American Diabetes Association 74th Scientific Sessions

June 13-17, 2014; San Francisco, CA – Obesity – Draft

Executive Highlights

This ADA was quieter on the obesity pharmacotherapy front (in contrast to ADA 2013, which was a pretty busy conference for obesity as the first ADA after the launch of Vivus’ Qsymia [phentermine/topiramate ER] and Arena/Eisai’s Belviq [lorcaserin]). As a surprise, there were no abstracts on Qsymia this year, for example. The new data that was presented on anti-obesity pharmacotherapies centered on their ability to treat prediabetes and prevent type 2 diabetes – we’re very glad to see data move in this direction. Data on this front was presented at ADA for Belviq (99-OR) and Orexigen/Takeda’s Contrave (bupropion/naltrexone; 1046-P), and Novo Nordisk announced such data for its liraglutide 3.0 mg a few days later at ENDO. We think this focus on the prevention of obesity comorbidities will be more commercially successful than prior messaging centered on broader weight loss messages, since it could help gain more coverage by payers and side-step a general culture in which HCPs don’t view obesity as a medical condition requiring pharmaceutical treatment. Indeed, Orexigen has indicated that it/Takeda’s launch plans for Contrave especially target people with prediabetes and type 2 diabetes (including potentially developing a DPP-4/Contrave fixed-dose combination). If Contrave and Novo Nordisk’s liraglutide 3.0 mg are approved by the FDA this year (Contrave PDUFA date and liraglutide Advisory Committee are both September 11), we think the obesity pharmacotherapy area will be particularly interesting at the next ADA. The meeting will offer some hints on how invested Takeda and Novo Nordisk are in these agents (how much floor space in the exhibit hall will each dedicate to their respective drug?) and if they can make larger strides in this underdeveloped market than Vivus and Eisai have mustered so far.

In our report below, talks that we thought were particularly notable are highlighted in yellow; those that were not included in our daily coverage are highlighted in blue.

Table of Contents 

Obesity

Oral Presentations: New Developments in Clinical Obesity

Liraglutide 3.0 mg for Weight Management in Obese/Overweight Adults with Type 2 Diabetes: Results from the SCALE™ Diabetes 56-Week Randomized, Double-Blind, Placebo-Controlled Trial (97-OR)

Melanie Davies, MD (University of Leicester, United Kingdom)

Building on topline results originally released in March 2013, Dr. Melanie Davies offered a comprehensive overview of the phase 3a results from the 56-week SCALE Diabetes trial, which assessed the efficacy of Novo Nordisk’s liraglutide 3.0 mg for weight management in 846 overweight or obese adults with type 2 diabetes. At baseline, study participants had an average weight of 105.9 kg (223 lbs.), BMI of 37 kg/m2, and A1c of 8.0%. Treatment with liraglutide 3.0 mg led to significantly greater weight loss at 56 weeks compared to placebo. Specifically, participants in the liraglutide 3.0 mg arm achieved an average weight loss of 5.9% from baseline, compared to 4.6% with liraglutide 1.8 mg and 2.0% percent with placebo. Treatment with liraglutide 3.0 mg also resulted in clinically meaningful reductions in A1c level as well as in systolic blood pressure. The most common side effects were gastrointestinal issues like nausea and diarrhea. Liraglutide was generally well tolerated, with no new safety signals identified.

  • Essentially half (49.9%) of the participants randomized to liraglutide 3.0 mg achieved at least 5% weight loss, compared to 35.0% with liraglutide 1.8 mg and 12.7% with placebo. In the liraglutide 3.0 mg arm, 22.1% achieved weight loss of at least 10%, compared to 13.3% of those given liraglutide 1.8 mg and 3.8% of those given placebo.
  • Participants in the liraglutide 3.0 mg arm achieved an average reduction in A1c of 1.3%, compared to an average reduction of 0.4% in the placebo arm. At 56 weeks, 72.3% of participants in the liraglutide 3.0 mg arm and 22.9% of participants in the placebo arm achieved an A1c of 7% or lower. Participants in the liraglutide 1.8 mg arm experienced an average A1c reduction of 1.1%; 69.6% of participants in the liraglutide 1.8 mg arm achieved an A1c of 7.0% or lower.
  • Participants in the liraglutide 3.0 mg and 1.8 mg arms experienced greater improvements in systolic blood pressure compared to participants on placebo, with a mean reduction of 3.5%. There were no differences in diastolic blood pressure between the liraglutide and placebo arms.
  • Dr. Davies commented that there were no pancreatitis events observed during the trial. She stated that there was a mean increase of 10 units in lipase activity within the liraglutide arms.
  • No fatal adverse events occurred, with the exception of one death that occurred after the study due to stroke. 92.9% of participants taking liraglutide 3.0 mg reported adverse events (8.8% serious, 12.3% severe, and 9.2% leading to withdrawal). Nausea, diarrhea, constipation, and vomiting were the most common adverse events. By 24 weeks, most all nausea events were resolved.
  • Dr. Davies pointed out that participants on sulfonylurea background therapy had higher incidences of hypoglycemia. For participants on sulfonylurea background therapy, 43.6% in the liraglutide 3.0 mg arm experienced symptomatic hypoglycemic episodes, compared to 27.3% in the placebo arm. For participants not on background sulfonylurea therapy, 15.7% in the liraglutide 3.0 mg arm experienced symptomatic hypoglycemic episodes, compared to only 7.6% in the placebo arm. Less than 3% of participants on sulfonylurea background therapy and liraglutide 3.0 mg experienced a severe hypoglycemic episode.
  • No differences in safety and tolerability were observed between liraglutide 3.0 mg and 1.8 mg, except for gastrointestinal adverse events. 65% of participants in the liraglutide 3.0 mg arm reported having gastrointestinal issues (e.g.,  nausea and diarrhea), whereas only 56% of participants in the liraglutide 1.8 mg arm and 39% in the placebo arm experienced GI adverse events.

