Hello from the French Quarter! We are back again with our coverage of the final day of the Obesity Week meeting, which wrapped up on Friday. Day #4 was headlined by two exciting poster presentations: Novo Nordisk detailed positive three year results for the phase 3 SCALE trial for liraglutide 3.0 mg in the treatment of prediabetes, and Rhythm Pharmaceuticals announced phase 2 results supporting the efficacy of the novel MC4R agonist setmelanotide in the treatment of leptin receptor deficiency, a rare genetic form of obesity. We also visited an especially lively exhibit hall (where we got our blood pumping by running on anti-gravity treadmills! – Cool, AlterG!).
Below we share our top seven takeaways from this incredible day of learning. In case you missed it, check out our previous coverage of days #1-2 and day #3 of the meeting. We are already looking forward to next year’s Obesity Week in the nation’s capital!
Top Seven Highlights
1. The three year results of Novo Nordisk’s phase 3 SCALE trial were presented in poster form, demonstrating the potential of the GLP-1 agonist liraglutide to produce weight loss and health-related quality of life improvements in people with prediabetes.
2. Rhythm Pharmaceuticals presented a poster detailing positive initial phase 2 results supporting the safety and efficacy of the novel and potentially first-in-class melanocortin-4 receptor (MC4R) agonist setmelanotide in the treatment of leptin receptor (LepR) deficiency obesity.
3. A symposium on the effects of diet and exercise on weight loss evolved into an indirect debate between Dr. David Ludwig and Dr. Kevin Hall on the importance of macronutrient content versus simple caloric content for weight loss.
4. Dr. Holly Wyatt (University of Colorado, Aurora, CO) emphasized one of the biggest challenges for patients living with obesity and their clinicians –maintenance of weight loss. She is so smart.
5. A symposium on engaging minorities in weight programs reinforced, yet again, that there is no one-size-fits-all solution to weight loss in light of the vast racial, ethnic, and cultural diversity in American society.
6. Director of the Burke County School Nutrition Program Ms. Donna Martin (Waynesboro, GA) provided an inspiring presentation on the initiatives she implemented to improve nutrition in public schools in her county.
7. Obesity Week featured a bustling exhibit hall headlined by expansive booths from Novo Nordisk and Eisai, as well as an anti-gravity treadmill demo from AlterG.
Top Seven Highlights
1. The three year results of Novo Nordisk’s phase 3 SCALE trial were presented in poster form, demonstrating the enormous potential of the GLP-1 agonist liraglutide to produce weight loss and health-related quality of life improvements in people with prediabetes. A multinational population of individuals with prediabetes and overweight or obesity were advised to adopt lifestyle changes (500 calories/day reduction and ≥150 min/week exercise) and randomized to receive either once-daily liraglutide 3.0 mg (n=1505) or placebo (n=749). Individuals treated with liraglutide were significantly more likely to achieve categorical weight loss over three years, with 25% losing between 5-10% body weight, 14% losing between 10-15% body weight, and 11% losing ≥15% body weight (versus 14%, 7%, and 3% of individuals on placebo, respectively). This is remarkable to see how well the “super-responders” are doing, three years out. 40% of individuals on placebo gained weight over the course of the trial, as compared to under 15% of those treated with liraglutide. Furthermore, across both the liraglutide and placebo treatment arms, with greater categorical weight loss came significantly larger improvements in health-related quality of life (as measured by the IWQOL-Lite questionnaire, measured on a 100-point scale; p <0.001). From an overall baseline IWQOL score of ~71, individuals who lost up to 5% body weight (n=554), 5-10% body weight (n=358), 10-15% body weight (n=201), and ≥15% body weight (n=132) respectively increased their scores by an average of approximately seven, 10, 13 and 16 points. These results highlight the promise of liraglutide as a treatment for prediabetes – a condition that is present in epidemic proportions (86 million people in the US alone), but for which there are currently no approved therapies. Although the fact that liraglutide is already approved for both diabetes (as Novo Nordisk’s Victoza, a 1.0 mg dose) and obesity (as Novo Nordisk’s Saxenda, a 3.0 mg dose) represents an important advantage in acquiring a prediabetes indication, we continue to strongly believe that far more work is necessary (e.g., getting prediabetes guidance from FDA) before any progress could be made on this front.
