November 12-16, 2018; Nashville, TN; Full Report – Draft

Greetings from Nashville, where our team attended Obesity Week 2018. We have compiled reports from all four days into highlight categories of obesity and diabetes therapy, diet outcomes, patient-centered thinking, big picture, and exhibit hall. For additional coverage check out our initial preview, days #1-2 highlights, and days #3-4 highlights.

Obesity and Diabetes Therapy Highlights

GLP-1 Aficionado Dr. Dan Drucker’s Keynote: “GLP-1s Have Had a Good First 35 Years—The Next 35 Years Might Be Even Better.”

Kicking off the final day of Obesity Week 2018, University of Toronto’s Dr. Dan Drucker delivered an all-encompassing keynote on everything related to GLP-1 receptor agonists. Dr. Drucker is a true luminary when it comes to GLP-1s, and every sentence of this hour-long talk was essentially highlight-worthy. Dr. Drucker took the audience along for a journey on the past 30+ years of GLP-1 research, starting with his own pioneering research that started out with “dumping GLP-1 on a bunch of cells and trying to figure out what it did.” He detailed research elucidating the mechanism of GLP-1 receptor agonism, its effects in the brain, the future of multi-agonists with GLP-1, and its future in diabetes, obesity, and NASH treatment. So much has happened with GLP-1s in the past three decades, and Dr. Drucker believes the future might hold even greater successes for the class—we agree as the class has improved substantially in terms of various applicantions. We’ve picked out some of the most salient and intriguing points from Dr. Drucker’s talk below:

• Dr. Drucker enthusiastically spoke on the potential of dual and tri agonists with GLP-1 as the future of diabetes and obesity pharmacotherapy. Regarding Lilly’s GLP-1/GIP dual agonist (now dubbed tirzepatide), which had landscape-altering and highly impressive phase 2 results presented at EASD 2018 last month, Dr. Drucker endowed high praise by commenting that “this is probably as good as we’ve seen with a phase 2 investigational agent.” As a reminder, the dual agonist conferred a rather unprecedented 2.4% A1c reduction and ~25 lbs weight loss at 26 weeks with the highest tested 15 mg dose. Lilly is now in the process of initiating a phase 3 program—called SURPASS—which will be composed of eight different studies. Dr. Drucker noted that achieving this level of weight loss in a diabetes drug not necessarily optimized for weight loss is quite the impressive accomplishment.

  • Dr. Drucker also applauded the large number of doses that were investigated in Lilly’s phase 2 program for terzepatide. He explained that, in his opinion, the most common reason that investigational agents fail is insufficient dose ranging. Successful programs tend to have studied up to six different doses with multiple up-titration regimens, while those programs that produce disappointing results are often non-optimized on dose-ranging and do not fully maximize the value of the molecule being studied. Dr. Drucker underscored that he’s been banging this drum for increased dose ranging to companies for over 15 years—still, inadequate investigation of various doses still persists, much to his chagrin. We couldn’t agree more on this front, and point to recent EASE results for Jardiance in type 1 diabetes, which showed intriguing data on a lower dose of empagliflozin in which DKA events were not elevated. We imagine that this finding was only made possible by Lilly/BI’s willingness to explore multiple different doses in these trials.

  • One of the keys to future success of multi-agonists will be predicting which partners work best with GLP-1. Dr. Drucker explained that in animal models, “all of these tri-agonists are wonderful” and can achieve “bariatric surgery-like results” in terms of weight loss and A1c reductions. It’s unlikely that these results will perfectly translate to humans—after all, Dr. Drucker noted that animals aren’t able to express the severity of GI side effects as well as humans are. On this front, research will have to improve in determining which combinations of molecules actually stand the best chance of succeeding in humans. Dr. Drucker explained that there’s “no end to the chimeric molecules we can create and combine using chemistry,” painting a limitless landscape in relation to the possibilities of multi-agonists. However, the system surely can’t afford investing $25-$50 million dollars for every single molecule—“we’re going to have to make some educated bets [on which ones will work].” We’re curious to hear what Dr. Drucker sees as the next step in making these “educated bets”—perhaps improved computational modeling of interactions, or new paradigms in pre-clinical trials?

• Dr. Drucker predicts that GLP-1s will ultimately prove to be an effective therapy for NASH. Supporting this claim, he pointed toward data from the phase 2 LEAN study demonstrating positive changes in human liver histology with liraglutide treatment. While it appears as if Novo Nordisk is no longer investigating liraglutide in NASH, it is currently studying semaglutide in a phase 2 NASH study, which is expected to complete in 2020. We appreciate this enthusiasm from Dr. Drucker on the potential of GLP-1s in NASH, and hope to see more companies investigate them in this condition which still has no approved therapy. GLP-1s appear to be underrepresented in the NASH competitive landscape, with only four GLP-1s or GLP-1 multi-agonists being studied for such a population. A ringing endorsement from a GLP-1 expert such as Dr. Drucker should signal that a huge potential exists for GLP-1s in NASH.

• “We’re going to see a great deal of pharmacogenomics in the next year or two.” Dr. Drucker commented that one of the most important learnings from the SCALE program for liraglutide in obesity was the revelation that “we don’t need to treat for long periods of time to see who will respond to treatment.” He pointed out that in SCALE, after four months there was a clear sorting of responder and non-responders to liraglutide. Seeing this, he expects a wave of research in the coming years to see if genetic variations in and around the GLP-1 receptor can be used to predict responders and non-responders. Will this approach work? Dr. Drucker gave a tentative “yes” on it working a “little bit.”

• In comments he called a “little bit provocative,” Dr. Drucker remarked that 75%-80% of published reports regarding cellular GLP-1 receptor localization in tissues are probably not correct. Dr. Drucker noted that detection of cell localization of the GLP-1 receptor is extremely difficult—his lab has used a multitude of techniques (including PCR, western blotting, immunocytochemistry, in situ hybridization) and tried to be quantitative in this methodology; however, they’ve still struggled in producing quality data on GLP-1 cellular localization. As a result, Dr. Drucker advocated for caution when looking at such data in the literature, remarking that “the literature is fraught with mis-localization of the GLP-1 receptor that has produced a lot of confusion in the field.” We imagine that this uncertainty over where a GLP-1 receptor agonist may actually be interacting on the tissue-specific level only adds to the ambiguity regarding its mechanism of action in producing extra-glucose lowering effects, such as cardioprotection.

Real-world and Post-hoc Saxenda Data Suggests Marked Improvements in Persistence and Weight Loss with SaxendaCare; Dose-escalation May Take ~3x Longer Than Label Suggests; Equal Efficacy in BMI ≥50

Novo Nordisk presented three exciting posters on Saxenda (liraglutide 3.0 mg) over days three and four of Obesity Week. Two were post-hoc assessments of a real-world, retrospective EMR study on Saxenda which found a mean 7% weight loss after six months of treatment with the obesity therapy in Canada, and the last was a post-hoc analysis of the phase 3 SCALE study conducted prior to Saxenda’s approval, which found a mean 8% weight loss with Saxenda after 56 weeks. Given that Novo Nordisk has identified obesity as one of its four key focus areas for the future and Saxenda as a key growth driver, we expect more data examining the therapy’s efficacy in a wide variety of patients and settings to emerge in the near future.

• Real-world effectiveness of liraglutide 3.0 mg and SaxendaCare for weight management in Canada. We were particularly excited for this one; we’ve been waiting for an update on the SaxendaCare program, a 16-week program at the start of Saxenda treatment meant to support patients in comprehensive obesity management (encouraging emails and calls from a diet/exercise coach), since it was unveiled in 3Q17. To assess the program’s efficacy, this study compared real-world persistence and weight loss in patients taking Saxenda and enrolled in SaxendaCare (n=119) compared to those only taking Saxenda (n=184) in EMR data from six publicly funded secondary care weight and diabetes management clinics in Ontario, Canada. After four months (the length of the SaxendaCare program), 83% (99/119) of the enrolled cohort remained adherent to their Saxenda therapy compared to 57% (105/184) of those not enrolled (p<0.001) – wow! This difference remained significant at six months (72.3% vs. 40.8%, p<0.001). Moreover, the mean treatment difference with liraglutide for those enrolled in SaxendaCare was 7.9 months versus 5.2 months for those not enrolled (no p-value given). Taking a closer look at the Kaplan Meier curve for persistence (below), the effect of SaxendaCare becomes even more evident – persistence rates of the enrolled group plummeted after the program completed, almost meeting the persistence rate of those not enrolled at 10 months. To us, this suggests that indefinite continuation of SaxendaCare (or a similar program) might be helpful in ensuring long-term persistence. On efficacy, 71% of patients enrolled in SaxendaCare achieved ≥5% weight loss compared to 49% of those not enrolled (p<0.01), and 39% of those enrolled achieved ≥10% weight loss versus 24% of those not enrolled (p<0.05). What’s more is that SaxendaCare appeared to support weight loss independent of persistence to Saxenda. Taking only those who persisted with treatment for six or more months in each group, 74% of those enrolled in SaxendaCare achieved ≥5% weight loss compared to 55% of those not enrolled (p<0.05), and 42% of those enrolled lost ≥10% compared to only 29% of those not enrolled, though this difference was not significant. On a grander scale, we were thrilled by the percentage of patients (38%) who were enrolled in SaxendaCare, and we would love to know how this compares to the percentage of patients worldwide on Saxenda. All taken together, we are thoroughly impressed by the impact on persistence and efficacy of SaxendaCare and think that these results make a strong case for manufacturers of obesity therapies to offer a complete weight management program in addition to pharmacotherapy.

