In this report, we provide our full coverage of the second annual Obesity Week, a joint effort by The Obesity Society (TOS) and American Society for Metabolic and Bariatric Surgery (ASMBS) to share the latest in obesity research, policy, and practice. The six-day conference featured presentations from key opinion leaders including Dr. Lee Kaplan (Massachusetts General Hospital, Boston, MA), Dr. Philip Schauer (Cleveland Clinic, Cleveland, OH), Dr. Donna Ryan (Pennington Biomedical Research Center, Baton Rouge, LA), and Dr. C. Ronald Kahn (Harvard Medical School, Boston, MA), on topics ranging from the future of obesity drugs to the mechanisms of metabolic surgery to the effectiveness of various public policy interventions.
In the pharmacotherapy arena, we saw exciting new data from Arena/Eisai – on glucose lowering with Belviq (lorcaserin) and on an exciting lorcaserin/phentermine combination – as well as additional SCALE data on Novo Nordisk’s Saxenda (liraglutide 3.0 mg for obesity; approved on December 23). We also heard frank commentary on the cost of the latest obesity medications and thoughts on the use of generic medications. On the whole, we heard a lot of heartening optimism regarding the prospects of obesity drugs on the market: following the hard-fought approvals of the past few years, a number of KOLs expressed confidence that drug options will become a more favored option. We did hear multiple calls for algorithms to help providers decide between different weight loss agents, especially because there appear to be discrete populations of responders and non-responders to each drug therapy approach and because providers do not have enough time during the average patient visit.
With regard to public policy, the debate continues over which interventions (calorie labeling, school nutrition programs, even a cap-and-trade approach) are likely to have the greatest impact. As several speakers noted, there is unlikely to be a silver bullet solution but rather the need for a collaborative set of various interventions as well as significant paradigm shifts in multiple sectors of society. In addition, we heard a diverse set of perspectives on the latest in bariatric surgery, from the mechanisms behind its effects on weight and glycemic control to drug therapy’s role in sustaining weight loss post-surgery. Excitingly, we had the opportunities to sit down with keynote speaker Dr. Jim Marks (Robert Wood Johnson Foundation, Princeton, NJ) as well as the head of Novo Nordisk’s new obesity research unit, Dr. Kevin Grove (Novo Nordisk, Seattle, WA) for a captivating set of interviews.
Below, we organize our comprehensive coverage into six areas: 1) Weight Loss Drugs; 2) Healthcare Delivery, Policy, and Advocacy; 3) Bariatric Surgery and Devices; 4) Additional Topics; 5) Interviews; and 6) Exhibit Hall. Titles of talks that were not published in our day-of reports are highlighted in blue while the titles of what we thought were the most notable presentations are highlighted in yellow. For our day-by-day highlights, see our reports from days #1-2, #3, #4, and #5-6.
- Executive Highlights
- Weight Loss Drugs
- Oral Presentations: Intervention & Clinical Studies – Pharmacotherapy and Metabolic Effects of Energy Imbalance
- Early Effects of Lorcaserin on Glycemic Parameters in Obese and Overweight Patients with Type 2 Diabetes Mellitus
- Additional Analyses of the Weight-Lowering Efficacy of Liraglutide 3.0 mg in Overweight and Obese Adults: The SCALE Obesity and Prediabetes Randomized Trial
- Weight Loss with Liraglutide 3.0 mg is Associated with Improved Health-Related Quality of Life (HRQoL) and Treatment Satisfaction in Overweight or Obese Adults with Type 2 Diabetes (T2D): The SCALE Diabetes Randomized, Double-Blind, Placebo-Controlled 56-week Trial
- Liraglutide 3.0 mg Reduces Body Weight and Improves Health-Related Quality of Life (HRQoL) in Overweight or Obese Adults without Diabetes: the SCALE Obesity and Prediabetes Randomized, Double-Blind, Placebo-Controlled, 56-week Trial
- Symposium: Weight Loss as Diabetes Therapy
- Symposium: Update on Pharmacology in Obesity Care
- Decision Making Regarding When, in Whom, and Considerations About Prescribing Medication
- How to Handle Side Effects: Which Medication to Choose and Off Label Usage of Medication
- Use of Medications for Pediatric Patients With Obesity
- Scientific Session: The Obesity Society Pharma Forum
- Corporate Symposium: Assessing Cornerstones for Successful Weight Loss - Building a Foundation that Really Works (Supported by Orexigen/Takeda)
- Corporate Symposium: Challenging Obesity – Patient, Provider, and Expert Perspectives on the Roles of Available and Emerging Therapies (Supported by Novo Nordisk)
- Expert Perspectives on the Management of Adult Obesity: Current Treatment Algorithms
- Expert Perspectives on Lifestyle and Pharmacological Interventions
- Future Perspectives: Potential Roles of New and Emerging Pharmacotherapies for Managing Obesity
- Panel Discussion
- Corporate Symposium: Individualizing Management of Obesity – New Strategies for Long-Term Success (Supported by Eisai)
- Oral Presentations: Intervention & Clinical Studies – Pharmacotherapy and Metabolic Effects of Energy Imbalance
- Healthcare Delivery, Policy, and Advocacy
- Keynote Speaker
- Oral Abstracts: Policy – Money Talks: How Business and Economic Policies Can Reduce Obesity
- Oral Abstracts: Population Health – Timing is Everything: Temporal Shifts in Obesity Etiology and Disparities
- Scientific Session: Exploring the Relative Impact and Effectiveness of Obesity Policies
- Reach and Relative Cost Effectiveness of Childhood Obesity Interventions and Policies
- Evaluation of New York City Obesity Policies: Large Volume Drink Ban and Supermarket Tax Credits
- Calorie Labeling: Persistent Effect of Understandable Caloric Information on Sugary Beverage Purchases
- Scientific Session: AACE Partner Session – Weight Loss Therapy of Cardiometabolic
- The AACE Obesity Care Model and a New Diagnosis of Obesity
- Natural History of Cardiometabolic Disease and Evidence-Based Approaches to Risk Stratification
- Rational Use of Weight Loss Therapy to Treat and Prevent Cardiometabolic Disease
- Panel Discussion
- Panel Discussion: Access to Care
- Symposium: Labeling Obesity As A Disease – Does This Label Help or Hurt the Cause?
- Symposium: The Obesity Society Food Industry Forum – Calorie Labeling: Who’s Paying Attention and Why
- A Historical Perspective on Calorie Labeling at FDA
- Menu Labeling in Action: Restaurant & Food Service Realities
- Potential Benefits of Calorie Labeling on Restaurant Menus
- Panel Discussion
- Corporate Symposium: Scalable Solutions to Manage Obesity and Type 2 Diabetes (Sponsored by Weight Watchers)
- Moving the Prevention of Type 2 Diabetes into the Broader Public Health: The Promise of a Commercial Weight Loss Program to Scale Prevention Efforts
- Effects on Glycemic Control and weight of the Weight Watchers Program for People with Type 2 Diabetes
- Panel Discussion
- Bariatric Surgery and Devices
- Oral Abstracts: Top Ten Papers
- Oral Abstracts: Emerging Tech & Surgical Innovations
- Oral Abstracts: Metabolic
- Pre-Conference Course: Metabolic Surgery – What is State of the Art in 2014?
- Rationale for Metabolic Surgery
- Unifying Gastric and Intestinal Mechanisms
- The Role of Microbiota
- Post-Operative Management of Diabetes
- State of the Art Medical Devices
- State of the Art Pharmacotherapy, Diet, and Lifestyle
- Going Beyond BMI
- How to Maintain Weight Loss and Diabetes Remission
- How Close Are We to a "Medical Bypass"?
- Pre-Conference Course: Fundamentals of Bariatric Surgery for Surgeons
- Pre-Conference Course: Masters in Behavioral Health – Eating and Weight Problems Pre- and Post-Bariatric Surgery
- Symposium: Basic Science of Bariatrics – Critical Update
- Additional Topics
- Keynote Speaker
- Oral Presentations: Intervention & Clinical Studies – Randomized Weight Loss Trials and Correlates of Success
- Symposium: ASMBS Integrated Health Keynote Speaker, Presidential Address & Town Hall
- Symposium: Treating T2DM – Do We Have It All Wrong?
- How Can We Close the Gap Between the True Onset of Disease and the Initiation of Treatment?
- Insulin Hypersecretion and Food Additives: Cause of Obesity and Diabetes?
- Hyperinsulinemia as the Culprit: Surgery Provides the Clues
- Exhibit Hall
Weight Loss Drugs
Oral Presentations: Intervention & Clinical Studies – Pharmacotherapy and Metabolic Effects of Energy Imbalance
Early Effects of Lorcaserin on Glycemic Parameters in Obese and Overweight Patients with Type 2 Diabetes Mellitus
Elisa Fabbrini, MD, PhD (Washington University, St. Louis, MO)
Dr. Elisa Fabbrini presented data suggesting that Arena/Eisai’s Belviq (lorcaserin) may lead to improvements in glycemic control that are independent of its effects on body weight. A post-hoc analysis of the BLOOM-DM study (n=509) found a significant improvement in fasting plasma glucose (FPG) with Belviq compared to placebo after two weeks, prior to any significant difference in weight loss between the two groups. Specifically, from a baseline of ~160 mg/dl, the Belviq group experienced an average reduction of ~27 mg/dl while the placebo group experienced an average reduction of ~15 mg/dl (p<0.001). Additionally, at week 12 (when the first A1c measurements were taken), the Belviq group had an average A1c reduction of ~1% (vs. ~0.5% with placebo; baseline of 8%) despite having lost <4% of their body weight. For comparison, the Look AHEAD trial found that an ~8.5%-9% weight loss was associated with an average A1c reduction of 0.6%. Notably, significant improvements in FPG and A1c were also seen in patients who did not achieve ≥5% weight loss with Belviq. Such data validates Eisai/Arena’s extensive investigation of Belviq’s effects in diabetes patients. We wonder if a type 2 diabetes indication might be a possibility down the road, although from recent updates (see our Arena 2Q14 report), the companies seem to be more interested in an indication for smoking cessation.
Questions and Answers
Q: You have a drug approved for diabetes that’s trying for a weight loss indication, and now you have a drug for weight loss that’s apparently trying for a diabetes indication. Are both drugs approved for those new indications?
A: Lots of drugs come out that are approved for something and then you really see the effects afterwards. Diabetes is so closely associated with obesity. It’s not approved for diabetes, just for weight loss. This was a post-hoc analysis, so it’s early to draw any definitive conclusions. For now, it’s just approved for weight loss.
Q: Did you measure glucagon?
A: No, but that’s a good point.
Q: There have been reports of a 5-HT 2c receptor on the liver. Do you think this was a result of direct action on the liver receptor or the neural connection?
A: The hypothesis in animals seems to be that it’s mediated through a receptor on POMC neurons that works on the liver through sympathetic effects, rather than through the receptors on the liver. We think it’s a central effect.
Q: You mentioned the effect on hepatic insulin sensitivity as a hypothesis. Since it’s centrally acting, there’s evidence that it might affect cravings for certain types of foods with different carbohydrate quality.
A: That’s a good point. We can’t draw a mechanistic conclusion. Data on cravings of macronutrients was not reported in the trial, but that’s another possible mechanism. There could be a selective effect on cravings. We don’t know.
Additional Analyses of the Weight-Lowering Efficacy of Liraglutide 3.0 mg in Overweight and Obese Adults: The SCALE Obesity and Prediabetes Randomized Trial
Frank Greenway, MD (Pennington Biomedical Research Center, Baton Rouge, LA)
Dr. Frank Greenway presented results from new analyses of the SCALE Obesity and Prediabetes trial, demonstrating that 92% of participants treated with Novo Nordisk’s Saxenda (liraglutide 3.0 mg for obesity) lost weight compared to 65% of the placebo group. Categorically, 63% of the Saxenda group lost at least 5% body weight (vs. 27% of the placebo group); 33% lost at least 10% (vs. 11% with placebo); and an impressive 14% lost at least 15% (vs. 4% with placebo). Dr. Greenway also presented data specifically for trial completers at 56 weeks: participants on Saxenda experienced a mean weight loss of 9.2% vs. 3.5% for those on placebo – this beats the 8% and 2.6% seen in the primary analysis. In addition, participants in all BMI subgroups (from overweight to Class III obesity) experienced similar weight loss ranging between 7.4% and 9.3%. These new analyses, which Novo Nordisk also reported in a press release, continue to strengthen the efficacy profile for Saxenda – for more background on the trial, please see our past coverage of results presentations at this year’s AACE and ICE/ENDO.
- We also heard updated numbers on the slight increase in breast neoplasms in the Saxenda group of the trial. Dr. Greenway presented data showing that for pre-malignant breast neoplasms, the Saxenda group had a rate of 0.12 events/100 patient-years (PYR) vs. 0.08 events/100 PYR in the placebo group. For malignant breast neoplasms, the Saxenda group had a rate of 0.27 events/100 PYR compared to 0.16 events/100 PYR in the placebo group. This imbalance in breast cancer events was a significant focus of the FDA Advisory Committee meeting for Saxenda in September (which ended with a 14-1 vote in favor of approval) and is also included as a warning in the drug’s label (as approved in late December) – we assume this was because the signal was relatively unexpected. During Q&A, Dr. Greenway noted that that similar results were seen in clinical trials of Orlistat and said one possible explanation for the imbalance is that women can more easily feel lumps in their breasts when they lose weight.
Questions and Answers
Q: What was the overall withdrawal rate?
A: For completers, it was about 75% of the liraglutide group and 64% of the placebo group.
Q: Were there any other doses tested?
A: No. there have been other doses tested, but not in this one trial.
Q: Regarding side effects, you said that these were similar to other studies?
A: Yeah, there were 3.0 mg studies and 1.8 mg studies against placebo in the diabetic population. The side effects we’re seeing are similar to those seen in the non-diabetic population.
Q: How are the complications of seeing lumps in the breasts due to weight loss?
A: Well this was seen in other studies where there was weight loss. It was seen in Orlistat trials years ago. One hypothesis is that when women lose weight, it’s easier to feel lumps in the breasts because a lot of that fat tissue goes away with weight loss.
Q: So there was similar percentage weight loss in all four different BMI groups – was that absolute weight loss?
A: No, those weight loss numbers were percentages. They lost similar percentages of body weight across the BMI spectrum.
Weight Loss with Liraglutide 3.0 mg is Associated with Improved Health-Related Quality of Life (HRQoL) and Treatment Satisfaction in Overweight or Obese Adults with Type 2 Diabetes (T2D): The SCALE Diabetes Randomized, Double-Blind, Placebo-Controlled 56-week Trial
Robert Kushner, MD (Northwestern University, Chicago, IL)
Dr. Robert Kushner presented data from the SCALE Diabetes trial showing improvements in health-related quality of life with Novo Nordisk’s Saxenda (liraglutide 3.0 mg for obesity). The study assessed quality of life and treatment satisfaction based on scores from two questionnaires: the Impact of Weight on Quality of Life (IWQoL) and the Diabetes Treatment Satisfaction Questionnaire status (DTSQs). After 56 weeks, the mean change in IWQoL-Lite score was an increase of 12 points with Saxenda vs. 8 points with placebo. This difference was primarily driven by a significantly greater improvement in physical function. While there was no statistically significant difference between the groups in other individual components of the score (self-esteem, sexual life, public distress, and work), the Saxenda group experienced improvements within the range typically considered clinically meaningful (7.7-12 point change). Patients treated with Saxenda also reported significantly greater improvements in treatment satisfaction: mean change in DTSQs score was an increase of ~4 points with Saxenda vs. ~2.5 points with placebo. In our eyes, such results have favorable implications for patient adherence and suggest that the need for injections with Saxenda may not be a deal-breaker for many patients, at least in light of the drug’s other benefits.
Questions and Answers
Q: You mentioned thyroid cancer and an earlier speaker mentioned breast cancer with this drug. We don’t know the mechanism, but there is concern that malignancies would take longer than a year or two to develop. Will the FDA require post-marketing studies or surveillance to address this?
A: It’s already been submitted to the FDA and gone through an Advisory Committee meeting, so we’re just waiting for the FDA. We don’t know what they’ll say. We know liraglutide is already on the market and undergoing long-term trials at 1.8 mg.
Q: With the primary purpose of investigating malignancies?
A: Among other things.
Liraglutide 3.0 mg Reduces Body Weight and Improves Health-Related Quality of Life (HRQoL) in Overweight or Obese Adults without Diabetes: the SCALE Obesity and Prediabetes Randomized, Double-Blind, Placebo-Controlled, 56-week Trial
Ken Fujioka, MD (Scripps Clinic, San Diego, CA)
Dr. Ken Fujioka presented data showing quality of life improvements, in both physical function and mental health, from the SCALE Obesity and Prediabetes trial. The three assessments used in this study were: (i) SF-36v2, a generic measure of health status; (ii) IWQoL-Lite, which looks at the impact of weight on quality of life; and (iii) TRIM-Weight, which evaluates key impacts of prescription anti-obesity medications on patient functioning and well-being. Dr. Fujioka pointed out that all domains regarding physical health from the SF-36v2 results trended in the right direction – specifically, the overall physical health score increased by ~3.7 points with Saxenda (vs. ~2 points with placebo). Similarly, the IWQoL-Lite scores for physical function, self-esteem, and sexual life all showed significant improvements (within the 7.7-12 point clinically significant range) in the Saxenda group. The TRIM-Weight results demonstrated a statistically significant improvement in weight management with Saxenda vs. placebo, while all other domains (daily life, treatment burden, experience of side effects, and psychological health) showed relatively little difference. To us, these results suggest favorable implications for patient adherence and indicate that the need for injections with Saxenda may not be a deal-breaker for many patients, at least in light of the drug’s other benefits.
Questions and Answers
Q: Do you think the nausea has any direct effect on initial weight loss? As in patients don’t eat and then lose weight.
A: I believe there is a little bit of an effect.
Comment: I have looked specifically at nausea with liraglutide. The patients who reported nausea did have slightly greater weight loss over a one-year period compared to those who didn’t report nausea. It’s not the only mechanism of weight loss.
Symposium: Weight Loss as Diabetes Therapy
Lifestyle Modification and Pharmacotherapy for Weight Loss in Adults with Type 2 Diabetes
William Yancy (Duke University, Durham, NC)
Dr. William Yancy presented data showing improvements in diabetes control with a range of medications approved to treat obesity. He pointed out that Orlistat has a greater impact on glycemic control compared to newer obesity medications, presenting clinical trial data showing a 1.2% reduction in A1c with the drug (vs. 0.2% with placebo) at 52 weeks, as well as greater improvements in pre- and post-meal plasma glucose. Orlistat, of course, has many side effects that limit its popularity outside clinical trials. Arena/Eisai’s Belviq (lorcaserin) was close behind, with a mean A1c reduction of ~1% compared to 0.5% with placebo at 52 weeks. Dr. Yancy also presented studies showing that Orexigen/Takeda’s Contrave (naltrexone/bupropion) was associated with a 0.6% A1c reduction (vs. 0.1% with placebo) and that Vivus’ Qsymia (phentermine/topiramate) was associated with a 0.4% A1c reduction (vs. 0.1% on placebo), both at 56 weeks – we know that all these branded drugs (especially the last two) have also been associated with much higher scores. In addition, Dr. Yancy pointed out that phentermine alone has not been shown in randomized, placebo-controlled trials to lead to meaningful changes in A1c or significant reductions in insulin or oral diabetes drug doses. While head-to-head trials would be needed to accurately compare the A1c-lowering efficacy of these various medications, such findings do highlight the overlap between diabetes and obesity medications and suggest that it should at least be possible to treat one condition without exacerbating the other. We hope to see more drugs indicated for both diabetes and obesity in the future; Novo Nordisk has led the way with its obesity indication for liraglutide (Saxenda [liraglutide 3.0 mg for obesity]) and we have also seen encouraging data showing improvements in glycemic control with Belviq.
