22nd European Congress on Obesity (ECO) 2015 Executive Highlights
Ahoj from Prague, where we will miss listening to the wide range of lovely accents as the 22nd European Congress on Obesity (ECO) has wrapped up. The Congress boasted an exciting lineup of events all the way through to the end, including presentations on topics ranging from new SCALE analyses to the first ever EASO Obesity Media Masterclass that offered up-close access to some of Europe’s biggest names in the field to the soda tax. Please see below for our top ten highlights of days #2-4 (as well as an honorable mention) and check out our day #1 highlights for a refresher on the first day of the conference.
1. Dr. Luc Van Gaal (Antwerp University Hospital, Antwerp, Belgium) presented new data from a post-hoc analysis of the SCALE trials, demonstrating that Novo Nordisk’s Saxenda (liraglutide 3.0 mg) has both weight independent and weight dependent effects.
2. In the first ever EASO Obesity Media Masterclass, Drs. Hermann Toplak (Medical University of Graz, Graz, Austria) and Luc Van Gaal expressed low hopes for reimbursement of obesity pharmacotherapies in Europe in the near future.
3. Dr. Hermann Toplak (Medical University of Graz, Graz, Austria) shared his concerns about the potential requirements of long-term CVOTs for obesity drugs, arguing that they will likely restrict availability of new agents and stifle innovation. We concur.
4. In a poster, Zafgen presented positive efficacy and safety data from its ZAF-201 phase 2 trial of beloranib in severe obesity.
5. Dr. Arne Astrup (University of Copenhagen, Copenhagen, Denmark) presented a subgroup analysis from the SCALE Obesity and Prediabetes trial that compared the efficacy and safety outcomes between weight loss responders (≥5% weight loss) and non-responders (<5% weight loss). This was fascinating.
6. Dr. Carel Le Roux (University College Dublin, Dublin, Ireland) labeled obesity as a “chronic brain disease” in the Media Masterclass and emphasized the need to better understand its central mechanisms.
7. Continuing the focus on the brain, Dr. Abdul Dulloo (University of Fribourg, Fribourg, Switzerland) pointed to the “insulin resistance prone” brain, brain-adipose neural cross-talk, and “adipostats” as areas that warrant priority research.
8. Dr. Simon Barquera (National Institute of Public Health, Mexico City, Mexico) presented preliminary positive data on the impacts of Mexico’s soda tax and shared his insights on the lessons and upcoming challenges surrounding the policy change. This was a profoundly interesting talk.
9. From the audience, Dr. Carl-Erik Flodmark (Lund University, Lund, Sweden) shared new positive results from the AMOS study’s five-year follow-up during the Q&A of a debate on the appropriateness of bariatric surgery for adolescents.
10. There was a decent amount of focus on brown adipose tissue research, which Dr. Luc Van Gaal highlighted in the Media Masterclass’ session on “what’s hot in the science of obesity.” That’s for sure!
Top Ten Highlights
1. Dr. Luc Van Gaal (Antwerp University Hospital, Antwerp, Belgium) presented new data from a post-hoc analysis of the SCALE trials, demonstrating that Novo Nordisk’s Saxenda (liraglutide 3.0 mg) has both weight independent and weight dependent effects. Using data from three SCALE trials (SCALE Diabetes, SCALE Obesity and Prediabetes, and SCALE Sleep Apnea; n=4,883), this analysis used a statistical mediation model to determine the degree to which each of the secondary endpoints was dependent upon weight loss, ranging from 0% (none of the effect mediated by weight loss) to 100% (effect all mediated by weight loss). The findings demonstrated that endpoints that were mostly driven by weight loss included: apnea-hypopnea index (100%); Impact of Weight on Quality of Life-Lite (IWQoL-Lite) total score (100); diastolic blood pressure (100%); HDL cholesterol (100%); waist circumference (100%); triglycerides (97%); and IWQoL-Lite physical function score (88%). On the other hand, those that were largely independent of weight loss included: use of oral anti-diabetic drugs (18%); fasting plasma glucose (26%); and A1c (31%). Dr. Van Gaal concluded that weight loss was thus a significant predictor of many secondary metabolic endpoints, including ones that are mostly driven by weight-loss independent mechanisms; however, glycemic control parameters were predominantly independent of weight loss. During Q&A, when it was suggested that similar weight loss through lifestyle intervention could achieve the same metabolic improvements, Dr. Van Gaal noted that the differentiating factor is weight maintenance: lifestyle intervention for three years typically does not maintain weight loss while treatment with Saxenda for three years can. While we were not surprised to learn that the glycemic parameters were not entirely weight-driven (considering Saxenda is a higher dose of a diabetes drug), these findings indeed offer a quite valuable demonstration of the multifaceted benefits of weight loss. Of course, as Dr. Van Gaal rightfully pointed out, the key challenge is the maintenance of such benefits over a long period of time. Given how nascent the obesity drug market is we are curious to what extent patients and providers will conceptualize these agents as chronic therapies rather than one-time fixes – while chronic use is likely necessary to achieve maximum benefit, we imagine that historical restrictions on chronic use of drugs like phentermine and the limited long-term data on newer options may present barriers for some.