• Real-world medication persistence and dosing with liraglutide 3.0 mg in Canada. Pooling the two cohorts from the above poster, this investigation found that mean persistency with Saxenda was 6.3 months, with more than half of patients who initiated liraglutide 3 mg persisting on treatment for at least six months and ~two-thirds persisting for at least four months. On dosing, investigators found that 91% (283/311) of Saxenda patients were able to reach the maximum dose (3.0 mg), in an average ~79 days – nearly 3x longer than the label recommends (28 days for dose escalation – page 17). As a reminder, dose escalation is recommended for Saxenda to reduce therapy’s known GI side-effects (primarily nausea and vomiting). Based on these analyses, investigators concluded that, in a real-world setting, patients may continue taking Saxenda for more than six months, and individuals may take longer to reach the maintenance dose of Saxenda compared with label recommendations. 

• Efficacy and safety of liraglutide 3.0 mg in adults with obesity/overweight: BMI <50 kg/m² vs ≥50 kg/m². This post-hoc analysis of the phase 3 SCALE study for Saxenda found that those with a BMI <50 achieved slightly greater weight loss compared to placebo (estimated treatment difference 5.5%, 95% CI: 5.0%-5.9%) than those with a BMI ≥50 (estimated treatment difference 4.1%, 95% CI: 6.0%-2.3%), though the difference between the BMI groups was not significant. Perhaps more importantly, both groups experienced significant improvements in physical function scores (as measured by the SF-36 questionnaire) and quality of life (as measured by the IWQOL-Lite questionnaire), though treatment effects were once again independent of baseline BMI for both metrics. Investigators underscored the importance of BMI independence with these findings – those with a BMI ≥50 have markedly greater morbidity and mortality, impaired quality of life and physical function, as well as presenting significant clinical and surgical challenges. As such, the statistically indistinguishable efficacy of Saxenda between the two groups in this study represents an important win for this demographic of patients who so desperately need care.

Dr. Aaron Kelly Calls for GLP-1 Agonists as Part of First-line Treatment for Pediatric Obesity; SGLT-2 Inhibitors as Widely Prescribed as Phentermine

University of Minnesota’s Dr. Aaron Kelly suggested that GLP-1 agonists might be able to fill the massive treatment gap between lifestyle interventions and bariatric surgery in well-responding pediatric patients. Initially spurring this hypothesis was a small (n=12) crossover study in which GLP-1 agonist exenatide reduced BMI by 1.7 kg/m², body weight by 3.9 kg, and fasting insulin by 7.5 mU/I (all p<0.05) in adolescents age 9-16 with extreme obesity over the course of three months. This informed a larger pilot RCT which found a subtracted-difference 3% reduction in BMI with exenatide vs. placebo at three months and a 4% reduction at six months with similar safety profiles to adults. However, there was a huge amount of heterogeneity in individual results (see below) – a trend which Dr. Kelly noted is present in nearly all obesity pharmacotherapy. As such, the need to identify strong-responders to GLP-1 agonists became imperative, especially in pediatrics where concomitant medications are seriously discouraged. Accordingly, he and his team pooled and analyzed the data from the crossover and pilot RCT, identifying sex (treatment effect in female [-4.78%] vs. male [0.76%], p=0.007) and appetite at baseline (treatment effect in high [-4.28%] vs. low [1.02%], p=0.028) as significant predictors of change in BMI at three months. The former was inexplicable to Dr. Kelly, but he noted that the latter aligns well with GLP-1 receptor agonists’ proposed mechanism of action in weight loss – promoting satiety in the brain. Interestingly, baseline BMI, BMI percent change at one month, age, incidence of nausea, vomiting, or other gastrointestinal symptoms and satiety scores did not predict 3-month responses. We are encouraged by this data, and certainly see room for these highly efficacious therapies in pediatric treatment algorithms to move the needle against the childhood obesity and type 2 diabetes epidemics. That said, we believe many questions surrounding the long-term safety, tolerability, adherence, psychosocial effects, and efficacy will need to be answered before GLP-1s in pediatric obesity become reality, much less common practice. That said, Dr. Kelly thinks it may be closer than we think. Based on several ongoing studies he expressed optimism in FDA/EMA approval for use of GLP-1 agonists in pediatric populations with obesity in the not so distant future. Specifically, a Novo-Nordisk sponsored trial (n=228) investigating the effects of liraglutide in 12-17 year-olds with obesity over one year is estimated to complete in August 2019, and Dr. Kelly’s lab is conducting a similar study (n=100) for exenatide in severe pediatric obesity, with completion expected in December 2019. If approved, he hopes that intensive GLP-1 agonists will accompany lifestyle modification as part of first-line treatment for pediatric obesity.

• Dr. Aaron Kelly compared medication uptake between the obesity and diabetes markets. According to a retrospective analysis of US prescriptions from 2012 and 2015, the number of dispensed anti-diabetes prescriptions was 15 times the number of dispensed anti-obesity prescriptions, despite the indicated population for obesity medication being about five times larger than for diabetes medication. Not highlighted by Dr. Kelly was the interesting fact that SGLT-2 prescriptions in 2015 matched those of phentermine – the most widely prescribed anti-obesity therapy in the US according to Dr. Ryan. According to the same retrospective analysis, the adoption rate of SGLT-2 inhibitors was nearly exponential during 2012-2015, while the adoption rate of new anti-obesity pharmacotherapies was linear.

Gelesis100 Positive in Pivotal Phase 3 Glow Trial, Significant +2% Weight Loss in Six Months vs. Placebo, ~20% Reduction in Fasting Serum Insulin, HOMO-IR in those with FPG ≥90 mg/dL; Drs. Ryan and Aronne Express Excitement

Gelesis presented the full results of its pivotal phase 3 GLOW trial (n=436) for Gelesis100, a non-systemic hydrogel that rapidly absorbs water in the stomach and mixes with food, imparting a feeling of satiety to the user – demonstrating superior weight loss compared to placebo over six months of treatment (6.4% vs. 4.4%; p=0.0007). Notably, the therapy did not meet the co-primary endpoint of 3% super-superiority (statistically significant and clinically meaningful difference) vs. placebo on weight loss. That said, investigators highlighted a clear separation between responders and non-responders in the study, with those achieving at least 3% weight loss by the end of eight weeks with Gelesis100 going on to lose ~10% at six months compared 2% for non-responders (no p-value given). Moreover, 27% of the Gelesis100 ITT population compared to 15% of the placebo group were “super-responders,” defined as achieving at least 10% weight loss. On diabetes-related outcomes, Gelesis100 conferred an impressive 19.6% (p<0.05) reduction in fasting serum insulin and 21% (p<0.01) reduction in HOMO-IR vs. placebo in completers with a fasting plasma glucose level ≥90 mg/dL at baseline (n=121 for Gelesis100 and 111 for placebo). Adverse events were prevalent in both study arms, with 71% of participants in each experiencing at least one. The only safety signal came for any gastrointestinal AE, of which 43% (n=96) of those on Gelesis100 experienced at least one compared to 34% (n=72) in the placebo arm (p=0.0248). Mechanistically, we learned that Gelesis100 likely acts through stretch receptors in the stomach to propagate a signal of fullness to the brain. To be sure, given the unsustainable trajectory of the obesity epidemic in the US, we are excited to see innovative and creative approaches to the obesity epidemic, provided they are demonstrated to be safe and attainable for patients. To this end, we would be very interested to hear of the pricing for Gelesis100, should regulatory approval be given.