Symposium: Update on Pharmacology in Obesity Care
Decision Making Regarding When, in Whom, and Considerations About Prescribing Medication
Robert Kushner, MD (Northwestern University Feinberg School of Medicine, Chicago, IL)
Dr. Robert Kushner provided an overview of the obesity drug landscape to help attendees make prescription choices deliberately, confidently, and (importantly, given the increasing time pressure on doctors) quickly. To do so, he focused on the points of differentiation between Vivus’ Qsymia (phentermine/topiramate), Arena/Eisai’s Belviq (lorcaserin), and Orexigen/Takeda’s Contrave (naltrexone/bupropion). He pointed out that cost is an issue for many patients, and that out of the three new obesity drugs Contrave appears to cost the least, with the other two being more expensive for many patients. In terms of clinical factors, Dr. Kushner noted that Contrave is the one out of the three that is not scheduled, although he doe not see that as a showstopper for Qsymia or Belviq. Comparing results from different pivotal studies, he suggested that high-dose Qsymia seems to show the strongest weight-lowering efficacy. As an aside, he remarked that completers’ analyses of weight loss trials are more relevant to patient care than intent-to-treat analyses, as it is understood that some patients will not respond to the medication. In his conclusion, he expressed desire for clear-cut algorithms that would help providers predict which patients are more likely to respond to each obesity medication.
Questions and Answers
Q: I know you said that there are no algorithms for these drugs, but what factors make you choose certain medications for certain patients?
A: Because we have no predictors for responsiveness, the way I do it is kind of unfortunate: I back into it. I take the list and process-of-eliminate it out. It can be done largely by side effect profile. I hope we get to the point where we have better predictors and markers.
Q: Do you keep patients on these drugs for maintenance of weight loss?
A: I leave patients on the medications for the long term. I don’t have this conversation in detail with patients in the beginning. If patients ask if it’s for life, I tell them that it will be for the long term, and that if it works we will keep them on it. I’ll say that if we consider taking someone off the drug, we really need to consider what we have to do to keep them at the same calorie intake without the suppression of appetite. We can use the window of medication time to focus on behavioral changes, including physical activity.
Q: As a bariatric surgeon, we get a certain amount of efficacy with bariatric surgery that often is not enough to get patients to a normal weight. Which one of these drugs might be best for that population?
A: That is an untapped and scientifically exciting area. All of us clinicians working with that population know that weight regain is devastating for these patients, because at that point they believe that there is nothing left for them. We are frankly still dabbling and gaining experience, and drug therapy in that patient population is an area that needs more deliberate investigation.
Q: Victoza in diabetes can cause mild increases in lipase, along with nausea. I discontinue the drug when that happens. When liraglutide is used at the higher dose for obesity, how prevalent are those effects, and should it be discontinued?
A: Studies have shown the elevation in lipase. When the drug was stopped, the levels came down, and it does not appear to be directly related to pancreatitis. In the latest study, there were no cases of pancreatitis at the 3.0 mg dose. You may still see higher lipase levels, but the data I see does not make me want to stop the drug. Patients can continue on the drug with slight increases in lipase.
Q: Can you describe the evidence that was used to decide that lorcaserin would be a scheduled drug?
A: I don’t know what evidence that was, actually. There is no addictive potential that I know of.
Comment: It is a new agent, the first in its class.
How to Handle Side Effects: Which Medication to Choose and Off Label Usage of Medication
Caroline Apovian, MD (Boston Medical Center, Boston, MA)
Dr. Caroline Apovian provided recommendations on how to handle the side effects of obesity medications (used both on- and off-label). Describing obesity treatment as a process of “trial and error,” she first provided background on the side effects of currently approved drugs: Arena/Eisai’s Belviq (lorcaserin), Vivus’ Qsymia (phentermine/topiramate), and Orexigen/Takeda’s Contrave (naltrexone/bupropion). She characterized Belviq as generally well-tolerated, offering modest weight loss with a relatively benign side effect profile, and explained that Qsymia’s two components help mitigate each other’s side effects, though she discouraged the use of phentermine for patients with anxiety or a history of heart disease. She also noted that the gradual step-up dosing regimens for Contrave and Qsymia generally attenuate the side effects that patients experience and endorsed the use of GLP-1 agonists and SGLT-2 inhibitors for patients with both obesity and diabetes. Dr. Apovian then offered a sneak peek at the new ENDO obesity guidelines (expected to arrive in December), which she suggested will acknowledge the off-label use of obesity medications for the many patients who lack insurance coverage for newly approved drugs. For patients in this situation, Dr. Apovian recommended a step-wise approach of prescribing generic phentermine and then adding topiramate, or vice versa. For those who cannot tolerate phentermine or topiramate, Dr. Apovian recommended trying bupropion in combination with naltrexone or zonisamide as well as liraglutide, exenatide, pramlintide, or an SGLT-2 inhibitor. Notably, she also characterized metformin as a useful option even for patients without diabetes due to its beneficial effects on body weight.
- Dr. Apovian also presented data (Munro et al., British Medical Journal 1968) showing that intermittent use of phentermine was associated with comparable weight loss relative to continuous use. In this study (n=68), patients who received phentermine 30 mg every four weeks had very similar weight loss trajectories as patients who received the drug continuously for 36 weeks. Given that generic phentermine is not approved for long-term use, Dr. Apovian suggested that intermittent use can be a viable and less expensive option for some patients.
Use of Medications for Pediatric Patients With Obesity
Aaron Kelly, PhD (University of Minnesota, Minneapolis, MN)
Dr. Aaron Kelly covered the use of obesity drugs in adolescents in a talk that, by nature, ventured far from many of the drugs’ approved labels. That point alone underscores how great an unmet need exists for better obesity drugs to be available for younger patients, given that severe pediatric obesity rates continue to rise even while overall pediatric obesity rates appear to possibly be plateauing. A key point we took away from Dr. Kelly’s talk was that the newest generation of obesity drugs – Qsymia, Belviq, Contrave, and Saxenda – will be undergoing pediatric PK and safety/efficacy studies over the coming few years, with some trials already having begun. Manufacturers of obesity and diabetes drugs often pursue these studies due to FDA requirements, as well as the opportunity provided by law for a six-month patent extension in return for the successful completion of these studies. In both obesity and diabetes, however, we wonder if these studies could be put to better use as a foundation for formal pediatric indications, rather than just fulfilling FDA safety requirements. If newer and better options are made available to severely obese pediatric patients, Dr. Kelly believes that pharmacotherapy could deliver mean weight loss in the range of 15%-20%. Read our ECO 2013 Day #4 Report for Dr. Kelly’s presentation of data on exenatide use in adolescents.
Scientific Session: The Obesity Society Pharma Forum
Early Development: Pharmacologic, Supplements, and Device Session for Up and Coming Obesity Treatments
Thomas Hughes, PhD (Zafgen, Cambridge, MA)
Zafgen CEO Dr. Thomas Hughes discussed the therapeutic potential of the company’s lead anti-obesity candidate beloranib. He presented data from a phase 2 clinical trial of beloranib, (a twice-weekly injectable methionine aminopeptidase 2 [MetAP2] inhibitor) which demonstrated significant placebo-adjusted weight loss (8-11 kg on average, depending on the dose) after 12 weeks, mediated mainly by reduced hunger and increased breakdown of adipose tissue. The drug was shown to be well tolerated at the target dose of 1.2 mg, although adverse events including sleep disturbances and GI effects were seen at higher doses. Dr. Hughes also highlighted the three ongoing trials of beloranib: (i) a phase 3 trial in Prader-Willi syndrome (a rare genetic disorder associated with obesity); (ii) a phase 2a trial for obesity associated with hypothalamic injury; and (iii) a phase 2b study in severe obesity. We continue to think Zafgen’s pursuit of specialty indications is very smart from a business and regulatory perspective and were excited to see Zafgen present at the conference, as the company looks to be a strong emerging force in the obesity market. For more background on Zafgen, please see our coverage of the company’s 3Q14 update.
- During Q&A, Dr. Hughes expressed interest in better understanding the effects of episodic treatment with beloranib, given that “this is what patients do with drugs all the time.” As we agree that lack of patient adherence can often lead to this behavior, we would be curious to see more trials investigating this treatment pattern for obesity medications in general. While we suspect efficacy would not reach the levels seen with chronic treatment, this could be a valuable option for some patients, particularly those for whom cost is a major barrier. See Dr. Caroline Apovian’s (Boston Medical Center, Boston, MA) thoughts on the intermittent use of phentermine in her presentation.
Questions and Answers
Q: What percentage of patients had adverse events and how many stopped the trial due to those events?
A: We lost very few patients at the low doses. We lost half of the patients on the top dose of 2.4 mg in the long-term study, almost all due to sleep disturbances. We saw 25% to 30% with sleep-related adverse events and a correspondingly similar number above placebo with GI effects at the top dose. At the lower doses, there was no difference from placebo; dropouts were uncommon and the side effect profiles were placebo-like.
Q: Is the hunger suppression due to increased ketones?
A: In animals, we can’t see a difference in timing. In humans, ketones go up after two weeks of treatment, which is long after hunger goes down, so we don’t think that’s driving it. The average increase is only to 400 mM, which is relatively low, so we don’t think there’s evidence for that as the mechanism.
Q: What was the maximum weight loss and was weight loss maintained long-term?
A: To get to the maximum weight loss, you have to go longer. Based on our current data, in which the longest treatment period was three months, weight loss was 11 kg on average at the top dose and 8 kg at the lower dose, though some patients lost 10 kg to 12 kg at both doses. We’ll have longer-term data from the six-month readout next year, and that trial also has a one-year endpoint.
Q: Did baseline BMI or baseline fat mass play a role in determining percent weight loss? And you said there were no abnormalities in the lab results, but more specifically, were there any findings related to liver function or bone markers?
A: We did liver function tests and saw no remarkable issues. If anything, they tend to improve a bit over time. We haven’t studied bone markers robustly but we have begun to collect data. FGF21 is thought to stimulate bone resorption, but we haven’t seen evidence of that. I’m not a huge proponent of modeling things you haven’t seen, and the results suggest that if you have weight to lose, you lose the same kilo value no matter what. It’s not BMI-dependent, and there’s no cutoff above which you don’t lose weight. Our highest BMI was in the mid 50s.
Q: When you look at the weight loss, it goes down, plateaus, and then starts to go up. If one tried a therapy washout and then started therapy again, would you eliminate the regain?
A: Those last data points were from the washout when the drug was stopped. We wanted to see whether there was a substantial rebound or continued weight loss, and this suggests a need for chronic treatment. We are interested in understanding the effects of episodic treatment. There is a paradigm from a regulatory perspective to go for that and this is what patients do with drugs all the time. I’d love to talk about that. In animals, it works quite well.
Corporate Symposium: Assessing Cornerstones for Successful Weight Loss - Building a Foundation that Really Works (Supported by Orexigen/Takeda)
Combining Efforts to Achieve Weight Loss Goals
Scott Kahan, MD, MPH (Johns Hopkins Bloomberg School of Public Health, Baltimore, MD)
Dr. Scott Kahan discussed the benefits of combining various obesity therapeutics, stressing that the combination of pharmacotherapy and lifestyle intervention has strong potential to improve outcomes. Noting that “the good news is that we now have a number of excellent pharmacotherapy options,” he provided commentary on the different obesity drugs available. He brought up the pricing advantages of Orexigen/Takeda’s newly launched Contrave (naltrexone/ bupropion), pointing out that the companies have set Contrave’s price point at no more than $70 a month (see our coverage of Contrave’s launch for more details on pricing and the drug’s savings program). In addition, during Q&A, Dr. Kahan explained that he would personally shy away from prescribing generic naltrexone in combination with bupropion for three reasons: (i) it is off-label; (ii) generic naltrexone is offered only at a 50 mg dose, which is not as well-tolerated as the 8 mg dose in Contrave; and (iii) the generic combination may not be much less expensive than Contrave. Although Contrave has not been on the market long enough to see the full impact of these pricing decisions, we always like seeing access for patients being made at least a little bit easier. In addition, Dr. Kahan noted that Vivus’ Qsymia and Arena/Eisai’s Belviq are generally well-tolerated, commenting that the forced titrations in clinical trials lead to worse side effects than what is typically observed in practice. He also expressed excitement about the greater “therapeutic leverage” in the obesity field created by the emergence of new medications, explaining that providers now have additional options if their initial choice does not work for certain patients.
Q: Is obesity-related hypoglycemia reversible?
Dr. Louis Aronne (Weill Cornell Medical College, New York, NY): Yes, it’s been cured using growth factors in animals and humans. You reduce the amount of neuronal oxidative stress and give stem cell mechanisms time to catch up. That’s why people lose their appetite when they go on diets. When you lose weight, leptin levels go down.
Q: Is the weight loss observed in new pharmacotherapies independent of lifestyle intervention?
Dr. Kahan: No, I think of them as helping the lifestyle intervention. All of the clinical studies include lifestyle intervention.
Q: What happens when patients stop weight loss medications?
Dr. Kahan: There certainly are some cases where medications help patients get off the hump. But the standard of care is that these are chronic medications, just like hypertension and diabetes.
Q: Is there any evidence for combining pharmacological agents?
Dr. Kahan: In general, no. There was recently a preliminary study on phentermine and lorcaserin for safety. But there has been no efficacy data yet. Studies are ongoing for this.
Q: What’s your view of potentially integrating pharmacotherapy with bariatric surgery?
Dr. Aronne: There are a lot of cases with this as effects wane post-surgery and adding pharmacotherapy can help. Diet has effects like medicine and many patients forget diet after surgery. Medications can help get the diet back. Look at dietary interventions as part of the whole physiological process. I believe medications should be used in bariatric surgery. In the future, I see less invasive surgical interventions along with medications.
Q: If a patient is already on naltrexone, can you just add bupropion?
Dr. Kahan: Yes, but I would personally shy away from that because: i) it is off-label; ii) generic naltrexone is only at a 50 mg dose, which isn’t well-tolerated and Contrave is at a lower dose and more well-tolerated; and iii) the only reason to do that is if it’s cheaper and with the savings program that Takeda has put together, that very well may not be the case.
Corporate Symposium: Challenging Obesity – Patient, Provider, and Expert Perspectives on the Roles of Available and Emerging Therapies (Supported by Novo Nordisk)
Expert Perspectives on the Management of Adult Obesity: Current Treatment Algorithms
Donna Ryan, MD (Pennington Biomedical Research Center, Baton Rouge, LA)
Dr. Donna Ryan discussed the efficacy providers can expect with various treatment options for obesity, including lifestyle (3% weight loss with a typical program, 8% with a more intense approach), medications (at least 10% if accompanied by lifestyle intervention), and surgery (16% with gastric band and over 30% with gastric bypass and sleeve gastrectomy). She urged providers to reserve higher-risk procedures like bariatric surgery for higher-risk patients and to use indicators of metabolic health like waist circumference in addition to BMI in order to identify patients who are at highest risk. In addition, Dr. Ryan stressed the importance of negotiating weight loss goals and treatment plans with patients, saying that providers should not discourage patients from setting ambitious goals as long as they are honest about what would be required to achieve them.
- During Q&A, Dr. Ryan called on AACE and TOS to develop algorithms for obesity medications comparable to those available for type 2 diabetes drugs. In her view, the only option for clinicians now is to steer patients away from contraindicated medications, and more standardized guidance could go a long way toward enabling physicians to practice personalized medicine.
Expert Perspectives on Lifestyle and Pharmacological Interventions
Caroline Apovian, MD (Boston Medical Center, Boston, MA)
Dr. Caroline Apovian highlighted several common elements of successful behavioral approaches to weight loss, including frequent contact with a trained professional, specific goals, use of meal replacements, self-monitoring, and physical activity. She stressed that cost is a major obstacle for many lower-income patients with regard to both behavioral interventions and access to weight loss drugs, sharing that many of her patients cannot afford to join a gym or commercial diet program, let alone afford new obesity drugs. As one possible solution, she suggested that greater use of mobile technology and internet-based interventions could potentially allow providers to reach a larger patient population, even if the efficacy is not as high as that seen with face-to-face programs.
Future Perspectives: Potential Roles of New and Emerging Pharmacotherapies for Managing Obesity
W. Timothy Garvey, MD (University of Alabama, Birmingham, AL)
In a presentation on the mechanisms, safety, and efficacy of the newest obesity medications, Dr. W. Timothy Garvey commented that the regulatory successes of Vivus’ Qsymia (phentermine/topiramate) and Arena/Eisai’s Belviq (lorcaserin) helped lead to an “explosion” of drug development in obesity by demonstrating feasible pathways for approval. As of the FDA approval of Novo Nordisk’s Saxenda, four obesity medications have been approved since 2012. While there is still a long way to go on the access front, this progress over the last few years gives us hope that the medical community is slowly moving beyond its wariness of new obesity drugs and that patients and providers will soon have a wider array of options to treat obesity. Despite this progress, Dr. Garvey highlighted several key unknowns in obesity drugs that must be clarified in future research, including (i) long-term durability; (ii) the effects of continuous vs. intermittent therapy; (iii) the efficacy and safety of combination therapy; and (iv) the proper role for weight loss medications after bariatric surgery.
Q: How do you decide which drug to use?
Dr. Donna Ryan (Pennington Biomedical Research Center, Baton Rouge, LA): We don’t have guidance like in diabetes. We need the same thing in obesity but we don’t have it. Now we just look at the contraindications, steer patients away from harmful drugs, and try to negotiate with patients. That would be a good thing for AACE and TOS to take on: developing rational approaches to using medications and how to choose medications and personalize the choice.
Dr. Timothy Garvey (University of Alabama, Birmingham, AL): I’m on it.
Dr. Caroline Apovian (Boston Medical Center, Boston, MA): We need a little data first.
Q: We use Wellbutrin XL [bupropion hydrochloride extended release] with generic naltrexone to make do, and that gets good results.
Dr. Garvey: This pertains to other combinations where the individual components are approved for other indications. I know clinicians do this. It’s hard to get the right doses in an extended release format and get the escalation right. You’re putting patients at a greater risk of side effects. And it’s off-label, so there’s some medical-legal risk. There is a lot of scientific data with these formulations and dose escalations; a lot of effort went into this. I’d advocate using approved preparations in the interest of safety.
Q: Is body weight reset? What does it depend on?
Dr. Apovian: The data suggests that body weight is reset. There’s a certain weight your body wants to be. We know with bariatric surgery, unlike with diet and exercise, patients lose weight and most stay there. They’ll lose 100 pounds and it’s as if their body reset the set point lower. Data from surgery trials suggests that it’s due to changes in the gut hormone milieu – changes in satiety hormones that you don’t see with diet and exercise. People can lose weight on diet and exercise, but afterwards, their ghrelin levels go up and they get really hungry; their PYY goes down. Hormones are challenging your weight loss efforts to get you back to the set point where your body was comfortable. With surgery, you do change the set point. Beyond that, we don’t know what else it takes to reset the set point. If we did, you’d have a cure for obesity.
Dr. Ryan: There’s lots of individual variation in metabolic adaptation. African-American women have greater degrees of adaptation, which is probably why they lose less weight. African-Americans lose less weight, and that’s not explained by adherence. There’s a lot of variation in this.
Q: What are the guidelines for stopping a drug?
Dr. Garvey: The FDA has provided an off-ramp: if you haven’t lost 5% of your body weight, then stop the medication because we don’t want patients on drugs without a certain level of benefit. The advantage of multiple drugs is you can start another one if one doesn’t work. It’s more exciting to have more tools and options.
Corporate Symposium: Individualizing Management of Obesity – New Strategies for Long-Term Success (Supported by Eisai)
Pharmacotherapy for Obesity
Ken Fujioka, MD (Scripps Clinic, San Diego, CA)
In a talk devoted mainly to an overview of the three recently approved obesity medications (Arena/Eisai’s Belviq [lorcaserin], Vivus’ Qsymia [phentermine/topiramate], and Orexigen/Takeda’s Contrave [naltrexone/bupropion]), Dr. Ken Fujioka predicted a significant expansion in the obesity drug market in the coming years. He claimed that the current state of the field has changed dramatically from as recently as five years ago, when treatment options were significantly more limited than they are today. Despite the relatively low current level of usage (as evidenced by the results of an audience poll; see below), Dr. Fujioka expressed confidence that the use of weight loss medications is on the rise, saying that the availability of more options will slowly lead to growth in the overall market. In his view, the key first step is determining which drugs are most appropriate for which patients – the current lack of guidance in this area has led Dr. Donna Ryan (Pennington Biomedical Research Center, Baton Rouge, LA) to call for the development of algorithms for obesity medications comparable to those available for type 2 diabetes drugs. Despite the promising developments in pharmacotherapy, Dr. Fujioka acknowledged that bariatric surgery “will beat any diet or medication I can give,” especially in terms of diabetes remission.
