In this full report, we synthesize our coverage from the 3rd World Congress on Interventional Therapies for Type 2 Diabetes and the 2nd Diabetes Surgery Summit (WCITT2D and DSS-II) held in London, UK on September 28-30. The meeting drew 700+ attendees from nearly 60 countries and was truly a “World Congress” as it was planned in collaboration with the ADA, IDF, EASD, Diabetes UK, the Chinese Diabetes Society, and the Diabetes India Association. As we discussed with meeting organizer and bariatric surgery extraordinaire Dr. Francesco Rubino (King’s College London, UK), this year’s conference notably featured greater consensus compared to the last WCITT2D in 2011, due to growing clinical data on metabolic surgery. Over the meeting’s three days, we had the opportunity to hear insights on a wide range of topics from the science behind metabolic surgery to debates on the clinical use in diabetes to the policy implications. We heard a significant amount of agreement behind a push to intervene earlier with surgery, as speakers including Drs. Lena Carlsson (University of Gothenburg, Sweden), Robert Eckel (University of Colorado, Aurora, CO), and Harold Lebovitz (State University of New York, Brooklyn, NY) argued for intervention as early as in prediabetes. In addition, speakers pointed to the need to move away from the research paradigm of achieving endpoints through only surgery without medications, encouraging the field to redefine the term “remission” and be more open to multimodal treatment. The meeting also featured lively commentary and debate over the positioning of bariatric surgery within the diabetes care model and if we should rebrand the intervention as “diabetes surgery.” Speakers debated on the current state of outcomes data and the unmet need of certain patient populations, as the meeting concluded with Dr. George Alberti’s (Imperial College, London, UK) presentation on a new algorithm for diabetes management, which accounted for attendees’ live voting throughout the conference. Additionally on the device front, we heard Dr. Alan Cherrington (Vanderbilt University, Nashville, TN) present new positive results from the first in-human trial of Fractyl’s duodenal mucosal resurfacing procedure. Please see below for details on these highlights and more, with titles in yellow marked as ones we found particularly notable.
Detailed Discussion and Commentary
Diabetes Care – Epidemiology and Limitations of Conventional Treatments
Cardiometabolic Risk in Type 2 Diabetes
Robert Eckel, MD (University of Colorado, Aurora, CO)
Dr. Robert Eckel presented a quantitative analysis of cardiometabolic risk factors associated with type 2 diabetes, noting that improved glucose control confers lower cardiovascular risk but ultimately pointed out the significant limitations of existing conventional therapies. He began by stating that while recent decades have seen a marked decrease in cardiovascular death, women with diabetes still experience four times greater rates of cardiovascular death than those without diabetes and men with diabetes experience two times greater rates than those without. Dr. Eckel then selected and assigned values (for the percentage of risk they represent) to six cardiometabolic risk factors associated with type 2 diabetes (hyperglycemia, obesity, hypertension, dyslipidemia, inflammation, thrombosis) and presented the current evidence to support the level of impact they have. Hyperglycemia accounted for 15% of the increased cardiovascular risk according to Dr. Eckel; though he acknowledged that past clinical data has offered a complicated picture of the relationship between glucose control and cardiovascular risk, he ultimately supported the view that improved glucose control is associated with lower risk. With regards to the other risk factors, he assigned a 15% impact on risk to hypertension, 25% to dyslipidemia, and 10% to thrombosis. However, he noted the lack of data on the effects of obesity (and waist circumference in particular) and inflammation on cardiovascular risk. In terms of waist circumference, Dr. Eckel advocated for the need for better data to develop locally-adjusted guidelines for different countries and ethnicities. He concluded by estimating that 35% of cardiovascular risk in type 2 diabetes can be mitigated by treating all of these risk factors, but reminded the audience that that still leaves 65% of the risk that isn’t reduced by conventional therapies. Dr. Eckel’s presentation thus helped set up the prevailing notion that current standard of care is not adequately effective in reducing mortality and morbidity in type 2 diabetes and that better options are needed – and that metabolic surgery may provide such an option.
- Dr. David Nathan’s (Massachusetts General Hospital/Harvard Medical School, Boston, MA) presentation reiterated the similar idea that type 2 diabetes is associated with an excess risk of cardiovascular mortality and morbidity that conventional treatments aren’t able to mitigate. He pointed to previous clinical trials that showed that while relative risk reduction with conventional treatments is greater in people with type 2 diabetes than in the general population, the absolute risk of people with type 2 diabetes with treatment is still higher than the risk of people without diabetes on placebo.
Clinical Outcomes of Bariatric/Metabolic Surgery
Durability of Diabetes Control and Reduction of Micro- and Macrovascular Complications of Diabetes in the SOS Study
Lena Carlsson, MD, PhD (University of Gothenburg, Sweden)
Dr. Lena Carlsson pushed for the use of bariatric surgery in obese individuals with prediabetes, presenting new data on the prevention of complications in this patient population. She demonstrated analyses of the Swedish Obese Subjects (SOS) study, specifically comparing the risk reductions between the surgery and control groups in participants with prediabetes at baseline. Dr. Carlsson first showed that those in the surgery group had an 87% risk reduction in progressing to type 2 diabetes at 15 years compared to the control group. With regards to complications, the surgery group had a 45% risk reduction in micro- and macrovascular disease at 20 years; specifically, those in the surgery group had impressive risk reductions of 80% for microvascular disease overall, 82% for eye complications, and 92% for neuropathy complications. Similarly, Dr. Carlsson stressed for early intervention in type 2 diabetes, as she noted that a smaller percentage of participants with long disease durations experienced remission compared to those with shorter disease durations, which translates to weaker prevention of complications. In addition, she examined the recently published analysis on healthcare costs of surgery, pointing out that participants with longer diabetes duration saw higher costs in the surgery group while newly diagnosed participants had no significant difference in costs between the surgery and control groups (presumably due to longer remission and greater complications prevention).