Several KOLs expressed considerable excitement at Gelesis100’s potential. In her Tuesday keynote on winning combinations and new directions in obesity pharmacotherapy, Dr. Donna Ryan mentioned Gelesis100 alongside GLP-1 agonists liraglutide and semaglutide, extolling its innovative use of a new target (stretch receptors in the stomach) for obesity therapy; she also projected that it, “will be approved soon.” In Dr. Louis Aronne’s talk on weight loss maintenance, he noted that one of the only paradigms that current obesity pharmacotherapy is unable to affect is the microbiome. However, based on hypotheses from Gelesis that mechanical stimulus to the gut promotes tissue repair through increased mucus production (which is also beneficial to microbiota), Dr. Aronne believes that Gelesis100 may prove to be a meaningful step in the right direction.

Abundant Excitement for Semaglutide in Adults, Pediatrics, and Post-bariatric Surgery

Multiple speakers expressed early enthusiasm in Novo Nordisk’s semaglutide for wide-spread obesity treatment.

• Dr. Donna Ryan asserted that semaglutide will produce ~twice the amount of weight loss than liraglutide 3.0 mg (Saxenda) in adult patients. Indeed, semaglutide conferred ~14% mean weight loss at its highest dose over the course of 52 weeks, compared to ~8% with liraglutide in the SCALE-Obesity and Prediabetes trial. As background, this is not the first time that we’ve heard Dr. Ryan express optimism in semaglutide. With respect to the SELECT CVOT, which seeks to provide clinically relevant data about semaglutide for obesity while creating a yardstick in obesity pharmacotherapy for CV outcomes, Dr. Ryan proclaimed at ENDO 2018, “If in four years, we have evidence that a lifestyle intervention plus semaglutide produces a reduction in CV events and potentially CV mortality, it would be a game-changer for our field. One of the things that has really held obesity care back is that we don’t have this evidence that weight loss produces a reduction in CV events. It’s been shown with bariatric surgery (through SOS and other studies), but we don’t have this for medical weight loss. We need to show improvements in these hard endpoints to really legitimize our field.” Currently, only Arena/Eisai’s Belviq (lorcaserin) has a CVOT in the books, which demonstrated non-inferiority on three-point MACE relative to placebo. We have high hopes that SELECT could bring more attention to medical management of obesity. 

• Following his talk on exenatide use in adolescents with obesity (see below), University of Minnesota’s Dr. Aaron Kelly briefly conveyed his hope in semaglutide as a treatment for pediatric obesity. He did give the one caveat that the safety and tolerability in this population must be thoroughly vetted and pointed efforts to identify high responders should be undertaken before prescribing.

• Similar to Dr. Ryan, Scottsdale Healthcare Bariatric Center’s Dr. Robin Blackstone called semaglutide a potential game-changer, specifically with regards to attenuating weight re-gain post-bariatric surgery. According to a recent meta-analysis, two-thirds of patients regain ≥20% of weight lost, five years after a gastric bypass. As she sees it, obesity and weight-regain should be treated as aggressively as hypertension, and semaglutide has the potential to truly move the needle on weight loss maintenance after surgery.

Post-Hoc Analysis for Phase 3 VERTIS Trials Demonstrates Ertugliflozin’s Efficacy in Patients with Overweight and Obesity

A post-hoc analysis of three phase 3 trials (VERTIS MONO, VERTIS MET, and VERTIS SITA2) for Merck/Pfizer’s SGLT-2 inhibitor Steglatro (ertugliflozin) demonstrated its efficacy on A1c lowering, blood pressure reduction, and weight loss. A total of 1544 patients were included in the analysis. On A1c lowering, 5 mg ertugliflozin gave a 0.8% least-squares mean reduction from baseline while the 15 mg dose gave a 0.9% drop (placebo gave 0.1% drop). Approximately 41% of patients on 15 mg ertugliflozin achieved an A1c lower than 7%, compared to 32% for 5 mg ertugliflozin and 16% for placebo. On systolic blood pressure, least-squares mean change was a 4.6 mmHg reduction from baseline for both 5 and 15 mg treatment, compared to a 0.8 reduction for placebo. Ertugliflozin treatment was associated with a 3.1 and 3.2 kg drop from baseline for 5 and 15 mg doses, respectively, while placebo showed a 1.2 kg drop. These results for patients with overweight and obesity are comparable to results seen in the overall population, and support ertugliflozin’s use in this population.

Reflections on the STAMPEDE trial: five years later

Five years after the STAMPEDE trial, Dr. Stacy Brethauer (Cleveland Clinic, Cleveland, OH) and Dr. Debbie Horn (UTHealth McGovern Medical School, Houston, TX) spoke from surgical and medical perspectives, respectively, about the results. As a reminder, the STAMPEDE trial compared the effectiveness of bariatric surgery versus intensive medical therapy in achieving diabetes remission (A1c ≤6.0%) in obese patients (BMI 27-43 kg/m2). Results showed significantly higher proportion of patients who underwent surgery achieved the primary endpoint of A1c ≤6.0% compared to those who only received intensive medical therapy.  Five years later, Dr. Brethauer focused on the “high quality data” from the study that demonstrates the superiority of “[bariatric] surgery over standard or intense medical therapy.” He also said diabetes patients would benefit most from the surgery and that there is a need for surgical trials with combination therapies. Offering a medical perspective, Dr. Horn advocated for an arm of the experiment with the combination of medical therapy plus medical obesity treatment, or even another arm that is those two treatments combined with surgery. She made the point that medical therapy interventions were still successful in many diabetes patients, not to the degree of surgery, but also are less intensive therapy to begin with. An unfortunate reality is that many patients with obesity do not have health insurance that covers bariatric surgery or cannot afford to pay out of pocket. Below are some of the presented five-year results of the STAMPEDE trial:

Diet Outcomes Highlights

Virta Two Year Follow-up Shows ~Sustained Effect with 54% Type 2 “Reversal,” 0.9% A1c Drop, 12 kg Weight Loss in Intent-to-Treat; “Two Years is a Lot Like One Year”

Virta Health presented two-year outcomes data from its low-carb/high-fat ketogenic diet + continuous remote care in a late-breaking poster, demonstrating sustained efficacy in diabetes “reversal,” A1c reduction, and weight loss from its ongoing five-year, non-randomized, controlled trial. As Virta Head of Research Dr. James McCarter said to us in the poster hall today, “Two years is a lot like one year.” The data shows sustained engagement (194/262, or 74%, continuing in the program), a solid -0.9% A1c reduction (baseline 7.7%), 10% body weight loss from a baseline of 250 lbs, and a notable 54% of completers achieving diabetes reversal (A1c <6.5% + on no meds except metformin). In the most challenging intent-to-treat analysis – treating missing data as a “failure” – 38% of patients still achieved reversal at two years. Notably, only ~27% of the population was taking diabetes medications at two years (excluding metformin; baseline: 57%), and average insulin dose had fallen from 82 u/day at baseline to 16 u/day at two years (this figure presumably includes those who have eliminated insulin altogether). From a cardiovascular health perspective at two years, systolic and diastolic blood pressure were down 6 mmHg (baseline: 132 mmHg) and 3 mmHg (baseline: 82 mmHg), respectively, HDL was up 8 mg/dl (baseline: 42 mg/dl), and triglycerides were down 44 mg/dl (baseline: 197 mg/dl). Total LDL cholesterol was elevated by 11 mg/dl (baseline: 104 mg/dl), but Dr. McCarter noted that in published one-year outcomes, LDL particle number trended down and that large, buoyant particles prevail (a lower risk phenotype) – it’s not clear if that composition is reflected in two year data. The intent-to-treat analysis shows that mean beta-hydroxybutyrate (blood ketone) levels remain stable from year one to year two (both ~0.27 mmol/L), signifying continued degree of adherence to the ketogenic diet. The data imply that a good portion of the participants are not in strictly defined nutritional ketosis long-term – how do their A1c, weight loss, reversal, etc. outcomes compare to those who are firmly in ketosis? Dr. McCarter commented that “Virta’s nutritional and behavioral guidance is individualized for patient success and sustainability. While some patients chose to stay in ketosis long-term, others use improved insulin sensitivity to enjoy greater dietary flexibility while staying generally on the lower spectrum of carbohydrate consumption.”