- Results from an audience survey illustrated the current gap between guidelines and clinical practice with regard to obesity pharmacotherapy. Around 50% of respondents agreed that the majority of their obesity patients were candidates for pharmacotherapy, but an overwhelming 60% responded that they prescribed obesity medications to 10% or fewer of their patients. Cost and access are one of many causes of the treatment gap, and will be key pieces of the puzzle to address before obesity drugs can really take off on a large scale.
Combination Weight Management (WM) Pharmacotherapy with Lorcaserin (LOR) and Immediate Release (IR) Phentermine (phen)
S Smith, T Garvey, F Greenway, W Soliman, S Zhou, R Fain, K Fujioka, L Aronne
This pilot study (n=238) investigated the safety and efficacy of combination therapy with lorcaserin (Arena/Eisai’s Belviq) and phentermine for 12 weeks (safety was the primary endpoint and the effect on weight management was secondary). Arena and Eisai reported topline results at the end of October, announcing that the data showed no exacerbation of adverse events with the combination and that the combination was also associated with more than double the weight loss observed with lorcaserin alone. The double-blind study randomized participants to one of three groups: (i) lorcaserin 10 mg twice daily (BID) plus two doses of immediate-release phentermine 15 mg once daily (QD); (ii) lorcaserin 10 mg BID and phentermine 15 mg BID; and (iii) lorcaserin alone, with all participants also receiving standardized diet and exercise regimens. Results showed no significant difference between the three treatment arms in the rate of serotonergic adverse events: 37% in the lorcaserin BID only group; 42% in the lorcaserin BID + phentermine QD group; and 41% in the lorcaserin BID + phentermine BID group. These adverse events included headache, dizziness, vomiting, diarrhea, nausea, fatigue, dry mouth, insomnia, and anxiety. Regarding efficacy, weight loss was significantly greater in the combination treatment groups compared to lorcaserin alone: at week 12 in the completer population, the mean weight loss was 3.8%, 7.3%, and 8.7% (from a baseline of ~105 kg [~231 lbs]) for lorcaserin BID only, lorcaserin BID + phentermine QD, and lorcaserin BID + phentermine BID, respectively.
- The incidence of treatment-emergent adverse events was similar across all three treatment groups: 64% of the lorcaserin BID only group; 67% of the lorcaserin BID + phentermine QD group; and 68% of the lorcaserin BID + phentermine BID group. The only adverse event that led to study drug discontinuation in more than one participant was headache, which occurred in two participants in each of the three treatment groups.
- There was one case of atrial fibrillation in the high-dose phentermine group, which was considered by the investigator to be related to study treatment. No further details were provided on the poster, but we expect this to be closely monitored in future studies. In addition, one case of patellofemoral arthritis and one case of appendicitis were reported in the lorcaserin BID + phentermine QD group. The combination groups also experienced slight increases in pulse rate while the lorcaserin only group experienced a slight reduction: -1.9 bpm for lorcaserin BID; 1.1 bpm for lorcaserin BID + phentermine QD; and 3.1 bpm for lorcaserin BID + phentermine BID.
- Participants in the combination groups achieved significantly greater weight loss compared to the lorcaserin only group; weight loss at 12 weeks also had not yet plateaued. At baseline, mean body weight was ~105 kg (~231 lbs) and mean BMI was ~38 kg/m2 in all groups. In the modified intent-to-treat (mITT) population, mean weight loss at week 12 was 3.3%, 6.7%, and 7.2% for lorcaserin BID, lorcaserin BID + phentermine QD, and lorcaserin BID +phentermine BID, respectively. In this same population, the percentage of participants achieving ≥5% weight loss was 28%, 59%, and 71% for the three respective groups. The percentage of trial completers achieving ≥5% weight loss was 33%, 68%, and 84% for lorcaserin BID, lorcaserin BID + phentermine QD, and lorcaserin BID +phentermine BID, respectively. Notably, weight loss at 12 weeks in the two combination groups was still on a downward slope, suggesting that average weight loss could potentially reach the level (~10%) seen with Vivus’ Qsymia (phentermine/topiramate).
- In Arena’s 3Q14 financial update, management discussed future plans based on these study results, including the possibility of taking this specific “limitation of use” out of Belviq’s label and/or looking further into pursuing a fixed-dose combination. We hope to see more on this front as we believe combination medication will be so important in the future.
Healthcare Delivery, Policy, and Advocacy
Building a Culture of Health: The Childhood Obesity Story
Jim Marks, MD, MPH (Robert Wood Johnson Foundation, Princeton, NJ)
Dr. Jim Marks delivered a well-attended keynote address on how the Robert Wood Johnson Foundation (RWJF) and its partners are “building a culture of health” to fight childhood obesity. Dr. Marks emphasized that the solution will require a multitude of approaches, commenting that “there is no silver bullet but instead a silver buckshot” and that progress will require partnerships with players outside of healthcare. He detailed recent successful efforts in New York City and Philadelphia, stressing that it is possible to bring down pediatric obesity prevalence through truly comprehensive change. Additionally, Dr. Marks discussed RWJF’s work in funding research and evaluation to build a solid evidence base for prevention, as well as the many community interventions and partnerships that the foundation supports, including the Healthy Schools Program, the Food Trust, and the Partnership for a Healthier America. He highlighted the importance of working with industry and recognizing companies when they do the right thing, applauding certain commitments from major companies including Disney and Sesame Street. In closing, Dr. Marks stressed that RWJF plans to focus on reducing disparities, drawing attention to pregnant women and young children, building public interest, and engaging more with the healthcare sector. Expressing gratitude for the opportunity to speak, he emphasized to researchers in the audience that their work will have the greatest impact if it produces sustained results with implications for a broad population.
Questions and Answers
Q: Out of the numerous initiatives at RWJF, which one would you say has the single greatest impact on prevention of obesity?
A: I’m not sure if I could name one. What we have found is thrust for policy is central to our strategy. We have seen declines occurring in multiple places. There needs to be a change in culture – it has to be in schools since that’s where kids consume a lot of their calories. But I can’t say that there is only one initiative. And I don’t want to. The natural tendency is to ask what is the silver bullet? I want to think about the bigger picture.
Q: There has been some leveling off and declining of obesity rates for children and to some extent for adults as well. People are thinking we’ve solved the problem for now. How do you overcome that false sense of security?
A: This is a central issue and we’ve seen this in public health time after time. As we recognize signs of progress and that it works, people take their foot off of the gas. But we can’t do that here. We need to get to the point where our rates were the same as those prior to the increases. Another way to think about it is to look at percentiles. 95th percentile was just the top 5% of kids, but now that’s the top 20%. We have a long way to go. But when you’re in a deep hole, you’re taught to stop digging. Keeping the pressure on is a challenge for all of us. We have new areas to emphasize more. It won’t be sustained unless we, as a nation, embrace that health is central for the chance at a good life.
Q: You’ve talked about building a culture of health and the media push to bring attention to that. But unfortunately, the media has also increased weight stigma and created a lot of negative effects for body size and shape. A lot of your interventions are aimed at childhood obesity but we’re also seeing lean children struggling with metabolic syndrome. I’m wondering if any efforts have been made to shift the conversation away from childhood obesity to one for kids of any shape and size.
A: Yes, we recognize that there is probably real risk in many different populations and the stigma makes it harder. Can we improve the emphasis on healthy weight? Maybe, but it decreases a sense of urgency. Yet we think we do need to add that to discussion. People need to make sure that there are differences in weight and they are not related to personal choice. This is why the environmental part is so important to us. We’re not sure if we know all we can do in this, but we have to make it something that everyone can be healthier in.
Q: Regarding engaging health care providers, only Medicare has recently started paying for nutritional services. But so many providers aren’t paid for it. Do you have any thoughts on working on this?
A: Yes, this is one of the real challenges for us. Overall, in 1980, we were the costliest healthcare country per capita but we were roughly tied with the second most costly. Now we are the most costly and 50% higher than any other country. The greatest challenge is the amount of disease we have – we need good surgery but more importantly, we need fewer people who need surgery. There is no question that payment reform is crucial. There has been a lot of discussion on capitated payment and there are other ways for less costly interventions. For example, the Y and its diabetes prevention program – this arrangement delivers the program at about one-fourth the cost of if it were run in the clinic. There are a whole series of financing mechanisms. For example, social impact bonds can be applied.
Q: You mentioned that the cultural change is occurring much more among whites. Other than the Philly example, we really have none for minorities. How can we deal with that disparity issue?
A: We see this as a central issue – disparities are issues that are core to our nation and we see them by race, income, and geography. We have some promising elements that we think we can look more carefully at. In schools, programs that are serving low-income populations have made more changes. This may have been because they had further to go – we don’t have that information. But the Philly story shows that you can make impact. The visibility of the First Lady in those communities also gives us hope. But we definitely need to work more.
Q: There have been several interventions made simultaneously in the pediatric population. What evidence is available to give to policymakers? In the media, we see comments going both ways in that some interventions are effective and others are not. What is the state of evidence?
A: What I hope I made the case for is the fact that these communities are seeing declines is evidence that a series of changes will make changes. I cannot say that it was one thing alone but it’s an aggregate. When we look at school programs, can schools do it? The answer was yes. It’s similar to clinical intervention. Will doctors adhere to this treatment? If they make those changes, will it affect their behaviors? The answer is yes. Now that we’ve got intervention, is it affecting physiological measures? We’ve done studies showing that most changes in schools lead to lower BMIs in kids. We have a similar kind of architecture or array of research in schools, which is where we’ve got more ability to control what’s being done. In communities, it’s all of those. If we gave everyone bariatric surgery, it would cure the epidemic. If we gave everyone counseling, it would cure the epidemic. All of those help and some help more than others. But it’s very difficult to get randomized trials in societal interventions.
Q: The USPSTF is reviewing a recommendation on childhood obesity in 2015. Is RWJF involved in that?
A: We’re not directly engaged in that. We hope the research funded through our programs can help the committee come to a decision on what’s known and what’s not known. It’s a strength of theirs to look at data dispassionately and we should respect that. But we hope they recognize the seriousness of the problem and that sometimes they will need to make decisions that do not require randomized controlled trials because it’s just not feasible.
Oral Abstracts: Policy – Money Talks: How Business and Economic Policies Can Reduce Obesity
Comparative Effectiveness of Three Policy Alternatives for REducing Added Sugar Consumption: How do Cap and Trade, Taxation of Added Sugars and Taxation of Sugar-Sweetened Beverages STack Up in Terms of Impact on Obesity and Type 2 Diabetes?
Kristina Lewis, MD (Kaiser Permanente, Atlanta, GA)
Dr. Kristina Lewis presented on a modeling study (coauthored by Dr. Sanjay Basu [Stanford University, Stanford, CA]) that compared a cap-and-trade model to reduce added sugar consumption vs. more conventional taxes on sugar-sweetened beverages (SSBs) or on added sugars, with obesity and diabetes prevention as the ultimate goal. A sugar cap-and-trade policy would specify a common threshold for added sugar for every manufacturer of food products. Manufacturers that exceed the threshold would need to purchase “sugar credits” from manufacturers that are under their quota, or would need to reformulate their foods to include less sugar. Over time, the government could reduce the quota to pressure the collective industry to reduce the added sugar content in food. Although the results of the modeling study were intriguing – a 1.7% reduction in obesity prevalence and a ~20% reduction in diabetes incidence, beating the more conventional sugar taxes – the analysis (as with many modeling studies) was built on a number of simplifications and assumptions. Dr. Lewis acknowledged that it is ultimately voter sentiment, and not analyses like these, that will be the deciding factor in selecting a large-scale approach to incentivize the production of healthier food.
Oral Abstracts: Population Health – Timing is Everything: Temporal Shifts in Obesity Etiology and Disparities
The Association between BMI and Diabetes in US Adults: Examination of Secular and Race/Ethnic Trends
Sandra Albrecht, PhD, MPH (University of North Carolina Chapel Hill, Chapel Hill, NC)
Dr. Sandra Albrecht presented data showing that out of all morbidly obese individuals (BMI >40 kg/m2) in the US, Mexican-Americans appear to have experienced the largest increase in diabetes prevalence compared to other racial/ethnic groups. Citing data from NHANES (n=12,614), she demonstrated much higher diabetes prevalence among morbidly obese people in 2007-2012 compared to 1988-1994. While this was true for all racial/ethnic groups studied (whites, blacks, and Mexican-Americans), Mexican-Americans felt the greatest impact. However, Mexican-Americans did not experience correspondingly greater increases in waist circumference, suggesting that this group may experience greater metabolic consequences at a lower waist circumference than other populations. These findings illustrate the need for further investigation of the behavioral and physiological differences among various racial/ethnic groups and suggest that the already worrisome disparities in diabetes between Mexican-Americans and whites may grow even wider if left unaddressed – see our coverage of a related Diabetes Care article to learn more.
Questions and Answers
Q: Did you adjust for waist circumference when adjusting prevalence of disease? Did that adjustment affect the disparity?
A: When I added in waist circumference, it did not get rid of the disparity in terms of race/ethnicity.
Q: Did you look at prediabetes?
A: We also looked at prediabetes. What we saw there was a little opposite of the picture with diabetes. At a lower BMI, the prediabetes prevalence was higher.
Q: When looking at the category of morbid obesity, did you adjust for BMI?
A: For within BMI categories, we looked at the mean BMI change and the mean waist circumference change. It only increased very little in relation to the waist circumference change.
Scientific Session: Exploring the Relative Impact and Effectiveness of Obesity Policies
Reach and Relative Cost Effectiveness of Childhood Obesity Interventions and Policies
Steve Gortmaker, PhD (Harvard School of Public Health, Boston, MA)
Dr. Steve Gortmaker opened the session with an introduction of the CHOICES study (Childhood Obesity Intervention Cost Effectiveness Study), which evaluates various cost-effectiveness measures for different childhood obesity interventions in the US. Specific measures include cost per BMI unit reduction and cost per 1% obesity prevalence reduction. Looking at school physical education, sugar-sweetened beverage (SSB) taxes, and bariatric surgery, Dr. Gortmaker pointed out that no single intervention can lead to even a 1% prevalence reduction, illustrating the need for a multifaceted approach. However, he noted that many preventive interventions (an SSB tax or physical education) are significantly more cost-effective than some obesity treatments, with some even leading to cost savings. For more economic analyses on obesity, please see our coverage of the McKinsey Global Institute’s report, which estimated the costs of the epidemic ($2 trillion per year!) and analyzed the impact of various interventions.
Questions and Answers
Q: We can’t really assess QALYs and DALYs in kids and BMI isn’t just BMI. Maybe it’s worth adding one more outcome to study the reduction in severe obesity prevalence?
A: We are trying to model this as best we can to see the whole distribution but the only interventions that have targeted severe obesity are treatment interventions. The data has been pretty sparse and we haven’t seen any data on SSB taxes for BMIs over 40 kg/m2.
Q: When looking at cost, how do you distinguish between fixed vs. marginal costs?
A: We are generally focusing on marginal costs. I’m assuming for fixed costs, you’re talking about how much it would cost to buy a new law. We are assuming that the program is up and running so we’re just looking at the operating costs.
Q: Regarding effectiveness, you’re modeling out to ten years? There are a lot of interventions out there and we don’t have data for ten years so you must have assumptions in your modeling. How sensitive are your estimates to those assumptions and other things?
A: For SSB taxes, we’re paying for ten years of interventions. We’re assuming that this is how consumption is going to change under that new regime and we’re assuming that it stays there. Of course, it’s ideal to have natural data. We’ve been looking at Mexico and the public health policies there. If you look at tobacco, once you implement those higher tobacco taxes, intake did drop and it was pretty much sustained and levels out. Elasticity has worn out over time or at least stayed there.
Evaluation of New York City Obesity Policies: Large Volume Drink Ban and Supermarket Tax Credits
Brian Elbel, PhD, MPH (NYU School of Medicine, New York, NY)
Dr. Brian Elbel followed with a bit of a reality check, stressing that as obesity and policy research is still in its infancy, many interventions (and attempts to study them) will disappointingly fail early on. For example, research on the effectiveness of New York City’s large-volume drink ban was terminated early because the ban was overturned soon after implementation. In another case, a study found that the opening of a new supermarket with support from tax credits did not lead to significant changes in household food availability or consumption, with less than one-third of local residents even noticing that the supermarket had opened. While these examples illustrate how far this research has to go, Dr. Elbel urged the audience not to be discouraged, as he believes there is still significant potential for a strong return on investment in this area of research.
Questions and Answers
Q: I have confirmation on your findings from the new supermarket. I was talking with someone from Harvard Business School and he had opened ten new beautiful stores in food deserts and carefully monitored what people were purchasing. They ended up purchasing the same stuff and your findings are consistent with that. The question is what would happen with longer periods of time.
A: Thank you, that’s a good point and yes, we’re excited to look at longer periods of time.
Q: You have a great story – you should publish this. I drive three miles to a grocery store and if there was a brand new supermarket, I would probably still go to my local loyal store. How much of a cultural influence like this do you think impacts change?
A: There is a certain perception that if you build it, they will come. There wasn’t really any educational rollout with this store. So we could do that and break through some of those barriers and forces of habit. It would be interesting to think about how this might work in a different scenario.
Calorie Labeling: Persistent Effect of Understandable Caloric Information on Sugary Beverage Purchases
Sara Bleich, PhD (Johns Hopkins Bloomberg School of Public Health, Baltimore, MD)
Dr. Sara Bleich presented more optimistic data on obesity interventions, sharing study results demonstrating that incorporation of more understandable information on SSBs’ calorie content into nutrition labels led to changes in purchasing behavior among black adolescents. Specifically, her team posted signs equating the calorie content to an equivalent amount of exercise (e.g. “this soda is equal to 50 minutes of running”) in corner stores throughout Baltimore and consequently, adolescents purchased fewer sugar-sweetened beverages and more water and diet soda (while this is generally a positive trend, some recent evidence challenges the common perception of diet soda as a healthier alternative to SSBs). We especially loved the idea of Dr. Bleich’s “dream,” represented in this artistic rendering in The Atlantic, in which all calorie labeling includes more understandable information for consumers. We agree that the issue of relatability is too often overlooked by public health officials and that translating the science into information that is accessible to the public will be absolutely critical in the fight against obesity.
Questions and Answers
Q: Did you see corresponding increases in buying water and diet beverages? Did you look at other things they bought like snacks or fruits?
A: We saw switching – we were seeing more purchasing of diet sodas and water. In terms of purchasing behavior for other things, that’s our next study.
Q: Did you see any preconceived notions of the healthfulness of diet sodas? I’ve personally been feeling conflicted about this.
A: The most interesting thing they said was, “diet sodas are disgusting,” but they have also never tried it. So interestingly, they had strong views about taste but not about health.
Q: Were there differences between people who came in with peers vs. those who came in alone? Peer pressure could be a huge factor.
A: I only have anecdotal evidence that with groups, there would be a lot more murmur about the signs. But we didn’t measure this and we should next time.
Q: Did you see migration of soft drinks to high-energy drinks like Red Bull or Monster?
A: Yes, we did actually. And that’s not a good thing, as kids don’t understand that these beverages are also unhealthy.
Q: All your stores were intervention stores and the interventions all looked like they had about the same effects. What happened in stores that you weren’t able to intervene in? Do you have any outcomes data on stores that said “no way” to the study?
A: We didn’t collect that information. In our next store study, we will have full proper controls.