- Drs. Robert Eckel (University of Colorado, Aurora, CO) and Harold Lebovitz (State University of New York, Brooklyn, NY) echoed similar sentiments, stressing the benefits of intervening early with bariatric surgery in acknowledging the role of beta cell function in disease progression. In a following panel discussion, Dr. Eckel emphasized that type 2 diabetes “is not an insulin resistance paradigm” but instead a “defect of beta cells” – thus surgery in an early onset patient can make a beta cell work more effectively in time. In addition, Dr. Lebovitz exclaimed that the “prediabetic ones are the ones with the opportunity,” noting that once someone has type 2 diabetes, the individual has lost enough beta cell function to lose out on surgery’s benefits. While surgery may not be the scalable solution we are looking for in prediabetes, it is certainly encouraging to hear the support for an additional treatment option for a patient population that has very little guidance on treatment and prevention of type 2 diabetes.
Reduction of CV Disease and Death After Bariatric/Metabolic Surgery
Ted Adams, PhD (University of Utah, Salt Lake City, UT)
Dr. Ted Adams included new data from Dr. Bjorn Eliasson et al (University of Gothenburg, Sweden) in his discussion of the clinical data supporting cardiovascular disease and mortality reduction following metabolic surgery. The observational cohort study – recently published in The Lancet – compared cardiovascular outcomes by matching people with type 2 diabetes who underwent Roux-en-Y gastric bypass (RYGB) surgery (n=6,132) to those who did not undergo surgery (n= 6,132 patients) over five years. The results found that at five years, the percentage of deaths in the control group was 19% vs. 7% in the surgery group, thus making for a mortality reduction of 58% for RYGB (p<0.0001). The surgery group also experienced a 49% risk reduction in fatal or nonfatal myocardial infarction compared to the control group (p=0.021). Additionally, the findings demonstrated a 59% risk reduction in the cardiovascular death (p=0.026). Five-year absolute risk of cardiovascular death was 5.8% in the control group and 1.8% in the RYGB group. These impressive results helped Dr. Adams make his larger point that the clinical evidence appears to support the benefits of metabolic surgery on cardiovascular outcomes. That said, while these numbers are certainly impressive, we understand the limitations of the study being an observational one and agree with the emphasis of other speakers throughout the day who noted the need for more randomized controlled trials on the subject to better understand the effect and its magnitude.
Panel Discussion: Benefits and Safety of Bariatric/Metabolic Surgery – Short- and Long-Term
Throughout panel discussions, speakers repeatedly pointed to the need to move away from the research paradigm of achieving endpoints through only surgery without medications, as they encouraged for more multimodal treatments. Drs. Harold Lebovitz (State University of New York, Brooklyn, NY), Robert Ratner (ADA, Alexandria, VA), Philip Schauer (Cleveland Clinic, OH), and John Dixon (Baker IDI, Melbourne, Australia) opened a morning panel discussion by discussing the flaws of defining remission as the lack of medication use. Specifically, such a definition makes it difficult to fairly compare the outcomes of surgery vs. medications and leads to a clinical disconnect between the two treatment options as Dr. Dixon exclaimed, “we’re trying to stop medications while we’re meant to treat risk.” Both Drs. Dixon and Richard Grant (Kaiser Permanente, Oakland, CA) criticized the dichotomy, emphasizing that surgery and medications should work together as treatment paradigms should use both jointly. Dr. Nicholas Finer (University College Hospital, London, UK) also raised the important point that medications are becoming an increasingly better option that should not be ignored in the context of surgery’s efficacy, as he referenced to SGLT-2 inhibitors in view of the positive EMPA-REG results. Indeed, as surgery and devices gain more supporting evidence, we see the future as one in which combination therapies also include treatment options that involve a combination of these modes (i.e. drugs, devices, surgery). However, such a clinical reality must begin with research designs that study these treatment options in combination rather than separately, including studies which incorporate weight loss medications as part of the pre- and post-op treatment options for individuals undergoing bariatric surgery.
- In a similar vein, using alternatives to remission as endpoints garnered broad support among the speakers. Considering the recurring emphasis that surgery and medication should not be viewed in dichotomy, Dr. Lebovitz suggested that endpoints in surgical clinical trials could be redefined to include A1c, lipid levels, and blood pressure to better align with endpoints in other medical therapy trials and to better reflect and predict the risk of complications. Further complicating the issue of how to define remission as an endpoint, several speakers touched on the ambiguity of when medication should be discontinued following bariatric surgery. Dr. Ratner advocated for an individualized approach: for instance, individuals who were indicated for statins prior to surgery should stay on statins for life while individuals with no complications prior to surgery probably should not need medication post-operatively. On the other hand, Dr. Geltrude Mingrone (Catholic University, Rome, Italy) raised the concern that post-surgery hypoglycemia is a large driver of medication discontinuation. Certainly, these complex clinical nuances in the reality of bariatric surgery are important to take into account in the research process – while the literature in this field has been growing quickly, these discussions remind us of how young the area really is and its ongoing state of evolution in better defining its path to clinical translation.
