April 1-4, 2017; Orlando, FL; Preconference and Days #1-2 Highlights – Draft

Executive Highlights

Greetings from Orlando (the city of the happiest place on earth!). ENDO 2017 is well underway, and we bring you 27 (!) interim highlights spanning diabetes technology, diabetes therapy, and obesity. Scroll down for insights from Drs. Irl Hirsch, Anne Peters (who spoke six times in 24 hours!), Bill Polonsky, Robert Vigersky, Rich Bergenstal, and so many others… and check out our conference preview to see what’s in store for the final days of this meeting!

Top ENDO 2017 Highlights – Diabetes Technology

1. At Medtronic’s intimate corporate symposium (our small team made up 10% of the room), Diabetes Unit Medical Director Dr. Robert Vigersky announced that the 1,000-patient MiniMed 670G outcomes RCT is expected to begin recruitment this month. Impressively, it’s the biggest type 1 trial since the DCCT and will pit 670G hybrid closed loop against SAP, pump alone (no CGM), and MDI. Wow! He also shared that the 670G pediatric study (ages 7-13) is almost complete, will read out data around mid-summer, and be submitted to the FDA by the end of the year.

2. We’ve heard almost entirely positive commentary on the blinded, retrospective FreeStyle Libre Pro. Dr. Irl Hirsch stated that the device has been “amazing” and that he and his colleagues have been “surprisingly impressed. It’s really changing the way we do things already.” As expected, some desire real-time data and we’ve heard some complaints of over-reporting of hypoglycemia (consistent with the FDA summary data).

3. In an early-morning Dexcom-sponsored symposium, we learned that initial Medicare beneficiaries have filed for reimbursement for therapeutic CGM through Liberty Medical, and Integrated Diabetes Service’s Mr. Gary Scheiner evaluated three approaches to adjusting boluses based on CGM trend information.

4. IDC’s Dr. Rich Bergenstal kicked off ENDO pre-conference proceedings with a talk on the rise of CGM (“the dawn of a new era,” including MDI), outcomes beyond A1c (“no patient is average”), report standardization, and “pumps with brains.” In Q&A, Dr. Bergenstal mentioned 670G experiences at his clinic, where the mantra for patients is “Let it work, let it work, let it work.”

5. In a small room of 30 people, UW’s Dr. Irl Hirsch opined on the importance of downloading patients’ data and the infrastructure required to fit it into clinical workflow. He also recommended CGM to determine the magnitude of patients’ glycation gap and mentioned that Roche will reportedly start the Accu-Chek Insight CGM pivotal trial this summer (presumably in the US, as it’s already out in Europe).

6. In her fifth appearance of the morning, USC’s indefatigable Dr. Anne Peters offered her insights on diabetes tech topics ranging from access, to education, expectation management, physician burnout, and more. Along the way, she threw in her belief that Medtronic is actively pursuing Medicare coverage for 670G, and news that the field is now working on obtaining Medicaid and Medi-Cal coverage for CGM. Quotable quotes below.

7. In the tech portion of the exhibit hall, we learned that the ongoing Medtronic customer access phase consists of >710 patients (bigger than we expected; 110 are employees with diabetes!), and Companion Medical’s InPen made its exhibit hall debut. We also visited Abbott’s, Dexcom’s, Insulet’s, and Tandem’s booths.

Top ENDO 2017 Highlights – Diabetes Therapy

1. In a showdown that rivaled the Wrestlemania convention occurring next door at the same time, the highly respected Drs. David Nathan and Daniel Drucker engaged in a heated debate over the value of new diabetes drugs in type 2 diabetes care. The debate was a big one, with attendees listening with bated breath. We note our view that from a high level perspective, Dr. Drucker's presentation relied heavily on randomized controlled clinical trial data -- this is, of course, high level evidence that doesn't incorporate "real world" experience or patient preferences that may impact adherence or side effects like weight or hypoglycemia. It was somewhat surprising that someone typically as evidence-based and data-driven as Dr. Nathan had a presentation without nearly as much real clinical trial data. His part of the debate relied somewhat more heavily in our view on anecdotes, innuendo, what some would term secondary manipulated analyses, and what we would characterize as opinion in some cases devoid of patients. To boot, his analysis included generalizations about finance that are somewhat time-consuming to source – we think it’s great that he brought those in, as long as the generalizations are apt, and we’ll be working on some analysis around that!