Scientific Session: AACE Partner Session – Weight Loss Therapy of Cardiometabolic
The AACE Obesity Care Model and a New Diagnosis of Obesity
Jeffrey Mechanick, MD (Mount Sinai Hospital, New York, NY)
In his talk on the new AACE/ACE framework for obesity management, Dr. Jeffrey Mechanick stressed the need for a significant paradigm shift and for greater urgency in how the healthcare community approaches obesity – as he frankly put it, “our current framework is failing us.” He argued that the field must transition from a BMI-centric approach that assumes a linear relationship between caloric intake and obesity to a more complications-centric, chronic disease model that takes into account the many complex underlying causes (we see Dr. Arya Sharma’s [University of Alberta, Edmonton, Canada] as an example of this). Dr. Mechanick also suggested that one factor contributing to poor reimbursement for obesity therapies may be a perceived lack of demand. He noted that discussions at the AACE/ACE Consensus Conference on Obesity in March showed a clear disparity between providers’ and payers’ beliefs regarding reimbursement. During the conference, a number of providers pointed to the need for better reimbursement as one of the most vexing challenges in caring for patients with obesity; when insurance industry representatives were asked why reimbursement was not a higher priority, their response was that “nobody’s asked for this.” We see this as a perfect illustration of the need for more effective communication between the various stakeholders in the healthcare system, the utility of patient advocacy, as well as a wider understanding of the urgency of the obesity epidemic.
Natural History of Cardiometabolic Disease and Evidence-Based Approaches to Risk Stratification
W. Timothy Garvey, MD (University of Alabama, Birmingham, AL)
Dr. W. Timothy Garvey attempted to unravel the complex relationship between obesity and metabolic dysfunction, saying that while there are clear epidemiological and clinical links between obesity and type 2 diabetes, the pathophysiological relationship is less well understood. He focused on insulin resistance as the key risk factor for progression to metabolic syndrome, type 2 diabetes, and cardiovascular disease, stressing that while obesity is a contributing factor, it is not perfectly correlated with insulin resistance. He highlighted visceral fat and adiponectin as two potentially useful indicators of metabolic risk in obese patients. He emphasized that while biomechanical complications of obesity should not be overlooked, “ it is the presence or absence of metabolic syndrome that determines survival and cardiovascular risk, not obesity.” Therefore, given limited healthcare resources and skyrocketing obesity rates, Dr. Garvey urged providers to focus on metabolic risk factors as a way of directing treatment toward patients who are likely to derive the most benefit.
Rational Use of Weight Loss Therapy to Treat and Prevent Cardiometabolic Disease
W. Timothy Garvey, MD (University of Alabama, Birmingham, AL)
Dr. W. Timothy Garvey discussed the best approaches for reducing cardiometabolic risk in obese patients, stressing that “weight loss works no matter how it is achieved.” He presented evidence that weight loss achieved via lifestyle intervention, medication, or bariatric surgery can lead to favorable changes in glycemia and other risk factors, and he urged providers to make weight loss a greater priority for type 2 diabetes patients, as it can often be more effective than adding another diabetes medication. He cautioned against automatically jumping to the conclusion that bariatric surgery is the most effective way to achieve remission of type 2 diabetes: discussing results from the STAMPEDE trial, which showed significantly higher rates of diabetes remission with surgery compared to intensive medical therapy, he argued that many of his colleagues could have achieved the same results with a sufficiently aggressive pharmacological approach. Dr. Garvey also said he would like to see a trial evaluating the effects of bariatric surgery vs. medication-assisted weight loss (specifically with obesity pharmacotherapies) to help clarify whether some factor unique to bariatric surgery leads to such impressive improvements in glycemic control or whether significant weight loss accomplished by other means could lead to the same results.
Q: I’m a surgeon and I’d like to know 10% weight loss from what baseline? If you have a patient with a BMI of 50 kg/m2, is 10% weight loss enough to prevent diabetes?
Dr. W. Timothy Garvey (University of Alabama, Birmingham, AL): In studies there have been stratified analyses by initial BMI. 10% body weight loss does as much to prevent diabetes in people with a baseline BMI of 29 kg/m2 as 39 kg/m2 and 40-45 kg/m2. Just because BMI is high doesn’t mean you shouldn’t aim for 10%. In the range of 50 kg/m2 there’s not too much data, but in the lower 40s down, 10% loss gets you the same kind of benefits regardless of initial BMI. Do you have information on high BMI patients? Should we aim for more?
Comment: No, I’d like to know.
Q: Adiponectin is made exclusively by adipose tissue. Why do patients with visceral adiposity and complications have lower adiponectin?
A: When fat cells are insulin resistant, they produce less. We don’t know what’s regulating that, but they make less adiponectin. It’s not known why.
Q: I understand that with an individual patient I’ll use my judgment and treat more aggressively if I need to. These are great guidelines but compared to the Edmonton staging system it seems like this doesn’t take a holistic approach. It focuses only on metabolic comorbidities. I could have a patient with severe sleep apnea and joint pain who may need more aggressive treatment.
Dr. Jeffrey Mechanick (Mount Sinai Hospital, New York, NY): This is not a purely metabolic survey of complications. The checklist includes biomechanical and other complications. You do bring up a good point. What is metabolically healthy? Does this entity really exist? You may not manifest features of insulin resistance or metabolic syndrome but having excessive adiposity you do have biomechanical complications and behavioral and other complications. You’re probably not healthy with increased weight and adiposity, even if you lack features of insulin resistance. The bottom line is that we need to clarify with metrics and composite scores to gauge risk – that’s the purpose of moving away from BMI.
Q: The more extensive criteria include the impact on mental health?
Dr. Mechanick: Yes, it includes psychosocial, behavioral, stigma, gallbladder, sleep apnea.
Dr. Garvey: It’s an advance framework because we’re still getting feedback. We need something to resonate across the spectrum to get concerted action. It’s a framework, not a done deal. We’ve gotten that suggestion from lots of sources, that it’s too metabolic. We’ve taking that to heart. Feeling and function is the realm of clinical judgment. It’s hard to quantify these things. Is there solid data that weight loss improves things like depression and poor self-image? The data is not solid in a lot of areas. It’s hard to write guidelines that address them. Some things you have to leave to clinical judgment to decide whether those are valid to justify aggressive therapy. Let us know if you have suggestions for how to incorporate them.
Q: Obesity stage two starts with a BMI >25 kg/m2?
Dr. Garvey: We felt that if you are overweight or obese with complications, that degree of adiposity is adversely affecting your health.
Q: The guidelines showed you can consider bariatric surgery in stage two. That means it could be indicated for someone with a BMI of 25 kg/m2?
Dr. Garvey: Other guidelines are superimposed over this. I would say no. I would follow the AACE/TOS/ASMBS guidelines. I would say no, but someone with a BMI of 28 kg/m2 and severe complications can benefit from aggressive weight loss.
Dr. Mechanick: I get the point. There are some inconsistencies. You’ve interpreted the guidelines correctly. Someone could have excess fat so their BMI is abnormally high, say 25.1 kg/m2, and say that they had extremely severe diabetes – an A1c of 13% that was recalcitrant to every intervention. You know they’re going to get sicker and sicker. There is a premise that weight loss will help. There’s also evidence in the surgery literature that if you really go into the studies, it’s a mixed population. They’re trying to capture just obese patients, but some are contaminated by those who were not obese but treated with surgery and derived some benefit. It’s not as low as 25 kg/m2, and it’s mostly Asian patients where the BMI is shifted down. Yes, you’re correct. It’s an advance framework, and we have latitude to push the envelope, to change the way we think. We need to think within a preventive care paradigm, not just a tertiary one. With an A1c of 13% you’d better hurry up, should you just wait until the weight goes up and you trigger some cutoff where bariatric surgery gets reimbursed? The final form will be no, surgery will not be recommended for someone with a BMI of 25.1 kg/m2, contrary to what a lot of surgeons feel. But I think maybe in some cases, it’s a possibility.
The goal is to stimulate the thought process. The next step may not be where we are in ten years, but we need to move closer to bending the curve. Being too tame has not worked to our advantage. This is a national security issue, in terms of having a healthy army, and it’s an economic issue. Some countries will not be able to afford to take care of this problem. India can’t afford to take care of it, so they’ll have greater unemployment, greater poverty, and greater sickness. This country can’t afford to take care of it, especially in terms of racial disparities and the pediatric and super obese getting worse.
Panel Discussion: Access to Care
ACA Update: The Future of the Health Insurance Exchange
Chris Gallagher (Obesity Action Coalition, Tampa, FL)
Mr. Chris Gallagher opened the panel discussion by expressing frustration with obesity discrimination in various state health insurance exchanges, explaining that neither the US Department of Health and Human Services (HHS) nor state policymakers have been willing to address the issues. However, he did characterize the Office of Personnel Management’s guidance encouraging insurance carriers for federal employees to cover obesity services as “one good victory.” Specifically, the guidance emphasized that obesity treatment is not cosmetic and that the condition does not stem from a lack of willpower. We applaud the Office of Personnel Management for putting this message forward and hope to see similar guidance extended to state health insurance exchanges in the future.
A Decade of Obesity Treatment Advocacy: Lessons Learned From Success and Failure
Henry Alder (Ethicon, Cincinnati, OH)
Mr. Henry Alder spoke about the process of advocacy itself, providing advice from his experience working with payers. He encouraged advocates to work with employers, as they have quite a bit of leverage when it comes to establishing coverage policies. In addition, he emphasized the importance of having as much evidence as possible (as policymakers and payers can come in with preconceived notions) and treating payers as allies rather than adversaries. Several speakers throughout the session also compared the advocacy work surrounding the coverage of obesity treatment today to that of mental illness in the past. We certainly applaud the advocacy work discussed in this session, and we hope that these efforts along with an expanding obesity pharmacotherapy market will push payers to see increasingly more value in obesity treatment.
Symposium: Labeling Obesity As A Disease – Does This Label Help or Hurt the Cause?
Obesity Should Be Labeled as a Disease
Richard Atkinson, MD (Obetech Obesity Research Center, Richmond, VA)
Dr. Richard Atkinson argued that defining obesity as a disease is essential in order to shift to a new treatment paradigm that is more effective than the “ancient flawed belief system” that currently dominates the field. He explained that obesity is a biological problem that involves an organ (adipose tissue) with multiple etiologies. Considering the numerous genes contributing to obesity, he stated that, “no two people on earth have the same type of obesity.” Additionally, he stressed that obesity almost invariably leads to complications. He harshly called out the medical establishment for its “encyclopedic ignorance” about obesity, saying that there is overwhelming evidence that diet and exercise do not work for the vast majority of patients and that much more effort is needed to understand the complex causes of obesity and develop more effective treatments. He argued that labeling obesity as a disease will be crucial for combating the pervasive prejudice against the condition – see a presentation by Dr. Rebecca Puhl (Yale Rudd Center for Food Policy and Obesity, New Haven, CT) on the topic of providers stigmatizing obesity – and enabling greater respect (and funding) for the field within the research community.
Obesity Should Not Be Labeled as a Disease
Adam Tsai, MD (University of Colorado, Anschutz, CO)
Dr. Adam Tsai, assigned to argue the opposing view that labeling obesity as a disease hurts the cause, opened his presentation by saying that obesity is sometimes but not always a disease. He provided arguments of the financial cost of a disease classification and the potential for “disease mongering” leading to over-marketing of drugs. In addition, Dr. Tsai discussed the psychological impact of the word “disease,” presenting findings from various studies showing that some people can feel less empowered once told they have a disease. He urged the field to be aware of these potential disadvantages even though many agree that the benefits of classifying obesity as a disease outweigh the risks. Concluding, Dr. Tsai suggested that providers should encourage patients to always maximize their health behaviors, to ensure that the disease label is not used as an excuse for poor adherence and to make sure that this label does not exacerbate harmful weight stigma.
Q: We’ve shown that in the National Weight Control Registry, people who succeed have received a medical trigger for weight loss. Relabeling it from a disease to a disorder won’t change how people see it. There are stereotypes that come with it like laziness. Continuing to call it a disease speaks to the fact that it is not a choice. It happens, for reasons you’ve spoken to.
Dr. Adam Tsai (University of Colorado, Denver, CO): We all agree that there’s a strong genetic predisposition, but the number ranges from 30% to 60%-70% in systematic reviews. If it’s in the middle, then it’s 50%, which means it’s still 50% lifestyle.
Dr. Richard Atkinson (Obetech Obesity Research Center, Richmond, VA): Weight is under voluntary control for short periods of time. If you voluntarily try to reduce your breathing rate from about 15 times per minute to 10 times per minute, you can do that with no problems, but not long term. Your body's physiology will return your breathing to baseline, and obesity acts just like that to return your body weight to baseline. For those who don't consider obesity a disease, adenovirus 36 is a respiratory virus that causes obesity. If I am infected with Adv36 and sneeze on you, then you catch obesity. How is that not a disease? Some of the etiologies of obesity clearly are "diseases."
Q: The existence of obesity as a disease was proposed by multiple sources before the last couple of years. Why is this a conversation we’re having now? If it’s already classified as a disease, what is the consequence for either argument?
Dr. Tsai: We’re discussing it again because the AMA is perceived as the face of organized medicine. I’m not a member, but I think the perception is if the AMA supports the classification, it will lead to better reimbursement, more research, etc.
Dr. Atkinson: When I was asked to do this, I thought, oh my god, at The Obesity Society, we’re still trying to decide? I was appalled.
Q: In your experience in America, has classifying it as a disease helped anecdotally or not? There are potential benefits, but there’s a political risk that politicians have ticked the care box and think that’s all you need to do and not do prevention.
Dr. Atkinson: Politicians will do what is easy. Laws with little scientific evidence about obesity do not improve the health of obese people. If politicians can be educated rather than just "tick off the box", we may be able to convince them to put more money into basic research and better treatments will be developed.
Dr. Tsai: You asked if anything’s changed. I don’t think public perception has. Opinions are still all over the map. The memory of the American public is very short.
Q: The closest analogy I can see is hypercholesterolemia in Australia is not considered a disease but there are a lot of similarities. What’s your view on that?
Dr. Tsai: It’s not considered a disease in Australia? Do doctors get reimbursed for prescribing medications?
Q: It’s considered a risk factor. I think hypercholesterolemia and obesity are similar.
Dr. Atkinson: One thing in the paper from the Obesity Society (Obesity 2008 Jun;16(6):1161-77) about calling obesity a disease was the problem of definition of disease. Many conditions such as diabetes and hypertension are considered diseases, but under the definition that was being used for obesity, none of these are diseases. That’s why they ended up giving a wishy-washy definition of obesity as a disease because it’s so hard to define “disease.” In my opinion, it comes back to defining diseases as abnormalities of organ systems. Excess fat is an abnormality of the adipose organ and should be defined as a disease.
Symposium: The Obesity Society Food Industry Forum – Calorie Labeling: Who’s Paying Attention and Why
A Historical Perspective on Calorie Labeling at FDA
Geraldine June (EAS Consulting Group, Alexandria, VA)
Ms. Geraldine June reviewed the history of FDA nutrition labeling requirements and discussed the most recent proposed label guidelines that should be implemented this year, almost a decade (!) after the FDA first sought public input on the issue. Among other changes, the new label will more prominently feature the calorie content and number of servings in each food item and will include a category for added sugars. Ms. June also addressed the new menu labeling regulations mandated by the Affordable Care Act – these will require restaurants and “similar establishments” to list the calorie content of each menu item adjacent to its name and provide statements about suggested daily caloric intake and the availability of additional nutrition information. As a reminder, the FDA recently finalized its calorie labeling guidelines after sorting through over 1,000 public comments since 2011. During Q&A, Ms. June also questioned the effectiveness of “traffic light” labeling systems that mark products as good (green), bad (red), or neutral (yellow), suggesting that they might be too simplistic and fail to account for consumers’ individual needs. We certainly believe that the presentation of nutrition information must take into account health literacy issues, but agree that a delicate balance between simplicity and utility must be achieved.
Questions and Answers
Q: When is the FDA going to enact calorie labeling?
A: The law could’ve been enforced when it was signed, but the FDA thought it was important to propose finalized regulations. There are lots of controversial issues: should calorie labeling be in grocery stores? Should it apply to alcoholic beverages? The FDA has to wade through comments and issue final recommendations. It doesn’t publicize when it will finalize them until it’s ready. When the regulations are finalized, it will get a lot of press. I don’t have any information that they’re not going to finalize them in this administration, but I don’t know. (See our coverage of the FDA finalization of calorie labeling rules in early December for these answers)
Q: Was there a reason that percent daily values were not required for sugar and protein?
A: There is no recommended daily value for sugar.
Q: In the UK, we have a traffic light system. That might make things clearer, so why not do that?
A: The FDA would need to do consumer research in this country. There’s some concern about the good food/bad food concept. What consumers need to eat depends on the individual. With the GMA (Grocery Manufacturers Association) system, it’s important to highlight certain nutrients of public health concern, including calories. It’s a matter of what gives the most information, and you always have to see if the label information is misleading.
Menu Labeling in Action: Restaurant & Food Service Realities
Deanne Brandstetter, MBA, RD (Compass Group North America, Charlotte, NC)
Foodservice industry representative Ms. Deanne Brandstetter discussed several practical challenges involved in implementing menu labeling requirements, including enormous variability in the calorie content of restaurant meals, high turnover among staff, and an increase in customizable menu options. She also presented results of focus group surveys evaluating consumers’ preferences about how nutritional information is communicated; not surprisingly, people generally preferred simple, positive messages that did not come across as preachy (of course, this sort of survey does not answer the question of what impact various messages have on actual consumer behavior). Ms. Brandstetter also suggested that the most meaningful impact of menu labeling requirements may be their influence on industry rather than on consumers, as such transparency can push industry to provide healthier choices to consumers. As one example, Ms. Brandstetter cited similar efforts by the Culinary Institute of America that have led many restaurant chains to reduce the calorie and sodium content of their menu items and offer more fruits and vegetables.
Questions and Answers
Q: How do you think cultural factors come into play here? We’ve done research with different groups and found that different cultures respond very differently to the same message. Some people welcome a big stop sign but other people are offended. Do you have any sense of that?
A: I honestly can’t say. The focus groups were a representative sample of customers at those restaurants but they may not be representative of others. That’s one of the challenges; there’s such a huge spectrum.
Potential Benefits of Calorie Labeling on Restaurant Menus
Christina Roberto, PhD (Harvard School of Public Health, Boston, MA)
In response to the widespread perception that calorie labeling on restaurant menus has been proven ineffective, Dr. Christina Roberto argued that the existing (and fairly limited) body of research on the topic is essentially mixed. She explained that some studies show no effect of such labels on customers’ caloric intake and others show a slight positive impact. Dr. Roberto noted that more long-term data will be needed once menu labeling is implemented nationally to assess its overall effect, and she echoed Ms. Deanne Brandstetter’s (Compass Group North America, Charlotte, NC; see above) suggestion that the policies could have an important impact on public health via their influence on industry even if they ultimately do not change consumer behavior. Dr. Roberto also argued that nutrition labels in their current form are too “clunky” and endorsed the use of formats like traffic lights (green = good; yellow = neutral; red = bad) or exercise equivalents (how much exercise would be required to burn off the number of calories in the product; see Dr. Sara Bleich’s [Johns Hopkins Bloomberg School of Public Health, Baltimore, MD] presentation on this method) to more effectively communicate information to consumers. Despite the many limitations and unanswered questions in this area, Dr. Roberto believes the evidence thus far is promising enough to make menu labeling policies worth pursuing; as she summed it up in her final slide, “positive + neutral = why not?” However, several attendees disagreed during Q&A, saying that such an enormous investment of resources is not warranted for a policy that has not been shown to lead to weight loss or other clinically significant benefits.
Questions and Answers
Q: There’s been lots of opposition to the traffic light labeling system. It’s a double-edged sword with calorie labeling. As a professor of nutrition, I can tell you that university students understand calories but they don’t understand nutrient density. We did a study that found a correlation between depression and nutrient intake. When we switched to a nutrient-dense approach, it changed people’s food choices and their mental health. I think it would be great to have a traffic light or something that identifies the whole picture. How do we move to that?