Dr. Harold Lebovitz (SUNY Brooklyn, New York, NY): How can you do a clinical trial comparing medical therapy to surgical therapy when you use as the endpoint remission of diabetes, which can’t occur with medical therapy? It seems to me that medical therapy can never be equal because you already defined it so it can’t.
Dr. Robert Ratner (ADA, Alexandria, VA): So the definition that has been in use came out of a consensus conference held several years ago that was then published in Diabetes Care. I’m going to talk about it more on Wednesday in terms of what the appropriate definition should be. But you’re right, you’re always going to have a difference if one group by definition can never achieve remission. But what we need to do is distinguish between adequate therapy and arbitrary definitions between remission and cure.
Dr. Philip Schauer (Cleveland Clinic, OH): As you can see from randomized controlled trials, there’s quite a bit of variability in those endpoints. Most of them use remission and absence of medication as primary endpoint but not all. Our own study used an aggressive target of 6%, with or without medication. We also looked at remission as a secondary endpoint. But I agree – it’s sort of unfair if you take away the tool to achieve the endpoint. We thought 6% with or without meds is 6%. Most of those studies used remission as the endpoint.
Dr. John Dixon (Baker IDI, Melbourne, Australia): I couldn’t understand how you could come up with those criteria. It’s not surgery vs. medicine. It’s treating patients. I listened to a presentation on recurrence rates earlier. They come with this pride in being able to say that we stopped medications. I get worried about us separating surgery vs. medicines. We have this disconnect when we’re trying to stop medications and we’re meant to treat risk. I just don’t think it’s logical and I think we should be treating those patients medically and surgically together.
Dr. Lebovitz: I wanted to raise a point that I thought was pertinent: surgeons could redefine the endpoint in randomized controlled trials to A1c, LDL cholesterol, systolic blood pressure, etc. That’s what we do in medical therapy; we don’t say, “Gee, we need to get to one value.”
Dr. Robert Eckel (University of Colorado, Aurora, CO): This issue comes up in patients with type 2 diabetes who have undergone surgery – the question of whether statins should be stopped. I agree that with hypertension, the post-operative benefits are not sustained long-term. I think there are a lot of unanswered questions about cardiovascular risk that go beyond A1c.
Dr. Schauer: You can add to that the dilemma of having an A1c of 5.5%. Some endocrinologists would prefer them on metformin and the definitions of when we should remove medications is still a wide open issue.
Dr. Geltude Mingrone (Catholic University, Rome, Italy): I must say that we were afraid of hypoglycemic events. The reason why we choose not to use medication when the patients were under remission was related to hypoglycemia.
Dr. Lebovitz: In the clinical trials, it has been possible to get A1c to 6.5% for five, six, or seven years. We have to ask the question: how aggressive is the medical therapy in these clinical trials? ACCORD managed to keep A1c at 6.5% for over seven years. If we’re going to adequately compare medical therapy to surgery, we need to make sure the medical therapy is state-of-the-art.
Dr. Schauer: There are limitations to medical therapy. I can speak about our study, which had a fantastic endocrinology, Dr. Sangeeta Kashyap. In our study, most of our patients were on three drugs and half were on insulin at the beginning. They had an A1c of 9% at the beginning. With aggressive therapy, Sangeeta was able to get many much better by adding more modern GLP-1 agonists and insulin. But it wasn’t sustained. Part of that may be compliance, side effects, or tolerance. Medical therapy has its limitations.
Dr. Lebovitz: I agree it’s difficult. But in these big trials, we’re dealing with these same patients. We need to make sure the treatment is very aggressive to compare.
Dr. Stephanie Amiel (King’s College London, UK): What do we need to continue monitoring for glycemia? To what extent do we need medications for our post-surgical patients?
Dr. Ratner: An article recommended individualized follow-up, based on the prevalence of complications to begin with. To use the example from Dr. Eckel, an individual who has an indication for statin pre-operatively, shouldn’t ever come off the statin. If you have individual who comes into metabolic surgery with no complications and no indications for other medical therapy and they come into complete remission, you probably don’t need anything after about five years. On other hand, if there’s any indication of complications, they need to be actively treated post-operatively.
Dr. Anita Courcoulas (University of Pittsburgh School of Medicine, PA): I want to make one more comment. In all the medical therapy studies, the number of participants was much greater than even the pooled number of participants in the surgery studies. We have 300 individuals, where the treatment ranged from intensive medical therapy to lifestyle treatment. If we want to answer these questions about the change in medications, I think we need to do a prospective study.
Dr. Dixon: The issue here is what sort of follow-up. They need lifelong follow-up. Who should be doing it? It should be someone with an approach to metabolism. I don’t think they should be followed up by surgical practices except for surgical problems. For both diabetes and obesity, if they’re seeing an endocrinologist or going to a multidisciplinary center, then they’re in the ideal position to be monitored and to have their cardiometabolic risk assessed.
Dr. Amiel: Multidisciplinary is absolutely key. We don’t want patients going to two separate services.
Dr. Eckel: Type 2 diabetes is not an insulin resistance paradigm. It’s a defect of beta cells responding to hyperglycemia. What surgery does in an early onset patient, based on current literature, suggests that it’s making the beta cell work more effectively. A patient with a longer duration of diabetes on multiple oral agents or basal/bolus therapy is unlikely to be a long-term benefactor of surgery. A beta cell put at rest early on makes a lot of scientific sense.