• See below for a tabular comparison of key results from ten weeks (first presented at ADA 2017), one year, and two years for Virta. We note that although these results between one and two years are quite similar, the two-year results are slightly less robust across the board. Most diabetes and weight loss interventions show their greatest effect within the first year (if not the first few weeks/months), so the fact that they were nearly maintained without a major rebound across the population at two years is fairly impressive. We’ll be on the lookout for more creep back toward baseline metrics at future time points; however, even if there is regression, the legacy effect tells us that metabolic improvements, even if maintained for a short time, can still confer long-term benefits.

• Virta hopes to publish these two-year results in a “top tier” journal. Dr. McCarter noted that the paper will be published on a pre-print database in a couple of weeks. This publication will provide additional granularity on what was presented on the Obesity Week poster, including a breakdown on medication usage type and discontinuations. Looking ahead to the future, Virta also plans to publish data at 3.5 years and five years to compliment already published one-year-data, one year CVD biomarker data, and this two-year data. As a reminder, the study is scheduled to last five years.

  • Two-year data of the prediabetes cohort (n=116) is expected to be submitted for publication by year-end or early next year so should appear in 2019. As a reminder, 116 participants with prediabetes are enrolled in the Virta arm of the study. At ADA 2018, we heard impressive one-year data on this cohort: 82% retention, 61% achieving A1c <5.7%, no participants progressing to diabetes, and 12% weight loss. These results nicely dovetailed with efficacy seen in the type 2 cohort at one year – we’re curious to see if this alignment will continue into year two.

• As expected, a vast majority of the individuals who met Virta’s criteria for reversal after two years had also achieved reversal at year one (exact numbers not published). In other words, if Virta’s intervention doesn’t deliver diabetes “reversal” by one year, it seems highly unlikely that it would do so thereafter. In fact, the one-year publication says, “Most of the 1-year improvements in diabetes risk factors were achieved during the first 70 days of the intervention…About 60% of weight loss occurred in the first 70 days.” We wonder if this information is taken into consideration in benefit design: Should employers recommend different programs for participants who don’t see reversal at one year? Should Virta get paid more if the individual stays in the program and does see reversal at two years? Of course, “reversal” as a category is slightly problematic, as it’d be difficult to argue that an individual who is only taking metformin and has an A1c of 6.6% is not benefitting.

• Dr. McCarter gave us fascinating insight into the journey of health coaching and engagement over the course of two years: “Engagement remains good in the second year. We don't require the high frequency contact (multiple times daily) seen in the early phase of the intervention (first two months). We aim for a few contacts a week. Next year, we'll be writing a paper that explores predictors of patient success including frequency of contact. In the second year, topics of conversation between the patient and coach shift with more focus on life events and overall health (exercise, sleep, self-care, mindfulness, family) and less on basic nutritional education.” Nice!

• At one year, Virta estimated that its intervention saves $9,600 per patient per two years – mostly from eliminating costly medications – and Dr. McCarter expressed that these two-year outcomes data are consistent with that model. “They confirm the pharmaceutical savings as prescription spend declined further from one year to two years. We are working on a number of projects on system utilization savings beyond prescription spend that are encouraging. Overall the results we are seeing from the individualized treatment and continuous remote care platform are really extraordinary and demonstrate that long-term diabetes reversal including insulin elimination is possible without bariatric surgery.”

• This data arrives in tandem with Virta’s announcement of placing 100% of fees at risk. With this new policy, first-year payments will be delivered in two installments: (i) an enrollment fee after one month if 30-day engagement metrics are met and (ii) subsequent payments if pre-specified A1c reductions are met. Dr. McCarter noted that these two-year data gave Virta “the confidence to commit to those payment schedules.” When asked about the use of A1c as the benchmark for payment at one-year, Dr. McCarter explained that is was chosen “to simplify things for payers – we could have added weight, medication use and cardiovascular risk markers but we didn’t want to overly complicate things.” Past two years, payment will remain at-risk!

Hot Off the Presses Data from Dr. David Ludwig’s Group Further Supports Carbohydrate-Insulin Model of Obesity

To an anticipatory and packed audience, Harvard’s Dr. David Ludwig and co-author Dr. Cara Ebbeling presented freshly-published data in BMJ demonstrating that low-carb diets increased energy expenditures during weight loss maintenance. The study consisted of 164 adult participants randomized to high, moderate, and low-carb diets for 20 weeks after a run-in period where 12% weight loss was achieved. Participants in the low-carb diet groups displayed significantly higher energy expenditures, and this trend held especially true for those with high baseline levels of insulin secretion. These results align well with the carbohydrate-insulin model (CIM) of obesity, providing the strongest support yet for the validity of this model for explaining the rise in obesity prevalence. As a reminder, the CIM posits that high-carb diets produce excess postprandial insulin secretions, which then promote increased fat deposition and sparks a vicious cycle of increased hunger and slowing metabolic rate to exacerbate weight gain. Read on below for more details on the results, design, and implications of this study.

• Total energy expenditure significantly differed between diets, with low-carb diets displaying the highest total change in energy expenditures. The change in total energy expenditure was increased 91 kcal/day for low-carb diets compared to moderate-carb diets, and increased 209 kcal/day for low-carb diets compared to high-carb diets. Moreover, a significant linear trend emerged of 52 kcal/day for every 10% decrease in the contribution of carbs to total energy intake. The graph below highlights these results, with the purple line representing low-carb diet averages, yellow representing moderate-carb diet, and pink being high-carb diet data.

• Dietary effects on energy expenditure were most amplified in participants with high baseline insulin secretion levels. For analysis, participants were divided into tertiles based off of baseline insulin secretion levels before the weight-loss run-in period. It was seen that those in the highest tertile of insulin secretion levels displayed the largest energy expenditure difference between low and high carb diets (figure below). Dr. Ludwig’s group suggests that this analysis could point to subgroups of patients (i.e. those with high insulin secretion levels) who may benefit most from low-carb diets.

• Study Design: 164 adults between the ages of 18-65 years-old with a BMI of 25 or more were enrolled for participation in the study. Before randomization, a run-in phase was conducted to first promote a weight loss of 12%, followed by a brief period of weight stabilization. Participants were then randomized into either the high-,moderate-, or low-carb diet for the 20 week test phase. During this test phase, diets were adjusted every two weeks in order to maintain weight loss within two kg of the level achieved before randomization.

We view this data as a crucial landmark in research supporting the carbohydrate-insulin model of obesity. One of the knocks against the CIM has been a dearth of evidence investigating its applicability to controlled feeding studies. On this front, this study led by Dr. Ludwig represents the longest and largest feeding study to test the CIM. The CIM has also been challenged by some recent meta-analyses, which appear to indicate no meaningful differences in energy expenditures between low-fat and low-carb diets; however, the authors on this study note that most of the studies included in these analyses are short term (often less than two weeks in duration), making them insufficient to study an adaptation to a low-carb diet that can often take at least two to three weeks. This study, being 20 weeks in length, explores new space in determining the effects over a longer period of time.

Patient-Centered Thinking Highlights

Dr. Jamy Ard Assesses Patient Expectations in Commercial vs. Medical Weight Loss Programs, Opportunities and Challenges of Poor Reimbursement; Underscores Unreasonable Expectations Placed on People with Obesity

Wake Forest’s Dr. Jamy Ard assessed the vastly different patient expectations for commercial and medical weight loss management programs and identified opportunities and challenges within the poor medical reimbursement landscape for obesity therapy. As he sees it, obesity is a unique disease inasmuch as patients can choose between commercial and medical weight loss programs. For the former, patients expect the program to be: (i) elective – they can opt in or out at any time; (ii) a la cart – they pick; and (iii) self-paid. In contrast, patients expect medical programs to be: (i) medically necessary – similar to any prescribed treatment; (ii) all-inclusive – diet, gym, psychologist, etc.; and (iii) insured. However, when patients’ approach the healthcare system, they’re beliefs (particularly around coverage) are challenged due to the many barriers driving costs to patients. Most notably, obesity treatment requires more frequent visits (and co-pays) than any other disease. Moreover, the variety of provider types in obesity treatment (dietitian, physical therapies, psychologist, etc.) means that some may not be covered, and ambiguous insurance regulations (such as CMS’ definition of intensive behavioral therapy for obesity, which only covers PCPs in a primary care setting) often influence treatment choice as well as the length of time before a treatment is available. To this end, standards of what a weight management program entails and is expected to provide must be established. Lastly, given that obesity is a chronic disease, a long-term (possibly indefinite) commitment from patients to treatment (and costs) is required. All this said, Dr. Ard identified several opportunities for providers to reduce costs to patients – primarily through bundled payments. At Wake Forest, where Dr. Ard works, the health system was able to reduce costs of their weight management program for employees to ~$2400 by bundling its various components, of which ~10% was passed on to the patient (but could also be covered if the patient had met her/his deductible). This is a huge improvement over the ~$3,500, with 47% of the cost attributed to patient, if all components of the program were billed separately. With respect to pharmacotherapy, which is often under-reimbursed, Dr. Ard encourages patients to shop around on GoodRx.com for best prices before purchasing, and he noted that behavioral health codes can also often improve reimbursement for in-person visits. Looking to the future, Dr. Ard highlighted the immense potential for value-based care in obesity, which he believes will positively impact disease resolution by placing emphasis on diabetes remission while bringing value to patients, providers, employers, and insurers.