A: It’s really hard. I’m studying calorie labeling because that’s what we’re doing. We take small steps in public health, and calorie labeling is a good starting point with less opposition. Other countries do traffic lights, but a lot of it is voluntary. We need data, but it’ll be a political issue as well as a scientific one.
Q: In the calorie labeling studies where the control city is different from the treatment city and you report a decreased calorie intake, does that mean it was significantly lower in the treatment city vs. the control city? If so, do you know if the treatment city had a lower calorie intake to begin with?
Dr. Christina Roberto (Harvard School of Public Health, Boston, MA): A significant decrease means we saw a downturn in the treatment city. We look at the difference in the difference and try to account for a difference at the start. We’re looking at the changes.
Q: So they do look at the treatment city before calorie labeling started?
Dr. Roberto: Yes, exactly.
Q: If the control city started lower, they might not have as much room to go down?
Dr. Roberto: In New York City, one city was a bit lower and went up; in Philadelphia, it was higher and went down, but not in ways that were meaningful. The picture is mixed across studies.
Q: You mentioned one study where they followed up by phone to see if labeling decreased the frequency of people’s visits to restaurants. What was the outcome of that?
Dr. Roberto: There was no impact.
Q: I applaud you for the study design that included a follow-up on food intake later in the day. It doesn’t matter if we don’t know whether people compensate. We need more data on this. You said positive + neutral = why not? I say we have lots to figure out, so why move forward without more data?
Ms. Sylvia Rowe (SR Strategy, Washington, DC): All three presentations pointed to the importance of understanding the consumer.
Q: Is there any individual-level information on whether the people using the information are the people who would benefit most? Are people who are overweight or at risk using the information, or is it preaching to the choir?
Dr. Roberto: A lot of the studies look at subsets, and there is a bit of that. People who are more inclined to look at nutrition facts are more inclined to look at menu labeling. Other systems like traffic lights in a cafeteria seem to affect a broader swath.
Q: Is it clinically meaningful? We need to ask that question with supplements and certainly with this area. What is clinically meaningful?
Dr. Roberto: There was a paper published on quantifying the energy gap, trying to figure out what it would take to reverse obesity. If we wanted to make progress for a kid, something like a can of soda a day less would be meaningful. I’m a clinician; I have this conversation every day. People are blown away by a 2,000-calorie pizza. That concept resonates with them. For the patients I work with, most like labeling.
Q: We need more fine tuning on the meaning of “works.” We’re going to an extraordinary effort to maintain healthy weight and reduce the weight of people who are obese. I heard nothing about weight. Is there any data showing a change in weight? It seems like that should be the primary endpoint. People lie; good scales don’t lie. You can have all the suppositions in the world, but finding out is better.
Dr. Roberto: There are people doing studies with weight data. That part of the trajectory of labeling is being introduced.
Q: Is this a preventive strategy or a treatment strategy? Who are you targeting?
Ms. Deanne Brandstetter (Compass Group North America, Charlotte, NC): It’s the consumer’s right to know and consumer demand. We’re doing it as a company even though we may not be subject to the regulations because there’s consumer demand.
Q: What is the potential effect? Are you trying to improve the health of the country or just informing people?
Dr. Roberto: I think it’s both. At a minimum, people have a right to know. If you’re against labeling, do you think we shouldn’t have nutrition facts? It’s in the same spirit. In the public health community, of course, we hope that it goes beyond that and has a health impact.
Ms. Geraldine June (EAS Consulting Group, Alexandria, VA): The information is needed for consumers. People grossly underestimate the number of calories in food. We need to give them the information they’re demanding to improve their health.
Ms. Rowe: The key question is whether there’s a gap between knowledge and behavior or whether we can’t effectively convey knowledge.
Q: Who is this reaching? There’s evidence that the current strategy is less likely to be effective with people with lower incomes and higher risk. There’s a risk that we’ll leave behind the people who need the information most. There are other ways to communicate information – traffic lights, other educational campaigns. How do you consider that?
Ms. Brandstetter: There are definite settings in which it doesn’t seem to have an impact and we need to use other strategies. The best example is blue-collar manufacturing workers. They just don’t see it. We use more silent health tactics there, or stealth health (we’re not allowed to say that anymore) to pull them along.
Dr. Roberto: With any labeling effort, there’s not a single person who would say that this is the solution. We need to think about it in the context of other interventions. Maybe there’s not a direct link between labeling and weight but there might be with labeling along with five other interventions. It’s part of a bigger picture.
Q: It’s great to change behavior but the greatest impact will come from changing industry. Since 2009 when labeling was researched and enacted, has there been a reduction in calories offered?
Ms. Brandstetter: I can’t cite specific studies but I think some show that. The Culinary Institute of America’s R&D Collaborative involved the top 40 restaurant chains working on actionable stuff. As a result of that group, we’ve seen a significant decrease in calories on the menus of people who participated, along with an increase in fruit and vegetables and a decrease in sodium. Our goal now is to act as a springboard and get the rest of the industry to follow.
Dr. Roberto: There was a paper showing a reduction in calories of 12% in food chains. It’s hard to attribute that to menu labeling but there’s a hint of an effect.
Q: I’m glad you mentioned variability. We quantify calories in restaurants and we see giant variability. These are challenges that need to be explained but have you been successful in reducing the variability?
Ms. Brandstetter: On package labels, a variability factor of 20% is allowed. When you look at restaurants, where the meal is being prepared by a person, you would expect more variability than in packaged food. There will be a lot of variability if you want a hand-crafted meal. Variability will never leave the system. It’s how we teach people how to use calories. It’s not an absolute number, but you can compare it to other dishes or other restaurants.
Q: I’ve worked for fast food restaurants, and I appreciate your sample menu showing tremendous variation not even in the preparation but in calculated calories. Do you report calories for plain pizza, extra cheese, pepperoni? How do you amplify it? How do we make that meaningful? A single number won’t accurately reflect the situation, but people want a simple system.
Ms. Brandstetter: Technology will play a big part. Online ordering with customization or kiosk ordering allows you to build a custom item and it tallies the calories and gives you the option of saying at the end that you want something else. That will play a role in helping customers be more accurate and providing meaningful information.
Ms. June: That illustrates the difficulty in implementing the requirements. There’s variability, and the law tried to envision the difficulty by exempting certain things. The FDA has to struggle trying to figure out the best way to provide information and give consumers data showing which number is most helpful.
Q: You keep talking about hope, saying we hope that these things will improve health. The issue the pharmaceutical industry ran into is that we were gung ho until we looked at adverse events. There were negative effects and unintended health consequences. Hedonic messaging can result in people consuming more hedonic food, thinking that they can overcome the negative impact on health. People overeat things that they assume are healthy because of the stoplight labeling. There are potential unintended consequences. How do we know we’re not doing harm when we myopically look at a single goal?
Dr. Roberto: I disagree. People are aware that things can backfire. I was focused on calorie labeling.
Q: Even with the study you cited, men ate more calories after labeling.
Dr. Roberto: One open question is whether adolescents will eat more. Adolescent boys eat more across the board, but the majority of studies show that most people don’t eat more calories, with maybe a few exceptions.
Q: Most of these studies are on fast food and sit-down restaurants. There are lots of all-you-can-eat buffet restaurants, where there’s no restriction on how much you can eat and lots of sensory stimulation. Have there been any studies on labeling those foods and seeing if people eat less because of the label?
Dr. Roberto: I haven’t seen a buffet restaurant one, but cafeteria studies mimic that. I would imagine that is the case, and there are positive studies from that setting.
Corporate Symposium: Scalable Solutions to Manage Obesity and Type 2 Diabetes (Sponsored by Weight Watchers)
Moving the Prevention of Type 2 Diabetes into the Broader Public Health: The Promise of a Commercial Weight Loss Program to Scale Prevention Efforts
David Marrero, PhD (Indiana University, Indianapolis, IN)
Dr. David Marrero argued that in order to have a large-scale impact, diabetes prevention efforts must be implemented through broadly accessible and scalable programs. He explained that while the Diabetes Prevention Program (DPP) produced impressive results in a clinical trial setting (~6% weight loss and 58% reduced risk of progression to type 2 diabetes), scalability remains a major challenge. Even with implementation efforts from the YMCA and the National DPP, the program is currently offered in only ~2,000 locations nationwide. On the other hand, Dr. Marrero highlighted that Weight Watchers offers a lifestyle intervention program based on very similar principles to the DPP, which has delivered mean weight loss of ~6% and A1c reductions in clinical trials with prediabetes patients. In comparison to the YMCA DPP’s ~2,000 locations, Weight Watchers has ~25,000 locations nationwide, as well as the advantages of a well-established reputation and a much more accessible design. In his view, such gains suggest that commercial weight loss programs can be a cost-effective way to confront the diabetes epidemic on a large scale.
Effects on Glycemic Control and weight of the Weight Watchers Program for People with Type 2 Diabetes
Patrick O’Neil, PhD (Medical University of South Carolina, Charleston, SC)
Dr. Patrick O’Neil presented results from a clinical trial suggesting that a modified version of Weight Watchers could be an effective, scalable option to facilitate weight loss and A1c reductions in people with type 2 diabetes. The trial found that patients who participated in the standard Weight Watchers program, augmented with access to a certified diabetes educator, experienced significantly greater weight loss (4.1% vs. 1.4%) and A1c reductions (0.6% vs. no change; baseline = ~8%) after six months compared to a control group that received only one session with a registered dietitian. Additionally, 33% of participants in the Weight Watchers group achieved a target A1c ≤7% at six months, compared to 13% of the control group. While upcoming 12-month data will provide more insight into the longer-term effectiveness of such programs, Dr. O’Neil believes that these early results can represent a new scalable option to treat type 2 diabetes.
Q: Regarding the standard care of diabetes in the trial, one session is not the standard of care for diabetes. That seems more like a control group, where you give people one intervention and a brochure. In a diabetes center, people come back frequently.
Dr. Xavier Pi-Sunyer (Columbia University, New York, NY): In most clinics, patients see a dietitian once if they’re lucky. They come back to the doctor for therapeutic treatment but the counseling is very minimal. One visit is not unusual. They had their own physician in the study.
Dr. Patrick O’Neil (Medical University of South Carolina, Charleston, SC): They were under the active care of a doctor independent of the study. They got one session with a dietitian as part of the trial. That level of nutrition counseling is not unusual.
Q: It would be great to see if there was a systematic evaluation of medication requirements. Was there any difference between the groups?
Dr. O’Neil: We’re evaluating that for the 12-month report. It wasn’t evaluated in the six-month report.
Q: I’m not 100% sure about the Weight Watchers diet, since we’re going toward a low-carb approach for diabetes. We looked at lifestyle intervention with low-carb vs. high-carb diets and found greater medication reduction with the low-carb diet and better improvements in glycemic control. When you’re thinking about transitioning from diabetes prevention to diabetes, you need to tailor the diet.
Dr. Gary Foster (Weight Watchers, New York, NY): That’s why it was a modified program. The program is out in the marketplace. That’s what the CDE is there for. We disproportionately encourage consumption of fruits and vegetables, but if you have type 2 diabetes, that could get you into trouble if you just eat fruit. The CDE customizes the diet and talks about low-glycemic food. The data is not that compelling about low-glycemic index foods. It seems that the weight loss drives A1c reduction. We need a scalable program but one that’s customized for type 2 diabetes. That’s sometimes contradictory but more often complementary.
For prediabetes, the best diet is the one the person will maintain. People don’t do well when you prescribe a low-carb diet, or a high-carb diet, or whatever. I have type 1 diabetes and I like Weight Watchers because it gives me points that I can decide how to use. It lets me stay within the boundaries for weight loss and gives me customization I can control. It’s a very smart and good approach. You could tweak it to make it glucose-friendly; most of us know that.
The 2013 Guidelines for the Management of Overweight and Obesity in Adults Recommended Weight Loss Treatment for Up to 140 Million Americans
J Stevens, E Oakkar, Z Cui, J Cai, K Truesdale
Dr. June Stevens presented a poster demonstrating that an astounding 65% of American adults are recommended for behavioral weight loss treatment based on the TOS/ACC/AHA 2013 guidelines for the management of overweight and obese adults. The study examined NHANES data from 2007-2012 to estimate the proportion of American adults recommended for weight loss treatment based on the 2013 guidelines from The Obesity Society (TOS), American College of Cardiology (ACC), and American Heart Association (AHA). Compared to the NIH Heart, Lung, and Blood Institute (NHLBI) guidelines from 1998, these updated guidelines increased the number of adults recommended for treatment by 21%, from 24 million to 140 million (~65% of American adults). Of those 140 million adults, 83% are recommended for pharmacotherapy and 23% for bariatric surgery. As the poster points out, such findings have important implications for the implementation of obesity provisions in the Affordable Care Act (ACA).
- An important policy development regarding these dangerous levels of obesity is the recent USPSTF “B” recommendation to provide intensive behavioral counseling interventions to overweight or obese adults with additional cardiovascular disease risk factors (including prediabetes). While the guidance document emphasizes the impact on cardiovascular disease, much of the rationale stems from the Diabetes Prevention Program (DPP), and weight loss is acknowledged as an important net benefit. This guidance is primarily directed toward providers, and we hope it will lead to a greater understanding of the importance of behavioral counseling and greater comfort implementing such interventions. The USPSTF recommendation should also have a significant impact on patient access to behavioral counseling, as the ACA requires new insurance plans to provide preventive care (as defined by the USPSTF “A” and “B” recommendations) without cost-sharing – see our related piece on the USPSTF diabetes screening recommendation to learn more.
Bariatric Surgery and Devices
Oral Abstracts: Top Ten Papers
The REDUCE Pivotal Trial: A Randomized Sham-controlled Trial of a Dual Intragastric Balloon for the Treatment of Obesity
Jaime Ponce, MD (Chattanooga Bariatrics, Chattanooga, TN)
Dr. Jaime Ponce presented positive pivotal results on the ReShape Duo, part of a relatively fresh category of temporary-use devices for obesity. The therapy (full name: ReShape Duo Integrated Dual Balloon) consists of two linked balloons that are inserted endoscopically into the stomach and inflated, remaining in place for six months before removal. The inflated balloons are designed to occupy space in the stomach and induce feelings of satiety, helping patients lose weight and more easily adapt lifestyle changes that will serve them even when the device is removed. ReShape Medical submitted a PMA for the Duo to the FDA this past summer. Dr. Ponce outlined that the device is targeted to meet the unmet needs of patients with BMIs between 30-40 kg/m2 who do not want surgery, filling a treatment gap between drug therapy and surgery. The quick eight-minute insertion procedure and ~14 minute removal procedure are quite impressive and differentiate the device from surgery from a patient experience perspective.
- The pivotal study found that the Duo yielded excess weight loss (EWL) of 25% vs. 11% with a sham comparator group (ITT analysis). This beat the pre-specified 7.5% superiority margin. Responder rate with the Duo was fairly high, with roughly half of the Duo group achieving EWL of at least 25%. Notably, two-thirds of the weight loss from the six-month treatment period persisted six months after the device was removed – a key finding for the temporary therapy. Overall, there was nothing too worrying in the safety/tolerability data – GI side effects were common initially but abated over the course of the study. A mid-study change in the device design ameliorated an increase in gastric ulceration that was observed early on. See abstract A105 in the abstract book for more details.
Oral Abstracts: Emerging Tech & Surgical Innovations
First Human Experience with a Novel, Swallowed, Self-Emptying, and Excreted Intragastric balloon for Weight Loss
Evzen Machytka, PhD (University of Ostrava, Ostrava, Czech Republic)
Dr. Evzen Machytka presented pilot data on Allurion’s Elipse, a swallowed, self-emptying excreted intragastric balloon. The Elipse is swallowed as a capsule, remaining attached to a narrow capillary tube that follows the capsule through the mouth and esophagus and is used to fill the capsule-balloon once it reaches the stomach. After roughly three months, a valve in the balloon opens, deflating the balloon and allowing it to pass through the rest of the GI tract. In his introduction, Dr. Machytka clearly outlined the perceived advantages of the Elipse over other intragastric balloons: (i) the Elipse requires neither endoscopy nor sedation; (ii) there is no removal appointment required – this is an advantage for patient convenience as well as safety, in case patients are lost to follow up; (ii) the Elipse is thinner than other balloons and remains in the stomach for a relatively short duration, lowering the likelihood of GI complications. See our report on pivotal data on the ReShape Duo for a different approach to intragastric balloons.
- In the pilot study, patients (n=8) lost a mean of 12% excess body weight over six weeks (the balloons were modified to deflate after six weeks rather than three months). The result was on the modest size, but further tests will examine a longer duration of time in-stomach as well as inflating the balloon to larger volumes, which should improve efficacy. Nearly every patient experienced nausea and vomiting, which is to be expected given that the study protocol prohibited the use of anti-nausea medications – such medications, as well as nausea education, will be introduced in subsequent studies. On the whole there were no major unexpected safety or tolerability issues. Mean device fill time was 15 minutes (the future goal is <10 minutes), and all eight balloons were successfully excreted through the GI tract. In one case a balloon deflated early due to a “manufacturing defect,” while in the other a patient withdrew because (as Dr. Machytka shared with a chuckle) they “no longer enjoyed eating.”
Oral Abstracts: Metabolic
Long-Term Outcomes in Roux-En-Y Gastric Bypass Patients: 10-13 Year Data
Nabeel Obeid, MD (New York University, New York, NY)
Dr. Nabeel Obeid presented results from a prospective follow-up study showing durable weight loss and metabolic benefits ~10 years following bariatric surgery. The study (n=328) evaluated weight loss, comorbidity status, and rates of complications and revisional surgery in roux-en-Y gastric bypass surgery patients, with data collected every year for up to 13 years (though data from 10 to 13 years was consolidated into a single data point). Results showed that patients achieved an average 60% excess weight loss (EWL) after the 10-year mark, and only 35% of patients (mostly in higher baseline BMI categories) did not achieve an EWL ≥50%. The rate of diabetes remission at 10 years was 58% (mean A1c was 5.7% from a baseline of 6.6%), and remission rates for hypertension and hyperlipidemia were both 46%. Regarding the surgery’s adverse events, 87% of patients experienced at least one nutritional deficiency, but rates of other complications and revisional surgery were fairly low (12% for internal hernias [the most common long-term complication] and 9.1% for revisional surgery). During Q&A, Dr. Philip Schauer (Cleveland Clinic, Cleveland, OH) critiqued the study’s 46% follow-up rate, saying that it would be ideal to have a higher follow-up rate in the range of 70% to 75% (we felt this was very ambitious); however, we agree with Dr. Schauer’s ultimate conclusion that this data will make significant progress toward filling the literature gap regarding long-term outcomes of bariatric surgery – a sentiment that we have commonly heard (see our coverage of the Cleveland Clinic Obesity Summit and the JAMA “weight management” themed issue).
Questions and Answers
Q: Your follow-up rate was low and then it jumped up to 50%? Was there a difference between those who followed up initially and those you had to track down? Could that explain the relatively high internal hernia rate?
A: We didn’t look at that but it would be interesting. There is an element of selection bias in that regard; people being followed up may have had better results. There was a relatively high internal hernia rate over the entire duration. At the time of the operation, the techniques were different.
Dr. Philip Schauer (Cleveland Clinic, Cleveland, OH): This is a gap in the literature that we have. It’s difficult to get this data out. I like how you tried to track long-term complications and nutritional issues. However, due to relatively poor follow-up, you’re probably underestimating the problems. I think this will be hard to get published because the standards of percent follow-up are now around 70%-75%. There are some ways to track people; it’s expensive and time-consuming, but using third-party groups to at least get phone data, even weight data would be fairly accurate compared to in the office. I’d encourage you to try to get funding to track folks because this would be a good contribution to the literature.
A: This is a difficult area with observational long-term studies. I will say there have been studies showing ways to improve follow-up. A lot of it is patient incentives. I agree with your point, but there have been some long-term studies recently published with an even lowerpercent follow-up. It is very difficult but it’s something to consider moving forward.