2. Dr. Jens Øligaard presented 21-year data from the Novo Nordisk-sponsored Steno-2 trial, which randomized 160 participants with type 2 diabetes/microalbuminuria to either intensive multifactorial treatment vs. standard of care for eight years (at which point both groups began to receive intensive treatment for ethical reasons, since patients in the intensive group were at significantly lower risk for microvascular and macrovascular disease). Results at 21-years follow-up further corroborated the benefits of intensive multifactorial therapy – glucose-lowering, blood pressure-lowering, and lipid-lowering simultaneously.

3. Dr. Lawrence Blonde discussed the advantages of combination therapy, suggesting that while we wait for a long-term clinical trial comparing simultaneous vs. sequential approaches, the data we have right now hints at the superiority of combinations.

4. In an absolutely incredible talk – that she termed the “most bizarre I’ve been asked to give” – Dr. Anne Peters offered practical tips for endocrinologists and physicians to advocate for broader public health changes in their communities. YES!

5. A MannKind-sponsored dinner symposium featured three diabetes experts on inhaled insulin Afrezza – Drs. Bruce Bode, Jeremy Pettus, and Janet McGill positioned the product as the only available faster-acting insulin in the US (as Novo Nordisk’s faster-acting aspart is still under FDA review). It’s very unfortunate the way that this product came onto the commercial landscape with so much weakness; it’s notable, however, that extremely well-regarded endos favor the product and we’ll be very interested to see how it goes.

6. Dr. Leigh Perreault advocated for the attainment of normal glycemia – by any means – as a method of diabetes prevention in people with prediabetes.

7. Nephrologist Dr. Robert Stanton expressed some reservations about the renal benefit of SGLT-2 inhibitor empagliflozin demonstrated in the EMPA-REG OUTCOME trial.

8. The prolific and somewhat controversial Dr. Kasia Lipska framed diabetes care for the elderly in terms of three main goals: (i) Improve symptoms, when present; (ii) Reduce the risk of acute and chronic complications, when pertinent; and (iii) Minimize the harm and burden of therapy, always. Much easier said than done on all three.

9. Diabetes therapy companies were out in full force at ENDO 2017. Most notably, Lilly’s booth featured a patient affordability and access section for the first time, highlighting the company’s direct-to-patient discount insulin program. Very excitingly, we learned for the first time about Lilly efforts to engage health plans to create new benefit structures for insulin – ideally, the company hopes to convince health plans to exempt insulin from patients’ deductibles and eliminate co-pays for insulin. We also visited engaging booths from Amgen, AstraZeneca, Janssen, Merck, Novo Nordisk, Rhythm, and Sanofi.

Top ENDO 2017 Highlights – Obesity

1. Dr. Tricia Tan presented results from a three-day study (n=18 patients with obesity) in which a 10.5-hour subcutaneous infusion was able to replicate the relative concentrations of three gut hormones – GLP-1, oxyntomodulin (OXM), and PYY – following Roux-en-Y gastric bypass (RYGB) surgery.

2. Dr. Stacy Brethauer, a top bariatric surgeon at the Cleveland Clinic, detailed fascinating insights from the Obesity in the America survey, revealing widespread misconceptions in public knowledge of obesity. A majority of Americans (81%) consider obesity to be the most serious health problem facing the nation (tying cancer as the top issue ahead of diabetes [72%], heart disease [72%], mental illness [65%], and HIV/AIDS [46%]) and yet only 38% consider obesity to be a disease. 78% of people considered diet and exercise to be the most effective weight loss method, with weight loss surgery (59%) and prescription obesity medications (26%) far behind.

3. Dr. Steven Kliewer (University of Texas Southwestern Medical Center, Dallas, TX) described his pioneering work uncovering the mechanism of action for FGF21, an obesity drug candidate of growing interest. His studies suggest that FGF21 targets brown adipose tissue by two separate pathways – a direct route and an indirect route via the brain – thereby providing “both the fire and the fuel” to increase energy expenditure and promote weight loss.

