EASD 2013 noticeably lacked significant discussion of pharmacotherapies for obesity – an embodiment of the difficult regulatory environment in the EU. We heard very little on Vivus’ Qsiva (the EU name for Qsymia; phentermine/topiramate ER), Arena/Eisai’s Belviq (lorcaserin), Orexigen’s Contrave (bupropion/naltrexone), and Novo Nordisk’s Victoza (liraglutide) for obesity. The dearth of discussion around these drugs reflects the challenging regulatory landscape, which has brought setbacks to several obesity drugs candidates: earlier this year, the EMA requested a pre-approval CVOT for Qsiva, and Arena withdrew its EU MAA for Belviq when it recognized that the CHMP was going to recommend against approval. The question remains what it will take for the EMA to approve an anti-obesity agent. The EMA’s decision on Contrave (expected in 2014) may provide some insight, especially since the EMA will look at the drug’s interim CVOT data when making its decision. Alternatively, at ECO, Dr. Nick Finer (University College Hospital, London, UK) hypothesized that Victoza might be next to market in the EU, since it is a gut hormone rather than a centrally acting compound like the other obesity candidates (for more details on his comments, please see page 18 of our ECO Day #2 report at http://www.closeconcerns.com/knowledgebase/r/f9de4ac7).
Instead, the conversation on anti-obesity measures focused on bariatric surgery, particularly who should undergo these procedures. Dr. Lars Sjöström (University of Gothenburg, Gothenburg, Sweden), former primary investigator of the Swedish Obesity Subjects (SOS) study, and Dr. Ele Ferrannini (University of Pisa, Pisa, Italy) both strongly critiqued the current BMI-based eligibility criteria for bariatric surgery. They explained that BMI does not predict surgery’s impact on diabetes prevention or remission. In contrast, metabolic factors, particularly beta cell function (according to Dr. Ferrannini) offer a more accurate prediction of who will best respond to the procedure. In his discussion of bariatric surgery, Dr. Ferrannini also detailed how biliopancreatic diversion improves insulin resistance more so than roux-en-Y gastric bypass. Dr. Ferrannini referenced an ongoing trial that suggests that the positive effects of BPD could be due to its stimulation bile acids secretion; this result indicates that bile acids could be an potentially promising treatment approach.
- Executive Highlights
- Obesity, Prediabetes, and Metabolic Surgery
- Oral Presentation: Technologies to Transform Diabetes
- Oral Presentations: Beta Cell Function in Vivo
- Symposium: Bariatric Surgery in Type 2 Diabetes – An Update
- Satellite Session: 6th CIBERDEM Annual Meeting
Obesity, Prediabetes, and Metabolic Surgery
Oral Presentation: Technologies to Transform Diabetes
INTERIM 12 MONTH RESULTS FROM A POST MARKET CLINICAL TRIAL OF DJBL TREATMENT OUTCOMES IN SUBJECTS WITH TYPE 2 DIABETES AND/OR OBESITY
Julian Teare, MD (Imperial College, London, UK)
Dr. Julian Teare enthusiastically shared results from a 12-month study of GI Dynamics’ EndoBarrier, calling the gastrointestinal liner, “a genius invention.” The study enrolled 45 participants with type 2 diabetes (mean age: 50 years; mean diabetes duration: 5 years; mean BMI: 40 kg/m2). After 12 months of wearing the EndoBarrier, A1c declined by 1% from a baseline of 8.5% - we note that nearly all of the decline came in the first three months, with no noticeable change in A1c over the next nine months. Mean total body weight loss was 10% (-26 lbs from a baseline of 245 lbs), representing a 4.4 kg/m2 drop in BMI. Questions and skepticism definitely arose on the safety side, as there were a total of 13 device removals, nearly one-third of all patients in the study. Only three were categorized as “device related” (melena, anchor movement, abdominal pain), another five were due to “patient preference” (e.g., discomfort; we thought this could have been considered “device related”), and the last five related to “bleeding risks” (i.e., other comorbidities or new medications). Dr. Teare countered in Q&A that the average duration of implant was 10.5 months, meaning most patients made it the whole year (we wish he had discussed median implant time as well). He also mentioned that the number of explants in this study was higher than in previous studies of EndoBarrier. We look forward to data from Dr. Teare’s upcoming 160-patient study start next year, which will compare EndoBarrier N=80) to standard medical therapy (n=80). Notably, it will also include two-year follow-up, so it will be possible to see what happens to glucose and weight post-explant – that was a key piece of missing data in this study. For more on the device, including the status of the US ENDO trial, see our report at http://www.closeconcerns.com/knowledgebase/r/74d4f90f.