Q: All of the things you looked at were issues for super obese patients. What are you currently doing with them?
A: This study sheds light on the realities of long-term outcomes with these patients. With one definition, almost half don’t achieve adequate weight loss. Gastric bypass should still be offered. Duodenal switch is another option but there are problems with nutritional deficiencies. It does shed light as to the long-term outcomes.
Q: Are you still doing standard gastric bypass for super obese patients?
A: Yes, but the lengths may be longer.
Q: Was the 2.7% mortality in six years related to the surgery or something else?
A: It was all-cause mortality, ranging from immediate postoperative sepsis to venous thromboembolic events. Other unrelated causes included colon cancer, gallbladder cancer, and suicide. The 2.7% was over the duration of the whole study. The average time of death was six years but that doesn’t mean all the deaths were within that time.
Q: You said you saw patients or contacted them by phone. What percentage was followed up with each method? Did you have them fill out a phone questionnaire to see how well correlated it was to validate the dataset?
A: We saw one third of the patients in the office, another third had a phone interview and PCP data, and one third was just contacted by phone. There was no formal review of the questionnaire over the phone vs. in person, but it was the same questionnaire.
Pre-Conference Course: Metabolic Surgery – What is State of the Art in 2014?
Rationale for Metabolic Surgery
Walter Pories, MD (East Carolina University, Greenville, NC)
Dr. Walter Pories characterized modern bariatric surgery as an entirely new discipline compared to the conventional procedures of the past, with novel concepts, treatments, professional relationships, and research visions. He noted that bariatric surgery can lead to resolution of metabolic syndrome as well as type 2 diabetes and provocatively claimed that gastric bypass is the “single most effective approach to the prevention of cancer.” According to Dr. Pories, bariatric surgeons work within broad metabolic teams and must keep up with the various languages of endocrinology, molecular biology, and genetics. Providing a clinical example, he discussed the misunderstandings of endocrinologists who give obese patients with diabetes large amounts of insulin, supposedly in order to overcome insulin resistance. Dr. Pories stressed that insulin resistance is not directly related to insulin levels and presented data showing reduced insulin doses following bariatric surgery despite no change in insulin resistance. He argued that insulin interferes with gluconeogenesis and might raise mortality, and should therefore be used as conservatively as possible. Dr. Pories concluded on an optimistic note, welcoming bariatric surgeons into a field that he said is “producing results that once were thought impossible.”
Unifying Gastric and Intestinal Mechanisms
Francesco Rubino, MD (King’s College, London, UK)
Dr. Francesco Rubino tackled the question of which underlying mechanisms contribute to type 2 diabetes remission following bariatric surgery, pointing out that combining gastric and intestinal mechanisms can lead to more efficacious results. He highlighted that restriction is not responsible for most of surgery’s benefits; rather, changes in gastrointestinal physiology, physical and chemical alteration of endoluminal stimuli, and other changes in metabolic regulation drive most of the effects. Dr. Rubino presented evidence that GLP-1 is not a principal mediator of diabetes remission after bariatric surgery and urged the field to think outside the box when conducting future research on the subject. He proposed that other factors such as paracrine mechanisms, changes in gut microbiota, and alterations in bile acid metabolism may contribute to these effects, although more work is needed to confirm those theories. Notably, Dr. Rubino also pointed out that combining gastric and intestinal mechanisms in bariatric surgery can increase weight loss while simultaneously yielding improvements in glucose metabolism. For example, he highlighted how procedures such as sleeve gastrectomy can enhance the GLP-1 response while intestinal operations such as duodenal-jejunal bypass can improve oral glucose tolerance. Dr. Rubino concluded by pushing the field to develop new surgical procedures rather than slowly moving forward from what we know, emphasizing the importance of better understanding the mechanisms behind surgery.
The Role of Microbiota
Lee Kaplan, MD, PhD (Massachusetts General Hospital, Boston, MA)
Obesity expert Dr. Lee Kaplan discussed the hot topic of the gut microbiome and its impact on the broad range of physiological effects resulting from bariatric surgery, saying that the microbiome can best be thought of as a new organ made up of 8,000 cell types. Dr. Kaplan illustrated how the microbiome’s composition changes significantly following bariatric surgery; interestingly, the microbiome does not revert from its obesity-linked profile to a non-obese profile, but rather settles at a new third equilibrium. In addition, he presented data showing that fecal transplants from mice that have undergone bariatric surgery can induce weight loss and increased energy expenditure in germ-free mice. Given these and other recent findings, Dr. Kaplan advocated for an updated model of weight regulation in which a “cauldron of activity” from factors including nutrients, microbiota, the intestinal mucous layer, and bile acids collectively stimulates regulatory responses from the GI tract and the central nervous system.
Questions and Answers
Q: Do the germ-free rats maintain the bypass microbiota?
A: These were short-term experiments. You’d anticipate that over time, the microbiota would be pushed back. I said it was an organ because it’s influenced by the host, the rest of the body. Over time, we anticipate that the microbiota will revert to the appropriate microbiota of the animal it’s in over several weeks or months, though we haven’t measured it. More importantly, it’s causing increased energy expenditure through some mechanism. We don’t understand what that is, but it becomes a target for treatment to reproduce those effects.
Post-Operative Management of Diabetes
Sangeeta Kashyap, MD (Cleveland Clinic, Cleveland, OH)
Dr. Sangeeta Kashyap argued that baseline beta cell function appears to be the most important determinant of type 2 diabetes remission following bariatric surgery. She explained that most of the baseline characteristics that differ between remitters and non-remitters (e.g., age, duration of diabetes, insulin dependence, baseline A1c) are correlated with severity of beta cell failure; specifically, patients with better beta cell function prior to surgery are more likely to experience type 2 diabetes remission post-surgery. If this is indeed the case, it strengthens the argument that bariatric surgery should be an option for diabetes patients who are not quite at the BMI threshold for bariatric surgery. On the other hand, surgery may not be as effective in securing diabetes remission in patients with severe obesity and longstanding diabetes, the patient population in which it is most commonly used. Dr. Kashyap also shared her thoughts on which medications are most appropriate for patients with type 2 diabetes following bariatric surgery, though she emphasized that the evidence on this issue is far from conclusive. She suggested that patients who experience no remission of diabetes after surgery should be treated with insulin (as they likely have very little beta cell function remaining), and that those who relapse following initial remission could benefit from drugs like SGLT-2 inhibitors and GLP-1 agonists that cause additional weight loss and raise adiponectin levels.
Questions and Answers
Q: We looked at a similar issue but called it refractory hyperglycemia. Non-remitters could be people with some improvement but they do not experience remission or they do experience remission and then relapse. Refractory hyperglycemia is what happens for people who never respond at any time, which is completely different. They had no beta cell function, and they lost weight but didn’t respond. Did you see similar issues if beta cell function was still there?
A: That’s probably a different phenotype other than type 2 diabetes. Measure C-peptide levels before surgery. If you have a response to type 2 diabetes agents like GLP-1 agonists, then you’d expect a heightened response. With MODY or autoimmune-mediated diabetes, we’ve seen improvements in the first six months but then a rebound. But no matter what type of diabetes, even type 1 diabetes, we see an initial favorable effect. We’re not sure what happens afterwards. That might be the reason for the refractory cases. I would measure islet autoantibodies.
Q: We did and they were normal.
A: Okay, then they’re type 2s. It could be part of the adiponectin story: a reduction in the receptor response to adiponectin in muscle and liver. It might be genetic; we showed that in people with a family history of diabetes, receptors were downregulated. Some people might have a genetic predisposition to not respond to surgery. We need tools to figure out who those people are.
Q: Did you measure lean mass?
A: Most results showed a 10% reduction in lean mass. We didn’t see that to be a factor; it had to do more with fat loss and adiponectin response.
State of the Art Medical Devices
Stacy Brethauer, MD (Cleveland Clinic, Cleveland, OH)
Dr. Stacy Brethauer provided an update on novel devices with metabolic implications, including transoral gastroplasty (TOGA), endolumenal vertical gastroplasty, primary obesity surgery endolumenal (POSE), and vagal nerve blockade, noting that these are all still investigational in the US. Notably, he pointed out that GI Dynamics’ EndoBarrier leads to good control of diabetes but will likely face challenges with payers, particularly due to the need for re-implantation. Dr. Brethauer also highlighted the usefulness of the ReShape Duo intragastric balloon as a bridge to surgery by helping bariatric patients with their pre-surgery weight loss. Overall, he summarized that these new devices generally have a low rate of serious events and can lead to moderate short-term weight loss, though long-term outcomes are still unclear.
State of the Art Pharmacotherapy, Diet, and Lifestyle
Robert Kushner, MD (Northwestern University Feinberg School of Medicine, Chicago, IL)
Dr. Robert Kushner reviewed the five key obesity treatment recommendations from the 2013 AHA/ACC/TOS guidelines: (i) identifying patients at risk for CVD, diabetes, and all-cause mortality; (ii) counseling patients about the benefits of weight loss; (iii) prescribing a diet to achieve reduced calorie intake; (iv) implementing a comprehensive lifestyle intervention program (diet, physical activity, and behavior modification of six months or longer) for patients who need to lose weight; and (v) selecting patients who could benefit from bariatric surgery. Based on these guidelines, he stressed that weight loss of as little as 3%-5% is clinically meaningful and that there is no significant difference among various diets as long as calorie reduction is achieved. Regarding bariatric surgery, Dr. Kushner explained that the data was not strong enough to lower the BMI threshold at the time the 2013 guidelines were created. Acknowledging the controversial nature of the issue, he did not offer further commentary but stressed that these guidelines help primary care providers understand that they can offer more options to their patients in addition to diet, lifestyle, and pharmacotherapy.
Going Beyond BMI
Philip Schauer, MD (Cleveland Clinic, Cleveland, OH)
In a forceful yet familiar argument, bariatric surgery expert Dr. Philip Schauer argued that current guidelines recommending surgery only for patients with a BMI >35 kg/m2 are arbitrary and not in line with the latest evidence. He presented data from several meta-analyses and clinical trials (including three-year results from the STAMPEDE study), demonstrating that patients with a lower BMI can still experience significant weight loss and improvements in glycemic control from surgery. While he acknowledged that more data from randomized controlled trials with hard clinical endpoints is needed to fully understand the long-term effects of metabolic surgery in this population, he believes that current evidence supports its consideration for patients with a BMI between 30 kg/m2 and 35 kg/m2 and poorly controlled diabetes as well as the currently indicated population. See our coverage of the Cleveland Clinic Obesity Summit for more of Dr. Schauer’s thoughts on the BMI threshold for bariatric surgery.
Questions and Answers
Q: We’re following guidance from 1991 and we’re almost in 2015. What do we need to do to change this?
A: The evidence is mounting. When the guidelines were published last year, some studies weren’t published yet. Evidence is key. We are seeing some changes in behavior: guidelines from NDF in 2011 included BMI as low as 30 kg/m2. AACE and ADA include surgery as more of a standard therapy. We’re getting there. Hopefully now we can collate studies together and analyze hard endpoints.
Q: How do you respond to doctors who are afraid of getting sued?
A: The evidence is strong for offering surgery to people with a BMI of 30 kg/m2 who are not well-controlled. That can be strongly defended; surgeons shouldn’t fear that.
Q: But getting to surgery too late is also a strong predictor of worse outcomes.
A: People being sued for offering surgery late? We’re not there yet.
Q: BMI sounds like a bad measurement. The other axis was uncontrolled diabetes, and there seems to be consensus that the earlier you take care of that, the better. An A1c cutoff of 7% might be too high. Will there be change on that side?
A: I think so. We’re seeing earlier referrals. It’s traditional to refer people for a surgical intervention when they have poorly managed disease, heart disease, or other examples. Surgery gets deferred because of the risk. There’s a trend toward earlier intervention but we’re not there yet. For people who are well controlled with a BMI of 32 kg/m2, you can’t make the argument that surgery is a good choice. With an A1c between 7% and 8% on medications, there’s probably a window of opportunity and it should be considered.
How to Maintain Weight Loss and Diabetes Remission
Josep Vidal, MD, PhD (Hospital Clínic Universitari, Barcelona, Spain)
Dr. Josep Vidal discussed the various factors influencing whether or not patients with type 2 diabetes experience remission following bariatric surgery. He, like Dr. Sangeeta Kashyap (Cleveland Clinic, Cleveland, OH; see above), argued that among baseline patient characteristics, beta cell function is likely the most important determinant of remission. Not surprisingly then, most predictors of relapse (e.g., insulin dependence, baseline A1c, diabetes duration) are correlated with greater beta cell impairment. He also cited evidence demonstrating higher remission rates with gastric bypass compared to sleeve gastrectomy (strengthening gastric bypass as the golden standard of bariatric surgery) and stressed the importance of concerted efforts to sustain weight loss after surgery, as weight loss and diabetes outcomes typically go hand in hand. The verdict is still out on the underlying mechanism behind bariatric surgery’s effects on diabetes (see our AHA days #3-4 report for one novel hypothesis), but Dr. Vidal presented evidence suggesting that GLP-1 is not the primary culprit.
How Close Are We to a "Medical Bypass"?
Carel Le Roux, MD (University College Dublin, Dublin, Ireland)
Looking toward the future, Dr. Carel Le Roux discussed the potential of personalized medicine in obesity and the prospect of “medical bypass” treatment. He highlighted the wide spectrum of responders in the SCALE clinical trial program for Saxenda: while some participants (8%) gained weight, 15% of the participants lost at least 15% of their weight – this heterogeneity of response is well known in obesity, and holds true for other obesity agents as well. Based on this data, Dr. Le Roux asserted that we can bring personalized medicine to obesity if we can determine which patients respond best to which pharmacotherapies. Notably, he pointed to what he called “medical bypass” treatment, which consists of meal replacements, diet, pharmacotherapy, and medical devices (such as GI Dynamics’ EndoBarrier), as a treatment option that has not been adequately explored. While acknowledging that this intervention may not have quite the level of efficacy of bariatric surgery, Dr. Le Roux argued that it doesn’t have to, as the greatest unmet need is for more options to fill the treatment gap between lifestyle intervention and bariatric surgery.
Pre-Conference Course: Fundamentals of Bariatric Surgery for Surgeons
Non- Surgical Weight Management: Updates and New Meds – Primary Weight Loss & Weight Regain
Christopher Still, DO (Geisinger Health Care System, Danville, PA)
Dr. Christopher Still discussed how to alleviate the challenges of weight regain post-surgery and offered commentary on the various new obesity pharmacotherapies. He acknowledged that weight regain following surgery is not uncommon and typically occurs within one year of the procedure, and he encouraged providers to be on alert for for dietary indiscretion, depression, and any medications that can cause weight gain. Moving onto pharmacotherapies, he expressed frustration with the limited number of options despite the magnitude of the obesity epidemic. However, he was enthusiastic regarding the advantages of Vivus’ Qsymia (phentermine/topiramate), Arena/Eisai’s Belviq (lorcaserin), and Novo Nordisk’s Saxenda (liraglutide 3.0 mg for obesity). Following Dr. Still’s presentation of data showing up to 13% mean weight loss with Qsymia, Dr. David Tichansky (Jefferson Surgical Center, Philadelphia, PA) commented during Q&A that “Qsymia basically rivals lap banding.” Dr. Still characterized Belviq as the best-tolerated obesity drug, noting that it has the lowest discontinuation rate in clinical studies out of all available next-generation pharmacotherapies. He also expressed excitement about Saxenda, claiming that it will be a great option for patients with both obesity and diabetes, with the main downside being the need for injections (which may hurt patient adherence). Notably, during Q&A, Dr. Still also claimed that endolumenal devices will beat out pharmacotherapies in filling the treatment gap between lifestyle and surgery.
Pre-Conference Course: Masters in Behavioral Health – Eating and Weight Problems Pre- and Post-Bariatric Surgery
Pharmacotherapy for Weight Regain Following Bariatric Surgery
Kristine Steffen, PharmD, PhD (North Dakota State University, Fargo, ND)
Dr. Kristine Steffen highlighted the lack of data on obesity management following bariatric surgery, noting that the safety and efficacy of weight loss drugs during this time remains relatively under-studied. After reviewing the profiles of the obesity drugs on the market and under regulatory review, she lamented that the majority of her patients do not seek additional treatment after bariatric surgery until they have regained almost all of the weight they lost, at which point a drug intervention is less likely to be effective. Notably, in a comment following Dr. Steffen’s presentation, session moderator Dr. James Mitchell (University of North Dakota, Fargo, ND) mentioned that most of the components of new medications like Vivus’ Qsymia (phentermine/topiramate) and Orexigen/Takeda’s Contrave (naltrexone/bupropion) are available as generics and urged providers to prescribe them separately rather than opting for the very expensive approved combinations. While we understand that cost remains a major barrier and source of frustration for many patients and providers, it will be critical for providers opting for the generic route to understand the differences in formulation (release timing, etc.) between the branded combination therapies and their individual components.
Symposium: Basic Science of Bariatrics – Critical Update
Mechanisms of Metabolic Surgery: Beyond the Myth of Restriction and Malabsorption
Lee Kaplan, MD, PhD (Massachusetts General Hospital, Boston, MA)
Dr. Lee Kaplan opened his presentation with the provocative statement that “surgery works, but not the way our parents taught us.” While classical models of bariatric surgery focus on restrictions in food intake and nutrient absorption as the key underlying mechanisms, Dr. Kaplan cited substantial evidence supporting alternative theories. Studies in both animals and humans have shown that many of the effects of bariatric surgery (particularly gastric bypass), including decreased hunger, increased energy expenditure, and higher levels of satiety-promoting hormones in the gut, are the exact opposite of those seen with caloric restriction. For Dr. Kaplan, the evidence suggests that surgery works largely by altering the set point for fat mass: patients go in for the operation at their set point and wake up in an “overfed” state. The exact mechanism behind these effects is still unknown, but it is almost certainly multifactorial, as gastric bypass alters many components of the GI lumen, including nutrients, pancreatic enzymes, bile acids, and the microbiome.
Developmental Genes and miRNAs in Control of Body Fat
C. Ronald Kahn, MD (Joslin Diabetes Center, Boston, MA)
Dr. C. Ronald Kahn delivered a captivating opening keynote address on the role of developmental genes and microRNA (miRNA) in adipose tissue. After first highlighting the differences in fat distribution among individuals, Dr. Kahn took a deep dive into how these differences arise and how they impact adipocyte function. He illustrated the wide range of biological roles that these various fat depots play, pointing out the different functions and characteristics of white and brown fat as well as visceral and subcutaneous tissue. Dr. Kahn presented data from both mice and humans showing significant differences in the expression of developmental genes (including Shox2, En1, and Gpc4) between these fat depots as well as how such gene expression can vary depending on BMI and waist-hip ratio. Dr. Kahn also presented data showing that each adipocyte depot expresses a unique combination of miRNAs (short RNAs that regulate gene expression); notably, miRNAs and their processing enzymes (specifically one called Dicer) are down-regulated with age in subcutaneous adipose tissue, leading to abnormal fat distribution and whitening of fat (the opposite of the more metabolically advantageous browning of fat). As Dr. Kahn put it, developmental genes and miRNAs play a large role in programming adipocyte function and the body’s ability to handle metabolic stress, adding a new dimension to the complexity of metabolic regulation.
Oral Presentations: Intervention & Clinical Studies – Randomized Weight Loss Trials and Correlates of Success
A Randomized Controlled Trial Examining a Cost-Benefit Approach to Weight Loss Maintenance
Tricia Leahey, PhD (Brown University, Providence, RI)
Presenting findings from a study on behavioral incentives, Dr. Tricia Leahey argued that a shift in psychological cost-benefit ratio is one explanation for why long-term weight maintenance is so much more difficult than initial weight loss. She explained that many behavioral reinforcers that are present during weight loss (e.g., improvements in physical and mental health, social reinforcement, changes in appearance) are diminished during the maintenance phase, whereas the costs (e.g., increased physical activity, effort to resist tempting food) persist or even increase. She presented results from a randomized study demonstrating that patients who received ongoing social and monetary reinforcement for behavior change following weight loss successfully maintained an ~8% weight loss for ten months. On the other hand, a control group that received only a one-time class on maintenance strategies regained all the weight in the same time period. While behavioral incentives are one part of the picture, there are also powerful biological factors (such as lower resting energy expenditure and alterations in hunger/satiety signals) that promote weight regain.