4. At the pre-conference Obesity Management Workshop, Dr. Ken Fujioka (Scripps Clinic, La Jolla, CA) reviewed the major obesity drugs, offering pearls of wisdom on the clinical use of each one.

5. The official ENDO program kicked off with a Presidential Plenary on the microbiome, a clear reflection of the microbiome’s growing status as not only one of the hottest topics in obesity research, but an area of keen interest in metabolism and endocrinology on a wider scale.

6. Leading obesity researcher Dr. Rachel Batterham (University College London, London, UK) issued a provocative call for a change in the way in which obesity is both treated and researched.

Top Endo Fellows Highlights

1. New to Endo Fellows, Dr. Bill Polonsky provided an excellent primer for endocrinology fellows on assessing and managing diabetes distress, which he described as the much more common psychological phenomenon in diabetes vs. major depressive disorder.

2. In a brand-new addition to the Endo Fellows lineup, Dr. Irl Hirsch gave practical tips on how to use human and analog insulins in type 1 diabetes. Highlighting his now-signature statistics on the rising cost of insulin over the last few decades, Dr. Hirsch emphasized the importance of learning how to use human insulin to the endocrine fellows in the room, as he predicts more and more patients will be forced to resort to human insulin due to financial barriers.

3. Dr. Michael Riddell walked the endo fellows through his recently-published consensus statement on exercise and type 1 diabetes. In exciting news, he shared that various industry partners and researchers are interested in supporting the translation of the exercise decision-making tree outlined in the paper (which he admitted is a bit bulky for real-world patients/providers to use regularly) into a decision-making app (much more user-friendly!). Sanofi is supporting a revamp of the related www.excarbs.com website that Dr. Riddell developed alongside Drs. David Kerr and Helen Partridge.

4. Dietitian expert Ms. Alison Evert framed medical nutrition therapy as an ideal opportunity for personalization of treatment, and as an essential factor in helping patients titrate their insulin accurately.

5. In back-to-back sessions, Dr. Robert Eckel, former president of the American Heart Association, provided a comprehensive update of the current state of knowledge of macrovascular disease prevention in type 1 diabetes.

Top ENDO 2017 Highlights – Diabetes Technology

1. Medtronic 670G 1,000-patient outcomes Study: Recruiting to Start This Month; Pediatric Trial Data Expected Mid-Summer

At Medtronic’s intimate corporate symposium (our small team made up 10% of the room), Diabetes Unit Medical Director Dr. Robert Vigersky announced that the 1,000-patient MiniMed 670G outcomes RCT is expected to begin recruitment this month. Impressively, it’s the biggest type 1 trial since the DCCT and will pit 670G hybrid closed loop against SAP, pump alone (no CGM), and MDI. Sites will be across the US, Canada, and Europe. According to the ClinicalTrials.gov posting (last updated in October), the co-primary outcomes are A1c, severe hypoglycemia, and DKA. The trial isn’t expected to complete until 2020, so it will be some time until we see data. The posting actually shows an estimated enrollment of 1,500 patients – whoa! This is a remarkable sign of Medtronic’s commitment to this field, a potentially serious competitive barrier to entry (will others be able to leverage this data?), and will certainly address criticism that the 670G’s three-month pivotal study did not have a control group. We assume this study is in the high tens or perhaps even hundreds of millions of dollars range. As for the continued access phase from the pivotal trial, there has still been no severe hypoglycemia or DKA in over 50,000 patient-days (>130 patient-years) of auto mode use.

