsurgical therapy with regards to hard cardiovascular endpoints. The best we can do is draw conclusions from DCCT and UKPDS, which showed that tight glycemic control over even a few years can confer long-term benefits on hard endpoints. If that is true, what about surgery, which can give you a period of complete remission, which essentially is like infinitely tight control. We still have to find the data on that, but they are likely going to pan out as favorable. A recent article published that was quite controversial reported that 70-80% of patients who had diabetes remission after gastric bypass, but a third relapsed during the period of observation. What the literature failed to mention was that the disease was in remission for an average of 8.3 years. If a bit of tight control versus loose control showed a benefit in UKPDS and DCCT, imagine what over eight disease-free years would give you.
Integrative Concepts in Endocrinology and Endocrine Surgery – A Tale of Two Cities
Jeffrey Mechanick, MD (AACE, Jacksonville, FL & Mount Sinai Hospital, New York, NY), William Inabnet (Mount Sinai Hospital, New York, NY), Elise Brett, MD (Mount Sinai Hospital, New York, NY)
Dr. Jeffrey Mechanick joined a panel of two other bariatric surgeons to discuss a series of patient cases on bariatric surgery. The final case, a South Asian anesthesiologist whose very severe diabetes (baseline A1c of ~14%) went into remarkable remission following biliopancreatic diversion (A1c of 5.5% two years post-operation with no diabetes medications), launched a valuable discussion on the use of bariatric surgery to treat diabetes patients. Dr. William “Barry” Inabnet stated categorically that biliopancreatic diversion is the most effective antidiabetic surgical procedure, although it causes severe malabsorption that requires patients to take multiple supplements. He observed that gastric banding has largely fallen by the wayside, representing only around 5% of metabolic surgery procedures, while patient demand has driven sleeve gastrectomy rapidly upwards in terms of popularity. Dr. Inabnet and Dr. Elise Brett highlighted shorter diabetes duration, younger age, higher baseline C-peptide, and being female as factors that can predict relatively greater diabetes remission following bariatric surgery.
- On the safety front, an audience member raised the issue of recurring hypoglycemia as a phenomenon that she sees from time to time, and which she believes is being underestimated in the literature. Dr. Inabnet hypothesized that baseline beta cell mass might be a risk factor for this phenomenon, although he (and other bariatric surgeons we have heard at this meeting) did not appear to view it as anything but a very rare occurrence.
Stem Cells and Islet Cell Replacement Strategies
Alvin Powers, MD (Vanderbilt University, Nashville, TN)
Dr. Alvin Powers’ presentation on stem cell and islet cell-based therapies was largely focused on the mechanisms and key questions regarding beta cell function and decline in type 1 and type 2 diabetes. He listed our current inability to measure beta cells mass clinically as a huge limitation in the study of the mechanisms of type 1 and type 2 diabetes, given that rodent islets (in which most research is currently done) vary significantly from human islets. The longstanding school of thought in type 2 diabetes is that insulin resistance leads to increased insulin production and beta cell burnout and apoptosis, but a new theorized paradigm for beta cell decline is that beta cells are de-differentiating and being re-programmed to produce glucagon. Overall, Dr. Powers believes that beta cell dysfunction may be a more significant factor than beta cell loss in type 2 diabetes. Regarding specific therapies, Dr. Powers mentioned betatrophin (a peptide produced in the liver to stimulate beta cell proliferation) before turning to pancreas and islet transplants. Dr. Powers shared that results from NIH-supported studies of islet transplantation are expected in 2014, and if results are positive, a final study report may be submitted to the FDA in 2014-15 that could enable some centers to start doing islet transplants. Dr. Powers also expressed cautious optimism about stem cell-based therapies, including ViaCyte’s embryonic stem cell-based system and pluripotent stem cell-based therapies and research models, which he thinks will change the way we think about diabetes.
- Part of Dr. Powers’ presentation was given to a bit of diabetes myth-busting. In type 1 diabetes, the model put forth by the late great Dr. George Eisenbarth suggested that people were born with a standard amount of beta cells, which (following a cascade from genetic susceptibility and a triggering event) eventually are all destroyed by patients’ immune system. New data (Saisho et al., Diabetes Care 2013) suggests that baseline beta cell volume varies greatly from individual to individual, which could in turn have a substantial affect on the time between the triggering event and the diagnosis of type 1 diabetes. Dr. Powers underscored the need for a tool to measure beta cell volume clinically, as at the moment the only way to quantify beta cell mass is through an autopsy study. Another myth that Dr. Powers busted was that insulin production is reduced to zero in all type 1 diabetes patients, as evidence has emerged that many patients have trace levels of residual C-peptide function or insulin-positive cells. Understanding the mechanism behind the survival of these cells could provide valuable insight on mechanisms that could be used to design cell-based therapies for type 1 diabetes.
- In the realm of type 2 diabetes, Dr. Powers discussed a new theorized paradigm in which beta cells are re-programmed to produce glucagon, rather than undergoing apoptosis due to stress. This theory (found in Accili et al., Cell 2012), if proven, would raise the possibility of finding a way to reverse the re-programming process and restore cells to normal beta cell function. Overall, in type 2 diabetes, Dr. Powers believes that the main culprit with regards to beta cell failure is beta cell dysfunction, rather than beta cell loss.