Questions and Answers
Q: Do you have information on whether people who lost more weight had more success? Were some people right at 5% while others lost a lot more?
A: We statistically co-varied it so that there were no initial weight loss effects. Of course, there was some variability; people lost 5% to 14% of their initial weight.
Q: Some people have a hard time losing weight in the first place; they don’t even get to maintenance.
A: We wanted to make sure we had people who had lost enough weight that it was clinically meaningful. That’s why we had a 5% cutoff.
Q: You mentioned social support and compliments as a benefit of maintenance and weight loss. We’ve found that that’s a negative and that it becomes a cost. Since there’s some ambivalence there, have you looked at the interaction? There is a cost-benefit ratio, but people have ambivalence about behavior change. Do you have any thoughts about that?
A: We didn’t measure that. Participants were very motivated to maintain their efforts when they entered the study. Many had goals of losing more.
Q: There’s no doubt that this is practical. Did you distinguish between monetary and social support? Was either more helpful?
A: The treatment package was so hard to disentangle. We do have process measures examining social reinforcement vs. financial, so we could look at the association between that and weight loss.
Symposium: ASMBS Integrated Health Keynote Speaker, Presidential Address & Town Hall
Addressing Obesity Stigma in Health Care: Challenges, Remedies, and implications for Bariatric Care
Rebecca Puhl, PhD (Yale Rudd Center for Food Policy and Obesity, New Haven, CT)
Dr. Rebecca Puhl drew comparisons with other disease areas to underscore how behind the obesity field is with regard to the fight against stigma. A wide range of diseases and disorders, including cholera, TB, drug addiction, alcoholism, HIV/AIDS, and mental illness, have been associated with stigma. In each of these disease areas, society and public health leaders recognized that stigma was undermining treatment and prevention and therefore funded research and programs to reduce stigma. When it comes to obesity, Dr. Puhl stated frankly that stigma remains a “glaring omission” on society’s radar, even when it comes to healthcare professionals (the focus of her presentation). Recent research has shown that new doctors emerge from medical school with little understanding of obesity, which breeds frustration, stereotypes, and an aversion to address patients’ weight problems in a proactive manner. On the bright side, even modest interventions (such as brief videos or lectures) have been shown to dramatically improve students’ empathy for patients with obesity, reduce stigma, and increase students’ confidence in obesity treatment.
Symposium: Treating T2DM – Do We Have It All Wrong?
How Can We Close the Gap Between the True Onset of Disease and the Initiation of Treatment?
Jesse Roth, MD (Albert Einstein College of Medicine, New York, NY)
Dr. Jesse Roth encouraged attendees to think about glucose in terms of trajectories rather than ranges. He argued that the current definition of a normal glucose range, drawn from population studies, is much wider than the actual normal glucose range for any given individual. Rather than waiting for a patient’s glucose levels to rise above the a broadly defined normal range, Dr. Roth suggested that with more careful and consistent tracking of individual patients’ glucose, providers identify the earlier point when an upward trajectory begins, allowing for earlier treatment. He likened this strategy to pediatricians’ use of growth charts, where tracking trajectories is just as important as a patient’s height or weight percentile at any individual point in time. Dr. Roth painted a picture of a future in which providers could use personalized trajectories of glucose, A1c, insulin levels, and triglycerides to catch the onset of type 2 diabetes or prediabetes earlier. Dr. Roth applied similar thinking to BMI, arguing that there is no normal range and that there are differences in diabetes incidence at a given BMI range between racial/ethnic groups.
Questions and Answers
Q: Do you think assays have been standardized enough to do longitudinal studies of insulin and to watch the trajectories you talked about?
A: We can standardize assays when we want to, if there is demonstrated value. Big health systems often have their own assays. In the future, the changes you see in glucose and A1c will be followable.
Insulin Hypersecretion and Food Additives: Cause of Obesity and Diabetes?
Barbara Corkey, PhD (Boston University, Boston, MA)
Dr. Barbara Corkey critiqued the current conventional wisdom that assumes obesity to be caused by lifestyle choices and that characterizes type 2 diabetes as a failure to compensate for insulin resistance. With regard to obesity, Dr. Corkey believes the evidence suggests that the most important variable is involuntary control of energy metabolism. She hypothesized that this process becomes dysregulated at the cellular level in response to high fat and glucose intake. In type 2 diabetes, she presented data from animal studies suggesting that basal insulin hypersecretion may be the key initial pathogenic mechanism; at the very least, she argued that there is currently insufficient evidence to establish definite causal relationships in any direction between obesity, insulin resistance, and insulin hypersecretion. She also discussed how changes in the food production system over the past few decades, particularly an increase in additives and heavily processed foods, have likely contributed to these pathogenic mechanisms. In conclusion, Dr. Corkey urged researchers to take a broader view of the possible contributors to metabolic disease.
Questions and Answers
Q: It’s great to think outside the box because inside the box isn’t helping. We’ve been looking at how free fatty acids and inflammation can actually cause intramyocellular fat.
A: There are many possible approaches; they’re all hypotheses, and I encourage you to test them. I don’t want everyone to think I’m right because I’m usually not. If you think that’s the case, then go for it. All things that haven’t been tested are possible.
Comment: We showed years ago that beta cell hyper-responsiveness long precedes type 2 diabetes. We have not been looking in the right place.
Q: What about variations in diet? Insulin secretion can vary by 50% or more on a high-carb diet. What are your views on the primary approach to controlling calories with a low-fat diet?
A: For anyone on a diet, nothing works. You can lose weight easily and keep some off, but it always creeps up. Putting the onus on people to stick to a specific way of eating is from a basic perspective, not the solution. Physicians are in a difficult position because all they can do is treat people based on information or standard procedures. I favor a low-carb diet, but that’s theoretical. It’s less processed than other food sources, but I have no real knowledge to say it’s right.
Q: Antipsychotics are adding to the burden of type 2 diabetes. Are there some chemicals in those drugs that might stimulate hypersecretion?
A: To simplify, the same things that generate a signal in a beta cell or a fat cell also generate signals in the brain based on unknown input. Your point is well taken; that’s causing lots of problems. Rimonabant was a drug that mainly had an effect on the central nervous system but had very beneficial effects on metabolic tissues, but it caused suicidal ideation so it never made it. We have some examples that could be a starting point.
Q: We’ve shown that hypersecretion follows insulin resistance; they don’t happen at the same time. I disagree with that. We focus more on insulin degradation and clearance as a cause; it’s not all beta cell function.
A: I agree in terms of degradation. There are a number of good hypotheses that need to be tested.
Hyperinsulinemia as the Culprit: Surgery Provides the Clues
Walter Pories, MD (East Carolina University, Greenville, NC)
Dr. Walter Pories argued that the physiology of diabetes remission following bariatric surgery supports the hypothesis that insulin hypersecretion, not insulin resistance, is the key underlying mechanism of type 2 diabetes. Noting that basal insulin secretion is significantly higher in patients with type 2 diabetes compared to healthy individuals (though the rate is highest in patients with impaired glucose tolerance), he proposed that the key problem is not insulin resistance but instead an inability to further increase insulin production from an abnormally high baseline in response to meals. As further evidence for this hypothesis, Dr. Pories noted that metabolic function improves rapidly following bariatric surgery despite no change in insulin sensitivity; there is, however, a decline in insulin secretion. Given this evidence, he suggested that the field should perhaps reconsider its reliance on insulin therapy for patients with poorly controlled type 2 diabetes; this is easier said than done given the lack of safe insulin sensitizing agents, suggesting the huge unmet need for non-insulin therapies for more mature type 2 diabetes (SGLT-2 inhibitors are arguably the best suited current drug class for that task).
Jim Marks, MD, MPH (Robert Wood Johnson Foundation, Princeton, NJ)
Our team had an incredible opportunity to sit down with Obesity Week Keynote speaker Dr. Jim Marks and hear his perspective on the Robert Wood Johnson Foundation’s (RWJF) work in fighting childhood obesity and what he believes are the greatest challenges and opportunities in the field. As he did in his keynote address, he spoke eloquently about the importance of building a “culture of health”, which he stressed goes far beyond simply ensuring the absence of disease. He described how efforts like the Alliance for a Healthier Generation’s Healthy Schools Program have already made significant strides toward making community-level cultural changes and noted that the most interesting efforts in the future may emerge from outside the healthcare sector. Dr. Marks also cautioned against putting too much stock in technology as an agent of change, as he believes that the social and policy components of the healthcare system are far more powerful. He concluded on an optimistic note, saying that while American health and healthcare certainly has its flaws, “the underlying slope is improvement” and that “unfortunately, other countries are improving faster and that is harming US economic competitiveness and sense of well-being.”
Q: Thank you so much for meeting with us, Dr. Marks! At a meeting like this, there are lots of different pieces of the puzzle in which stakeholders in healthcare are coming together. As the efforts to work against childhood obesity stand now, what’s the area that you think currently needs the most focus?
A: When we think about the areas needing help, we’ve been encouraged by the signs of progress from places around the country that are reporting reductions in childhood obesity. But they’re early and they’re fragile. The early concern there is that the reductions tend to be more in white, high-income populations. So the problems with disparities, especially in African Americans and Hispanics, are in essence, growing because the progress is greater in the majority population. So this is clearly an area where we want to do more work in the future. The only place that we’ve seen slightly greater improvements in African Americans and Hispanics is in Philadelphia, so this is definitely an area of concern. But Philadelphia also gives us hope that targeting efforts to those families whose children are at great risk can be successful in improving their health.
Q: We’ve been really lucky to see what Partnership for a Healthier America (PHA) has been doing and have been impressed with their work. From an environmental perspective, we live in a country where corn is subsidized and I think that’s very curious for our international colleagues. We wonder if you could say a word about how the Robert Wood Johnson Foundation views this, big picture if not specifically?
A: So I won’t answer for corn specifically but what I will comment on in my remarks is how we’ve worked on obesity and what changes we think are needed. Largely, we’ve focused on social and community kinds of changes. We think that we can change the culture for families and make it easier for them to make healthier choices. What you described is one area where our previously structured subsidies support foodstuffs that are turning out to be less healthy than we would have liked. We need more support for fresh fruits and vegetables. But the real point is that we need to move toward a culture that supports health. Really, every sector needs to be involved, whether it’s transportation, agriculture, or the private sector. All of these have a role to play. If we had to say one statement, it is that health begins, is nurtured, protected, and preserved, in our communities and our families. It’s not so much the doctor’s office. And we need to recognize that imbalance in our society.
To put this in more context, what we found in our obesity work is that it’s a proof of concept of what it takes to create a change in culture. There are other examples but for our work, we learned a lot. Think about Earth Day and recycling – these are normal now but forty years ago, they were not. When I grew up, seatbelts and airbags – you couldn’t get them in cars and then they were extras you could purchase and now they’re routine and everyone uses them. There are ways culture changes can occur. We can think of obesity and its causes as one of the most difficult areas to change. It’s related to an environment of food and physical activity. We’ve supported a lot of work on the issue and we’ve seen progress and that gives us hope that we can see a broad culture of health embraced and developed. It also gives us recognition that obesity work won’t be sustained unless it is embedded in a bigger vision about an emphasis on health and well being.
Q: Yes, this idea of a culture of health is really powerful. Could you talk more about the leadership end there?
A: So on the issue of leadership, we have funded and supported lots of fellows and scholars over the years. Many – I was one – have stayed connected to the foundation but many have also not or have very intermittently so. We realized that this is a network that we hadn’t fostered or grown. So there are many very good, powerful scientific and other leaders that have lost connection to us and we to them. We weren’t using them well and they weren’t using us well when we were thinking about big issues for our nation. So we have started to invest a lot more in reconstituting our network.
The other issue that we see is that we need to reach out to leaders that are outside and beyond healthcare. Like I mentioned earlier, private industry, agriculture, or transportation. Or mayors or the Y. We need to bring them in and understand what they’re trying to accomplish and see how they can find that health not only fits into what they’re doing but also helps them succeed at their own primary purposes. We think there is a lot of opportunity and interest. That’s a part of leadership that we’re going to be more intentional about. We are also worried that our nation seems to becoming more contentious in its leadership. We’ve got to find ways for leaders to realize and be more comfortable with working across disciplines and sectors and that this is the kind of thing that brings the nation together. We frankly feel that that the healthcare issues and their costs and outcomes are at the point where they’re putting the nation at risk both economically and socially.
Q: Thank you – we know so many who share your views. Why do you think our leadership has come to this point where it’s so contentious?
A: There are a number of things. I don’t think of it as purposeful. I think of it as gradual. In the beginnings, say in 1980, we were the most costly country per capita for healthcare. But we could afford it and we were close to the second most costly country so we were not an outlier. Over the last three decades or more, we are now 50% higher than the number two country on a per capita basis. So there has been a lot of struggle and angst. If our science and policy changes have helped, they certainly haven’t helped enough. We were in the middle of the pack in terms of life expectancy in 1980 and now we’re last. So our proportion of GDP has grown and we’re getting bad outcomes. People are realizing that and especially because more of our businesses are global. So when business leaders look at where they’re going to move, healthcare costs are an important part of those decisions and we don’t look so good. We’re seeing that with the US, obesity rates and healthiness of a community more generally are becoming a factor in businesses’ decisions on where to move to and expand. There is no question that business is thinking along those lines when they’re thinking U.S. vs. other places.
Q: Switching gears a bit, Dr. Marks. If you had to pick one problem in obesity that you think is most solvable, what would it be and what would you do to solve it?
A: I can’t pick one and I won’t. The central thing about the obesity epidemic is that it’s an aggregate of lots of little changes that have occurred in our nation. The net effect is a gradual accumulation of inactivity and increased calorie consumption. I’ve spoken to medical students and have asked them if they have ever in their lives had to get up to change the TV station. No one raises their hands. That is a bit of a silly example but it illustrates the larger point that activity has been engineered out of our lives. When you go into most buildings now, stairwells are hidden behind a fire door and elevators are front and center. When you go into old buildings, stairways are prominent and sweeping and grand. And the elevator’s around the corner – a single elevator that is really only there to help move equipment or to help those with disabilities. All of those things are examples of the changes.
Your example of corn and corn syrup, when you look at the price of food over the last few decades, the one that has changed the least is that of sugar-sweetened beverages. And we know that the cost of food in a restaurant is probably only a small proportion of the total cost to get it to the customer. So it’s perceived as a great value to be given a large amount of food and companies can do that for little additional cost. And companies want to succeed. So that’s what they do. I don’t think they do it for malice. They do it for wanting to succeed and be profitable. Many of other changes were done for convenience. The consequences on health were largely unintended but they’re serious and now they’re going to be hard to reverse. So when we look at communities that have turned things around, no single action shows up. This doesn’t mean that there aren’t things that are more important than others or ones that are more likely reversed. We just can’t pick one and expect to succeed.
Q: So as you know, with Election Day having just passed, we’re from the San Francisco Bay Area and have been paying a lot of attention to the soda tax. We see this as a small seed of building that “culture of health” that the Robert Wood Johnson Foundation speaks of. From your perspective and experiences, do you have thoughts on this front?
A: I could give several examples of elements because I don’t think we’re all the way there. But we knew for children that it was important for schools to be healthy places. They needed more activity and a wider availability of healthier foods. We funded a group that I’ll mention in my remarks. This came together through the Clinton Foundation and the American Heart Association and is called Alliance for a Healthier Generation. We funded their Healthy Schools Program, which was created as a recognition program that took science from the NIH and CDC and others and said what changes in schools we can make. These were broken up into activities, in physical education and in before- and after-school programs, and into food in lunch lines as well as competitive food outside lunch lines. They even looked at support from faculty and staff. They then gave them an array of changes that they could make. We now have 25,000 to 30,000 schools participating. On average, each school makes seven or eight changes. We know that the schools that make the most changes show a downturn of obesity rates in their kids. So that’s a type of culture change if you will.
Also years ago, schools around the country were starting to change what was going to be available in vending machines. Los Angeles was one of the first cities and the cities were all different – some said only water, some said no more than 8 ounces, some based their policies on caloric density – how many calories per ounce. The net effect is that national companies couldn’t sell efficiently when policies were different in each school. So the American Beverage Association came and met with the Alliance for a Healthier Generation and asked what could be standards that would be good for health that could be standardized or recommended. No matter how rigorous those standards were, the companies could adjust their products and packaging to meet them. But they couldn’t do it on a school-by-school basis. So they did negotiate and they did an evaluation to track what had happened. They found that calories shipped as beverages to schools fell by, I think, about 90%. In several examples, we see this power of local change as a driver of national voluntary and regulatory policy. The industry also did some other things that made it easy for schools. Most schools sign “pouring” contracts that last ten to 20 years and are only with Pepsi or whatever. They’ll provide signs in the school or the football field scoreboard etc. The principal or PTA or someone gets some upfront money that can be used to help the school and a portion of future sales. The beverage association allowed any school that wanted to change the contract to reflect the new standards to do so with no penalties. This made it easier for schools that wanted to do this. That is a part of a culture change or an element in a broader culture change.
Q: There is so much room for improvement in addressing diabetes and obesity in particular in our country and world. Given that you have a perspective on so many different disease areas, can you think of other disease areas that people in diabetes and obesity can learn from? Can you provide any big takeaways from other disease areas’ efforts that have worked very well?
A: I think that there are always differences between disease areas. The most common one that people make comparisons to is probably tobacco. But I think there are really important differences. Tobacco is lethal when used as intended. Food is not that way. Food is part of every culture and part of celebration. So there is a nuance that is difficult for us to work with in the health community. How do we support and foster changes that are good for health but recognize the importance of food and family and celebration and culture? It’s the same for activity. I think it is useful to pay attention to those other areas but it’s also really important for us to recognize the differences. I actually think the most interesting solutions may come from outside health. What are other things out there that are going to change trajectories of other sectors? How might they be considered?
Q: Thank you. There has been a lot of research to redesign a large scalable program for diabetes and obesity prevention. For when those arrive, how do you think we are going to support them? Will this be from payers, government, or others? What do you think is most likely in terms of the logistics of implementing a large-scale intervention?
A: I don’t think that that’s the core question. The core question is how the cost is borne. So you may know that the YMCA now does diabetes prevention and that’s being paid for by United Health, an insurance company. It’s the first time that they’re paying for a service outside of the medical care setting. The Y did its own randomized trial and showed they can have similar effects to the Diabetes Prevention Program (DPP) and is now offering the program in a number of Y locations. United Health has clients who are willing to say that this is important. We can see this spreading, happening through Weight Watchers, churches, and schools are doing it for faculty. To me, right now, this is a natural extension of a fee-for-service model, which is how United Health is doing it. But it could come differently. Under government, if found that it was valuable under Medicare, that could lower overall costs. I would say there are some challenges for any of those.
But the part that I would comment on is that we’ve increasingly good medical care interventions possible. But I believe that the greatest challenge to providing good quality medical care to everybody who needs it is that we have too much disease in our nation and it is occurring too early in our life. So we need to make it fun to be active, not a chore. Healthy food is fun to eat and cool to eat – it’s not a deprivation. Those things will happen outside of healthcare. If I could think of a population measure to show what was happening and in more than just children, it would be age at diagnosis of diabetes. Because we know that it’s moving younger and younger, but as people are becoming more active and watching their weight more, we expect to see the age at diagnosis move up. That could become an early indicator that improvements in obesity is paying off with a decrease in disease.
Q: On a related note, Dr. Marks, we’re increasingly troubled by the incentives for young medical students going into areas where they’ll be addressing a lot of obesity and diabetes – primary care, of course, and other areas like endocrinology. If you could share any thoughts on this front, we would so appreciate it.