- As expected with such weight loss, improvements were also seen in a number of other metabolic and cardiovascular safety parameters: fasting glucose (-27 mg/dl from a baseline of 167 mg/dl), systolic blood pressure (-8 mmHg from a baseline of 138 mmHg), diastolic blood pressure (-3 mmHg from a baseline of 77 mmHg), total cholesterol (-9 mg/dl from a baseline of 167 mg/dl), LDL cholesterol, and triglycerides all improved as well.
- There were a fairly high number of device removals in this study. Three removals were classified as “device related” – melena (day 33), anchor movement (day 148), abdominal pain (day 283). On the latter, the patient wanted to keep the device in, but reached a point where she couldn’t. There were 10 “non-device related removals” – five were classified as “patient preference” and five related to bleeding risks (TIA, DVT, atrial flutter, gout needing NSAIDS, and an MI with stent insertion).
Questions and Answers
Q: Beautiful data, congratulations. Do the patients have any special dietary restrictions?
A: At the beginning of the study, they are on a liquid diet. Gradually, solid food is introduced. The initial phase does lead to calorie restriction. As they use the device, they go to a relatively normal diet.
Q: Were there changes in the dietary preferences of patients?
A: We haven’t put this into this study. In the next study, we will look at specific food preferences. Anecdotally, we do see a change away from high calorie foods to more high protein foods. It’s the same thing as you would see in gastric bypass, but we will assess it more formally.
Q: Was there a change in gut flora during/after implantation?
A: We will be looking at the microbiome in this subsequent study. How does the gut flora affect diabetes and obesity? It’s a huge question to be answered. We hope get insights from use of this device?
Q: What’s the follow-up on some of these patients. What happens post-explant to control of diabetes and weight?
A: I don’t have much from this study. But I do have company data. There is a gradual re-accumulation of weight and a gradual rise in A1c. It’s not at the same rate as the weight has been lost. It takes a lot longer for the weight to return. In the subsequent study, we will have a two-year follow-up to determine how long and durable the effect of the device is.
Q: Could the device remain in longer? Can you say whether people had the device could have it reinserted at a subsequent time?
A: There are some concerns about leaving the device in for longer. Our understanding will evolve over time about the optimal duration of use. Lots of patients had it and didn’t want it removed. They said, “Why are you taking it out? Why not leave in for longer? Can you put it back in?” The answer seems to be yes.
Q: I wanted to talk about another study sponsored by diabetologists that is to the interest of everyone. We’re looking at liraglutide plus EndoBarrier. We’ll also see what happens in the year after taking it out. Those are the answers we should have.
A: You also need to mention the inclusion criteria – failure on liraglutide to go on EndoBarrier.
Q: That’s right. You’ve got nowhere to go at that point besides increasing insulin.
A: It’s a question about where the role of devices should fit. The 15-year UKPDS data showed that earlier use in the development of diabetes might be beneficial and translate to a lasting benefit later in life. It makes more sense to me. I’m not a diabetologist. I’ve come to this arena with a fresh mind.
Q: Do you have any patient reported outcomes on this treatment? And second, you had nearly one third of all patients that had the device removed. Can you comment?
A: I can comment. In Holland, there was a six-month study and there was one removal. We seem to have a higher proportion of removals with the longer duration of the study. These are things that happen to people with diabetes. The average duration of implant was 10.5 months. Most people got pretty close to one year overall. With any intervention, there are those for whom it doesn’t work. Five people got some discomfort or it wasn’t working for them. That was patient preference. Patient-based outcomes were not a formal part of this study, but it will be a formal part of the next study.