Dr. Amiel: The other issue we need to consider is people with lower BMIs.
Dr. Schauer: There are some patients who are struggling on intensive medical therapy to get their A1c to decent level. You’re not saying those people shouldn’t get surgery, are you? Because that may be only thing that can get them to a reasonable level.
Dr. Ratner: Not at all, I’m talking about comorbidities, not hyperglycemia at all.
Dr. Lebovitz: If you treat the prediabetic, then you have the opportunity to stop diabetes. Once you have diabetes, you’ve lost enough beta cell function and the A1c will slowly rise. Over 10 years, you will get hyperglycemia. Prediabetic ones are the opportunity. The obese individuals with impaired glucose tolerance – those are the people who are going to do really well.
Q: I wanted to ask about the cardiovascular risk. How much do you think the cardiovascular disease is due to the hyperglycemia? When you look at ACCORD, it doesn’t look like it’s making much of impact. You have to do a meta-analysis. Is it fact that cardiovascular problems are more related to obesity, lipids, blood pressure? When we talk about A1c, are we doing much for cardiovascular disease?
Dr. Eckel: The estimates I provided in my last slide reflected clinical trial evidence on how macrovasualr events relate to risk factors. I gave 15% for hyperglycemia. I graded other risk factors at a similar level, which was purely subjective based on my review of the literature. If you could control all 5 components of metabolic syndrome, you only reduce the risk by 35%. Looking at David Nathan’s presentation of DCCT data, the type 1 diabetes patient has normal lipids and better hypertension, but still have diabetes. However, the 57% risk reduction benefit suggests that glucose control might be more important in patients with type 1 diabetes.
Q: Can you differentiate between patients who went into remission on one hand and patients who benefitted from surgery on the other hand. Was it only those who went into remission who benefitted? Or was it sometimes the case that those who were hardest to treat benefitted but didn’t go into remission?
Dr. Schauer: Certainly in our study with the average A1c around 9%, many surgical patients went from 9% to 7% – a 2% drop – which is a huge clinical benefit even though they didn’t reach remission.
Q: I want to come back to the semantics of term remission. Remission is an unhelpful term. Claiming remission is wrong. Reaching a normal A1c with treatment with medication is not remission. Similarly, with surgery the operation is still working on the physiology. It has parallels with pharmacotherapy. It’s not remission, it’s treatment. These patients don’t have normal glycemia, they have big excursions up and down. It’s confusing to talk about it as remission rather than good treatment and good control that allows people to come off medication.
Dr. Schauer: If remission is not the best endpoint, Harold, what is it? Is it an A1c of 6.5%?
Dr. Lebovitz: I think you measure the A1c. If you get a mean A1c of 6.4%, that’s what you say. We do that with all of our treatments. We say what do we get for our money. And then we try to correlate that with complications. We don’t have much data. When you look at DCCT curves that look at mean A1c over a period of six years and decrease in complications, you get the greatest benefits going from 9% to 8%. With 7% to 6% and 6% to 5%, there are little to no benefits. So I think it is really looking at how you drop the A1c to what level to see how much you’ve done for the patient.
Novel Operations and Device-Based Interventions
Endoscopic Duodenal Mucosal Ablation
Alan Cherrington, PhD (Vanderbilt University, Nashville, TN)
Dr. Alan Cherrington presented new positive results from the first in-human trial of Fractyl’s duodenal mucosal resurfacing procedure. The findings demonstrated a mean A1c reduction of 1.2% (p<0.001) at six months, with fasting glucose reductions dependent on the length of the procedure’s catheter. In this study (conducted in Chile), patients with type 2 diabetes (n=39) with a (fairly high) average baseline A1c of 9.5% and BMI of 31 kg/m2 received one of two sizes of the Revita DMR balloon catheter (a smaller size that ablates <6 cm [n=11] and a larger size that ablates >9 cm [n=28]). Interestingly, the long segment cohort experienced a significant decrease in fasting glucose (p<0.05) though the short segment did not. The long segment cohort also saw lower postprandial glucose at six months (p<0.0001), similarly indicating that the length of the ablated segment impacts the efficacy of the procedure. Of the 18 participants with baseline A1c between 7.5% and 10% in the long segment cohort, 10 had reduced their diabetes medications at six months while eight had not. Dr. Cherrington also pointed out that results of meal tolerance tests demonstrated both fasting and post-prandial effects. Additionally, the long segment cohort experienced a significant weight loss of 2%-4%, or 2 kg (4.4 lbs) on average (p<0.05), although Dr. Cherrington noted that there was no discernible relationship between magnitude of weight loss and glycemic improvement. He concluded that the procedure is one that is generally well tolerated with a reassuring safety profile, supporting upper gastrointestinal intervention as a potential novel target to improve glycemia in type 2 diabetes. Looking forward, he noted that future directions include procedure optimization, testing under more controlled study conditions, and establishing durability of effect and clinical utility.
