Obesity Week Executive Highlights
Greetings from Boston, where winter is definitely on its way. Our team has just wrapped up the first two days of the second annual Obesity Week, where The Obesity Society (TOS) and American Society for Metabolic and Bariatric Surgery (ASMBS) have teamed up to provide six full days on the latest and greatest in obesity research and care. The conference has so far had a packed agenda, featuring presentations from the likes of Dr. Lee Kaplan (Massachusetts General Hospital, Boston, MA) and Dr. Philip Schauer (Cleveland Clinic, Cleveland, OH) on topics ranging from pharmacotherapies to the state of the art in metabolic surgery. Below, we bring you our top ten highlights (along with an honorable mention) from these first two days and check out our conference preview to see what’s coming up throughout the rest of the week.
1. We heard enthusiastic commentary regarding the advantages of Vivus’ Qsymia (phentermine/topiramate), Arena/Eisai’s Belviq (lorcaserin), and Novo Nordisk’s Saxenda (liraglutide 3.0 mg for obesity) from several speakers during a session on non-surgical approaches to weight management.
2. Zafgen CEO Dr. Thomas Hughes (Zafgen, Cambridge, MA) discussed the therapeutic potential of the company’s lead anti-obesity candidate beloranib in a presentation of positive phase 2 data.
3. Dr. Christopher Still (Geisinger Health Care System, Danville, PA) forecast that endoluminal devices (like GI Dynamics’ EndoBarrier) could eventually win out over drugs for obesity.
4. Several speakers suggested that providers could prescribe generic obesity medications over more expensive branded combinations.
5. Obesity KOL Dr. Lee Kaplan (Massachusetts General Hospital, Boston, MA) discussed the impact of the gut microbiome on the broad rage of physiological effects resulting from bariatric surgery.
6. Dr. Carel Le Roux (University College Dublin, Dublin, Ireland) discussed the future potential of personalized medicine and “medical bypass” treatment for obesity, involving diet, lifestyle, and drugs.
7. Several speakers argued that baseline beta cell function is the most important determinant of type 2 diabetes remission following bariatric surgery.
8. Dr. Francesco Rubino (King’s College, London, UK) 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.
9. Bariatric surgery expert Dr. Philip Schauer (Cleveland Clinic, Cleveland, OH) argued that current guidelines recommending surgery only for patients with a BMI >35 kg/m2 are arbitrary, recommending a lower absolute threshold and a more individualized approach.
10. A forum on the food industry featured lively discussion of the public health benefits and practical challenges associated with nutrition labeling requirements.
Top Ten Highlights
1. We heard enthusiastic commentary regarding the advantages of Vivus’ Qsymia (phentermine/topiramate), Arena/Eisai’s Belviq (lorcaserin), and Novo Nordisk’s Saxenda (liraglutide 3.0 mg for obesity) during a session on non-surgical approaches to weight management. Dr. David Tichansky (Jefferson Surgical Center, Philadelphia, PA) commented that “Qsymia basically rivals lap banding” after Dr. Christopher Still (Geisinger Health Care System, Danville, PA) showed efficacy data demonstrating up to 13% mean weight loss with the drug. Dr. Still labeled Belviq as the best-tolerated obesity drug, noting that it has the lowest discontinuation rate in its clinical studies out of all the available next-generation pharmacotherapies. He also expressed excitement for Saxenda, claiming that it will be a great option for patients with both obesity and diabetes, with the only downside being the need for injections (which may hurt patient adherence).
2. Zafgen CEO Dr. Thomas Hughes (Zafgen, Cambridge, MA) 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 as the company looks like an emerging force in the obesity market. Please see our coverage of the company’s 2Q14 update (its first as a publicly traded company) for more detail and commentary on the company’s latest business and pipeline developments.
3. At another point in the day, Dr. Christopher Still boldly commented that “endoluminal devices are going to beat out pharmacotherapies” for obesity. Even if these devices can deliver better efficacy, it is hard to compare the convenience of a pill to anything else, although these devices may be best for patients beyond the reach of drugs but not quite at the level of full-scale bariatric surgery. Dr. Stacy Brethauer (Cleveland Clinic, Cleveland, OH), in an update on novel devices with metabolic implications, noted that the EndoBarrier leads to good control of diabetes but will likely face challenges with payers, particularly due to the need for re-implantation. The presentation also covered the ReShape Duo intragastric balloon, highlighting its usefulness as a bridge to surgery by helping bariatric patients with their pre-surgery weight loss (results from a pivotal trial on this device will be presented on Tuesday morning).