- With regard to specific cell-based therapies, Dr. Powers began with betatrophin, a peptide made in the liver during periods of insulin resistance that stimulates beta cell proliferation (Melton et al., NEJM 2013). Dr. Powers believes that in the next decade, we will discover ways to enhance beta cell mass using exogenous peptides like betatrophin. A major problem in designing cell-based therapies is finding a reliable cell source. ViaCyte has produced insulin producing cells using embryonic stem cells, and designed an encapsulation device to protect them from immune attack (BetaLogics is working on a similar system, which we heard discussed at GTC Bio – read our coverage). Dr. Powers expressed even more enthusiasm about human inducible pluripotent stem cells (hiPSCs), which he thinks will transform the way we think about diabetes. Also at GTC Bio, the Joslin Institute’s Dr. Rohit Kulkarni gave a presentation on hiPSCs, expressing a similar level of enthusiasm (read our coverage of that presentation). These cells can be used as a way to more effectively study type 1 and type 2 diabetes therapies, in addition to their more direct therapeutic value.
Symposium: Endocrinology for the Non-Endocrinologist
Progress in Diabetes Care Technologies
Carol Cheney, MD (Reno Medical School, Reno, NV)
Catering her presentation to a non-endocrinologist audience, Dr. Cheney gave a general overview of diabetes care technologies including insulin delivery systems, new insulins in development, CGMs, integrated systems e.g. artificial/bionic pancreas, smartphone applications, and novel approaches to glucose monitoring. We were glad to hear Dr. Cheney emphasize the importance of pump and CGM downloads, a repeated theme also heard at the 2014 Clinical Diabetes Technology Meeting. Additionally, Dr. Cheney touched on improved device connectivity, noting the potential that cloud-connected systems might have to improve patient experience and even clinic flow. In terms of glucose monitoring, Dr. Cheney seemed optimistic about novel approaches like implanted chips/nanosensors and immunoflourescence systems as well as the Google contact lens. Lastly, Dr. Cheney gave examples of smartphone applications that her patients find helpful for diabetes self-management, including Glucose Buddy, Glookolog, CalorieKing, and Go Meals (by Sanofi). While more of a broad-strokes discussion, we appreciated the much-needed non-endo diabetes care briefing that AACE provided with this symposium.
- Dr. Cheney highlighted new insulins in development, specifically noting the potential benefits of Novo Nordisk’s Tresiba (insulin degludec). She highlighted Tresiba’s longer half-life relative to Sanofi’s Lantus (insulin glargine), improved flexibility in intervals between dosing, and reduced pharmacodynamic variability. We note that Tresiba is not currently FDA approved, but is on the market in the EU and elsewhere (sales of ~$14 million in 1Q14).
- Looking much further down the line, Dr. Cheney expressed excitement about the development of “smart insulin.” Such a product would be injected once a day and involve a complex with both glucose and insulin receptors, thereby forcing insulin and glucose to compete to remain on the matrix. Essentially this glucose-responsive molecule will push insulin off the matrix and into the bloodstream as blood glucose values fall and vice versa as glucose rises. Dr. Cheney believes that such competitive inhibition within normal glucose range will be a significant advancement for patients on insulin. We learned earlier this month that Merck will be moving its glucose-responsive insulin (L-490) into phase 1 development. Read our investor briefing report for more details on L-490 and a more thorough background on the compound’s mechanism.
- Dr. Cheney noted that for years her patients have been asking for a way to monitor their glucose without fingersticks and now we are actually moving towards novel approaches like implanted chip/nanosensor and immunofluorescent systems as well as the Google contact lens to monitor glucose. Novel glucose monitoring systems include Abbott’s Flash Glucose Monitoring and Medtronic’s Enlite sensor (see our coverage of these earlier this year at ATTD 2014). For more background on the Google[x] contact lens (equipped transmitter to send glucose levels from tears to a nanosensor), read our coverage from the 2014 JP Morgan Healthcare Conference.
New Strategies for Obesity Management: Risk Stratification and Long-Term Weight Control
Alan Garber, MD (Baylor College of Medicine, Houston, TX)
Dr. Alan Garber’s presentation on obesity for the non-endocrinologist went beyond conveying data and treatment recommendations for obese patients, and also addressed some of the lingering counterproductive assumptions regarding the causes of obesity. He argued strongly against viewing obesity as a lack of willpower, especially given that willpower is generally not considered in the treatment of other lifestyle-related conditions (i.e.: cigarette smoking and lung cancer). Dr. Garber also encouraged the audience to think more broadly about the causes of obesity, suggesting that simply living in the US puts individuals on the road to obesity. Other key ideas he emphasized were the need to define obesity by its complications and the need to set realistic weight loss goals (5-10% is enough to see an improvement in complications). In his discussion of specific pharmacotherapies for obesity, he appeared very positive on Vivus’ Qsymia (phentermine/topiramate), highlighting the synergistic action of the two component molecules and relatively strong efficacy. Interestingly, while he also mentioned Arena/Eisai’s Belviq (lorcaserin) and Novo Nordisk’s liraglutide 3 mg (which he characterized as likely the most effective monotherapy for weight loss), he did not mention Takeda/Orexigen’s Contrave (naltrexone/bupropion). Dr. Garber argued that there is little reason to not treat type 2 diabetes patients with agents that cause weight loss, or are at least weight neutral.