- These results were later presented again by Dr. Manoel Galvao (Gastro Obeso Center, Sao Paulo, Brazil) in a well-attended Fractyl-sponsored corporate symposium. In this presentation, we got an in-depth look at how the procedure works in practice, complete with an endoscopic video of the procedure. As background, the procedure borrows the upper endoscopy technique to insert a balloon catheter (the Revita DMR System developed by Fractyl) into the patient’s duodenum, expand the sub-mucosa using saline, and then ablate the mucosa with hot water. Despite the apparent extreme nature of the process (we imagine it has more potential to scare off patients than the standard oral pharmacotherapies), Dr. Galvao emphasized that there were minimal adverse events found in the study and after the mucosa heals, the ablated area remains virtually indistinguishable from the rest of the duodenum. The main adverse effect associated with the DMR procedure was duodenal stenosis. However, Dr. Galvao underscored that this only occurred in early study participants and that the incidence decreased as the physicians mastered the procedure. In addition, the condition was effectively treated with a single endoscopic dilation. For more on Fractyl’s work and previous clinical data of this procedure, please see our recent interview with the company’s CEO Dr. Harith Rajagopalan.
- Fractyl’s Revita DMR system has generated quite a buzz at this conference, with many leaders in the field expressing intrigue. During a panel discussion on device-based interventions, several panelists named DMR as one that they thought would still be around in five years. These votes of confidence are corroborated by Fractyl’s very strong advisory board consisting of Dr. David Cummings (University of Washington, Seattle, WA), Dr. Lee Kaplan (Massachusetts General Hospital, Boston, MA), Dr. Francesco Rubino (King’s College, London, UK), Dr. George Alberti (Imperial College, London, UK), Dr. Carel Le Roux (University College, Dublin, Ireland), Dr. Alan Cherrington (Vanderbilt University, Nashville, TN), Dr. John Amatruda (formerly Merck, New York, NY), and Dr. Geltrude Mingrone (Catholic University, Rome, Italy).
The Gut in the Physiology and Pathophysiology of Metabolic Diseases (Supported by Novo Nordisk)
The Gut as an Endocrine Organ – Role in the Regulation of Glucose Homeostasis
Daniel Drucker, MD (Lunenfeld-Tanenbaum Research Institute, Toronto, Canada)
Dr. Daniel Drucker offered a less than rosy view of the metabolic effects of bariatric surgery by cautioning against a potential increased risk of colorectal cancer. He highlighted several studies that suggest that the alteration of the gut can result in an adaptive response in the form of proliferation, which could increase the risk of cancer. In particular, Dr. Drucker made the point that several of the hormones that are upregulated from a metabolic perspective, including GLP-1, are essentially growth factors and could cause concern from a mitogenic perspective. Dr. Drucker suggested that physicians should be asking in the back of their minds “what does GLP-1 do in the colons of my patients when its been elevated for 10 to 15 years?” Ultimately, he championed the need to think beyond glucose and body weight to the potential mitogenic effects when considering metabolic surgery. That said, Dr. Drucker noted that he is not necessarily against the use of GLP-1 agonists or metabolic surgery, but is only suggesting the recommendation for patients who have a familial history or genetic predisposition to colon cancer to undergo colonoscopies, which he noted as a good clinical practice in patients not at risk as well. Dr. Drucker’s commentary provided food for thought on the non-obesity or diabetes related effects of metabolic surgery and, in our view, underscores the point that there is not enough data on the long-term outcomes of metabolic surgery.
The Anti-Incretin Theory: The Role of the Gut in the Physiology and Pathophysiology of Glucose Homeostasis
Francesco Rubino, MD (King’s College, London, UK)
In this presentation, Dr. Francesco Rubino encouraged attendees to question the idea that obesity causes type 2 diabetes, pointing to contradicting clinical observations and the emerging role of the gut. While Dr. Rubino acknowledged the parallel between the diabetes and obesity epidemics, he raised the concerns of distinguishing association from causation, noting that the signs and symptoms of a disease doesn’t necessarily equate to a relationship of cause and effect. He turned to clinical observations that do not match up with this commonly accepted link between diabetes and obesity, stating that 20%-40% of people with type 2 diabetes do not have obesity and that only 30%-40% of morbidly obese individuals have type 2 diabetes. He also pointed to the “obesity paradox” in which diabetes often occurs in people with BMI under 30 kg/m2, suggesting that those with higher BMI values are at lower risk. Interestingly, Dr. Rubino also shared data demonstrating that the prevalence of diabetes in morbidly obese individuals (BMI≥50 kg/m2) is lower than in those with a BMI of 30-50 kg/m2. Similarly, the high prevalence of type 2 diabetes in lower BMI ranges in non-Caucasian racial groups (i.e. Asians) raises similar concern. Noting that the idea of obesity causing diabetes is similar to “fitting a square peg in a round hole,” Dr. Rubino framed the proposal of type 2 diabetes as an intestinal disease touching on recent research from surgery that suggest that the condition involves the imbalance of incretin and anti-incretin actions, beta cell proliferation, and gut factors. Concluding, Dr. Rubino shifted to examining the bigger picture as he suggested that the gut’s role as the first organ exposed to the environment supports its potential significance in rising epidemiology trends (which have so far been more commonly attributed to a one-way relationship between obesity and diabetes). While a relatively unconventional idea, Dr. Rubino’s pioneering questioning brings the complexity of the diabetes/obesity connection to light, as we further understand the mechanisms and interactions behind novel treatment options to re-examine our current knowledge in a way that can be as far reaching as rethinking our public health interventions.