- The SCALE trial is distinctive in its use of quality of life outcomes. To echo the sentiment of the recent FDA workshop on outcomes beyond A1c, we are pleased to see outcomes beyond body weight beginning to emerge in the obesity/prediabetes arena. Clearly effective obesity and prediabetes care involves so much more than pure weight loss, and we should strive for pharmacotherapies that, like liraglutide, improve the lives of individuals on top of their weight benefits. One key would be proving quality of life is connected to adherence – of course we know this is true, but it’s got to be proven.
2. Rhythm Pharmaceuticals presented a poster detailing positive initial phase 2 results supporting the safety and efficacy of the novel and potentially first-in-class melanocortin-4 receptor (MC4R) agonist setmelanotide in the treatment of leptin receptor (LepR) deficiency obesity. LepR deficiency obesity is an ultra-rare orphan disease, affecting ~1% of individuals with severe, early-onset obesity (between 500-2,000 Americans, according to Rhythm’s estimates); currently there is no approved treatment for LepR deficiency obesity. The poster detailed data for the first patient enrolled in this open-label clinical trial, who experienced substantial reduction of both weight and hunger. With setmelanotide treatment, the LepR patient lost almost 20% body weight over the course of 22 weeks (56.4 lb weight loss from a baseline of 288 lbs). Furthermore, the patient experienced a substantial reduction in subjective hunger from a baseline of 9 (on a 0-10 Likert scale with 0 representing no hunger and 10 representing extreme number) to 1.5. Setmelanotide was well-tolerated with no severe adverse events reported. These results provide important proof-of-concept for setmelanotide’s potential to treat this orphan disease. Rhythm is currently in the process of enrolling more candidates into the clinical trial in hopes of demonstrating setmelanotide’s effectiveness in more LepR patients. This same trial was recently featured in the New England Journal of Medicine for showing sustained and steady weight loss (~4 lbs/week) and marked hunger reduction with setmelanotide in two patients with a different rare form of genetic obesity, pro-opiomelanocortin (POMC) deficient obesity. As we heard from Dr. Lee Kaplan (Massachusetts General Hospital/Harvard Medical School, Boston, MA) at a symposium on promising novel therapies in obesity care on Day #1 of the conference, several other genetic obesity conditions are characterized pathophysiology downstream of the melanocortin 4 receptor that setmelanotide targets, suggesting that this drug may have even broader applicability beyond LepR and POMC deficient obesity.
- To complement this clinical trial, Rhythm has also launched the Genetic Obesity Project to support greater genotyping and diagnosis of genetic forms of obesity, such as POMC and LepR deficiency. The spectrum of the presentation of genetic obesities is not well-understood, and it is very plausible that a substantial proportion of people with obesity may have a form of the disease that is setmelanotide-responsive.
3. A symposium on the effects of diet and exercise on weight loss evolved into an indirect debate between Dr. David Ludwig and Dr. Kevin Hall on the importance of macronutrient content versus simple caloric content for weight loss. Dr. Ludwig (Boston Children’s Hospital, Boston, MA) is well known as a champion of the carbohydrate-insulin model, which points to high-carb, low-fat diets as the culprit for the nationwide rise in obesity. He emphasized that major evidence for this point of view comes from five recent meta-analyses, all of which demonstrate inferiority of low fat diets compared to higher fat diets for weight loss. (Specifically, a 2015 meta-analysis in Lancet, demonstrating that low-carbohydrate diets led to significantly greater weight loss [weighted mean difference of 1.15 kg] than low-fat diets in a review of 18 recent weight loss trials.) Dr. Ludwig also reviewed animal and human studies showing less fat accumulation and faster metabolic rate on higher fat and low glycemic index diets. Dr. Hall (NIH, Bethesda, MD), by contrast, hypothesizes that fat loss is a balance of fat intake and net fat utilization. He believes that although reduced carbohydrate intake shifts the body into a fat oxidation mode, it does not equate to fat loss. He qualified his retort by stating that many of his points actually coincided with the carbohydrate-insulin model, save for a few key details. However, Dr. Hall did have room for a caveat – although he disagreed with the assumptions of the carbohydrate-insulin model, he conceded that there may be positive health effects of reduced carbohydrate intake that do not relate to energy expenditure.