• The 670G pediatric study (ages 7-13) is almost complete, will read out “3.5 months from next week” (~end of July) and be submitted to FDA by the end of the year. As of October, 71 subjects were enrolled (27 are in a continued access phase). A rep told us that a feasibility study for use in children ages 2-6 is in the works (n=50; half 5-6 years old and half 2-4 years old) and may begin sequentially following approval down to age 7. As a reminder, the MiniMed 670G is contraindicated in <7 year olds and those on <8 units of insulin per day (boxed warning). See our previous coverage here.
• Dr. Vigersky admitted the oddity with the 670G’s current CGM labeling: patients aren’t allowed to bolus off Guardian sensor readings (adjunctive use only), but the hybrid closed loop system can change the basal rate every five minutes. Dr. Vigersky hoped that this oddity will be ironed out soon by the FDA. This could suggest Medtronic is seeking a non-adjunctive claim for the Guardian Sensor 3, joining Dexcom’s G5 as the only other therapeutic CGM (and paving the way for 670G Medicare coverage).
  
  • >35 meetings between Medtronic and the FDA in the years leading to the pivotal trial allowed the FDA to move at “warp speed” during the three-month approval process. In these meetings, preliminary data, pilot data, and the pivotal trial format were discussed. Talk about commitment from both sides! We wish the FDA had resources to give every company and product this level of commitment.
• Dr. Vigersky clarified that 670G is an iterative improvement, but asserted that it’s likely “better than what we’re doing now.” Despite Medtronic’s deliberate efforts to refer to 670G as “first gen” and “hybrid closed loop” and not an artificial pancreas (see our initial coverage of the approval), he did note that higher expectations remain within mainstream media. Dr. Vigersky pointed to CNN, Time, CBS News, and Business Insider stories saying the FDA approved an artificial or bionic pancreas. Medtronic will certainly be ironing out these expectations during the ongoing customer training phase and leading up to the broader 670G launch expected this June.
• Upon seeing 670G data for the first time, an acclaimed neuroendocrinologist exclaimed “This study has uncovered the dark matter of glycemic control! We need to find out what’s going on behind this!” He was referring to the different basal profiles overnight, and hypothesized that a change in neurotransmitter secretion/regulation may be responsible for the presence or lack of the dawn phenomenon. The doctor asked if Medtronic had done EEGs on these patients. Of course, the answer was no, but he raised an important point: having the same basal rate every single night in type 1 diabetes (and probably late-stage type 2) is not physiologic. Automated insulin delivery may prove an excellent, scalable model for studying physiology and glucose metabolism, but without the hassle of doing a glucose clamp. We wonder what additional lines of research this might unlock!

2. FreeStyle Libre Pro Mania: Mostly Enthusiasm, Some Hesitation Based on Lack of Real-Time Data and Accuracy in Hypo

ENDO 2017 has been full of almost entirely positive commentary on the blinded, retrospective FreeStyle Libre Pro. Dr. Irl Hirsch stated that the device has been “amazing” and that he and his colleagues have been “surprisingly impressed. It’s really changing the way we do things already.” Florida Diabetes Center’s Dr. Damon Tanton, USC’s Dr. Anne Peters, and DTS’ Dr. David Klonoff also seemed highly satisfied with the device. Drs. Tanton and Peters both acknowledged that, while it’s nice to offer patients real-time CGM so as to induce behavioral modification, a significant proportion of patients don’t want to deal with any hassle whatsoever. For these individuals, a tiny patch that requires no maintenance and can be mailed to the clinic after 14 days of wear is a great solution – providers learn so much about the patient’s behavior and insulin regimen and can adjust therapy and advice accordingly. Since Libre Pro launched last fall, Dr. Tanton has gathered continuous glucose data from >100 additional patients that he wouldn’t have been able to convince to wear a calibration- or action-requiring device otherwise – that’s huge! Dr. Klonoff offered a more specific anecdote of a patient who had been consistently testing in the 140s at night and didn’t believe it when he was told he had an A1c of 7.5%. Dr. Klonoff had him wear Libre Pro for two weeks, and was able show him his wild postprandial excursions, which were especially prominent at night, and especially noteworthy on Christmas night. With this data at his disposal, Dr. Klonoff convinced the patient to begin insulin therapy, which he had previously resisted. This is one of the the key values of blinded professional CGM – not only does it allow the provider to check in on a new therapy or behavior change (keeping all other things equal), but it can also serve as a very persuasive teaching aid – a picture is worth far more than hundreds of isolated blood glucose readings! Still, some clinicians seemed resistant to the idea of blinded CGM; for example, Mr. Gary Scheiner said that he’s never blinded a Dexcom G4 Platinum sensor for a patient. A common argument against real-time data is that it may incite a patient to alter his/her behavior, to which Mr. Scheiner responds, “Yes, that’s the point!”