Questions and Answers

Q: Can you tell us more about the participant who died?

A: This patient died after the 52 weeks of the study. The death was 44 days after the trial ended, so about six weeks later. It was a male in his fifties who had cardiovascular complications and he had a stroke. We don’t believe it had to do with the treatment.

Q: Have you thought about the weight loss being due to the sulfonylureas?

A: We haven’t compared that yet, but the majority of participants were not on sulfonylurea therapy.

Q: Can you comment on the side effects of nausea with regards to the weight loss seen early on?

A: The percentage of nausea seen was about 15%. There is some suggestion that nausea and GI side effects may correlate with weight loss, but we haven’t specifically looked at this in the study. Overall though, the rates of nausea are relatively low compared to other GLP-1 agonists.

Early Diabetes Remission After Gastric Bypass Surgery is Explained by Exclusion of the Foregut (101-OR)

John Kirwan, PhD (Cleveland Clinic, Cleveland, OH)

Dr. John Kirwan presented a clever study suggesting that exclusion of the foregut in roux-en-y gastric bypass (RYGB) is key to the surgery’s glycemic effects. The Cleveland Clinic team, including famous bariatric surgeon Dr. Philip Schauer, placed G-tubes in the excluded stomach during the RYGB procedures of 14 people with obesity and type 2 diabetes (average BMI of 49.2 kg/m2, and A1c of 7.5%). The G-tube enabled researchers to conduct mixed meal tolerance tests (MMTTs) as if the foregut had not been excluded during the procedure. Compared to a pre-operative oral MMTT, both post-operative MMTTs caused a greater level of insulin secretion, with the oral MMTT causing the greatest amount of secretion. Similarly, the post-operative oral MMTT identified the greatest levels of C-peptide secretion and beta cell function. In contrast, a similar degree of improvement in insulin resistance was seen for both the oral and the G-tube post-operative MMTTs. These results suggest that adaptations arising from the foregut exclusion might provide a key mechanism for understanding diabetes remission after RYGB. The idea that skipping the upper intestine may remit diabetes suggests that a bad actor in the upper intestine might be involved in the etiology of the disease. Such a factor may be considered an “anti-incretin” – i.e., an intestinal peptide that causes diabetes instead of improving it.

  • The trial enrolled 14 people with obesity and type 2 diabetes who were undergoing RYGB. The average A1c was 7.5%, and BMI was 49.2 kg/m2. Eleven of the participants were women. Overall, participants had an average age of 46.5 years, and type 2 diabetes duration of 7.7 years.
  • When people received an oral MMTT post-operation their insulin response area under the curve (AUC; ~7,000 uu/mlŸ3hr) was significantly greater than either the G-tube MMTT (~4,000 uu/mlŸ3hr) or the pre-operation RYGB (~1,000 uu/mlŸ3hr). Similarly, people’s C-peptide AUC was greater during the post-operation oral MMTT (~2,000 ng/LŸ*3hr, than either the post-operation G-tube MMTT or the pre-operation MMTT (both ~1,000 ng//LŸ*3hr. In line with this, pancreatic beta cell function was found to be significantly better with the post-operation oral MMTT than for either the pre-operation MMTT or the post-operation G-tube MMTT (which had similar levels of function to one another).
  • Participants’ fasting blood glucose levels, fasting plasma insulin, and insulin resistance levels were similar whether the MMTT was delivered either orally or via the G-tube.
  • The idea that skipping the upper intestine may remit diabetes suggests that a bad actor in the upper intestine might be involved in the etiology of the disease. Such a factor may be considered an “anti-incretin” – i.e., an intestinal peptide that causes diabetes instead of improving it. In the past, we have heard that a potential anti-incretin has been identified: the NP266 peptide, which when virally overexpressed in mice increases fasting plasma glucose and deteriorates glucose tolerance. It is silenced in mice by duodenal jejunum bypass. It is elevated in the blood of obese humans and is reduced after RYGB. It is also overexpressed specifically in the intestines of animals with type 2 diabetes and is silenced by bypass.

Questions and Answers

Q: You mentioned the incretin effect – it has been proposed that could be glucagon or GIP. Did you look at those?

A: We do not have data on glucagon yet. We have debated whether we would go there. We are not sure how strong a role glucagon is playing. GIP and GLP-1 are obviously major candidates here. GLP-1 measurements show a pattern that is similar to insulin – an increase in GLP-1 with the oral administration, and regression with the G-tube. We have published some of these data where we see strong effects of GLP-1. In our animal studies there is some role that needs to be considered for the foregut. Particularly attractive I think is some kind of anti-incretin.

Q: Did you look at gastrin levels?

A: We have not measured gastrin in these patients. That could be a compensatory mechanism. It leaves a lot of work to be done.

Oral Presentations: New Developments in Clinical Obesity

Lorcaserin Can Improve Weight Loss in Patients with Prediabetes and Reduce Progression to Diabetes in Obese and Overweight Patients

William Soliman, PhD (Eisai, Woodcliff Lake, NJ)

Dr. William Soliman presented results from a post-hoc analysis of two trials (BLOOM and BLOSSOM) from Eisai’s Belviq’s (lorcaserin) phase 3 program showing that Belviq significantly reduced progression from prediabetes to type 2 diabetes (when diagnosis was defined by A1c but not by fasting plasma glucose) and also increased regression from prediabetes to euglycemia (when diagnosis was defined by A1c or fasting plasma glucose) over 52 weeks. Specifically, in patients with prediabetes at baseline as defined as A1c between 5.7-6.4% (n=2,256), only 3% in the lorcaserin arm progressed to type 2 diabetes compared to 7% in the placebo arm (p<0.017); in addition, 40% in the lorcaserin arm achieved euglycemia compared to only 30% in the placebo arm (p<0.001). However, in patients with prediabetes at baseline defined by FPG (n=1,133), the difference between lorcaserin and placebo for progression from prediabetes to type 2 diabetes was not statistically significant (2% on lorcaserin vs. 3% on placebo; p=0.327). Nonetheless, significantly more patients on lorcaserin still achieved euglycemia (52%) compared to patients on placebo (47%). Overall, these results suggest to us that lorcaserin’s effect on diabetes progression is somewhat modest – certainly longer-term analyses that would provide larger sample sizes of people progressing to type 2 diabetes would strengthen the association.