2. In the first ever EASO Obesity Media Masterclass, Drs. Hermann Toplak (Medical University of Graz, Graz, Austria) and Luc Van Gaal expressed low hopes for reimbursement of obesity pharmacotherapies in Europe in the near future. In response to a question on the degree of awareness and access of Europe’s two recently approved obesity drugs, Dr. Toplak noted that such drugs are perceived to add additional costs to the system and suggested that payers will likely be quite reluctant to reimburse them. He commented that while some countries have reimbursement, the majority of countries throughout Europe have none . Dr. Van Gaal echoed these sentiments, saying he is afraid that reimbursement “will not happen so quickly.” Interestingly, Dr. Van Gaal proposed a sort of post-hoc reimbursement paradigm as one potential solution: a treatment would be reimbursed for a given patient only if it demonstrated significant weight loss after a certain time period. We can see how such an approach might ease payers’ concerns, as it would address the issue described by Dr. Van Gall of patients who believe drugs can lead to weight loss without any lifestyle intervention and thus fail to see an effect. However, both speakers emphasized that their viewpoint, unsurprisingly, is that obesity treatments are worthwhile investments considering the costs of long-term complications in the future, but that the ultimate coverage decisions will be between each individual payer and company. These were indeed discouraging sentiments to hear, although we did not expect a very accepting reimbursement environment in such a new market for Europe, especially in light of the many challenges these products have faced in the US. As Orexigen recently expressed in its 1Q15 call, adding a diabetes indication to obesity drugs may ultimately be the most optimal route to increasing coverage and thus patient access in this region.
3. Dr. Hermann Toplak (Medical University of Graz, Graz, Austria) shared his concerns about the potential requirements of long-term CVOTs for obesity drugs, arguing that they will likely restrict availability of new agents and stifle innovation. After highlighting the sudden increase in approved obesity drugs in Europe after a long period of failures, he noted that cardiovascular safety issues have proven to be regulatory barriers for these drugs in the region. He expressed worry regarding mandatory pre-approval CVOTs for obesity drugs, arguing that Europe already has very limited treatment options and cannot lose further opportunities for more agents and innovation. Thus, Dr. Toplak proposed that approval decisions take into consideration the drug’s benefits on validated surrogates of cardiovascular risk from registrational trials rather than requiring long-term CVOTs. As background, Vivus’ Qsiva (phentermine/topiramate; known as Qsymia in the US) was rejected in 2013 as the EMA asked for a pre-approval CVOT; in the midst of resubmission, Vivus has reported “helpful” discussions with the EMA on Qsiva’s CVOT AQCLAIM. While it is encouraging to see collaboration with regulators at this level, we agree that these regulatory delays and requirements are hurting timely patient access to much-needed treatments and we hope that this trend does not continue for the region’s obesity drugs. In the US, the FDA does not have an across-the-board CVOT requirement for obesity drugs, but its requirements for diabetes drugs have been the focus of much debate in recent months. For more insights on these issues, please see our coverage of the FDA EMDAC’s meeting on the results of SAVOR and EXAMINE, where we heard many panelists take note of the larger issues surrounding the FDA’s current policy for diabetes drugs.