A: I think that’s a challenge because that’s caught up in the cost of the healthcare system. Most medical students graduate with a lot of debt, and that makes it hard to go into primary care or low remuneration specialties. They’re counseled on their debt too; they’re told if you’ve got $100,000 in debt, how much it will cost to pay it off, and what that means you can afford in terms of a house, a car, and other expenses. Diabetes as a preventative will not be something that’s ever reimbursed well. I suspect we’ll be moving much more toward mid-level providers: nurses, counselors at the Y doing the prevention work. Depending on the individual, some may need close medical advice, or close medical oversight, and others do not. I think we need to think more holistically as a society. Suppose you went to Walmart and you were prediabetic and their nurse said, “let me go and look at your shopping list and show you how to make changes.” That could be a kind of training that could be easily available at a Walmart. You don’t have to have a physician or even a serious dietitian.
What we want is for physicians to use their skills at the highest and best level and others to do so as well. Physicians have tended to think of medicine as an art, whereas nurses and others are used to following protocols. Lots of things can be developed into algorithms and protocols that will be very effective.
Q: Given the range of different approaches and research supported by the foundation, what’s one project getting started now that we should look out for?
A: I’ll tell you where I think we’ve got to be careful of overexcitement: technology. We get enamored with technology early and the spread is slower than we’d like. For example, ten years ago, they told us we would all by now, by 2010, have an individual genome and targeted therapies for our genome. Not yet. Electronic health records are the next best hope. It has potential, but it will only be realized if the incentives, the payment, the patients, all of that, are aligned in the right way. Otherwise it’s just a large data trove. It offers some simplification for doctors but it doesn’t change the paradigm of high-intensity care. So other social and policy issues will be the big drivers.
If I were to say which one, I think it’s the coming together of sectors of society, and the recognition that health is different from absence of disease. What people want is not health in the way we in healthcare think they want it; they want a good life. I’ve got two grandkids and a third on the way. I want to get to know my grandkids; I want to play with them. I like the work I do; I want to keep working. I may have to take care of the grandkids if their parents work. My best shot to be able to do those things, and to travel, is to maintain my health. Don’t smoke, watch what I eat, exercise, get my flu shots. I talked with L’Oreal in the past, and how do they market a product? They put in the lifestyle that potential customers want. We have to think of health that way. It’s the framing of health as the WHO definition: physical, social, and mental wellbeing. When you have health like that, then you have the best chance for a fulfilling life, warm relationships, a job that’s meaningful, a close family, and a close community. That’s the American dream: equality of opportunity. We’ve got to put health in the middle of that dream instead of framing it as the absence of suffering only. That’s maybe not what you were thinking with that question.
The other part, which I’ll say as my closing, is that people are very concerned about our health and healthcare. The only scientifically defensible position is optimism. A hundred years ago, one in four infants died before their fifth birthday; almost every family had that happen. People used to live 40 to 45 years; they live 30 years longer now. The leading causes of death were diarrhea, respiratory disease, things like that, which are now uncommon causes of death in this country. It’s sort of like the stock market with ups and downs, but the underlying slope is improvement. The problem is that other countries are improving faster at less cost. Our investment in technology is not allowing us to catch up or surpass them because it’s so rapidly dispersed. It’s social policies like healthcare and health insurance that are unique to each area.
Q: Dr. Marks, we can’t begin to thank you enough for sharing your time with us today. Your Foundation is a beacon to all working on public health and we’re so lucky that Obesity Week persuaded you to speak to the many thousands of doctors, nurses, researchers, policymakers, and advocates here and we thank you enormously for spending time with the small group of us as well.
A: Of course – and thank you so much for all you are doing on the public health front as well.
Kevin Grove, PhD (Novo Nordisk, Seattle, WA)
Our team had the valuable opportunity to sit down with Dr. Kevin Grove, who was hard at work during Obesity Week recruiting researchers for Novo Nordisk’s new obesity research center in Seattle, WA. He spoke in broad terms about the company’s strategy for the research unit, saying that he believes the pathways targeted by existing obesity medications represent the “low-hanging fruit” and that his goal is to delve deeper into mechanisms like reward circuits, energy expenditure, and fuel utilization in order to discover novel targets. He elaborated on how the company will want to move toward using human samples during the discovery process, as the applicability of findings from rodent models is often limited. Notably, he also argued that the greatest promise in the field likely lies in combination therapies. In addition, Dr. Grove discussed the mechanisms behind the company’s potential project of glucagon to be used with liraglutide and commented on how Novo Nordisk will want to seek out working with both large recognized institutions and smaller programs. He concluded by alluding to his own research on focusing on maternal health and nutrition during pregnancy to combat childhood obesity, emphasizing that, “if you ultimately want to end obesity and end diabetes, it’s about starting young.”
Q: Dr. Grove, thank you so much for spending time with us today and many congratulations on your new center! We heard you’ve been recruiting for the obesity center at this meeting. Could you say a little about on how that’s going and what you’re looking for?
A: We’re actually looking for a broad distribution of capabilities and levels. We’re recruiting for senior managers, principal scientists – who are the key innovators within scientific programs – down to the research associates, who are actually doing the work on a daily basis. It’s a very unique situation since there’s only one employee on the obesity research side now, and that’s me. But this was also one of the things that attracted me to the position – to be able to join a well-established, highly respected company like Novo Nordisk and build the Obesity Research Unit in Seattle from the ground up was a very unique opportunity. The marketing groups have done an incredible job launching the site for recruiting and I would say it’s been an overwhelmingly positive response with the amount and quality of people who are interested in positions at all levels. We also have the opportunity to collaborate, so we’ve seen communications on both sides of that.
Q: We had the chance to talk with Dr. Mads Thomsen at EASD about the intensified focus on obesity. He was explaining how there need to be new targets compared to what’s currently out there. I know you’re in the early phases right now but could you provide any clues on what kinds of targets Novo Nordisk will be looking at?
A: I can tell you a little about the strategy behind it. Mads is absolutely correct – if you look along the pipelines for all the major companies right now, you see a lot of overlap and commonality. That’s probably the low-hanging fruit. So now, it’s about rolling up the sleeves and getting down to the nitty gritty. A big plan of ours is to use clinical and more sophisticated models to obtain samples and analyses that dig deeper into the underlying mechanisms than what is typically looked at in a target discovery group. Unfortunately, about 95% of the research done in this area is in rodent models and this raises the question about whether or not the rodent model is the most applicable for humans. So if we can use samples from humans and higher species for our discovery base, then we can still use rodent models to validate new targets. In this way we are investigating systems directly relevant to humans - the challenge is obtaining the necessary human samples under appropriately controlled conditions.
Another challenge is how do you do that for the brain? Obviously it is not possible to obtain human brain samples for a discovery program, so we will have to be more creative and use various animals models with sophisticated manipulations to obtain samples relevant to humans. I’m a brain person, so I believe this is a critical component of the discovery plan. Ultimately, we need relevant samples to apply to our “high throughput” screening techniques to identify novel targets. We will use a lot of proteomics, genomics, transcriptomics, metabolomics, and a lot of computing power to guide us.
So I can’t really get into specifics but the things that are driving what we’re looking for are obviously food intake – that’s a critical factor of obesity. Humans are very unique in the ability that we eat when we’re happy, sad, mad, or bummed out, basically all the time. This is primarily driven by the reward value of food, and I think that’s a unique area to try and target. How do we suppress the rewarding values of food and make that drive more manageable? People are much better at cutting down on breakfast, lunch, or dinner. My biggest problem is that I had to outlaw M&Ms in my office area because they’re so easy to eat when you’re tired and you just grab a handful of them. So one area is looking how can you curb that. Another area is energy expenditure: brown fat and looking at heat spillage, which is wasted energy. That has a very proven track record in rodents but its relevance is unknown in humans. So we have to start getting a handle on whether that’s a viable target area: increasing brown fat energy expenditure. The third area that I’m very interested in is called fuel utilization. In fuel utilization, your biggest organ and biggest metabolic tissue is your muscle. We know that exercise is a fantastic way to lose weight but it’s also hard to sustain and often not sufficient. But if you can increase muscle utilization of glucose and fat and use that as a drain on your systems, just like exercise, this might be an opportunity to tap into. Ultimately in the end, it’s going to be a combination of novel targets. Suppressing food intake is not sufficient. Probably increasing energy expenditure by itself may not be sufficient as well. This is likely why there is a big gap between current pharmacotherapies and something like the gold standard of Roux-en-Y gastric bypass. Most of the pharmacotherapies usually only hit one of those targets - and right now it is mostly trying to reduce food intake. So our job is to identify new systems to fill that gap.
Q: In this stage now where you’re growing and building the program, is the main approach going to be to bring researchers together or are you looking for partnerships with big institutions, like other companies established in the obesity space?
A: It’s a good question and it’s going to have to be a balanced approach. There are certainly some very recognized institutes within the US and globally, whom you might easily identify. UT-Southwestern, Harvard, Johns Hopkins, University of Michigan – they all have really great obesity centers. But what you’re missing out with that are the really hard-working small programs that can drive the thinking outside the box. It’s coming to these meetings that allows you to dig deep into those types of science and it’s about being diligent and keeping your eyes open and walking around and seeing posters and being able to say, “wow that’s a really cool idea” and engaging those people. It will be a combination of those factors. Seattle itself, for example, has the University of Washington and some of the top diabetes and obesity researchers. It would be silly to not engage them. But we also have great resources within Novo Nordisk itself. While obesity as a focus is new here, Novo has been doing obesity for a while and it has some real depth of capability around the world. It’s going to be about everybody pulling together and searching the community and using our own discoveries and techniques and also getting out to the community and biotech as well.
Q: Last week, we learned during a company update call that one of the projects post-Saxenda would be a glucagon analog that would be used with liraglutide. We’d love to learn more about that approach.
A: I won’t go into any depth on it but I can talk about the novelty of it. What does glucagon do? It increases hepatic glucose production, so on the surface, it doesn’t make any sense. But there is published data that show that for some reason, when you combine it with GLP-1, it does have very successful weight loss potential. Glucagon and GLP-1 work in the brain differently. Thus, with the combination you're actually hitting two systems at once. But, in reality, we don’t really understand why the animals or human subjects don’t become hyperglycemic when treated with the GLP-1-glucagon combinations. So there is still a long way to go to understand how and why that works. Ultimately, we know that this will become a common strategy for our company, looking at possible combinations to put with GLP-1 agonists.
Q: We assume the research unit will initially be more broadly focused on discovery, but will the approach eventually transition to identifying one target and trying to bring it to patients as quickly as possible or will it remain broad?
A: That’s going to be more of the global effort. Our focus in Seattle will be early discovery, and we’ll be working on multiple targets simultaneously. Novo Nordisk in Denmark will take the lead for the transition to clinical applications because they’re already experts and set up to do that. It’s one thing to identify a protein, but to make that a drug is a different level, and that’s really not my expertise. My expertise is around discovery and looking at the biology behind it so we can identify what the possible efficacy is and what some of the safety issues might be. Novo Nordisk historically is an exceptional protein company, so it doesn’t make sense for us in Seattle to duplicate what they already do in Denmark. However, I believe I get the best part of the job.
Q: We’ve heard speakers point out the wide spectrum of responders in the SCALE trials and say that if we can determine who responds best, that’s our path to personalized medicine for obesity. Will Novo Nordisk do further research into that area?
A: I can’t comment much on that. I can talk about it as a global problem. There are not any therapeutics out there now that work for 100% of the patient population. You always have responders and non-responders, just like you do for diet. That’s really one of the things that I think is an issue we need to focus on. There are several drugs out there, and we know every one has patients that respond really well and some that don’t respond. The question is, are there non-responders that don't respond to anything, or will they respond to another drug target? The concept behind combinations is hitting as many targets as we can to get more complete penetration in the population and getting a greater percentage of patients to successfully lose weight. Humans are not all alike; we all have different backgrounds for the causes of our disease, whether it’s blood pressure or obesity. Think about the strategy for high blood pressure: doctors start patients on something they think will have the most success, and if that doesn’t work, they move to the next one. It’s very much the same in the obesity field. If we can discover predictors, that would be a real opportunity, but we’re still a ways away from that.
We’ll be focusing on combinations to get as many patients as possible.
Q: What are your thoughts about prediabetes? Will that be a focus of your research efforts? How much overlap is there between the two?
A: They go hand in hand for most patients and for most research models as well. We get stuck with some of the regulatory issues as well. For Novo Nordisk in the long term, it seems against what we would think a company would want to do, but ultimately it’s about diabetes prevention. When you’re treating obesity, you’re preventing diabetes at the same time. Our primary indication will be weight loss with the idea that if you improve weight you’re going to reduce diabetes risk. The group in Beijing will continue to look at prediabetes as part of their targets as well. We’ll keep an eye on it but it won’t be our primary indication.
Q: We’ve followed other obesity companies like Zafgen and Rhythm that are pursuing specialty indications, such as for severe obesity. What are your thoughts on the pros and cons of that? Do you think Novo Nordisk will look into severe obesity?
A: I’ve worked with almost every major pharmaceutical company as an academic, and I was part of the early discovery program for the Rhythm compound, so I’m very familiar with that. You have different strategies for large companies vs. small. Clinical trials cost hundreds of millions of dollars. There’s a very significant amount of clinical failure; fortunately Novo Nordisk doesn’t experience as many because we’re a very focused company. When you’re a small company trying to come up with hundreds of millions to get something into the clinic for generalized obesity, that’s very fiscally risky, so it makes sense to get into specialty diseases. For a larger company, I don’t think those sorts of judgments are as relevant. Novo Nordisk has a mandate to improve human health. So our focus in obesity is to develop drugs that will allow patients to safely lose weight, for all patient populations.
Q: Will the gut microbiome be a research target?
A: Absolutely. I recently published a paper on the programming of microbiome. My focus on the academic side is childhood obesity and pregnancy health and nutrition. There’s a lot of talk around the microbiome and its association with obesity but we don’t understand whether it’s a cause or an outcome of obesity and the associated changes. We’d be very remiss not to look at that as an opportunity to take something you might ingest to change the microbiome and cause weight loss. And your gut is your primary immune system; the gut is also the primary source of postprandial signals like GLP-1. Something going into the gut and affecting the microbiome could have a very beneficial effect. Right now I haven’t personally seen data saying it’s absolutely a deadlock target but it’s really fascinating. This is also a situation where human research is very viable. We can get those samples from humans, so my strategy would be looking at humans and how we can affect that. I’m not so certain that rodent models and other preclinical models will give the same answers about the potential safety and efficacy in humans.
Q: We’ve heard people say that one new treatment option could be to combine devices with pharmacotherapies. Do you think that’s a direction the field would move toward? Do you see potential in that at all?
A: I guess my goal for obesity therapies would not be so focused on devices, though they’re certainly used. Gastric banding has had variable successes, but it does work for some people. I don’t think you’d take anything off the table for treating the disease because I do believe if you treat obesity, you treat cardiovascular disease, you treat diabetes, you treat hypercholesterolemia – you treat all these things by treating obesity. We shouldn’t take anything off the table. Right now we don’t have the depth of phamacotherapies, so devices should still be on the table. Even Roux-en-Y gastric bypass has variability in weight loss; why is that? It’s the gold standard but it doesn’t work for everyone, so you have to look at the possibility that maybe a device would work for that patient. Don’t take anything off the table, but it wouldn’t be my primary focus in Seattle looking for the next generation of therapies.
Q: We feel that we may be at the beginning of a trend of obesity medications being used to treat diabetes and vice versa. How valid do you think that is? Is there enough overlap that eventually there could be a lot of medications approved for both?
A: It’s a combination. There are certainly things that overlap; GLP-1 is a good example. I have a patent on a drug that makes you healthier but you don’t lose any weight. The question is, is that a good drug therapy? If you don’t lose weight, it won’t be a weight loss drug but that person will be healthier. That’s a situation where you might prevent and treat diabetes but not treat obesity. I would argue that’s probably a limited market. So there will be drug targets that are specific to diabetes. TZDs are a perfect example; in fact one reason TZDs have had limited success is that they cause weight gain. So, again, you improve diabetes outcomes but not obesity. The patients’ target issues are not always the same. You have to consider that two thirds of the American population is overweight and one third is obese, but 12-15% is diabetic; some may be transitioning, but they’re not one and the same for everything. They’re closely associated and so there’s a lot of overlap, but there are also very specific treatments for the different populations. I’m a believer in putting as many tools in the toolbox for practitioners to treat these diseases because they’re incredibly common.
Q: Will there be cross-communication between obesity and diabetes at Novo Nordisk?
A: Absolutely. There’s just too much strength, history, and knowledge of what they’ve done in diabetes. I’ve worked with the company on the diabetes side for 10 yeas, and there will absolutely be significant overlap between the two sides.
Q: What are you most excited about at this conference?
A: I have to admit that I’ve spent most of my time running around to meetings, so I haven’t had the opportunity to attend many sessions, but one thing that I always love about The Obesity Society is that there’s a lot of really good basic science. I’ve always had a significant weak spot for any developmental or childhood obesity programs. I did just attend a session on that, and I think it has a big role to play in the prevention and understanding of childhood obesity, which is a difficult, challenging therapeutic target because of all the issues around it, but if you ultimately want to end obesity and end diabetes, it’s about starting in young people.
Q: What are your thoughts on the soda tax?
A: We have lunches provided at our site in Seattle and they’re all very healthy. We have soda machines there but the soda machines aren’t free; they actually charge quite a bit. You can still have soda but you have to pay for it as opposed to the free water. We get really nice healthy food, and when you get that for free people are very motivated to take it.
Top-tier Obesity Week sponsor Novo Nordisk’s prominently placed booth did not advertise any specific products, as Novo Nordisk does not yet have an obesity therapy approved at the time (Saxenda [liraglutide 3.0 mg for obesity] has now been approved by the FDA as of December 23). At the booth, sales representatives were eager to discuss the company’s new investment in obesity. Specifically, the literature and sales reps focused on the company’s new obesity research unit in Seattle. It is unfortunate that Saxenda’s FDA decision was pushed just beyond Obesity Week, as the meeting would have been a valuable unveiling for the new product.
As a platinum level sponsor of Obesity Week, Eisai took a large booth occupied a prominent position near the entrance to the exhibit hall, although the crowd was fairly sparse when we stopped by. In its typical coral and navy blue color scheme, the majority of the booth was devoted to touchscreens promoting Belviq (lorcaserin). Additionally, a body composition scanner and a stand presenting clinical trial data took up substantial real estate (as did a smoothie station at the center of the booth – a nice change of pace from all the coffee stands we’re used to seeing at exhibit halls!)
Takeda was present in full-force to spread the word on it and Orexigen’s newly launched obesity medication Contrave (naltrexone/bupropion), with its fairly large booth positioned at one edge of the exhibit hall and displaying a vibrant magenta and orange color scheme. Contrave’s logo (a set of vertical bars in a descending pattern, perhaps representative of the weight loss the product delivers) was stamped on large signs throughout the area – notably, each logo was accompanied by a warning about suicidal thoughts/behaviors and neuropsychiatric reactions. Several touchscreens invited attendees to learn about the drug’s clinical trial data and patient savings program. In addition, a television screen played a presentation describing the Scale Down patient support program, promoting the program’s personalized text messages and wireless scale. For more background on Takeda, please see our quick take of the company’s 3Q14 call last week; to learn more about Contrave, please see our coverage of its approval in September and its launch in late October.
Vivus displayed its signature purple and white booth near the front of the hall, advertising Qsymia (phentermine/topiramate ER) with the text, “significant weight loss for one year in obese patients.” The now-familiar translucent blue rendering of an obese individual stood on posters throughout the booth with a speech bubble exclaiming “significant weight loss that is clinically meaningful.” Pamphlets on Qsymia’s clinical safety and efficacy data were available for attendees along with interactive BMI charts. Much like Takeda’s promotion of Contrave’s Scale Down program, Vivus had a television presentation on Qsymia’s patient support program, Q and Me. We look forward to learning the latest on Qsymia during Vivus’ 3Q14 call this Wednesday – for more background on Qsymia’s performance, please see our 2Q14 report.
-- by Melissa An, Emily Regier, Manu Venkat, and Kelly Close