Posters

Sustained-Release Naltrexone/Bupropion Improves Glucose Control in Individuals with Prediabetes (1046-P)

P Hollander, B Walsh, K Gilder, A Halseth

This poster highlighted the greater weight and glycemic benefits of treatment with naltrexone/bupropion (NB; Orexigen’s Contrave) vs. placebo in overweight and obese subjects who had impaired fasting glucose, and not type 2 diabetes.  The study analyzed data for a subset of participants from the Contrave Obesity Research (COR) program, which consisted of four multicenter, 56-week, Phase 3 studies in overweight and obese individuals. All subjects received either 32 mg naltrexone sustained-release/360 mg bupropion SR or placebo. At the end of 56 weeks, people taking NB lost significantly (p <0.001) more weight than the control group (9% vs. 5%). Regarding NB’s glycemic effects, the NB ended the study with a greater fasting plasma glucose reduction of 11 mg/dl compared to PBO’s 7 mg/dl (p <0.013). The mean fasting insulin level dropped 30.4% in the NB arm. In contrast, in the control group, it only decreased 12.9% (p <0.002). We are encouraged by these results, and hope to soon see data on whether or not these improvements in glycemic measures in people with prediabetes on Contrave conferred a reduced risk of progressing to type 2 diabetes.

  • The analysis included 284 overweight or obese participants with impaired fasting glucose but not overt diabetes. Results from three out of four COR program phase 3 studies were used – COR-I, COR-II, and COR-BMOD – but the COR-DM study was omitted as it included only individuals with diabetes. From these trials, only individuals with baseline fasting plasma glucose between 100 and 126 mg/dl were included in the analysis. As a result of these criteria, the analysis only examined a small subset of the COR program’s initial enrollees, 284/4031 or 7%.
  • Baseline characteristics were similar between the NB and placebo groups. At baseline, both groups had a mean age of 51 years and a mean BMI of 37 kg/m2. In the placebo group, 68% of participants had dyslipidemia and 29% had hypertension, compared to 69% and 39%, respectively, for NB.
  • Participants in the NB group demonstrated greater weight loss along with better improvements in glycemic indices. The NB group had a mean weight loss of 9% from a baseline of 104 kg (229 lbs.), compared to 5% from 102 kg (225 lbs) baseline for the placebo group. In the NB group, FG decreased from 111.1 to 100 (-11.1 mg/dl) compared to a decrease from 109.4 to 104 mg/dl (-5.4 mg/dl) in the placebo group. Fasting insulin levels decreased by 30.4% in the NB group compared to 12.9% in the control, with similar baselines of 15.5 and 15.3 micro IU/ml, respectively. Insulin resistance (as measured by HOMA-IR) improved by 37.4% in the NB arm compared to -18.6% in the placebo arm; the baseline HOMA-IR was similar between groups, 4.2 and 4.1, respectively.

Symposium: Obesity in Our Youth

Drug Therapies for Pediatric Obesity

Lorraine Katz, MD (University of Pennsylvania, Philadelphia, PA)

Dr. Lorraine Katz presented favorable data on sibutramine and Orlistat for the treatment of adolescent obesity. Dr. Katz emphasized that the chronic nature of obesity calls for long-term pharmacotherapy. She showed that pharmacotherapy must be combined in treatment with lifestyle modification, presenting data that concurrent sibutramine and behavioral therapy led to larger BMI reductions (9%) than behavioral therapy alone (-6%). A trial of Orlistat for adolescent obesity also showed a modest mean BMI reduction of 1% over 52 weeks. Dr. Katz then reviewed the adult clinical data on Orlistat, lorcaserin (Arena/Eisai’s Belviq), and phentermine-topiramate (Vivus’ Qsymia), regarding weight loss and adverse events. Looking to the future, Dr. Katz underscored the need for more studies of pharmacotherapies in adolescents.

  • According to NHANES 2007-2008, fewer than 3% of adults take prescription medications for weight loss. Dr. Katz dispelled the many concerns regarding weight loss medications, stating that while the treatments are expensive, their reimbursements is improving. Additionally, she thinks that obesity is becoming more widely accepted as a disease. Similarly, she acknowledged the concern that these medications are dangerous by explaining that cardiovascular complications are being carefully examined.
  • Orlistat is the only drug currently approved for the treatment of obesity in people ages 12 years and older. Neither Arena/Eisai’s Belviq (lorcaserin) or Vivus’ Qsymia (phentermine-topiramate) are approved for children. Dr. Katz felt that these agents are a “long way off from pediatric approval.” This is because she thinks that the FDA will want to see more long-term cardiovascular outcomes data before exploring pediatric uses.
  • Dr. Katz explained that pharmacotherapy modifies the internal environment while lifestyle modification modifies the external environment. More specifically, pharmacotherapy affects the user’s hunger, food preoccupation, satiation and nutrient absorption. At the same time, lifestyle modification can alter exposure to foods, cues to eat, dietary restraint, and physical activity. Together, these modifications can create an additive effect.
  • Dr. Katz ended by highlighting several considerations that should be taken when prescribing weight loss medications. Firstly, although reimbursement is improving, the drugs currently cost $3-5 per day, and this often must be paid out of pocket. Secondly, lingering safety concerns still exist and data on the agents’ long-term use are needed. Lastly, Dr. Katz also mentioned that patients may have unrealistic weight loss expectations with medications. 