4. In a poster, Zafgen presented positive efficacy and safety data from its ZAF-201 phase 2 trial of beloranib in severe obesity. The double-blind trial (n=147) randomized participants (mean baseline BMI of 38 kg/m2 and body weight of 101 kg [~223 lbs]) to one of three doses of beloranib (0.6 mg, 1.2 mg, 2.4 mg) or placebo, given twice weekly. At 12 weeks, participants on 0.6 mg, 1.2 mg, or 2.4 mg of beloranib lost an average of 5.5 kg (~12 lbs), 7 kg (~15 lbs), and 11 kg (~24 lbs), respectively vs. 0.4 kg (~0.9 lbs) on placebo. In addition, beloranib treatment reduced patients’ sense of hunger and prospective food intake; blood pressure, LDL cholesterol, triglycerides, and hs-CRP (a marker of inflammation) were also decreased. On the safety front, adverse events were generally mild, transient, and self-limiting with no clinically significant abnormal laboratory measures, vital signs, or ECG findings. However, only ~43% of the 2.4 mg group completed treatment, with adverse events the primary reason cited for early withdrawal; sleep disorders were the most common adverse event, and no serious adverse events were deemed to be related to beloranib. Overall, this trial represents the longest duration of drug exposure in humans so far with its results demonstrating clinically meaningful weight loss and a relatively solid safety and tolerability profile (at least for the lower two doses). We are excited to see these positive findings (which follow positive phase 2 results for beloranib in hypothalamic injury associated obesity), as severe obesity remains on the rise with limited treatment options other than bariatric surgery.
5. The great Dr. Arne Astrup (University of Copenhagen, Copenhagen, Denmark) presented a subgroup analysis from the SCALE Obesity and Prediabetes trial that compared the efficacy and safety outcomes between weight loss responders (≥5% weight loss) and non-responders (<5% weight loss). As expected, the findings demonstrated that the Saxenda arm had significantly more weight loss responders compared to the placebo arm (63% vs. 27%) and that responders in both arms had greater improvements in glycemic, cardiometabolic, and quality of life outcomes compared to non-responders. However, both responders and non-responders in the Saxenda arm experienced greater improvement in fasting plasma glucose and systolic blood pressure compared to placebo, due to Saxenda’s direct effects (rather than effects driven by weight loss) on these parameters. Regarding safety, adverse events were mostly equivalent between responders and non-responders with the exception of gallbladder events, which were more frequent in responders than non-responders (3.4 events vs. 1.2 events in the Saxenda arm) – this adds support to the suggestion that this specific adverse event is driven by weight loss rather than by the drug itself.
- During Q&A, when asked about any predictors of responders vs. non-responders, Dr. Astrup highlighted that the initial weight loss has so far been the best predictor of whether or not the patient will lose more weight later on – notably, this was also suggested as a selling point for the drug in Novo Nordisk’s investor call regarding the launch. For more on new Saxenda data, please see our coverage of a similar subgroup analysis of SCALE Diabetes at this past ENDO.
6. Dr. Carel Le Roux (University College Dublin, Dublin, Ireland) labeled obesity as a “chronic brain disease” in the Media Masterclass and emphasized the need to better understand its central mechanisms. In a presentation entitled, “How the Gut Talks to the Brain,” Dr. Le Roux highlighted the brain as an “organ of importance” for obesity, noting the projections between the gut and the brain’s subcortical areas as well as the changes in brain activity seen during dieting or post-bariatric surgery. During Q&A, he also stressed that while the results of genome-wide association studies (GWAS) are limited, many of the genes that have been identified are related to the brain. This was echoed later in the day in an afternoon presentation on the genetics of obesity, in which Dr. Irena Aldhoon-Hainerova (Institute of Endocrinology, Prague, Czech Republic) stated that the majority of identified loci (gene locations) associated with obesity are involved in neuronal processes, specifically pointing to the FTO gene that is expressed mostly in the brain. Concluding, Dr. Le Roux stressed the importance of prevention and treatment, emphasizing that the physiological understanding of the brain’s role in obesity will be critical for advancing treatment options. We agree that this research area is especially promising in discovering new targets and may eventually make up a large portion of the market (see our day #1 highlights for such predictions). However, we wonder if neuropsychiatric events may become an increasingly prominent safety concern for providers and regulatory bodies if those predictions prove correct, although it has not been a significant obstacle for the approvals of current obesity drugs.