The Gut as an Endocrine Organ – Role in the Regulation of Food Intake and Body Weight
Steve Bloom, MD (Imperial College London, UK)
In this presentation, Dr. Steve Bloom offered an interesting take on the variance in weight loss effects associated with different GLP-1 agonists, suggesting that neural mechanisms of action may contribute to this difference. He reviewed liraglutide’s (Novo Nordisk’s Victoza at 1.2 mg or 1.8 mg and Saxenda at 3 mg) well-known effects on producing significant weight loss but noted the less impressive weight loss associated with dulaglutide, Lilly’s once-weekly Trulicity. While acknowledging that the product has the expected gastrointestinal side effects and works well for glycemic control in diabetes, Dr. Bloom pointed out that the weight loss is much less than would be expected. He suggested that this difference in weight loss effects between liraglutide and dulaglutide could be due to an inability of dulaglutide to cross the blood-brain barrier and a consequent inability to access the appetite centers of the brain. However this does not signal an end to the hope of significant weight loss with a once-weekly GLP-1 agonist – Dr. Bloom suggested that Novo Nordisk’s phase 3 once-weekly GLP-1 agonist semaglutide (see our recent coverage of the candidate’s positive phase 3a results) may hold the advantage in this regard due to its lipid side chain that might allow it to cross the blood-brain barrier. Ultimately, Dr. Bloom forecasted a partitioning of long-acting GLP-1 agonists in the future based on the method of their long-acting action. Indeed, there has been growing research behind the more centrally acting mechanisms of action in the GLP-1 class – please see our coverage of recent research on this from EASD for more. Dr. Bloom has received some negative publicity of late about his dealings with Coca-Cola – watch Closer Look for more coverage on this.
The Science Behind Metabolic Surgery (Supported by Novo Nordisk)
Role of the Duodenum in the Antidiabetic Effects of RYGB
David Cummings, MD (University of Washington, Seattle, WA)
Dr. David Cummings presented results from an innovative study investigating the mechanism of action underlying Roux-en-Y gastric bypass surgery (RYGB), suggesting the importance of nutrient passage through the duodenum in the surgery’s outcomes. While RYGB’s bypassing of the duodenum is known to substantially improve glucose homeostasis when there is little to no weight loss following surgery, the mechanism behind this effect is unclear. Dr. Cummings hypothesized that the effect could be due to (i) rapid delivery of food to the distal intestine (and be related to GLP-1 upregulation) or (ii) not delivering food to the proximal intestine. In an elegantly-designed study, Dr. Cummings showed that option two, duodenal exclusion, is likely responsible for the improved glycemic control. Insulin sensitivity increased in patients who underwent RYGB and food was excluded from passing through the duodenum. Passage through the duodenum via gastrostomy tube led to a loss of the insulin sensitivity benefit. Dr. Cummings highlighted the insulin sensitivity findings as the most important results of the study and concluded that nutrient passage through the duodenum strongly influences insulin sensitivity independent of weight change. In our view, Dr. Cummings’ data represent a first step in clarifying the mechanisms underlying the efficacy of less invasive devices that simulate aspects duodenal exclusion, such as Fractyl’s Revita DMR System and GI Dynamics’ EndoBarrier.
- Study design: Dr. Cummings designed a trial in which severely obese individuals with type 2 diabetes were removed from all diabetes medications one week prior to undergoing RYGB. After two weeks of normal oral feeding following the surgery, participants underwent meal tolerance, IV glucose tolerance, and hyperinsulinemic clamp tests. Next, participants underwent gastric feeding through a gastrostomy tube for two weeks, which allowed food to pass through the portion of the proximal duodenum that is bypassed with oral feeding following RYGB. The three tests were repeated before the participants were fed orally for another two weeks, after which the tests were repeated again.
- The results found that participants had statistically significant increased insulin sensitivity with oral feeding and duodenal exclusion following RYGB, but that the benefit was lost after two weeks of gastric feeding and duodenal passage. After another two weeks of duodenal exclusion, the increased insulin sensitivity was again observed. Dr. Cummings emphasized that participants lost little to no weight throughout the duration of the study, so weight loss is unlikely to account for the insulin sensitivity results. In a standardized meal tolerance test, both insulin and glucose had a faster spike and decline following a meal – closer to what is observed in people without diabetes – after RYGB and duodenal exclusion. Following two weeks of duodenal passage, the effect was attenuated and closer to the gradual rise and fall seen at baseline. Similar results for insulin levels were also observed in the IV glucose tolerance tests. The meal test also revealed that ghrelin levels were lower than baseline following RYGB, but there was no difference in ghrelin levels based on oral or gastric feeding, indicating that duodenal exclusion is not involved in that mechanism.