Surgical Therapies for Pediatric Obesity

Thomas Inge, MD, PhD (University of Cincinnati, Ohio)

Dr. Thomas Inge presented a strong case for the surgical treatment of pediatric obesity with data that such therapy can dramatically reduce BMI and associated comorbidities. Dr. Inge presented data on adolescent roux-en-Y gastric bypass (RYGB) surgery, in which mean BMI was reduced by 37%. Examining multiple studies, however, he pointed out the “fixed” effect, in which all subjects experience weight loss of about 35%, regardless of their starting BMI. Dr. Inge then presented data from the FABS-5 study, which investigated the long-term effects of RYGB surgery in adolescents. He found that people tended to sustain long-term weight loss, low fasting plasma glucose levels, and lower incidence of type 2 diabetes. However, nutritional health effects were mixed. Overall, Dr. Inge’s presentation provides a push towards surgery as an effective weight loss intervention.

  • According to Dr. Inge, 32% of children in the US are overweight, 16% are obese, and 5% are severely obese. He stated that only 2% of severely obese children respond to weight loss interventions, stressing the need for more intensive options like surgery.
  • Dr. Inge presented the idea of “surgery as biological therapy,” given it affects many different biological mediators of obesity. For example, gastric bypass surgery increases GLP-1, oxyntomodulin, and decreases leptin. Similarly, sleeve gastrectomy increases insulin secretion and gastric emptying among other effects.
  • “We may have been too conservative in 2004 when we recommended to only intervene with surgery in cases of BMI greater than 50 kg/m2,” Dr. Inge remarked. Dr. Inge explained that a “window” of opportunity exists to reverse severe pediatric obesity, since surgery reduces BMI the same amount regardless of the starting BMI. Therefore, this effect calls for intervention at a lower BMI rather than a higher BMI, if one is to bring a severely obese individual down to a healthy weight.
  • The FABS-5 study looked at people who underwent RYGB surgery as adolescents in 2001-2007. These people were compared to participants who had high BMIs as adolescents. These people were followed up with in 2011-2013. The study’s results showed long-term effects in favor of RYGB surgery. While the non-operated subjects gained 6% in BMI over eight years, RYGB patients maintained a BMI reduction of 33%. Ninety-four percent of RYGB patients had fasting plasma glucose levels <100 mg/dl compared to 82% of the non-operated subjects. From baseline to follow-up, diabetes incidence for RYGB patients dropped from 16% to 2%, while incidence for non-operated subjects remained at 10%.
  • There were mixed results on the prevalence of micronutrient deficiency at eight years between the RYGB and the non-operated participants. For example, 60% of RYGB subjects had hypoferritinemia (having a low amount of ferritin) compared to 7% of the non-operated subjects. Similarly, 45% of RYGB patients had anemia compared to 4% of the non-operated people. More RYGB patients had elevated PTH levels (51%) than non-operated subjects (26%). On the other hand, RYGB subjects fared better than non-operated subjects in low mean corpuscular volume (MCV; mean volume of a red blood cell) and low folate. Specifically, 19% of RYGB participants had low MCV (which can result from anemia) compared to 40% of non-operated subjects. Two percent of RYGB subjects had low folate whereas 22% of non-operated subjects suffered from this deficiency.
  • Dr. Inge also showed that sleeve gastrectomy has comparable weight loss effects to RYGB surgery – about a 35% BMI reduction. He also explained that sleeve gastrectomy is technically easier than other operations, having no GI anastomosis and mesenteric defects. In this procedure, the GI tract is also accessible to endoscopy and vitamin and mineral absorption is not altered. Sleeve gastrectomy also has the ability to convert the procedure to two other operations if necessary.

Questions and Answers

Q: Has there been any long-term follow-up for sleeve gastrectomy regarding weight loss? What are your thoughts on the comparison between gastric bypass surgery and sleeve gastrectomy?

A: There is no such pediatric data, but there are data from adult studies that show a 15-20% failure rate similar to gastric bypass surgery. Fundamentally, it’s probably the same outcome. In terms of the two types of surgery, we present data on both sides and we’re the honest broker. We don’t really know which one’s better yet, so we don’t declare one better than the other.

Q: What are your thoughts on surgery for hypothalamic obesity?

A: Bypass surgery tends to look better for the long term, compared to sleeve gastrectomy and band for hypothalamic patients.

Symposium: FGF21 in the Pathogenesis of Obesity

FGF21 and PPARs in the Regulation of Metabolism

David J. Mangelsdorf, PhD (UT Southwestern, Dallas, TX)

Dr. Mangelsdorf honed in on the manipulation of FGF-21 as a therapeutic mechanism. FGF-21 expression is regulated by PPARs and is induced in high levels in the liver, white adipose, brown adipose, and pancreas. Its action decreases fat storage, increases fatty acid oxidation, and increases energy expenditure, with pharmacologic administration in mice and primates suggesting beneficial effects in insulin sensitization, glucose/triglyceride/LDL levels, and weight reduction. However, administration has also been associated with bone loss, elevation of glucocorticoid levels, and inhibited female reproduction. By selectively knocking out beta-Klotho, a component of the heteromeric tyrosine kinase receptor that binds to FGF-21, Dr. Mangelsdorf was able to localize the insulin sensitizing effects of FGF-21 to the white adipose tissue and the weight reducing effects to the brown adipose tissue. Further experiments localized FGF-1’s effects on growth, female reproduction, and glucocorticoid levels to the suprachiasmatic nucleus in the brain. While it is unclear if this will apply in humans, hopefully the tissue-specific action of FGF-21 will allow for targeting of the protein’s beneficial effects while limiting its deleterious action – as a reminder, BMS currently has a PEG-FGF21 listed in development (phase 1), with both Amgen and Pfizer (PF-05231023; phase 1; human data presented here at ADA 2014 in 126-OR) also previously noted to be investigating the target.

Questions and Answers

Q: Can you tell us more about the circadian release of FGF-21?

A: In animals there is a circadian release of FGF-21 in relation to the feeding level; studies in humans are still out. I’m not sure what’s going on.