• Dr. Ard asserted that unique and unreasonable expectations are placed on patients/consumers who are seeking help managing their weight – most notably, that they must carry some of the financial cost (have some “skin in the game”) or else they will walk away. He underscored that, unlike any other disease, an assumption exists that a paying money will increase a patient’s engagement. To dispel this myth, he conducted a retrospective analysis of patient engagement and program outcomes in a medical weight management program in his own clinic according to those who were covered vs. paid out-of-pocket. After one year, the covered group had a 5% lower dropout rate (12.7 vs. 17.7, p=0.03), and no difference was found in weight change or percent of patients achieving 5%+ or 10%+ weight loss. Moreover, covered patients were younger (46.5 vs. 51.6) and lived in neighborhoods with lower per-capita incomes ($28,943 vs. $32,836), signaling stronger engagement with demographics that many weight management programs often try to target.

  • Other unrealistic expectations placed on patients with obesity, according to Dr. Ard, include: (i) the emphasis on self-care – patients must actively participate in their care every day, regardless of personal stressors or difficult circumstances; (ii) little help accessing treatment spaces – for example, a gym; (iii) managing stimuli – patients are expected to “put on their blinders” to advertisements within the obesogenic environment; (iv) care coordination; and (v) frequent provider encounters – visits weekly or every other week are often challenging to fit into busy lives with jobs, kids, etc. Taken together, Dr. Ard noted that these expectations suggest that quality of life of participants, as well as weight loss, must be evaluated in weight loss programs and taken into consideration in their conception.

In an earlier assessment of the current obesity treatment coverage landscape in the US, Dr. William Dietz underscored the disparity in providers and obesity prevalence in the US – 164 adults/PCP with a BMI≥35, 89 adults/PCP with a BMI≥40, and 50 children/PCP by a “back of the envelope” calculation. With this in mind, the US is “way behind the curve” in terms of reimbursement, especially seeing as dietitians and personal trainers/physical therapists more often comprise part of the “core team” in weight loss maintenance yet are less likely to be covered by insurance. Moreover, he noted that physicians are likely the least capable of implementing behavioral change therapy with their patients compared to dietitians, physical therapists/personal trainers, and psychologists.

Dr. Louis Aronne Assess Regulatory and Payer Thinking on Obesity, Gives Tips to Manufacturers; Provides Pearls for Breaking Through Weight Loss Plateaus

In an inspirational overview of weight loss maintenance, Cornell’s Dr. Louis Aronne cautioned manufacturers from trying to maximize obesity drug doses for efficacy at the risk of even minimal increases in side-effects and provided his “pearls” for overcoming the difficulties with weight loss maintenance. He prefaced his talk with a preemptive answer to the question, how long do patients with obesity need to be treated? Forever. Drawing a comparison to hypertension medications, Dr. Aronne noted that obesity medications cannot be stopped after weight loss is achieved; unfortunately, given the stubborn and multi-faceted nature of obesity, the foot can never be lifted from the gas. With this as backdrop, Dr. Aronne gave tips to manufacturers and providers on how to provide better obesity medication:

• To manufacturers, Dr. Aronne stressed that maximizing the dose and efficacy of obesity drugs should never come at the cost of even modest increases in side-effects, due to regulatory and payer thinking on obesity. He took the example of a payer who covers 50 million patients; given current obesity prevalence, this would mean that 16 million of them are indicated for pharmacotherapy. For payers, this translates to billions of dollars for medicines that, (i) may not in reality provide weight loss; and (ii) carry potential side-effects. On the latter, he gave the hypothetical of a side-effect that effects only one in 1,000 patients. If all 16 million covered patients took the therapy, that side-effect extends to 16 thousand people – certainly a significant number. It is for this reason that payers are less likely to cover obesity therapies and regulatory agencies are hesitant to approve pharmacotherapies for obesity, even with relatively strong safety profiles compared to other diseases. To this end, Dr. Aronne called for manufacturers to not continually increase the doses of therapies in studies, as those increases are often accompanied by increased side-effects without proportional efficacy. As an example of a drug that has been overdosed, Dr. Arrone pointed to phentermine – the most widely prescribed weight loss medication in the US. In 2013, a 28-week study revealed that there was only a very marginal benefit on weight loss to doubling phentermine dose from 7.5 mg to 15 mg (6.65% vs. 7.38%), with weight loss flattening out by the end of the study. Dr. Aronne noted that phentermine has been associated hypertension, lung, and heart problems, making it seems unwise to double the dose for 11% greater efficacy. Yet, to gasps from the audience, he revealed that the average prescription of phentermine is for 50 mg/day. In his words, “I just haven’t seen data to support [those prescribing habits].” For providers seeking to lower the phentermine dose of a patient, Dr. Aronne suggested weening the patient down rather than simply switching them to partially relieve perceived (though not actual) loss of efficacy on the part of the patient.

  • Dr. Aronne also noted that the traditional, monotargeted drug discovery process is not likely to succeed given obesity’s complexity. In his experience, targeting a single link along the biochemical mechanism of obesity is often unsuccessful for multiple reasons – efficacy is limited with a single target, agonism or inhibition in one area often leads to compensation in other parts of the pathway, and side-effects loom large in an imbalanced system, to give a few. As evidence, he noted that his lab has conducted clinical trials for 55 molecules, four of which have been approved. With this in mind, we would have loved to get Dr. Aronne’s take on emerging dual agonists with potential in the obesity landscape such as Lilly’s GIP/GLP-1 dual-agonist, which conferred ~25 lbs of weight loss at its highest dose in just 26 weeks during phase 2.

• Dr. Aronne provided evidence that weight loss maintenance is dependent on will power in many cases. To make this point, he highlighted a two-year trial comparing weight loss with low-carbohydrate, Mediterranean, and low-fat diets conducted at a research center in Israel. This paper rightly points out the common limitations of dietary trials – high attrition rates (15%-50% in one year), small size, short duration, lack of assessment adherence, and unequal intensity of intervention to name a few. By comparison, this trial was conducted through the cafeteria of a workplace which provided food to all members of the study, leading to a 95% adherence rate at one-year. Yet, despite this incredible adherence rate, peak weight loss was achieved at ~5 months, with patients regaining significant weight by the end of the two-year trial (see below). As for the biological underpinnings of weight regain, Dr. Aronne pointed to a 2011 study that found that a 14% reduction in fat content produced a neurological response (leptin) consistent with a 65% reduction in fat, meaning the body wrongly perceived itself to be starving. Poignantly put by Dr. Aronne, “this just isn’t fair.” Taken together, he believes these studies to give credence to pharmacotherapy as a means to bridge the treatment gap between behavioral change and bariatric surgery.

• As for how to break through weight loss plateaus, Dr. Aronne underscored that providers must be creative and persistent in their treatment. For example, one undervalued measure that patients can take is eating protein, rather than carbs, for breakfast; according to Dr. Aronne, this simple replacement can be extremely satiating. If a patient is entirely resistant to changing his or her diet, providers could encourage eating carbs last in meals, which has been shown to have a significant impact on postprandial glucose and insulin levels. Moreover, providers may encourage intermittent fasting, which Dr. Aronne has found often “re-activates” medication effects again, or a food diary. With respect to medications, he suggested being flexible on dose timing so as to maximize the satiating effects of medicine when patients need it most (perhaps at the end of the day rather than in the middle). Lastly, he reinforced that prescribers should continually reevaluate the need to add or change medications.