Diabetes Surgery: Indications and Model of Care – Presentation of Recommendations and Guidelines for Diabetes Surgery
Definition of Diabetes-Specific Goals and Success of Surgical Treatment
Robert Ratner, MD (ADA, Alexandria, VA)
Dr. Robert Ratner advocated for redefining the outcomes of surgical treatment by moving away from “remission” and more towards therapeutic targets to avoid the abrupt discontinuation of medications. As was discussed throughout the meeting, remission has been defined as the state at which the patient has no active pharmacologic therapy – an increasingly controversial definition as it sets up a situation in which the comparator (of medical therapy) can never succeed and in which the discontinuation of medical therapy becomes a goal of surgery. In addressing this, Dr. Ratner set forth his own personal recommendation as he pushed to no longer refer to remission or relapse but to rather set the achievement of specific therapeutic targets as the goal of surgery. In this paradigm, it is thus discouraged to discontinue medications post-operatively but rather to wean them as necessary to avoid hypoglycemia. As Dr. Ratner noted, setting targets on clinical parameters (i.e. A1c, weight loss) additionally provides the opportunity to examine the benefit at any stage within the intervention. With regards to complications, he recommended a patient-centered approach that maintains the indicated therapies for certain comorbidities or complications – like lipids or statins – post-operatively that may be weaned if necessary. Dr. Ratner also stressed that the term “cure” should only be reserved for situations where no further intervention is required and is not particularly appropriate for bariatric surgery as such an intervention more accurately reflects a longer-term treatment of diabetes that holds onto the potential of relapse. We certainly agree that labeling bariatric surgery as a “cure” can be dangerously misleading as it can set up unrealistic patient expectations, as we now well know from Dr. Ratner and other speakers that post-operative medication use and diligent follow-up is critical for the long-term success of surgery. We also agree that the use of therapeutic targets as goals for bariatric surgery, rather than discontinuation of medications, would be a step in the right direction as it is a more realistic determinant of patient success.
Integrating Medical and Surgical Therapies to Optimize Outcomes
Stefano Del Prato, MD (University of Pisa, Italy)
Dr. Stefano Del Prato (University of Pisa, Italy) touched on the potential of enhancing the outcomes of bariatric surgery with complementary pharmacotherapy. Dr. Del Prato called for the integration of medical and surgical therapies to help maximize the long-term beneficial effects of surgery. Specifically, he pointed to the promise of using pharmacotherapy to compensate for the different mechanisms underlying surgery, presenting data on how accompanying multidisciplinary medical weight management improved the weight loss in RYGB by ~8% at six and 12 months (Patel et al, Ann R Coll Surg Engl 2015). In addition, Dr. Del Prato showed recent data demonstrating that GLP-1 agonism enhances adjustable gastric banding in diet-induced obese rats with regards to food intake and body weight.
- Dr. Lee Kaplan (Harvard Medical School, Boston, MA) similarly illustrated the potential of targeting neural pathways that are not directly involved in surgery, as he presented knock-out rodent model data demonstrating that serotonin 2C receptor signaling is not required for surgery’s outcomes; thus notably, recent data has shown that the addition of lorcaserin (Arena/Eisai’s Belviq), which is a serotonin 2C receptor agonist, helped augment weight loss after RYGB. Dr. Kaplan therefore stressed that adding drugs whose mechanisms do not directly activate surgery’s outcomes are promising targets to provide additive effects alongside surgery – important considerations to take into account when choosing between different pharmacotherapies post-operatively, or even pre-operatively. Certainly, as Dr. Kaplan noted, the science behind bariatric surgery is important in not only understanding the mechanisms of the operation but also in understanding how surgery can participate in the broader treatment algorithm.
DSS-II: Indications to Diabetes Surgery and New Algorithm for Diabetes Management
George Alberti, MD (Imperial College, London, UK)
Dr. George Alberti presented a new algorithm for diabetes with indications for bariatric surgery, taking into account not only an individual’s BMI but also medical therapy and comorbidities. The algorithm is the product of several consensus statements attendees voted on throughout the conference. In a flowchart format, he walked attendees through the algorithm’s decision tree which recommends surgery to individuals with a BMI >40 kg/m2 and to those with a BMI >35 kg/m2 with inadequately controlled hyperglycemia; a “consideration” for surgery is recommended for adequately controlled individuals with BMI <35 kg/m2. For individuals with a BMI <35 kg/m2, the algorithm first suggests optimal medical treatment (first with non-insulin medications and then with insulin, if needed), only recommending surgery in the case that the individual continues to have inadequate control after these interventions. However, inadequately controlled individuals with one or more surgery-responsive cardiometabolic risk factors are recommended for surgery without first using insulin. This algorithm seemed to accurately represent the opinion of the majority of the attendees as the results of voting questions throughout the meeting demonstrated that many were comfortable with surgery for moderate or severe obesity with inadequately controlled diabetes despite lifestyle and medical therapy. We were glad to see the meeting be so responsive to the attendees’ thoughts and while this algorithm remains a work in progress, this set of guidelines helps pave the way for understanding the role of surgery within the model of care in type 2 diabetes. In addition, as surgery (and many other interventions) heavily rely on BMI, the meeting’s focus on and integration of additional patient factors (i.e. medical therapy, risk factors) brings us slightly closer to the ideal individualized and personalized approach for bariatric surgery.
In this panel discussion, speakers passionately debated the appropriateness of labeling bariatric surgery as diabetes surgery, touching on the state of relevant literature and the risks and benefits in different patient populations. Drs. David Nathan (Massachusetts General Hospital, Boston, MA) and Harold Lebovitz (State University of New York, Brooklyn, NY) strongly voiced their concerns that the data are inadequate for focusing this intervention toward diabetes, specifically referring to the lack of long-term evidence on complications in people with diabetes. Dr. Nathan additionally pointed out that, “there hasn’t been a single study where people were not selected based on their weight,” as surgery has not yet been studied with a focus on type 2 diabetes rather than on overweight/obesity. Drs. George Alberti (Imperial College, London, UK) and Philip Schauer (Cleveland Clinic, OH), however, refuted by pointing to the growth in data, which have demonstrated superior outcomes and include some long-term evidence, as well as the significant unmet need in this patient population (or as Dr. Alberti noted, “treatment for many patients right now is crap”). In addition, panelists including Drs. Robert Eckel (University of Colorado, Aurora, CO), Robert Ratner (ADA, Alexandria, VA), and John Morton (Stanford University, CA) further complicated the question as they noted the greater benefits in earlier intervention and in lower BMI ranges – therefore in some ways, it may seem that greater access to these patient populations provides the bigger bang for the buck. While we are encouraged by the science behind surgery’s impressive outcomes in type 2 diabetes and find it exciting to see this discussion come to life (this certainly would not have garnered much attention at the first annual meeting!), we agree with the need to be cautious around branding an intervention a certain way due to the complex implications surrounding the messaging to patients, providers, as well as policymakers and payers. We also feel that patients and providers may view bariatric surgery as an extreme option for type 2 diabetes, especially as there are many less invasive pharmacotherapies that have large phase 3 efficacy, safety, and cardiovascular outcomes trials attached to them.