Symposium: Stop Eating – Why That Prescription Does Not Work

Simplifying the Complex When It Comes to Clinical Care

Judith Wylie-Rosett, EdD, RD (Albert Einstein College of Medicine, Bronx, NY)

Dr. Judith Wylie-Rosett offered three strategies for the improvement of the clinical care of obese populations: (i) simplify the message, (ii) tailor the intervention to the patient, and (iii) share the decision-making with patients. To her point on simplifying the message, Dr. Wylie-Rosett brought up examples of how the new MyPlate graphic in the US and food labeling in the UK are not reaching certain demographic groups, and are not always effective in encouraging healthy behavior. For example, only 60% of Americans recognize the MyPlate graphic, of which are mostly women and college graduates. Regarding tailoring the intervention, Dr. Wylie-Rosett showed data identifying personal styles of lifestyle patterns (regarding eating, exercise, and coping) and discussed the effectiveness of using computer algorithms for goal setting guidance, which was described in the Models of Demonstrating and Evaluating Weight Loss (MODELS) study. Dr. Wylie-Rosett closed her talk by suggesting that clinicians consider incorporating the Canadian Obesity Network’s 5As (Assess, Advice, Agree, Assist, and Arrange) into their therapy, as well as motivation- and barrier-focused counseling to more effectively share the decision making with patients.

  • Eighty-three percent of Americans say they’re trying to eat more vegetables – a statistic that demonstrates that healthy diet campaign messages are reaching people in the US. However, Dr. Wylie-Rosett  emphasized that the simple proliferation of this message is not enough and does not necessarily reflect action. In particular, she highlighted that the message is not reaching men and low-income populations.
  • We need to make it “cool” to eat fruits and vegetables, according to Dr. Wylie-Rosett. Dr. Wylie-Rosett highlighted the HealthCorps School Project, a campaign designed to encourage teenagers to make healthier choices for themselves and their families. In particular, this program attempts to drive higher-level public health policy changes and is currently concerned with the high proportion of teenage students who skip breakfast before school. Their goal is to make eating breakfast the norm by identifying what would make it more socially acceptable to eat breakfast. 
  • Dr. Wylie-Rosett emphasized that communication with children requires “simplifying the message.” In order to help parents engage their children regarding behavioral changes, Dr. Wylie-Rosett developed Kid WAVE, an educational game designed to promote goal setting and enhance motivation. The game is targeted to overweight preadolescents age six to 11 years and attempts to make self-efficacy fun and engaging.
  • Dr. Wylie-Rosett emphasized that the use of computer algorithms to encourage behavioral change can be effective. This is particularly true if the focus is on personal style intervention and goal-setting guidance to mediate healthier eating habits. As evidence of these intervention’s efficacy, Dr. Wylie-Rosett cited the MODELS study. In this trial an intensive treatment that featured a counselor plus computer program resulted in an average weight loss of 7.4 pounds (3.4% of body weight).
  • Dr. Wylie-Rosett noted the great potential of phone apps as a method of simplifying pediatric diabetes management, and emphasized that current applications leave much room for improvement. Only 3.2% of weight loss apps endorsed physical activity strongly (“strongly” was defined as clear messaging that encouraged at least one hours of exercise per day). Similarly, only 1.6% of apps strongly encouraged eating fruits and vegetables, only 4.8% strongly encouraged eating a daily breakfast, and less than 2% strongly encouraged limiting fast food and take-out meals.
  • Dr. Wylie-Rosett encouraged the use of obesity counseling that incorporates the Canadian Obesity Network’s 5As: Assess, Advise, Agree, Assist, and Arrange. Citing the infrequent use of this technique, she also emphasized the potential of motivation- and barrier-focused counseling in sharing the decision-making process with patients in order to improve outcomes.

Questions and Answers

Q: Do you have any information about certain types of phone apps being more effective than others? There is a lot of excitement about one app, in particular, in which users can take pictures of food and compare it to other pictures in order to gauge caloric information.

A: It’s certainly a promising option for engagement children early. But think about the time that takes. These apps need to get simpler. Something that just requires a user to check a box would be much more effective.

Corporate Symposium: Type 2 Diabetes Mellitus and Obesity: Accepting the Challenges, Applying New Guidelines, and Defining Solutions to Optimize Patient Care (Supported by Novo Nordisk)

Accepting and Classifying Obesity as a Disease

Arya Sharma, MD (University of Alberta, Edmonton, Canada)

Dr. Arya Sharma pushed for the classification of obesity as a disease and illustrated the complexity of obesity, including its heterogeneity,, effects on health, and response to treatment. He underscored that obesity is a chronic and progressive condition that requires life-long treatment. Dr. Sharma explained the many flaws of BMI and its poor ability to predict myocardial infarction risk. Providing an alternative to BMI, he described the Edmonton Obesity Staging System (EOSS), which he and Dr. Robert Kushner (Northwestern University Feinberg School of Medicine, Chicago, IL) developed, and which has been shown to predict mortality more effectively than BMI.

  • The EOSS consists of five stages. Each of these stages is classified based on effects within the medical, mental, and functional arenas, with stage zero being the least severe and stage four being the most severe. For example, medical, mental, and functional effects are all absent in stage zero while they are all end-stage in stage four.
  • EOSS was shown to predict mortality in the NHANES III study. BMI classification, which includes overweight through class III obesity (BMI 40-49.9 kg/m2), showed little differentiation in mortality rate. On the other hand, EOSS stages zero through four had significantly different proportions surviving in each stage.
  • AACE also created a staging system for classifying obesity and its treatment. This model consists of both an anthropometric component (e.g., BMI) and a clinical component (complications).

Applying New Guidelines for Obesity Management

Holly Wyatt, MD (University of Colorado Denver, Denver, CO)

Dr. Holly Wyatt provided encouragement and direction to physicians on treating obesity. She pointed out recent advances in the field such as CMS’ reimbursement of behavioral interventions for obesity, AMA’s recognition of obesity as a disease, and the growing number of obesity pharmacotherapy options. Dr. Wyatt emphasized the need for lifestyle modifications, pointing out that they are the foundation of many obesity treatment models. She ended by discussing the rationale for weight loss medications, highlighting that these are an adjunct to lifestyle intervention and cannot be used alone.