  • To conclude his talk, Dr. Aronne provided several powerful examples of the persistency and flexibility required to maintain weight loss over substantial periods of time with pharmacotherapy and lifestyle interventions. See the photo below for one example, which required bupropion, canagliflozin, liraglutide, naltrexone, switching carbs for protein at breakfast, changing eating order (carbs last), topiramate, and semaglutide to achieve 16% weight loss maintained over four years. Notably, Dr. Aronne added that the patient felt more satiated than ever upon beginning semaglutide – adding to the hype we saw on days one and two for Novo Nordisk’s new GLP-1 agonist here at Obesity Week.

Patient Perspectives Panel Underscores Importance of Integrated Care and Emotional Health

The only patient-run talk at Obesity Week touched on shared experiences of poor interactions with medical professionals, the value of integrated care, and the importance of addressing mental health. Each patient speaker began by sharing memories from childhood of being bullied and being made to feel embarrassed about their weight, whether that was by a school nurse in front of their elementary school class, while playing sports at camp, or by friends and family with nicknames and mean comments. Universally, they shared that these experiences were the beginning of struggles with low self-esteem that would worsen into adulthood. Two speakers, Ms. Patricia Nece and Mr. John Sawyer, explained that it was their introduction to integrated care at the National Center for Weight and Wellness (NCWW) that changed the trajectory of their weight loss journey (we reported previously on Ms. Nece and Director of NCWW in 2016). Ms. Nece recalled how all of her past physicians had advised her to lose weight, but didn’t offer any help or support past that advice and made her feel judged and like a failure for dieting without results. At NCWW, patients had a more holistic experience of care, one that combined physicians, dietitians, exercise specialists and psychologists and involved shared decision-making between patients and professionals. Ms. Nece remarked that this shared decision-making was empowering and was one of the keys to her successful loss of 100 pounds.

• Ms. Michelle Vicari, known best for her blog dedicated to life and food post gastric bypass surgery, echoed the importance of mental health when struggling with obesity. Ms. Vicari shared that she previously believed all her problems would disappear if she just lost the extra weight, but despite losing 158 pounds as a result of her gastric bypass and then having plastic surgery to remove excess skin, she still had a lot of work to do “above the shoulder.” One takeaway these speakers emphasized was the need for medical professionals to approach each patient with obesity with nonjudgmental compassion and an understanding that each person’s journey and needs are different. We feel truly lucky to have been in the room for this discussion. Its raw emotion hit home for many individuals, whether they were medical professionals, had loved ones struggling with obesity, or they themselves identified with the speakers.

Big Picture Highlights

Dr. Donna Ryan Calls for ADA/EASD-esque Treatment Algorithm for Obesity; Calls to Industry for Multimodal Therapies, Combination Therapy RCTs, Realistic Expectations for Obesity Market

In a Monday keynote on weight loss pharmacotherapy, World Obesity Federation President Elect Dr. Donna Ryan advocated for greater therapy uptake, better patient selection, combination therapy, and a treatment algorithm for obesity similar to the ADA/EASD consensus statement on diabetes. As she sees it, the brand new individualized guidelines on second-line treatment (taking into account CV/renal disease, cost, etc.) and stepwise treatment algorithms for combinations in the ADA/EASD recommendation serve as valuable models for obesity pharmacotherapy. Moreover, in de-mystifying prescribing practices, guidelines could well improve uptake of these pharmacotherapies where it is so desperately needed. Until these guidelines are created, Dr. Ryan suggested selecting obesity medications based on potential dual-effects (e.g., Novo Nordisk’s Saxenda for both obesity and diabetes), and re-assessing efficacy after 12-16 weeks; if the patient has not achieved 4-5% weight loss at that point (signaling a strong response), then the medication should be stopped and a new one begun (this assumes payments will not be an issue). With this in mind, Dr. Ryan advocated strongly for greater use of combination therapies for obesity, pointing to this 12-week study demonstrating additive effects with co-administration of lorcaserin (Arena/Eisai’s Belviq) and phentermine as well as this trial of canagliflozin (J&J’s Invokana) and phentermine as examples. That said, she did acknowledge the need for further safety studies and a greater wealth of efficacy data for the inclusion of combinations in general treatment algorithms. Later in her talk, Dr. Ryan also briefly touched on the potential of GIP/GLP-1 and GLP-1/glucagon dual-agonists for obesity. Indeed, after Lilly demonstrated ~25 lbs weight loss in 26 weeks with its phase 2 GIP/GLP-1 dual-agonist and AZ/MedImmune demonstrated ~7.4 lbs of weight loss in just seven weeks with its GLP-1/glucagon dual-agonist in the same day at EASD 2018, we find it hard not to wonder if and when these therapies might be investigated in obesity – presumably, it won’t be too far off and we also hope therapy won’t be used in a vacuum. To be sure, obesity is a disease in serious need of better pharmacotherapies. As the great Dr. Naveed Sattar put at EASD 2018, “We still need safe weight loss drugs … We have excellent cholesterol, blood pressure, and diabetes drugs. Things are really, really good there. Yet, obesity and associated complications are rising, in part due to the obesogenic environment…Obesity is now, as I see it, the biggest challenge to those of us in the metabolic profession.”

• In a call to industry, Dr. Ryan laid out four ideas for obesity drug development moving forward:

  • Consider multimodal therapies to maximize and maintain weight loss. Companies should have consumer products, devices, apps, commercial programs for chronic weight management – in addition to medications.

  • Fund RCTs for combination medications. According to her, full-scale phase 3 studies are not needed to power for efficacy, and these will be necessary to improve treatment algorithms.

  • The emerging cadre of trained prescribers for obesity therapies is still small, and it will take a critical mass to affect normative behavior of providers. As such, industry should adjust its expectations and not let marketing get ahead of the market. As it stands, prescribing obesity specialists represent the leading edge of the market, which is sure to expand as PCPs become more comfortable with prescribing medication for weight loss. This assumes that payments will be there.

  • Re-think weight loss vs. weight loss maintenance. Might a cheaper drug exclusively for weight loss maintenance be possible?

• Dr. Ryan also expressed her concerns with current trends in drug discovery:

  • Orphan drug status and expensive, luxury product status of emerging biologics will do little to help the general obesity epidemic vs. low-cost agents and phentermine. To this end, Dr. Ryan speculated whether drugs being investigated under orphan drug status, such as Rhythm Pharmaceutical’s phase 2 melanocortin-4 receptor (MC4R) agonist setmelanotide, currently being developed for the treatment of leptin receptor (LepR) deficiency obesity, might be more widely applicable.

  • Where is the statin of obesity care? As she sees it, 37% of the population needs medication, and a cheap, generalizable, go-to statin-like therapy would be the holy grail of obesity therapy.

Dr. Steven Nissen’s Opening Keynote Highlights Link Between Obesity and CVD; Underscores Lack of Evidence for Weight Loss Drugs on Hard Outcomes

The engaging Dr. Steven Nissen (Cleveland Clinic, Ohio, United States) provided the opening session keynote at Obesity Week 2018, arguing for the link between obesity and cardiovascular disease risk. The selection of Dr. Nissen, a renowned cardiologist, to provide this opening keynote was especially fitting, considering that the theme of this year’s Obesity Week conference focuses on the intersection between obesity and heart disease. See below for some of the most salient points we picked out from Dr. Nissen’s powerhouse talk:

• Dr. Nissen pointed toward more recent and comprehensive analysis linking increasing BMI status with elevated CVD event rates. This analysis published in JAMA Cardiology in 2018 looks at the association of BMI with lifetime risk of CVD and finds that as BMI increases across the spectrum of five binned categories (underweight, normal weight, overweight, obese, morbidly obese), so does lifetime risk of CVD. Notably, this trend holds for both men and women, although it is more pronounced in men—key results from the study are reproduced in a figure below. Dr. Nissen called this a “terrific analysis” and emphasized how it looked at impressively long-term follow-ups of 25+ years. This comes in stark contrast to previous data that had challenged the association between obesity and CVD risk and raised the idea of the “obesity paradox.” Such data includes a 2013 JAMA meta-analysis that looked at all-cause mortality and BMI and concluded that “obesity overall was not associated with higher mortality, and overweight was associated with significantly lower all-cause mortality.” Dr. Nissen called this conclusion from the paper “bizarre” and noted that this study encompasses many common issues with analyses that support the “obesity paradox.” Oftentimes, these studies are confounded by smoking, which itself is associated with low body weight yet high CV risk. Moreover, these studies often do not look far enough in to the future—in order to observe the full effects of obesity, Dr. Nissen argues that the time horizon must be stretched (as it was in the aforementioned 2018 JAMA analysis). Finally, Dr. Nissen pointed out that some individuals with low BMIs are very thin because they have other chronic or incipient diseases that result in relative CV risk, blurring the lines between obesity and potentially elevated CV risk. Synthesizing these points, Dr. Nissen emphatically stated that he is “convinced that having a low body weight is healthy—not unhealthy.”