Policy Track: Cost-Effectiveness of Diabetes Surgery and Healthcare Policies
Results of the “Diabetes Surgery Policy Lab”: Challenges, Barriers, and solutions for the Implementation of Surgery as a Treatment for Type 2 Diabetes
Jennifer Rubin, PhD (King’s College London, UK)
Professor Jennifer Rubin shared the themes that arose from the meeting’s invitation-only “Policy Lab” to identify barriers to access of metabolic surgery and discussed actionable policy steps to address those barriers. The barriers and associated action steps addressed everything multiple aspects of the issue, including resources, knowledge, and processes – see below for the specifics. In a meeting filled with scientific data, we especially appreciate the presence of the Policy Lab as it paves the conversation for taking steps to turn the clinical guidelines from this conference into broader meaningful policy changes.
- There was wide consensus among the group (which included senior clinicians, academics, patient representatives, industry, and individuals engaged with health policy) that diabetes is a major challenge that is only going to get worse without a change in current practice. Most also agreed upon the efficacy and cost-effectiveness of bariatric/metabolic surgery.
- Professor Rubin grouped the barriers to increasing uptake of metabolic surgery that the group cited into three broad categories: (i) a lack of resources such as space, capabilities, and funding; (ii) inadequate understanding of the seriousness of the diabetes challenge and/or metabolic surgery and its outcomes among patients, clinicians, the policy community, and the wider public; and (iii) a lack of established processes in terms of how services are commissioned, delivered, and incentivized. Specific ideas for tackling these barriers ranged from seeking alternative funding sources (such as health impact bonds) to including a greater focus on metabolic surgery in the medical school curriculum to improving payer coverage of metabolic surgery.
- Professor Rubin concluded by offering the building blocks toward metabolic surgery policy change, stressing that people need to first understand the scale of the diabetes challenge as a whole and the role for metabolic surgery in diabetes treatment. After that, policymakers and payers must be convinced of the cost effectiveness savings associated with metabolic surgery, for which some feel more evidence is needed. Finally, action must be taken to improve the resource, understanding, and process barriers to metabolic surgery uptake. Professor Rubin also noted that there is a stigma attached to metabolic surgery as an obesity treatment and that reframing the procedure as a diabetes treatment may be helpful in focusing on the specific challenge being addressed. That said, several conference attendees have expressed resistance to reframing metabolic surgery as a treatment for diabetes without better clinical data to make the case.
Corporate Symposium (Sponsored by Medtronic)
Metabolic Surgery: From clinical Trials to Real World Experience
Francois Pattou, MD (University of Lille, France); Sayeed Ikramuddin, MD (University of Minnesota, Minneapolis, MN); Beat Müller, MD (Heidelberg University Hospital, Germany); Yves Reznik, MD (Centre Hospitalier Universitaire, Caen, France); Chris Pring, MD (Streamline Surgical, London, UK)
A Medtronic-sponsored evening corporate symposium touched on topics ranging from the clinical data behind metabolic surgery to the experience of implementing metabolic surgery as a treatment for type 2 diabetes in the real world. Dr. Francois Pattou (University of Lille, France) discussed the evidence on the weight-independent metabolic effects of gastric bypass, followed by Dr. Sayeed Ikramuddin’s (University of Minnesota, Minneapolis, MN) presentation on the current RCT literature on bariatric surgery vs. medical treatment for type 2 diabetes. Dr. Beat Müller (Heidelberg University Hospital, Germany) also shared the lessons learned during his experience with running the DiaSurg 2 randomized controlled trial to investigate RYGB vs. insulin as he pointed out the challenges of getting insurance companies to pay for the treatments) and surgeons’ lack of willingness to be involved in long-term follow-up (a concern we have often heard). The symposium shifted gears to more practical guidance for clinicians as Dr. Yves Reznik (Centre Hospitalier Universitaire, Caen, France) provided support on how to adjust drugs and monitor glucose before and after surgery. Lastly, Dr. Chris Pring (Streamline Surgical, London, UK) moved closer to advocacy and policy discussions as he emphasized the need for stakeholder engagement, standardization of care, and persistence when advocating for greater acceptance of viewing bariatric surgery as metabolic surgery. As a reminder, Medtronic recently launched a bariatric surgery tool, the GastriSail gastric positioning system, developed by its Minimally Invasive Therapies Group – and the company’s presence at this meeting is certainly very dominant with its status as visionary sponsor (the highest level of sponsorship).
-- by Melissa An, Helen Gao, and Kelly Close