  • Dr. Wyatt discussed the three major guidelines in obesity treatment: (i) AHA/ACC/TOS obesity guidelines, based on NHLBI evidence review, (ii) AACE/TOS/ASMBS obesity guidelines, and (iii) AACE obesity guidelines. She noted a few differences in these approaches. For example, the AACE obesity guidelines stage patients based on severity of complications and treatment intensity is based on staging.
  • “If you’re going to be good at treating diabetes, you must be good at treating obesity,” Dr. Wyatt emphasized. Throughout the discussion, she urged attendees to understand the importance of managing patients’ obesity and its high correlation with diabetes and other complications.

Corporate Symposium: Obesity Medicine: Brain, Behavior, and Targeted Therapeutic Management

The Neurological and Neurophysiological Mechanisms Involved in Obesity

Donna Ryan, MD (Pennington Biomedical Research Center, Baton Rouge, LA)

Dr. Donna Ryan started the symposium presenting on the neurological basis of obesity and how we can use this knowledge for more effective patient care. Opening with an emphasis on the severity of obesity (due to its rising prevalence and associated medical costs), Dr. Ryan explored why obesity is so hard to treat. Leptin deficiency and resistance were discussed, as well as other peripheral signals such as ghrelin and PYY. The brain regulates food intake via both the homeostatic and reward systems. Both these systems, Dr. Ryan explained, may be dysregulated in obesity. She also highlighted the genetic component of obesity, mentioning the growing number of identified risk alleles. Additionally, Dr. Ryan discussed the physiology of a person who has lost weight, explaining that such people experience a reduction in resting energy expenditure (REE) and changes in peripheral signals such as leptin and ghrelin. Dr. Ryan wrapped up her presentation by translating these findings into more effective patient communication. She emphasized that HCPs should not put all of the burden on patients, noting that the provider’s role is to “teach skill-building.” Dr. Ryan also noted that CMS will pay for 14 lifestyle intervention visits over six months for Medicare members who are obese. Dr. Ryan sees a slow movement towards encouraging providers to work on weight loss.

  • Leptin is a protein produced by fat tissue that mirrors total body fat stores and acts as a “satiety hormone.” Dr. Ryan stated that in very rare cases, obesity can be explained by congenital leptin deficiency, which can be treated by r-metHuLeptin. However in most cases, obese individuals have high leptin levels, meaning leptin is not having an impact on food intake. Therefore, the obesity may be due to leptin resistance.
  • fMRI studies show that the homeostatic and reward systems may be dysregulated in obese people. The homeostatic system consists of the hypothalamus and related neurocircuitry that regulates hunger and satiety through peripheral signals. The reward system is a diffuse circuitry that involves the prefrontal cortex and can sometimes override the homeostatic system. Results of fMRI studies have shown that obese individuals respond differently to food cues, in which the reward system often dominates. In addition, gliosis in the hypothalamus has been observed in obese individuals.
  • Dr. Ryan explained that after having lost weight, the individual has a metabolic handicap, which means that weight reduction leads to a reduction in REE. This reduces one’s metabolic requirements, making it more difficult to maintain weight loss. Similarly, in the reduced obese state, weight reduction affects signals that regulate food intake. Appetite signals such as ghrelin disproportionately increase and satiety signals, such as leptin and PYY, decrease. Therefore, weight loss becomes extremely difficult due to these problems in both energy expenditure and appetite regulation.
  • Dr. Ryan also addressed the genetic risk factors of obesity, showing that homozygous twins share the same body type more frequently than do heterozygous (fraternal) twins. Additionally, she highlighted how more risk alleles are being identified, with approximately 100 currently known. One study demonstrated that BMI increases with the number of neuronal risk alleles, illustrating a clear genetic component to obesity.
  • Referring to the NHANES study, Dr. Ryan showed how simply discussing a patient’s weight can have huge benefits on their prognosis. Patients who had such a conversation with their HCP were much more likely to desire to weigh less and make attempts to lose weight. Acknowledging that discussing obesity and overweight issues with patients is sensitive, she suggested HCPs initiate the conversation asking “Can I talk about your health and how your lifestyle is affecting it?” or “Can we talk about your weight?”
  • According to Dr. Ryan, three popular commercial programs that have strong evidence are Weight Watchers, Nutrisystem, and Jenny Craig. These programs can provide counseling via the web, telephone, or in-person and offer a variety of structured diet options.
  • Dr. Ryan noted that the HCP can have the role of prescribing medications, if necessary, regardless of the lifestyle intervention implemented.
  • Dr. Ryan was a proponent for meal replacements. She noted that one meal replacement a day (any meal that has a known caloric content) has been found to sustain weight loss more effectively than no meal replacements. Other factors that help sustain weight loss include continued behavioral intervention, continued medication use, as well as bariatric surgery.

Current and Emerging Pharmacotherapeutic Treatments for Obesity

Timothy Garvey, MD (University of Alabama at Birmingham, AL)

Dr. Timothy Garvey discussed the improvements in body weight, glycemic control, and blood pressure associated with weight loss medications as an adjunct to lifestyle intervention programs. While Dr. Garvey presented results that showed that weight loss drugs paired with lifestyle changes tend to produce significantly greater weight loss as compared with lifestyle changes alone, he was careful to note that weight loss drugs might not be the optimal therapy for everyone who is overweight or obese. He described various guidelines that can provide a framework for deciding when weight loss drugs might be appropriate, including the AACE obesity algorithm. Dr. Garvey also highlighted a relatively recent expansion in treatment, as both Arena/Eisai’s Belviq (lorcaserin) and Vivus’ Qsymia (phentermine/topiramate ER) were approved by the FDA in the summer of 2012. He concluded by discussing two drugs currently being evaluated by the FDA – Orexigen/Takeda’s Contrave (naltrexone/bupropion) and Novo Nordisk’s liraglutide 3.0 mg. Contrave’s PDUFA is September 11, while an Advisory Committee meeting is being held for liraglutide the same day.