7. Continuing the focus on the brain, Dr. Abdul Dulloo (University of Fribourg, Fribourg, Switzerland) pointed to the “insulin resistance prone” brain, brain-adipose neural cross-talk, and “adipostats” as areas that warrant priority research. In an assigned debate on central vs. peripheral regulation in obesity, Dr. Dulloo argued for a focus on central regulation. He noted that the brain is being increasingly regarded as an insulin-sensitive organ; however, in his eyes, the impairment of insulin action at the neural level in insulin resistant individuals is largely unstudied. In addition, Dr. Dulloo stated that the field is only at the “tip of the iceberg” in understanding brain-adipose neural cross talk, as the evidence to date has revealed little more than suggestions of sympathetic-sensory feedback control of lipolysis and thermogenesis and the potential roles of various depots of white and brown adipose tissue in these pathways. Lastly, Dr. Dulloo noted that the mechanisms surrounding weight set points are still awaiting discovery, as “adipostats” and “proteinstats” in the brain may be involved in the phenomena of weight fluctuations and caloric overcompensation. This presentation, in particular, revealed to us the magnitude of the uncharted territory in the study of the brain’s role in obesity. As even the mechanisms of action of existing centrally acting obesity drugs are not yet fully understood, we agree that there is much more research needed in this area; we expect to see Novo Nordisk play a significant role in filling this gap with its new obesity center.
8. Dr. Simon Barquera (National Institute of Public Health, Mexico City, Mexico) presented preliminary positive data on the impacts of Mexico’s soda tax and shared his insights on the lessons and upcoming challenges surrounding the policy change. Dr. Barquera shared that between 1Q13 and 1Q14 (the tax was enacted starting January 1, 2014), data from a commercial panel of consumers found a 10% decline in the purchase of taxed beverages, a 7% increase in the purchase of untaxed beverages (diet sodas, water, 100% juices, etc.), and a 13% increase in plain water purchases. Notably, he characterized the support of NGOs as critical to the successful passage of the soda tax, stating that previous campaigns consisted solely of academia vs. industry; in Dr. Barquera’s eyes, the ability of NGOs to effectively communicate to the public was notable in helping move the needle to defeat Big Soda. Importantly, Cr. Barquera emphasized that his group sees the soda tax as a complementary policy to decrease the obesigenic environment, not as the central or only component of a national obesity prevention policy. Interestingly, during Q&A, he also stated that the main factor that helped push the tax through in Mexico compared to other countries was likely the federal government’s search for fiscal reforms to increase government revenue at the time. The emphasis on soda and sugar-sweetened beverages is particularly relevant in Mexico since Mexico represents one of the major consumers in the world of SSB – indeed, 20% of the total daily energy intake comes from liquids and as Dr. Barquera pointed out, SSBs are linked to the development of obesity and diabetes as many recent meta-analysis show and diabetes represents the first or second cause of general mortality in the Mexican population. Moving forward, Dr. Barquera pointed to the new alliances against the soda tax as major challenges, as the sugar industry specifically has also now gotten involved with promoting communication campaigns to the public. (GREAT – GROAN!) Additionally, he stressed that improving access to water throughout the country will be critical in maintaining this shift to healthier beverage choices. We so admire the work that Dr. Barquera has done in Mexico and are thrilled to see these positive results, which we hope can be used as evidence to support future soda tax campaigns in the US. In the meantime, all eyes are on Berkeley, stateside …
9. From the audience, Dr. Carl-Erik Flodmark (Lund University, Lund, Sweden) shared new positive results from the AMOS study’s five-year follow-up during the Q&A of a debate on the appropriateness of bariatric surgery for adolescents. He stated that at the five-year follow up, 80% of participants responded yes to the question of whether or not it was a good decision to perform surgery at the age (13-19 years old) they had undergone the operation. As background, the AMOS study included 81 obese youth aged 13-19 years old who had undergone roux-en-Y gastric bypass (RYGB), conducting follow-up visits at one, two, and five years post-surgery. This group was compared to a BMI and gender-matched adult group undergoing RYGB from the Swedish Obese Subjects (SOS) study. These brief but notable findings follow the presentation of positive efficacy data from the same five-year follow-up at this past ENDO. While this data is positive, long-term studies on bariatric surgery in this population remain very limited and we believe that safety concerns surrounding nutritional deficiency are just as important. In fact, the debate featured some lively and heated arguments between Drs. Luigi Angrisani (Hospital San Giovanni Bosco, Naples, Italy) and Thomas Reinehr (Vestische Hospital, Datteln, Germany) on whether the lower adherence rates among adolescent patients should be a reason to not operate on this group, as lack of follow-up can result in very harmful complications later down the road. Indeed, when assessing the appropriateness of an operation as high-stakes as bariatric surgery, we agree that factors such as adherence and ethics must be taken into account.