Oral Presentations: Beta Cell Function in Vivo
BETA CELL FUNCTION AND INSULIN SENSITIVITY AFTER ROUX-EN-Y GASTRIC BYPASS IN PATIENTS WITH TYPE 2 DIABETES AND NORMAL GLUCOSE TOLERANCE
Kristine Bojsen-Møller, Degree (University of Copenhagen, Copenhagen, Denmark)
Dr. Kristine Bojsen-Møller presented a one-year study (n=10 people with type 2 diabetes and 10 with NgT) of people who underwent roux-en Y gastric bypass (RYGB) to determine the surgery’s impact on type 2 diabetes pathophysiology. People’s pathophysiology was profiled (using OGTT, hyperinsulinemic clamp, iv glucagon test, and dexa) pre-operation, one week post-op, three months post-op, and one year post-op. She found that the improvements in glycemic control seen after gastric bypass can be explained by the rapid improvement in hepatic insulin sensitivity, improved peripheral insulin sensitivity, and better beta cell function recipients experience.
- RYGB was associated with a BMI reduction of 10 kg/m2 (from a baseline of 49 kg/m2) and, in people with type 2 diabetes, an A1c decline from 7.0% to 5.7%.
- Dr. Bojsen-Møller found that people’s hepatic insulin sensitivity (as measured by glucose production) was increased at one week and remained at the improved level through one year.
- Peripheral insulin sensitivity (as measured by glucose disposal) was unchanged at one week and was improved at three months and one year. At one year, the improvement in peripheral insulin sensitivity was correlated with a person’s weight loss.
- Turning to beta cell function, Dr. Bojsen-Møller found that insulin secretion following an iv glucagon challenge remains unchanged in people with type 2 diabetes following RYGB. In contrast, people with NGT’s insulin secretion decreased overtime following their RYGB. Additionally, while insulin secretion after an iv challenge adapt to improved sensitivity in people with NGT at baseline, it does not adapt in people with type 2 diabetes.
- In response to an OGTT, however, people with type 2 diabetes’ insulinogenic index significantly increased from baseline to month three. It remained significantly elevated at year one. Thus, people with type 2 diabetes experienced an increase in beta cell function as measured by an OGTT.
- Additionally people with type 2 diabetes experienced large increases in GLP-1 though not GIP.
Questions and Answers
Q: Do you speculate that RYGB increased the incretin effect?
A: I would suggest that.
Q: I do not understand why the liver sensitivity improves. What is responsible for that?
A: We do not believe that it is the incretins impacting the hepatic or peripheral tissues. I think that it is only the caloric restriction and subsequent weight loss. It is only the improvement in beta cell that is due to incretin effect.
Q: If you restricted patients food intake for one week, would you get a similar impact on hepatic sensitivity?
A: Yes. There are studies showing even larger improvements in insulin sensitivity with caloric restriction in people with type 2 diabetes. It would be beautiful to have a larger study of this topic.
Symposium: Bariatric Surgery in Type 2 Diabetes – An Update
METHODS AND RESULTS OF BARIATRIC SURGERY
Dimitri Pournaras, MD (Imperial College, London, United Kingdom)
In an opening to the symposium dedicated to bariatric surgery and diabetes management, Dr. Pournaras presented an overview of outcomes from surgical weight loss interventions in patients with diabetes and made several suggestions for future practice. Importantly, he noted that in 2009, diabetes remission was redefined as maintaining a normal A1c <6% and a fasting glucose level <100 mg/dl for at least one year following surgery. Given these modifications to the criteria, diabetes remission rates have significantly dropped from calculations based on previous standards (e.g., for gastric bypass, rates are now 40% vs. ~60% before). Interestingly, Dr. Pournaras interpreted these findings as positive, claiming they support his view that we should be shifting measures of success away from remission rates, which are antiquated, to glycemic control, which is used as a gauge in all other diabetes treatments. Regarding type 2 diabetes recurrence, Dr. Pournaras noted that short-term remission rates are 43%, while long-term are 24%. He argued that we should look to cancer’s combinatorial treatment approach to amend our approach to bariatric surgery and diabetes care – we certainly agree with him that combination therapy, especially early in the course of type 2 diabetes, will result in better outcomes. In Dr. Pournaras’ opinion, our standard evaluation should “not be best medical therapy vs. surgery, but best medical therapy vs. best medical therapy plus surgery.” One study that assessed intensive medical therapy alone vs. combined with surgery found that using both doubled the percentage by which A1c levels were lowered, from 1.5% to 3%. In addition, Dr. Pournaras advocated on behalf of redirecting end goals for surgery to be focused on the reduction of diabetes related co-morbidities and macrovascular complications, as is currently being done in the evaluation of new diabetes drugs. In general, we left with the impression that Dr. Pournaras believes strong efforts should be made to bridge the separation between bariatric surgery and diabetes treatments in the conventional paradigm in order to improve patient outcomes.