  • Dr. Garvey presented data from clinical trials of Contrave and liraglutide, both of which are being evaluated by the FDA for indications as weight loss drugs. He noted that both may be approved for use in the US as early as the end of 2014. As background, the FDA requested a cardiovascular outcomes trial for Contrave, because blood pressure reductions associated with the use of the drug were less than anticipated with the weight loss tied to the drug. With regards to liraglutide, Dr. Garvey mentioned that nausea was reported in about 40% of patients taking the drug, but that side effects were manageable in most patients. It was also observed that high dose liraglutide might contribute to increased glycemic control as compared with other weight loss drugs, as a result of the incretin action of liraglutide. In the Q&A session, Dr. Garvey addressed this point, stating that a greater proportion of people taking high dose liraglutide are able to reach a goal A1c of 7% or lower, from an A1c of about 8%, than those taking other weight loss medicines.
  • Dr. Garvey highlighted the difficulty in deciding when it is appropriate to prescribe weight loss medicines, as compared to situations when weight management might best be addressed through lifestyle changes. He was careful to note that all weight loss medications have the same FDA indications, which include people with a BMI ≥30 kg/m2, or those with a BMI between 27 and 30 kg/m2 who also have a weight-related comorbidity. Dr. Garvey stated that it is best to discontinue the use of any weight loss medication if weight loss is less than 5% after 12 weeks on the maximal dose.
  • Dr. Garvey described the AACE obesity algorithm as a potential framework for making decisions regarding weight loss prescriptions. This algorithm first evaluates the complications associated with obesity in an individual, as well as the stage severity of those complications, in order to decide specific targets for improvement. Based on the targets chosen, patients and providers can implement a weight loss program of appropriate intensity. According to the AACE algorithm, weight loss medications should be used if the target values for complications have not been reached by the time the individual’s weight is at equilibrium following adherence to the specified weight loss program. Dr. Garvey also noted that weight loss drugs are always contraindicated during pregnancy.
  • Dr. Garvey touched briefly on the powerful ability of weight loss drugs to improve glycemic control and slow the progression toward type 2 diabetes. He stressed the application of weight loss drugs in individuals with prediabetes and metabolic syndrome in order to prevent diabetes, and also in those with type 2 diabetes to improve A1c levels. Dr. Garvey suggested that weight loss drugs can be so effective in promoting glycemic control in some individuals with type 2 diabetes as to decrease the need for more “conventional” type 2 diabetes drugs.

Questions and Answers

Q: How long should you maintain pharmacotherapy in patients with a positive response, and what is the rate of obesity recurrence like upon stopping pharmacotherapy?

Dr. Garvey: Right now, the data suggests that when you withdraw the weight loss medication, the patient often regains weight back to the level that would have been observed with lifestyle changes alone. Preliminary results seem to suggest that we really need to maintain pharmacotherapy over the lifetime of the patient to prevent weight regain following therapy. In reality, we need to develop more clinical based data and determine long-term strategies for reasonable treatment plans. In some people, if they have really made some lifestyle changes that are hard-wired, it might be possible to take those people off the medication at some point. It may be true in some people that it is necessary to stick with the medicine chronically, or it may be possible to administer pharmacotherapy for weight loss and maintenance intermittently over the long term. At this point, we really don’t have the data to answer that question with any certainty.

Q: What about drug-drug interactions?

Dr. Ryan: The main issue is with MAOIs. We don’t have a lot of evidence on lorcaserin with antidepressants. Otherwise, with anti-diabetic medications, the important thing to remember is that when you put people in negative REE, insulin requirements are greatly reduced. You must stop administering insulin and SFUs before you start the patient in negative REE. Otherwise, you’ll get hypoglycemia.

Q: If a patient were using liraglutide 3 mg for weight loss, could it be combined with metformin for even greater weight loss?

Dr. Garvey: I think so. You would probably see additive weight loss in a combination treatment with metformin and high-dose liraglutide. We don’t have data from any clinical trials for that combination at this point, but I think that would be the case.

Q: Do you think that using high-dose liraglutide might have even greater benefits where glycemic control is concerned than other weight loss medicines, given its indication as a drug for type 2 diabetes?

Dr. Garvey: I think some of that data is going to be announced at this meeting, in fact there was a company announcement that preceded this session which included some of that data on one slide. With high-dose liraglutide, we see a greater number of people achieve their goal of an A1c of 7% or lower, from an A1c of about 8%, than those taking other weight-loss medications. This is likely due to the incretin action of liraglutide, which is a GLP-1 receptor agonist. This suggests that glycemic control might be slightly enhanced by combining a GLP-1 receptor agonist with a weight loss drug.

Q: Do you feel that there is clinical inertia regarding weight-loss medications?

Dr. Ryan: I don’t think we use these medications enough. The FDA is extremely cautious – look at all the unapproved weight supplements. And physicians have been burned in the past. Now is the time to look at this again and to really become educated. For patients who need to lose weight, not for cosmetic purposes but for health purposes, and who are willing to put effort into it, these can be adjuncts.

Q: Are there concerns that more patients might choose not to make lifestyle changes in favor of weight loss medications as an easier way?

Dr. Ryan: These weight loss medicines serve to reinforce the patient’s efforts to change their lifestyle. They help to limit appetite, so that if the patient is making an effort to create and maintain a calorie deficit, the weight loss drug can reinforce that effort. It is true that it is possible to lose a bit of weight with a weight loss drug alone without any effort to diet, but to maximize weight loss the patient must also make an effort to lose weight by limiting calorie intake.

Q: Do artificial sweeteners disrupt the balance of satiety and hunger?