- To conclude the symposium, Dr. Barry Braun (Colorado State University, Fort Collins, CO), not a participant in the contentious diet debate waged by the previous speakers, added physical activity to the discourse. Surveying an extensive literature and prior work from his laboratory, he emphasized that the physical activity, meaning both habitual exercise and a single exercise session, alters the response to nutrients, especially carbohydrate. Prior exercise and training both sensitize the body to insulin and hasten the process of clearing glucose from the blood. Conversely, post-exercise nutrition changes the effectiveness of the exercise to sensitize the cells to insulin, so that following exercise with a high carbohydrate load appears to rapidly reverse the exercise benefits on insulin sensitivity. These results reinforce the interconnections between exercise and the energy and carbohydrate content of the diet in preventing obesity-related metabolic disease.
4. Dr. Holly Wyatt (University of Colorado, Aurora, CO) emphasized one of the biggest challenges for patients living with obesity and their clinicians – maintenance of weight loss. Conference hall attendance is usually indicative of what the “hot button” issues are in conference, and this session was no exception. As with other popular sessions, this one began with a full conference hall, with every seat occupied, attendees lining the walls, and some even sitting on the floor in the aisles. One challenge surrounding the issue of weight loss maintenance, according to Dr. Wyatt, is the lack of a clear definition of precisely what weight loss maintenance is, leading to ambiguous conclusions about long-term trends. In discussing the major contributing factors for weight loss versus weight loss maintenance, Dr. Wyatt noted that at first, caloric intake is the largest contributing factor to acute weight loss. However, physical activity was implicated as the largest contributing factor for maintenance. Regarding effective strategies for weight loss maintenance, she recommended obesity pharmacotherapies. By targeting the phenomenon of metabolic adaptation, these drugs excel at promoting weight loss maintenance (much more so they than do at promoting initial weight loss).
- The most memorable line from Dr. Wyatt's presentation was a critique of what she perceived as complacency in setting weight loss goals. She explained that "losing as much weight as you can in a finite period of time and THEN maintaining it works better. We are setting the bar too low." This assertion came from her unique perspective of serving as the medical expert in the reality television show "Extreme Weight Loss," where transformative weight loss yielded the best long-term results.
- Also of note, Dr. Wyatt's reviewed a recent publication in the February issue of Obesity which highlighted the effects of water and non-nutritive sweetened (NNS) beverages in the context of weight loss maintenance. Over the course of this one year study, participants assigned to consume 24 ounces per day of beverages sweetened by non-nutritive sweeteners (versus caloric sweeteners) maintained 6.21 kg weight loss versus 2.45 kg in the group assigned to consume 24 ounces of water daily (n=303, p<0.001). Both study groups consisted of obese (BMI=~33-34), mostly female (~80%) individuals. These results suggest that NNS beverages can be an effective tool for weight loss maintenance – perhaps providing a more palatable alternative for individuals who find it difficult to reduce their consumption of sugar-sweetened beverages.
5. A symposium on engaging minorities in weight programs reinforced, once again, that there is no one-size-fits-all solution to weight loss in light of the vast racial, ethnic, and cultural diversity in American society. Dr. Nia Mitchell (University of Colorado, Denver, CO) reviewed the results of the recently-completely SWITCH (Senior Wellness Initiative and TOPS [Take Off Pounds Sensibly] Collaboration for Health), a project designed to address obesity in African American women over the age of 50. According to Dr. Mitchell this is the demographic most likely to develop obesity, due to a combination of cultural views about acceptable body weight and unavailability of culturally-sensitive weight loss interventions (for context, 82% of African American women were overweight or obese in 2014). Through a low-cost series of peer-led weekly meetings featuring lessons on nutrition and exercise, the project showed preliminary success: the program had an impressive 79% retention rate after 52 weeks, and after one year 33% lost up to 5% of their initial body weight, and 48% lost over 5% of their initial body weight (n=48). Next, Dr. Flavia Mercado (Emory University, Atlanta, GA) presented strategies to engage the Hispanic community in weight loss programs – a prominent issue because only 5% of physicians are Hispanic, and the rate of obesity in Hispanic populations is twice that of non-Hispanics. Dr. Mercado underscored the importance of reducing early childhood obesity among Hispanics by educating families on obesity in a culturally-sensitive way and knowing how to tailor this messaging for particular communities (“not all Spanish is the same”). Finally, Dr. Nicolette Teufel-Shone (University of Arizona, Tucson, AZ) explored strategies that Native American communities have developed to address weight loss. Dr. Teufel-Shone emphasized that because the Native American community has strong social cohesion, the best strategies to promote healthy choices would be team challenges, engaging leadership and visibility, and changing community norms and tribal policies. Overall, these presentations thoughtfully illustrated that various communities view obesity in nuanced and different ways, so obesity management interventions must be tailored thoughtfully for each unique group.