4. We heard arguments from several speakers supporting the prescription of generics over branded obesity medications. For instance, Dr. James Mitchell (University of North Dakota, Fargo, ND) noted that most of the components of new obesity medications like 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. Dr. Still recommended prescribing generic phentermine for patients who cannot afford Qsymia. He noted that as long as patients are regularly monitored, generic phentermine is a “very safe medication,” though providers should be cautious about tolerability by slowly increasing the dose starting at 15 mg. We were surprised to hear such a vehement argument in this vein from the podium of a major medical meeting, and we worry that some providers may not understand the differences in formulation (release timing, etc) between the branded combination therapies and generic monotherapies. Still, cost does remain a major barrier for many patients, as well as an understandable cause for frustration for some providers.
5. Obesity expert Dr. Lee Kaplan (Massachusetts General Hospital, Boston, MA) discussed the hot topic of the gut microbiome and its impact on the broad range of physiological effects resulting from bariatric surgery – he recently spoke at an ADA/JDRF research symposium dedicated to the topic of the gut microbiome (read our highlights from day #1, day #2, and day #3 of the meeting). 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.
6. Looking toward the future, Dr. Carel Le Roux (University College Dublin, Dublin, Ireland) 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.
7. Drs. Sangeeta Kashyap (Cleveland Clinic, Cleveland, OH) and Josep Vidal (Hospital Clínic Universitari, Barcelona, Spain) argued that baseline beta cell function appears to be the most important determinant of type 2 diabetes remission following bariatric surgery. They 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 could be an option for diabetes patients that are not quite at the BMI threshold for bariatric surgery, and perhaps may not be as effective in securing diabetes remission in the patient population in which it is most greatly used: patients with severe obesity and longstanding diabetes. Turning to the choice between different procedures, Dr. Vidal cited evidence that gastric bypass surgery leads to higher rates of diabetes remission and sustained weight loss compared to sleeve gastrectomy.
- 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. In a separate course on pharmacology, Drs. Marjan Sadegh and Kevin Zinchuk (Brigham and Women’s Hospital, Boston, MA) also recommended close follow-up to prevent hypoglycemia in the post-bariatric-surgery patient population. As general guidelines for patients post-surgery, they suggested discontinuing sulfonylureas in the immediate post-operative period as well as stopping or reducing doses of oral agents in those who do not require insulin.
8. Dr. Francesco Rubino (King’s College, London, UK) 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 be contributing 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 mechanisms such as duodenal-jejunal bypass can improve oral glucose tolerance.
9. In a forceful yet familiar argument, bariatric surgery expert Dr. Philip Schauer (Cleveland Clinic, Cleveland, OH) 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 30-35 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.
- In a separate session, Dr. Robert Kushner (Northwestern University Feinberg School of Medicine, Chicago, IL) explained that the data was not strong enough to lower the BMI threshold at the time of creating the 2013 AHA/ACC/TOS obesity guidelines. 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 than diet, lifestyle, and pharmacotherapies to their patients.
10. A forum on the food industry featured lively discussion of the public health benefits and practical challenges associated with nutrition labeling requirements (such as those required by the Affordable Care Act). Foodservice industry representative Ms. Deanne Brandstetter (Compass Group North America, Charlotte, NC) discussed how communication of nutritional information can be incredibly challenging, as there is enormous variability in the calorie content of restaurant meals as well as an increase in customizable menu options. Dr. Christina Roberto (Harvard School of Public Health, Boston, MA) offered a rebuttal to the widespread perception that calorie labeling on restaurant menus has been proven ineffective; she argued that the existing (and fairly limited) body of research on the topic is essentially mixed, with some studies showing no effect of such labels on customers’ caloric intake and others showing a slight positive impact. In her view, the evidence thus far is promising enough to make such policies worth pursuing; 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 meaningful benefits.
- Speakers addressed the issue of how to most effectively convey nutritional information to consumers. In particular, there was some debate among attendees over the effectiveness of “traffic light” labeling systems that mark products as good (green), bad (red), or neutral (yellow). Ms. Geraldine June (EAS Consulting Group, Alexandria, VA) suggested that such systems might be too simplistic and fail to account for consumers’ individual needs, but Dr. Roberto argued that they could be a good replacement for the current “clunky” nutrition facts labels that are less user-friendly.
- In addition, several speakers and attendees suggested that the most meaningful impact of menu labeling requirements may come from their influence on industry rather than on consumer behavior. As an 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 instead offer more fruits and vegetables. Such impacts remind us of the potential benefits of the San Francisco Bay Area’s soda tax proposition – please see our deeper dive into this additional example of public health policy to learn more.
Honorable Mention
- Dr. Walter Pories (East Carolina University, Greenville, NC) stressed that insulin resistance is not directly related to insulin levels. Expressing frustration with endocrinologists who give obese patients with diabetes large amounts of insulin (supposedly in order to overcome insulin resistance), he presented data showing reduced insulin doses following bariatric surgery despite no change in insulin resistance. Dr. Pories argued that insulin interferes with gluconeogenesis and might raise mortality, and should therefore be used as conservatively as possible.
-- by Melissa An, Emily Regier, Manu Venkat, and Kelly Close