Dr. Ryan: A recent study compared the effects on weight loss of replacing sugar sweetened beverages with water or with artificially sweetened beverages, by randomizing subjects to either approach. Weight loss was shown to be slightly greater after six months in the group consuming artificially sweetened beverages. I will say that I've had my fair share of diet soda, and I haven’t lost a pound. I think that in some ways the body compensates for the decrease in calories associated with a switch to artificially sweetened beverages. At this point, there is no real evidence that replacing sugar-sweetened beverages with artificially sweetened beverages might thwart weight loss efforts.

Q: If this is about genetics, why is there a difference in obesity prevalence over the last 30 years?

Dr. Garvey: Genes are interacting with each other, with the environment, and with behavior. What we’re seeing is the obesogenic nature of environment. These environmental differences are bringing out more obesity in those with these certain genetic profiles.

Product Theater

A Novel Treatment Option for Chronic Weight Management (Sponsored by Eisai)

Farhad Zangeneh, MD (Diabetes and Osteoporosis Clinic, Sterling, VA)

Dr. Farhad Zangeneh gave a thorough presentation on Arena/Eisai’s Belviq (lorcaserin) as a new treatment option for obesity, illustrating its mechanism of action, efficacy, and safety. Dr. Zangeneh opened by stressing the need for a multifaceted approach to treating obesity due to the disease’s polymorphic and heterogeneous nature. Dr. Zangeneh also pointed out the need to improve the classification of obesity, beyond relying only on BMI. In explaining Belviq’s mechanism of action, he walked through serotonin’s role in weight management. Although not yet entirely understood, Belviq is believed to decrease food consumption and promote satiety by selectively activating 5-HT2C receptors in the hypothalamus. Turning to Belviq’s clinical studies of BLOOM, BLOSSOM, and BLOOM-DM, Dr. Zangeneh showed that statistically more Belviq users lost 5% and 10% of their baseline body weight compared to placebo. Those taking Belviq also showed improvements in glycemic control, lipid profile, and blood pressure. Regarding safety, the most common adverse reactions in people with diabetes were hypoglycemia (since SFUs and insulin levels need to be reduced when people lose weight), headache, and back pain; in those without diabetes, the most common adverse events included headache, dizziness, and fatigue. In closing the product theater, Dr. Zangeneh quoted Winston Churchill, “success is going from failure to failure without losing enthusiasm.” He went on to proclaim that although the field still has far to go in obesity treatment, it is moving forward with Belviq as a worthy option. We were glad to see his emphasis that longer trials are needed; that said, we are not confident that industry will have the resources to fund them.  

  • Belviq is indicated as an adjunct to a reduced-calorie diet and increased physical activity and is for adults with an initial BMI of 30 kg/m2 or greater, or 27 kg/m2 in the presence of at least one weight-related comorbid condition. Dr. Zangeneh highlighted that the safety and efficacy of Belviq with other weight-loss agents have not been established, advising providers to be wary of prescribing alongside other drugs. Similarly, the effect of Belviq on cardiovascular morbidity and mortality have not yet been clearly established. Eisai and Arena are conducting CAMELLIA-TIMI, a CVOT for the agent; the study is currently enrolling participants, and is expected to complete in October 2018.
  • Belviq’s binding to 5-HT2C is 11-fold stronger than to 5-HT2B and seven-fold stronger than to 5-HT2A. This is important because 5-HT2B receptors are thought to affect the cardiovascular system, which has generated some concern over their association with valvular heart disease. 5-HT2A receptors, on the other hand, are thought to affect the neurological system.  
  • Dr. Zangeneh stressed Belviq’s contraindication in pregnancy. Though Belviq is not associated with the teratogenicity risk of Vivus’ Qsymia (phentermine/topiramate), weight loss is not desired in pregnancy. Dr. Zangeneh pointed out that most obese patients are women and that providers must have honest conversations with all their female patients regarding this contraindication, ensuring that patients are on birth control, if necessary.
  • Belviq’s label indicates that it should be discontinued if a person does not have 5% weight loss at 12 weeks. Dr. Zangeneh explained that many of the pathological pathways involved obesity are still unclear and that different patients may only respond to certain mechanisms. Thus, some people may not respond to Belviq (or any anti-obesity medication), while other people may be super responders. We think that a critical improvement in the obesity field would be the discovery of ways to predict who will respond to a given medication – really that is the holy grail!
  • The results of the BLOOM-DM study showed effective weight loss in people with diabetes: 44.6% of participants lost ≥5% of their baseline body weight and 20.8% lost ≥10%. The BLOOM and BLOSSOM studies examined the use of people without diabetes. In these studies 53.9% of Belviq users lost ≥5% of their baseline body weight and 34.7% lost ≥10%. Dr. Zangeneh suggested that the weight loss was more pronounced in people without diabetes due to people with diabetes’ use of sulfonylureas, which can hinder Belviq’s effectiveness.
  • In people with diabetes, a 0.9% reduction in A1c level was observed in the average Belviq user, alongside improvements in blood pressure and lipids. In people without diabetes, systolic blood pressure was reduced by a mean 1.8 mmHg and diastolic blood pressure was reduced by a mean 1.6 mmHg. Less triglycerides were also observed in the lipid profiles of those on Belviq compared to those on placebo.
  • Dr. Zangeneh also introduced Belviq’s patient support programs, including its 15-day free trial offer and saving card.   

Questions and Answers

Q: How many days can we use this medication?

A: The longest data here is two years, but that’s the data. If my patient asks me how long she needs to be on Belviq, in DC, we say, “yes, no, maybe so.” It depends on the patient. If your lifestyle really improves, you probably won’t need it anymore. But, most of the medications you use can be used for longer anyways. But, do we need longer studies? Yes, definitely.

--by Melissa An, Eric Chang, Hannah Deming, Andrew Foley, Varun Iyengar, Emily Regier, Manu Venkat, and Kelly Close