6. Director of the Burke County School Nutrition Program Ms. Donna Martin (Waynesboro, GA) provided an inspiring presentation on the initiatives she implemented to improve nutrition in public schools in her county. Going above and beyond the guidelines for healthy school lunches stipulated in the Healthy Hunger Free Kids Act of 2010, Ms. Martin spent a great deal of effort in establishing initiatives such as serving 65 types of fruits and vegetables each week, redesigning cafeterias to be brighter and more attractive places to eat lunch, and offering spice stations for students to substitute sodium in food. As director of the largest rural county in the state, we were so pleased when Mr. Martin remarked that the children in her county are eating more fruits and vegetables than their parents (!) and that the healthy food now available in Waynesboro schools is sourced from local farms. Of course, carrying out and sustaining these initiatives has had its challenges – most notably the labor costs required to train employees to make so many diverse meals from scratch. Changing the perception of young children to enjoy eating whole grains, fruits, and vegetables is another challenge, but Ms. Martin noted that even simple acts such as cutting up fruit beforehand creates more appeal for students. “There’s plenty to eat,” Ms. Martin remarked, “but the problem is that kids are eating pizza and French fries all the time so they’re not used to that.” For the sustainability of these programs and their successful implementation across the country, Ms. Martin called for more research on school nutrition, especially since the perception of school nutrition has been largely negative and unhealthy. We are inspired by this example of policy change to combat the obesogenic environment that unfortunately pervades a majority of US school cafeterias.
7. Obesity Week featured a bustling exhibit hall headlined by expansive booths from Novo Nordisk and Eisai, as well as a fascinating anti-gravity treadmill demo from AlterG. Below we describe some of the most notable exhibits we visited:
AlterG’s relatively minimalistic booth highlighted its centerpiece: the anti-gravity treadmill, which, bottom line, is very cool. The booth itself was difficult to locate, and almost symbolic of AlterG’s recent foray into the world of obesity care. Our conversation with the booth representatives told a narrative of an initial target market of professional athletes for the anti-gravity treadmill. The company then expanded to the world of physical therapy, and around 2010, this expanded once more to providing a resource for people with obesity. “All of the gain, none of the pain” was the slogan of choice, and we were delighted to have the opportunity to test this for ourselves. The treadmill, markedly larger than a conventional treadmill, had all of its familiar staples – the start/stop buttons, the settings for speed, and the settings for incline percentage. (Yeah, we do this in our office.) The distinguishing factor was the setting that adjusted the percentage of the user’s body weight. Prior to stepping onto the machine, the user put on a pair of compression shorts called a “skirt” that served to form an airtight seal with the treadmill apparatus. It operated on the principle creating an air pressure differential – the higher the air pressure levels within the seal, the lighter the user would feel. (AlterG’s technology allows users to unload up to 80% of their weight – roughly equivalent to the weight one would experience on the moon!) During the test run, there was a discernible difference in weight-bearing, as lower weight percentage settings decreased the load on joints and tendons to the extent that it made higher speeds and inclines much easier. After the test run, we were pleasantly surprised to find that the most information-dense pamphlet was a packet that summarized the clinical research involving the anti-gravity treadmill. Although most of these studies were not nearly as large or as comprehensive as conventional clinical trials (but who cares!), we remain optimistic that this innovative treadmill will eliminate many of the barriers that impede adherence to physical activity programs in individuals with obesity, and provide an avenue through which patients can gradually gain self-confidence about exercise in a less physically-taxing way.