- The most common weight loss operations – adjustable gastric banding, roux en Y gastric bypass, and sleeve gastrectomy – have shown considerable success and safety, with very low in-hospital mortality rates (0.07% in 2013 as indicated by the NBSR) and significant improvements in A1c levels.
Questions and Answers
Q: On what basis do you decide what type of bariatric surgery a patient should receive?
A: If a patient doesn’t know the answer, we ask that they go back to a patient support group. These are the most educated patients you will ever meet. I listen to patients, they tell me the truth.
Q: Can you predict which patients will go into remission before doing the surgery?
A: I wish I could! Like I said, we need to know who benefits most. Having had diabetes for a long time and having been on insulin lowers your chance of remission, but that doesn't mean that those individuals should be denied surgery – in fact, they may be the ones who benefit the most. It is an area of ongoing study.
Q: Is bypass surgery better than sleeve gastrectomy? Also, with an EndoBarrier liner, how long do you keep it in?
A: The EndoBarrier liner is licensed for 12 months, but you can do repeated therapy. The picture of what happens after is less clear, some put the weight back on and some don’t. In response to your first question, there is no significant difference, though they do work in different ways. My feeling is that with bypass you get more weight loss, but we need more studies for long-term data on gastrectomy. It hasn't been around for very long so there are less data.
Q: Clearly a sleeve can be a different thing to a different surgeon.
A: The technique for sleeve gastrectomy is variable. We have to standardize what we do so that our data can be interpreted in a way that’s useful.
Q: You showed quite impressive data about clinical outcomes. Can you tell us about patient satisfaction and quality of life?
A: Quality of life data are out there. Every study I know shows very good improvements in quality of life. In our experience, these patients do very well. I’ve seen patients who have had pretty severe surgical complications and still do not regret having it. These are some of the most satisfied patients I have seen in surgical practice.
Q: What are advantages and disadvantages, both immediate and late, of bypass surgery and sleeve?
A: The biggest limitation is that there needs to be very close follow up.
Q: Have you explored the intragastric balloon as form of weight loss surgery?
A: We know that as soon as you remove the balloon you gain the weight back. It’s mainly a good option for patients who are too heavy for surgery or too high-risk to undergo another form for surgery.
Q: If you get second thoughts after the operation, is it possible to reverse it?
A: We tell patients that gastric bypass is irreversible, but technically you can reverse it. It is a very demanding and dangerous procedure, however. The sleeve is reversible but you gain the weight back straight away.
Q: Could you do an oral glucose tolerance test after bariatric surgery?
A: It’s safe and we have definitely done it, but we’ve moved away from this method and are using the new criteria for remission.
Q: You have not given any data on any long-term nutritional deficiencies.
A: Data are available. For both banding and gastric bypass, there aren’t any major concerns.