• Dr. Nissen highlighted data suggesting that being physically active—even if living with obesity—can significantly mitigate CVD risk. On the question of whether “you can be fit and fat,” Dr. Nissen reviewed convincing data on the utility of being physically fit even in light of living with obesity. Citing data from a 2016 study, Dr. Nissen showed that “if you’re fit [and living with obesity], you still have an excess risk [compared to normal weight], but it is reduced very substantially” when compared to patients with obesity who are not fit. In this vein, Dr. Nissen remarked that he “recognizes that it can be very difficult for people to lose weight—but if we can get them to exercise, we can reduce a lot of this risk.” In his practice, Dr. Nissen noted that he has a few patients that have obesity but are also very fit, and he explained how he strongly encourages them to stay fit even if it doesn’t appear to directly lead to weight loss.

• The impact of obesity treatments on hard patient outcomes still needs to be determined. Dr. Nissen drew laughs by presenting the slide below, which highlights the absolute dearth of evidence demonstrating benefits of obesity medications on clinically important outcomes. Dr. Nissen emphasized that until such data emerges, we’re essentially prescribing in the dark where only risks and costs are present. On this note, we’re hopeful to see results from Novo Nordisk’s SELECT CVOT for Saxenda, which will represent the first CVOT for an obesity medication to date. SELECT is aiming to demonstrate that clinically meaningful weight loss can reduce CV events and mortality; we imagine that proving benefits on hard outcomes such as these may help Saxenda and other obesity medications gain broader access to patients with better reimbursement from payers. However, it’s important to note that Saxenda (semaglutide) is a GLP-1, which themselves are thought to be cardioprotective, which may confound any results that link weight loss to CV benefit in this trial.

HHS Physical Activity Guidelines Updated for First Time Since 2008: Biggest Changes Include Guidelines for Preschoolers and Discussion of Sedentary Behaviors

NIH’s Dr. Rachel Ballard presented on major news dropping yesterday concerning the release of second-edition Physical Activity Guidelines by HHS – the first update to guidelines initially published ten years ago in 2008. These guideline updates were also simultaneously published in JAMA. On a very high-level view, the core of these guidelines have not changed much since 2008. Like 2008, these guidelines still suggest that adults engage in at least 150 minutes of moderate-intensity physical activity a week. Commenting on the infrequency of guideline updates and the lack of dramatic change between these two editions, Dr. Ballard noted that unlike dietary guidelines, where legislation mandates an update every five years, no such requirement exists for physical activity guidelines. Nevertheless, we see the release of these guidelines as a major event, especially in light of a burgeoning obesity prevalence epidemic. Read on for a few highlights from this announcement and commentary from Dr. Ballard:

• For the first time, physical activity guidance is included for preschool children aged three to five years old. The guidelines do not provide a concrete quantitative guideline for this group unlike how it does for other groups, but rather says that preschool-aged children “should be physically active throughout the day to enhance growth and development.” On this front, the guidelines advocate for adult caregivers to encourage active play. In our view, the inclusion of recommendations for this young age group—a first ever occurrence—is a positive identification of the need for earlier interventions in order to prevent obesity and other chronic conditions associated with inactivity.  

• A more robust discussion of sedentary behavior is also included. Sedentary behavior was not discussed in the 2008 guidelines; this newfound focus represents growing evidence concerning the interrelationship between sedentary behavior and mortality risk. Dr. Ballard noted that the explosion of evidence generated from the inclusion of accelerometry data allowed for this more robust consideration of how sedentary behaviors fit into health. The heatmap figure below was developed as background for the physical activity guidelines, and indicates that as sedentary time increases, mortality risk also increases; however, this risk can be modulated by the amount of physical activity an individual engages in. Because of this complex relationship between sitting time and physical activity (and how different combinations of these two variables generate varying levels of risk), the guidelines do not give strict guidelines on sitting time or how to break up sitting time during the day. As a general rule of thumb, the guidelines do recommend that adults in the US increase physical activity and reduce sitting time.

• These guidelines also eliminate a previous recommendation stipulating that physical activity for adults occur in bouts of at least ten minutes. Dr. Ballard noted this as a major change that may not on the surface seem as so. She noted that evidence no longer supports the requirement of physical activity occurring in these minimum prescribed durations; instead, any amount of physical activity—even if it doesn’t reach ten minutes per se—is still useful. To illustrate this point, she presented data relating relative all-cause mortality risk to physical activity amounts. Risk steeply drops from zero physical activity to ~50 minutes per week, representing that the greatest magnitude of benefit is achieved by having people who do not engage in physical activity at all start to engage at least a small amount.  

• Approximately 80% of US adults and adolescents are still insufficiently active. This is an especially sobering statistic and truly reflects how much progress still needs to be made in both communicating the necessity of physical activity and ensuring that all individuals have proper access to an environment that enables physical activity. Among adults, some progress has been made in increasing the percentage who meet these physical activity guidelines (see figure below); however, the overall rate still remains unacceptably low.

• An exhaustive research process was undertaken in the updating of these guidelines. Dr. Ballard highlighted that almost 21,000 titles in physical activity research were initially screened, and 837 articles were finally reviewed in the end in order to develop an evidence base for these guidelines.

Sweetened Beverage Tax; Says That Obesity Treatment Won’t Solve Prevalence Epidemic; Sobering Statistic—59% of 2-Year-Olds Today Will Have Obesity by Age 35

The renowned Dr. Steven Gortmaker (Harvard University School of Public Health, Cambridge, Massachusetts, United States) underscored that addressing the obesity epidemic will require going beyond assessing effectiveness—instead, the costs of these interventions must also be analyzed. Dr. Gortmaker’s work focuses on just that, and in this presentation, he ran through some key data that his group has published concerning micro-simulations of various childhood obesity intervention strategies. On a broad level, this project that his group has undertaken is called the Childhood Obesity Intervention Cost-Effectiveness Study (CHOICES), and aims to identify cost-effective interventions for childhood obesity within the five sectors of schools, community/government, early and out-of-school care, transportation, and clinical settings.

• The CHOICES model predicts that a national sugar-sweetened beverage (SSB) excise tax of one-cent-per-ounce would save $14.2 billion and prevent 576,000 cases of childhood obesity over ten years. Dr. Gortmaker presented cost-effectiveness analysis for three proposed interventions to curb childhood obesity: an SSB tax, the Smart Snacks school intervention that was implemented in 2010, and bariatric surgery on eligible adolescents with obesity. By the CHOICES model, the nationwide SSB tax was seen to be the most effective in terms of predicted net savings ($14.2 billion) and number of childhood obesity cases prevented (576,000) over ten years. The Smart Snacks program lagged far behind at $792 million in net savings and 344,640 childhood obesity cases prevented. Meanwhile, bariatric surgery was predicted to have a net cost of $303 million while not preventing any cases of childhood obesity. On this note, Dr. Gortmaker emphasized that bariatric surgery—while certainly very important from a treatment perspective in improving the lives of patients—does not make much of a dent on the obesity epidemic due its limited reach in the broader population. This point fit in with Dr. Gortmaker’s larger one regarding obesity treatment, as he remarked that we “can’t expect to treat our way out of the obesity epidemic.” Treatment makes too little a difference on obesity prevalence—“it’s too little, too late, and generally expensive.” Conversely, preventative measures that slow the rise of excess weight gain over long periods of time are key.

  • CHOICES predicts that the SSB tax would save ~$32 per $1 invested, compared to ~$5 saved for Smart Snacks. Dr. Gortmaker clearly advocated for the efficacy of such an excise tax for sugar-sweetened beverages, and called the Smart Snacks “a very expensive intervention” when compared to the SSB tax. Making the SSB tax even more appealing is that these saving don’t include the revenue that would be generated from the tax—an estimated $12.5 billion/year that could subsequently be further invested into prevention, creating a potential positive feedback loop.