• We have heard some concerns about FreeStyle Libre Pro over-reporting hypoglycemia (which is acknowledged on page two of the FDA summary data). One provider told Dr. Hirsch that he does not have diabetes but has worn Libre Pro, which tells him that he spends 120 minutes per day below 70 mg/dl. A second doctor from India stood up and echoed these sentiments, saying that his “thousands” of patients frequently report BGM readings of ~90 mg/dl corresponding to Libre readings of ~70 mg/dl. Abbott reps and Dr. Tanton have simply replied that it’s better to over-report hypoglycemia than the reverse, and that the Pro version is designed for the detection of trends over a 14-day period (not spot checks). If hypoglycemic episodes continually show up at specified times, then they should be further investigated. Libre Pro also uses a different algorithm than the consumer version, which is currently under FDA review (both adjunctive and non-adjunctive claims) and slated for a 2H17 US launch.
• Emory’s Dr. James Gavin tried FreeStyle Libre (consumer version) and is a fan. After Abbott’s symposium, he shared that he wore it for four hours, during which he swiped 13 times (in the middle of a meeting!). He loves how easy, convenient, and discrete it is. And most importantly, he mentioned that he learned something and changed his behavior based on those four hours alone. Time.com recently published an article talking about consumer (wellness) CGM devices in people without diabetes and we’ll be interested to see if this develops once devices are small enough, cheap enough, and easy enough to use for the masses. Fitbit has shown you can build a billion-plus dollar consumer business based on tracking one health metric (steps). Could CGM be next? There couldn’t be a more impressive advocate than Dr. Gavin, that is for sure.

3. Dexcom Symposium Offers Answers to Some Lingering Medicare CGM Coverage Questions

In an early-morning Dexcom-sponsored symposium, we learned that initial Medicare beneficiaries have filed for reimbursement for therapeutic CGM through Liberty Medical, and Integrated Diabetes Service’s Mr. Gary Scheiner evaluated three approaches to adjusting boluses based on CGM trend information. A Dexcom rep specified that Liberty Medical is currently the primary distributor of Medicare-covered G5 CGMs and meter/strips for calibration. (By our estimates, CMS’ decision to reimburse could open up the CGM market to ~1 million patients, though we’re not sure yet how smooth the process will be.) USC’s Dr. Anne Peters was relieved to see that both type 1 and type 2 diabetes are covered, not only for the access considerations, but because providers will not be burdened by having to send in proof showing that her patients have low c-peptide or are auto-antibody positive, which is necessary for insulin pump approval through Medicare. We hadn’t thought of this potential hassle, but that’s why it’s important to get perspectives from all stakeholders! Many in the audience were curious about the fine print in the Medicare document indicating that Medicare won’t cover the G5 if the patient uses a smart device. In chorus, Mr. Scheiner and Dr. Peters responded that Medicare won’t know, and they can’t know. Mr. Scheiner called it “one of those unenforceable rules,” as Dexcom will simply ship patients a G5 receiver, which is covered. Another common concern is that the Medicare bundle only supplies 60 strips per month and suggests that it will deny claims for additional strips. When asked how patients are to perform “checks” (in addition to the two calibrations per day), the Dexcom rep told us that’s still being worked out. This news is a huge win, but there is still some uncertainty here, which will most likely be cleared up over time.

• Mr. Scheiner evaluated three methods for adjusting bolus size based on the CGM’s rate of change. Ultimately, it is up to patients to decide which method works best for them.
  