Cancer, Obesity, and Diabetes
Derek LeRoith, MD, PhD (Mt. Sinai Hospital, New York, NY) and Yehuda Handelsman, MD (Metabolic Institute of America, Tarzana, CA)
Despite nagging public fear that diabetes and its related medications could increase the risk of cancer Dr. LeRoith emphasized, “the current totality of evidence on diabetes treatments and cancer risk should not change clinical practice. Practitioners must decide if remote yet plausible cancer risks weight more heavily than suboptimal glycemic control and higher likelihood of diabetes complications.” In fact, Dr. LeRoith pointed out that insulin use might minimize cancer risk since it reduces contributing risk factors to cancer progression like insulin resistance and hyperglycemia. Instead of withholding diabetes medications, both speakers recommended that earlier cancer screening and counseling on lifestyle change should be part of regular preventive care for patients with obesity and diabetes. Additionally, people who develop cancer at an early age should be screened for metabolic abnormalities.
- We appreciated the workshop’s emphasis on adherence, and on keeping patients on their diabetes medications, since rash action based on unfounded safety concerns could dissuade patients from necessary, beneficial diabetes therapies that would improve glycemic control and reduce hyperglycemia. Alarmingly, when polling the audience, almost 75% of attendees had patients that asked to change medications due to public fear that diabetes drugs (particularly glargine insulin) increase cancer risk. In fact, the opposite may be true as Dr. LeRoith noted that proper insulin therapy that improves glycemic control and reduces hyperglycemia might help minimize cancer progression by reducing endogenous insulin levels (a known growth factor).
- Metformin has also been shown to be beneficial in reducing cancer risk, and specifically it reduces endogenous insulin levels in patients with breast cancer (Goodwin et al., Clin Breast Cancer 2008). Dr. Handelsman noted that we don’t know the mechanism of such benefit, but suggested that metformin’s effect on improving metabolic status and reducing hyperinsulinemia could explain why metformin is protective.
- “The progression of cancer takes a long time,” Dr. LeRoith emphasized, “and most importantly it requires an oncogenic process. Insulin has not been shown to be oncogenic. However, once you develop cancer cells, exogenous insulin may promote progression, proliferation, and eventually metastasis.” Dr. Handelsman supported the focus on exogenous insulin’s effect on progression rather than causation. He noted, “When we try to make a correlation between insulin resistance and complications, we have a difficult time. But when we look at hyperinsulinemia and complications, suddenly the correlation is very clear.”
- Dr. Handelsman noted two future research questions: i) What role, if any, do various levels of hyperglycemia play in cancer development and ii) In patients with diabetes, do those with controlled glucose have a decreased risk of cancer compared to those with uncontrolled glucose? As was continually emphasized throughout the presentation, research on diabetes and cancer risk is relatively scarce, particularly of randomized controlled trials of large size and duration with the lone exception of the ORIGIN trial. The ORIGIN results laid to rest a lot of fears since over the six to seven years of the study, patients on insulin glargine had no increased risk for cancer vs. placebo. For more background on the ORIGIN Trial, see our full commentary from 2012.
Questions and Answers
Q: In the research of cancer patients with obesity and/or diabetes, are the increased deaths from increased tumor burden/mass or from infection as consequence of tumors?
A: It turns out those with obesity and diabetes do present with increased risk of death if they already have cancer. We think obesity/diabetes is its own epidemic but it drives later stages of cancer that are more aggressive. In fact, breast cancer patients with obesity/diabetes are more resistant to chemotherapy.
Q: Patients and house staff sometimes ask if the problem with detecting cancer in obese patients is not just the timeframe, but if screening is just technologically inadequate because the mammograms, colonoscopies, etc. are not getting around the obesity.
A: This is a valid point. Somebody who has colon cancer in their family shouldn’t be getting a colonoscopy at age 50, maybe they should start at 35. The questions is how early should we screen those with obesity? There are no real studies there, so at the AACE/ACE consensus meeting for diabetes and cancer risk, we arbitrarily decided age 40 is a good median for starting screening. Those consensus recommendations never existed before, but we’re hoping to change this.
Comment: With insulin resistance, the body has increased amounts of endogenous insulin, which means an increased growth factor in the body. I believe this has to do with the promotion of cancer.
A: This is exactly the thought process we are hoping to prove with future studies.
Q: Are there any large scale or major studies looking at people presenting insulin resistance, but at the time of cancer diagnosis actually an insulin deficiency? Would that be worthwhile to look at or would the preceding decade of hyperinsulinemia make that a moot point?
A: As of now, there are no good prospective studies in that area, though there exists an entire spectrum of patients with varying insulin resistance and hyperinsulinemia.
--by Manu Venkat, Jenny Tan, and Kelly Close