10. There was a decent amount of focus on brown adipose tissue research, which Dr. Luc Van Gaal highlighted in the Media Masterclass’ session on “what’s hot in the science of obesity.” Dr. Van Gaal noted that better understanding of the stimulation of brown fat will be helpful for future pharmacological treatments and mentioned irisin as a potential research target. In addition, Ms. Maud Giroud (University of Nice Sophia Antipolis, Nice, France) presented results showing that the microRNA segment miR-125b may play an important role in the control of white to brite (brown-in-white) adipose tissue; she demonstrated that its expression is downregulated in brown adipose tissue compared to white adipose tissue and that its injection inhibits mitochondriogenesis (which is involved in the formation of brown fat precursor cells) in rodent models. In another oral presentation, Dr. Meliz Sahuri Arisoylu (Imperial College London, London, UK) discussed research showing that acetate (an abundant short chain fatty acid) has the potential to “brown” white adipose tissue, as acetate treatment in the periphery led to a reduction in body adiposity as well as in liver fat and inflammation. Brown fat has become quite the up-and-coming research area for obesity, as we have heard specific references to it as a new intriguing topic at both Obesity Week and the GTC Bio Diabetes Summit. To learn more, please check out our coverage of the Harvard Stem Cell Institute’s recent research that identified two compounds that can convert white fat to brown fat in human cells.
Honorable Mention
- Dr. João Breda (World Health Organization, Copenhagen, Denmark) presented shocking 2030 projections by the World Health Organization (WHO) on the prevalence of obesity in Europe. These estimates come from the WHO Modeling Obesity Project, a collaboration between the WHO, the UK Health Forum, and the European Commission, and are based on data from 53 countries in the WHO European region. The projections estimate increases in prevalence of overweight and obesity in most EU countries, with many countries seeing a near-doubling their obesity prevalence and 1.1- to 1.3-fold increases in overweight prevalence from 2010-2030. At the highest end of the range, 89% of Irish men are projected to be overweight or obese in 2030. As prevalence rates in Europe reach and even exceed levels seen in the US, the limited treatment options in Europe become even more striking. Please see our full report on these projections for much more, including detailed country-specific estimates.
- In his plenary lecture, Dr. Geof Rayner (UK) illustrated the mismatch in resources between public and commercial spheres in the challenge to fight the obesity epidemic. Most notably, he pointed out how the combined marketing budget of Coca-Cola and Pepsi was $5.7 billion in 2013, while the World Health Organization’s (WHO) entire budget for the same year was only $4 billion – we believe these numbers perfectly depict the unfortunate battle we face in making advances in our built environment in obesity. In assessing the modern conditions of health, Dr. Rayner stressed how society has shifted its focus toward consumerism. As he characterized current responses to obesity as “often weak and self-interested,” he pushed for a future ecological framework of public health, in which the health of humans and eco-systems becomes one and the same, requiring new and different alliances and the reshaping of health conditions.
--by Melissa An, Emily Regier, and Kelly Close