• The CHOICES microsimulation model works through a sequential process of five major steps. First, the model generates a virtual population for the United States based off of 2010 Census data. Then, in order to create forward-looking data, population growth models and trends (including those for statistics such as BMI) are applied to this population to “age” it ten years. Individual factors such as body growth, dietary intakes, and other characteristics (like smoking status) are subsequently applied to this population to create a prediction for what a future population would look like, sans any major policy events. With this future population simulated, an intervention—whether that be on dietary intake of physical activity—is applied, and its effect on obesity is measured. Outcomes are then tabulated on obesity, healthcare costs, and mortality in order to determine the overall cost-effectiveness of a particular intervention.

• Dr. Gortmaker also presented sobering data from his group’s recent NEJM publication predicting that 59% of two-year-old’s today will develop obesity by age 35. We were especially struck by this specific prediction, which contextualizes how dramatically the obesity epidemic will affect those born into it. We certainly do hope that dramatic measures are taken to prevent this type of future.

Ms. Amanda Crandall Breaks Down Manifold Increases in Obesity Risk from Food Insecurity

University of Buffalo’s Ms. Amanda Crandall shared her research on the stress of food insecurity (FI) in adolescence and its effect on self-efficacy, reward sensitivity, and subsequent obesity risk. In 221 adolescents age 12-14 and their parents, Ms. Crandall measured reward sensitivity, self-efficacy for healthy eating, and psychological stress on sliding scales, ultimately constructing a flowchart delineating the manifold effect of food insecurity on obesity risk (see below). The psychological stress produced by food insecurity both reduced self-efficacy and increased reward sensitivity (which in themselves created a vicious positive feedback loop), all contributing to increases in energy intake and obesity risk. Moreover, it is important to note that food insecurity is only one of many often-associated social determinants of health – for example, poverty, housing instability, and safety issues. As such, treatment plans which only ask participants to buy (often more expensive) healthy food are often infeasible. At ADA 2018, UCSF’s Dr. Danielle Hessler dived further into these treatment plans, instead advocating for recommendations that patients go to a food bank or visit the 99-cent store to see what’s available, affordable, and healthy. We strongly agree with Dr. Hessler here – so many patients with diabetes face tough socioeconomic realities (which manifests itself in disproportionately higher obesity prevalence in low-income households), and individualization of care that factors in many social determinants of health is absolutely key to actually improve outcomes in all pockets of the population. That said, obesity, diabetes, and food insecurity are massive, overlapping public health problems, and reducing food insecurity alone can certainly have a strong impact. Geisinger’s Fresh Food Farmacy could be a model here. At JPM, we learned that A1c reduction with access to a Fresh Food Farmacy was ~2%, while the average A1c drop from FDA-approved diabetes drugs is only ~1% – that’s remarkable. Moreover, this prescription for healthy eating reduced monthly healthcare expenditures by 78%, from $18,000 to $4,000, making a compelling case for the value of healthy food access and education on healthy diet and lifestyle.

Dr. Marlene Schwartz Highlights Impressive Data Showing 20% Reduction in Soda Sales Following Public Policy Changes + Media Campaigns

Dr. Marlene Schwartz (University of Connecticut, Storrs, Connecticut, United States) highlighted recent data demonstrating the effectiveness of a three-year public health and policy campaign to reduce sugary drink consumption in Howard County, Maryland.  Fitting into a broader presentation on natural experiments in evaluating policy changes, Dr. Schwartz presented her group’s data from a 2017 paper published in JAMA Internal Medicine that demonstrated a 20% reduction in soda sales after Howard County implemented several public policies to encourage healthy beverage consumption in schools, child care, health care, and government settings, couple with a three-year long marketing campaign that created a 17 million impressions on residents. Several public policies were implemented during this time period that contributed to this overall effect; Dr. Schwartz highlighted a few that were thought to have the most outsized effect. One such policy was an ordinance enacted to make healthy foods and beverages more available in government-owned vending machines; another was The Maryland Healthy Eating and Physical Activity in Childcare Act that reached 10,000 children in childcare in Howard County specifically. The associated media campaign included 30-second TV spots on cable stations, digital ads, direct mail to county households, and other activities, all which contributed to the impressive 17 million impressions achieved over the three-year time period. The figure below, reproduced from the JAMA paper, clearly demonstrates the direct reduction in retail volume sales of sugary drinks—a reliable measure associated with consumption—in Howard County following the beginning of the media campaign, compared to a control store that had previously correlated with Howard County sales. We find this data to be very compelling on the effectiveness of combined policy changes and media campaigns on the issue.    

Exhibit Hall

Novo Nordisk

Novo Nordisk boasted prime real estate in the exhibit hall with a booth near the entrance that exclusively promoted Saxenda (liraglutide 3.0 mg). Signs erected in the booth proclaimed “When it comes to losing weight and keeping it off—We have the will. Now you can give us the power.” Obesity pharmacotherapy still experiences many barriers especially in prescribing practices of clinicians, and Novo Nordisk’s messaging here is clearly trying to bridge that disconnect between the efficacy of Saxenda and its underuse. We recently heard on Novo’s 3Q18 earnings call that greater recognition of obesity as a disease and generating higher prescriber engagement are two key goals for Saxenda’s success moving forward. On this note, Saxenda only holds <2% of total obesity prescriptions in the US (but does garner 43% of market value).

Elsewhere in the exhibit hall, Novo Nordisk also had another smaller booth that promoted Saxenda in a more indirect fashion. Here, prescribers could customize their own personalized posters detailing the obesity epidemic and complications/comorbidities associated with obesity to hang in their practicing offices. We imagine that booths like these are part of Novo’s stated goal to increase awareness of obesity as a disease and increase HCP engagement with obesity.

Aspire Bariatrics

Aspire claimed a sizable booth in the exhibit hall, touting the slogan “Where endobariatrics meets evidence-based medicine” and their AspireAssist, which is an endoscopic alternative to bariatric surgery. Successful patient profiles were highlighted in the booth, including two who maintained 100+ lbs of weight loss for five+ years after AspireAssist. Representatives emphasized the excellent safety profile of AspireAssist and its low rate of serious complications, along with data indicating sustained weight loss over four years with the treatment. As a reminder, AspireAssist received FDA approval in June 2016 and demonstrated positive results in its pivotal trial published in January 2017.

Medtronic

Medtronic occupied a spacious, central booth at Obesity Week, heavily devoted to its metabolic surgery equipment, though we were thrilled to see a small corner devoted to the company’s iPro2 CGM, a professional CGM for three to six-day wear. Also advertised was the product’s Nutrino Foodprint report, a photo-based meal logging intervention that pairs glycemic response (in-range vs. out-of-range) with meal photos – included in the myLog app for the iPro2, which allows users to view and log their blood glucose readings, food, and exercise data, available for free on iTunes and Google Play. Medtronic and Nutrino actually assign a letter grade from “A” through “F” to each meal photo based on the postprandial CGM trend (AUC, time-in-range, average glucose), with the “F” appearing in dark red and “A” in green. On the plus side, we are glad to see photo-based food logging paired with CGM, as this will be a huge driver of behavior change in our view. That said, we’re concerned about using glucose values for explicit grades, especially in a type 2 audience that already feels very judged and stigmatized around food.

Rhythm Pharmaceuticals

Rhythm, developer of MC4R agonist setmelanotide in leptin receptor (LepR)-deficiency obesity, conveyed a clear message on the backdrop of its sleek, two-person booth: “Hunger. Some people’s brains make it hard to focus on anything else.” Indeed, the company’s focus on biological predispositions to obesity (“uncommon obesity” as was labelled at the booth) has garnered attention and optimism from KOLs. At WCPD 2018, renowned metabolism expert Dr. Sadaf Farooqi referenced setmelanotide as a drug that may “finally help” with these rare conditions. Most recently, Rhythm reported results from a very small (n=3) phase 2 study demonstrating weight loss between 8%-22%of body weight over the course of ~one year. On the heels of these results, a phase 3 trial (n=10) for setmelanotide in LepR-deficiency obesity is currently enrolling, and is expected to complete in January 2020. This is supported by a $41 million mezzanine round of financing (completed in February 2017). Rhythm also has phase 2 programs for setmelanotide in other genetic obesity conditions, including Bardet-Biedl syndrome, Alström syndrome, and Prader-Willi syndrome (for which setmelanotide has an Orphan Drug designation). As a side note, on Day 2 of Obesity Week, Dr. Donna Ryan expressed her concern in orphan drug designation and luxury product status as trends in drug discovery, specifically calling out Rhythm Pharmaceutical’s setmelanotide as a therapy that might be more widely applicable than only LepR-deficiency obesity.

--by Martin Kurian, Peter Rentzepis, Sarah Kolk, and Kelly Close