Eisai displayed a large booth adorned with its classic red, white, and blue color scheme. Signage was dedicated to both Belviq (lorcaserin) and the recently released once-daily version, Belviq XR (lorcaserin extended-release). On one side, the booth featured tall touch screen displays with information on the drug’s clinical data, safety information, and patient support programs. In addition, pamphlets outlining drug details as well as reimbursement details with the company’s savings card were dispersed throughout the booth. Warmly welcoming representatives were more than happy to share information on Belviq and Belviq XR, also offering delicious healthy smoothies . On the other side of the booth, representatives sat behind a bar to answer any more specific questions about Eisai’s portfolio of obesity products.
Johnson & Johnson’s Ethicon had an impressively large and interactive booth. Underneath a revolving header inscribed with the Ethicon logo, representatives displayed the company’s line of products, headlined by an assortment of suture-assistant devices. A separate area of the booth was dedicated to Johnson & Johnson’s 7 Minute Workout App, giving attendees (and Close Concerns associates!) an opportunity to try out some of the app’s suggested short workouts as a respite from sitting in oral presentations all morning. Kelly’s family follows this app at home and loves it. We also refreshed ourselves with hydrating glasses of fruit-infused water and energizing freshly-made oat bars. Ethicon’s booth certainly emulated the company’s goal of shaping the future of surgery and creating innovative solutions in health care. This was further evidenced by a series of Ethicon-sponsored presentations over the course of Obesity Week on current and new approaches to the duodenal switch, building the successful and thriving bariatric program, and the potential of bundled payments resulting in increased bariatric surgery, all of which drew large audiences.
In contrast to Medtronic’s diabetes product line, the line of products displayed at Obesity Week’s exhibit hall was geared towards largely toward bariatric surgeons. The simple slogan, “Take a stand against obesity” sought to appeal to the surgeons’ role in dramatically improving patient outcomes through bariatric surgery. We’d love if this slogan could be a bit more broadly interpreted – c’mon, management, we’re counting on you! For example, one of Medtronic’s featured products, the ReliaTack articulating reloadable fixation device, claimed “superior access, stronger fixation, and lower cost of care.” With regards to reducing cost, the device accompanied the ReliaTack line of reloadable tacks, which dramatically increased the reusability of the tacking tool without requiring the purchase of a new tool after a limited number of tacks. This seemingly intuitive feature is again indicative of a growing trend of cost-effective quality of care, this time from the provider perspective. While we look sort of forward to learning more about Medtronic’s line of bariatric surgery devices in future conferences, we also look forward to learning how they are going to address obesity at a population level. The company is certainly a giant in the diabetes arena and it needs to generate similar success in the realm of obesity.
Unsurprisingly, Novo Nordisk dominated the exhibit hall, featuring two front-and-center booths each with an enthusiastic crowd of visitors. One booth at the very entrance – by far the biggest display in the exhibit hall – was dedicated entirely to Saxenda (liraglutide 3.0 mg). On its hanging posters, the booth boasted that Saxenda is “the first and only GLP-1 agonist” approved for chronic weight management with its ad featuring a woman holding up a pair of old larger jeans that are inscribed with “excess weight,” “high cholesterol,” “large waistline,” and “high blood pressure” (hinting toward the drug’s improvement in comorbidities). In the background, a video played discussing the “science of Saxenda,” and the mechanism by which GLP-1 receptors act. “It’s not about the will” to lose weight, the video explained, “it’s about having a way.” A second large both in the center of the exhibit hall was decorated in Novo Nordisk’s classic blue color scheme featuring a sign urging visitors to “rethink obesity.” Another display showed a diagram of the human body, indicating that obesity’s comorbidities affect nearly every organ system, and that even modest 5-10% weight loss can significantly reduce the risk of such comorbidities. The booth further featured a tea bar accompanied by an array of healthy snacks – a welcome change from the sugary fare found in most conference exhibit halls. The company’s commitment to obesity is clear, and we hope Saxenda’s continued high revenues can reinvigorate the stagnant obesity market and convince payers of the value of obesity pharmacotherapies.
Orexigen’s small booth contained a table with two sales representatives available to speak about the company’s obesity portfolio. The booth was unbranded, with no mention of Takeda-partnered Contrave (naltrexone/bupropion).
-- by Abigail Dove, Sam Haque, Jennifer Zhao, and Kelly Close