DIABETES PREVENTION AND REMISSION AFTER USUAL CARE AND BARIATRIC SURGERY
Lars Sjöström, MD, PhD (University of Gothenburg, Gothenburg, Sweden)
Dr. Lars Sjöström, former primary investigator of the Swedish Obesity Subjects (SOS) study, strongly critiqued the current BMI-based eligibility criteria for bariatric surgery. He argued that it is invalid to base the criteria around BMI since baseline BMI does not predict any treatment effects so far examined, including surgery’s impact on diabetes prevention or remission. Instead he believes that eligibility decisions should place more importance on metabolic variables. Indeed, he presented data suggesting that a person’s baseline insulin and glucose levels are better predictors of treatment effect than BMI. Reviewing the SOS’s results, Dr. Sjöström underscored that bariatric surgery is able to robustly prevent type 2 diabetes over the long-term in people who are prediabetic and nondiabetic obese. Additionally, in the short-term, bariatric surgery causes diabetes remission in the majority of people with type 2 diabetes undergoing the procedure. However, after 20 years, ~75% of initially remitted patients have relapsed. It is unclear though, if they remit to a less severe form of type 2 diabetes than they had pre-operation. What research does show, however, is that people are less likely to develop diabetes complications even if they do relapse. Notably, it appears that people who have had diabetes for shorter periods of time are more likely to experience remission. Thus, Dr. Sjöström called for people to treat deteriorating glucose metabolism early, and suggested that people with prediabetes should potentially be recommended for surgery.
Questions and Answers
Q: Thank you for sharing such an impressive result from this landmark study. Given your expertise, if you were to design your SOS today, which procedures would you recommend?
A: Weighing successful treatment and dangers, if I were to design the SOS today, I would randomize between usual care and intensive care and gastric bypass. Of course biliopancreatic diversion has more radical effects on the metabolism.
Q: What did you seen in NAFLD?
A: We have only liver enzymes, so nothing sophisticated there with which to look at the liver.
Q: Are there data in patients with BMI under 30 kg/m2? There are some ethnic groups who show substantial incidence of diabetes in the 25 kg/m2 range.
A: There are some published data between 27 kg/m2 and 35 kg/m2. There are several studies ongoing. I think the end result will show that gastric bypass will influence the diabetic state markedly.
Q: You showed us a quite high relapse rate in the entire operated group. Can you break this out by surgery?
A: We have data, but we had only on the order of 500 patients, so we are not powered to look at the results in the surgical subgroups – especially in gastric bypass, since that was not the main surgery performed. In our study, remission is not significantly different with bypass than the other surgeries, though this could be due to the powering.
Q: Do you think that even if remission is transient it is still having a long-term impact on complications? Or perhaps when you have the relapse the severity of the disease is reduced?
A: We must remember that our definition of diabetes is an arbitrary cutoff and does not describe the whole story. A lady in Madrid has a paper in press where she shows that even in patients who have relapsed after initial remission, other CV risk factors are still improved. So this might be the reason why we see an effect on diabetes complications despite the fact that patients relapsed into diabetes.
Q: Are there any guidelines available for the control of diabetes after bariatric surgery?
A: Most surgeons don't use any diabetes treatment at all during the first years after surgery unless they are part of a study. As diabetes relapses are seen after five to ten years, I think the clinical practice is to treat these patients. The first-line drug, as I understand it, is metformin. I don't think that there are generally accepted rules and there are no randomized studies proving how we should do this best. This certainly begs for more study.
Comment: If BMI is not an indication for the surgery and to operate on people with diabetes does not have very good results, then the main indication to operate is in people with impaired glucose tolerance.
A: I don't think that is the main conclusion. We have the best results in preventing diabetes in people with impaired glucose tolerance. I am not saying that we should not treat the diabetic patients. Even if they relapse it appears that they still avoid more diabetes complications. We have shown strong 20-year results on diabetes complications. I think we should operate on people with diabetes.
Q: You did not mention anything about safety concerns. Also can you comment on bariatric surgery’s cost-benefit?
A: We had five post-operative mortalities in the study. When we started in 1987 a lot of studies reported up to 5% post-operative mortality. We trained the surgeons heavily before they were allowed to recruit patients and that might be why we were able to keep the mortality low. On cost benefit analysis, we have some early analysis on our five — six year data. At that time, there was no cost benefit, but there was also no decreased benefit. If we repeated this study today I think we would have a cost benefit. We published a JAMA paper last year, showing that the use of medications was quite dramatically reduced as compared to the control group. More investigations must be done. It took us 13 years until we saw a significant effect on mortality so I think look at cost benefit at five, ten years is much too early.
PATHOPHSYIOLOGY OF BARIATRIC SURGERY
Ele Ferrannini, MD, PhD (University of Pisa, Pisa, Italy)
Dr. Ele Ferrannini described the pathophysiology of Roux-en-Y gastric bypass (RYGB) and biliopancreatic diversion (BPD). Detailing and comparing the two procedure’s effects, he demonstrated that BPD improves insulin resistance more so than RYGB. An ongoing trial suggests that the reason for this could be BPD’s stimulation of the secretion of bile acids. Thus, bile acids could be an interesting treatment option. Dr. Ferrannini also noted that current research suggests that the best way to determine if a person with diabetes will respond to bariatric surgery is their beta cell function – the better a person’s beta cell function the better the treatment’s effect. Dr. Ferrannini therefore echoed Dr. Lars Sjöström’s (University of Gothenburg, Gothenburg, Sweden) call for modifying the eligibility criteria to discount BMI and focus on metabolic parameters (in the case of Dr. Ferrannini specifically beta cell function).
Satellite Session: 6th CIBERDEM Annual Meeting
PREDAPS STUDY: DATA PRESENTATION
Francesc Xavier Cos, MD (Institut Catala de la Salut, Barcelona, Spain)
Dr. Francesc Xavier Cos presented baseline data from PREDAPS, a prospective, observational study being conducted of people with and without prediabetes in Spain (n=2,022). The aim of PREDAPS is to determine the risk of a person with prediabetes developing type 2 diabetes or vascular complications, and the risk factors associated with those progressions. Participants visited a participating primary care center and were between the ages of 29 and 75 years; people with and without prediabetes were enrolled (1:1). At baseline 21.5% of the 1,184 participants with prediabetes, 51.9% had prediabetes as defined by A1c and impaired fasting glucose, 26.7% only had prediabetes as defined by A1c, and 21.5% only had impaired fasting glucose. Risk factors positively associated with prediabetes included 1) age; 2) past family medical history of type 2 diabetes (particularly a maternal history); 3) past medical history of high blood pressure, dyslipidemia, or coronary heart disease; 4) gestational diabetes; 5) having offspring; 6) use of antihypertensive or lipid-lowering agents; 7) obesity; and 8) high triglycerides, fasting plasma glucose, or A1c. Risk factors negatively related with prediabetes included tobacco consumption and consumption of daily sweets. We wonder if the association of consuming sweets with not having prediabetes could be the result of people aware of their prediabetic status making lifestyle changes, including improving their diet. Unfortunately, Dr. Cos did not state what percentage of participants with prediabetes was aware of their disease status entering the trial. Dr. Cos is planning to follow the study population for ten years, though this is dependent on funding. We hope he is able to accomplish this as we think a fuller understanding of prediabetes’ pathology could help researchers develop agents to prevent the progression to type 2 diabetes. Additionally, it will be interesting to see how prevalent vascular complications are among people with prediabetes in this study.
Questions and Answers
Q: We are attending a lot of people of different ethnicities. How did you account for minority status?
A: We have not explored that yet. There is a very low rate of minorities across Spain. If we recruited minorities, we would likely find a disproportionate number of minorities in places like Barcelona. However, that would bias our overall recruiting.
Q: Don't you think that your cohort should start implementing the lifestyle protocol used in Look AHEAD?
A: Look AHEAD was also presented at ADA. To be honest, when we compare our data to other countries – it is clear that our standards are very high. Still, lifestyle is a challenge. We are also involved in the DE-PLAN project. The DE-PLAN project has obtained strong results in Catalonia. It took high-risk patients, was found to work and was cost efficient. So I think this is how we can implement lifestyle intervention in primary care. I think that doing four hours just one time and then providing reminders – like in the diabetes educator-PLAN- is reliable and doable. However, doing it with a coach is not affordable for any system.
-- by Adam Brown, Poonam Daryani, Hannah Deming, Jessica Dong, Hannah Martin, Manu Venkat, Vincent Wu, and Kelly Close