  • DirecNet Method. “The straight tax system.” If the arrow is straight up/down, this method advises increasing/decreasing the usual dose by 20%. If diagonal up/down, the method advises increasing/decreasing the dose by 10%. The main issue Mr. Scheiner sees with this method is in the case of a carbohydrate-rich meal; if you eat 100 carbs and usually take 1o units but see that you have an arrow pointing straight up or down, then you would add/subtract two units…“that might be a bit too much.”
  • Edelman and Pettus method. UCSD’s Drs. Steve Edelman and Jeremy Pettus (who both have type 1) base the bolus size on the anticipated glucose value in 30 minutes. For double up/down arrows, add/subtract 100 mg/dl from the glucose value. For a single up/down arrow, add/subtract 75 mg/dl from the glucose value. For a diagonal up/down arrow, add 50 mg/dl to the current value. Mr. Scheiner pointed out that the straight line trajectory assumed in this algorithm doesn’t happen in the real world, so the adjustments may be a bit “extreme.”
  • Scheiner Method. The Scheiner method is basically a more conservative Edelman et al. method. For double up/down arrows, add/subtract enough insulin to offset a 60 mg/dl rise/fall. For one up/down arrow, add/subtract enough insulin to offset a 30 mg/dl rise/fall. In the case of a diagonal arrow, do not adjust the bolus size. Mr. Scheiner recommends that the provider write out in explicit terms what the patient has to do on a sticky note (e.g. for two up arrows, add one unit to your regular dose…)

4. Dr. Rich Bergenstal on CGM, Automated Insulin Delivery

Just before hopping on a Chicago-bound flight to see Hamilton with his family, IDC’s Dr. Rich Bergenstal kicked off ENDO pre-conference proceedings with a talk on the rise of CGM – “the dawn of a new era” and the “setting of old traditions” in diabetes care. He broke his talk down into six main themes – outcomes beyond A1c, report standardization, SMBG, CGM in MDI, improved reimbursement for providers, and “pumps with brains” – along with four book recommendations scattered throughout. On devices, Dr. Bergenstal joked that BGMs will “look awful antiquated pretty soon,” that we are moving toward a system where CGM can be used effectively in both MDIs and pumpers (he advocated for intermittent CGM for type 2s), and that “pumps without brains” are a thing of the past. In Q&A, Dr. Bergenstal expanded on his experiences with the 670G. At his clinic, the mantra for hybrid closed loop is “Let it work, let it work, let it work” – the automated basal insulin delivery system works best when patients let go, which some type A users understandably find challenging. He also urged one questioner to think of the MiniMed 670G as the first computer or the first cellphone; it’s just the first generation, and it is safe, but iterative steps will result in more physiological performance (especially faster insulin). On outcomes beyond A1c, Dr. Bergenstal had a memorable gem: “No patient is average. When you start to treat patients as average you get into trouble. Why not use all of the data [i.e., CGM] and treat them with their life in front of you?” Regarding data reports, he continued his push for standardization (many companies have now adopted his group’s Ambulatory Glucose Profile), and made a strong case for reimbursing providers for remote analysis –  he is optimistic that reimbursement is coming. Dr. Bergenstal also recommended four non-diabetes books to attendees: The Gene: An Intimate History by Siddhartha Mukherjee; The End of Average by Todd Rose; The Undoing Project by Michael Lewis; and Reclaiming Conversation: The Power of Talk in a Digital Age by Sherry Turkle. See the full write-up below for more details and a rich [pun intended] Q&A transcript!

5. Dr. Irl Hirsch’s Tips for Smooth Diabetes Clinic Workflow

In a small room of 30 people, University of Washington’s Dr. Irl Hirsch opined on the importance of downloading patients’ data and the infrastructure require to make it fit in the clinic workflow. “Many of us don’t download in our offices and clinics due to the perceived cost in time and money. Is this the appropriate attitude in 2017?” He then showed a tongue-in-cheek cartoon in a which one young girl says to another “I don’t want to have a baby. I hear they take nine months to download.” Once the group stopped laughing, Dr. Hirsch explained that the first thing clinics need in-office is a person knowledgeable with payers, a person who can train patients, mechanisms to ensure that patient devices don’t get mixed up (Dr. Hirsch recommended stickers upon check-in), dedicated computers with a program that allows downloading of various meters, pumps, and sensors (he uses CliniPro, but thinks the field will move to Tidepool), and integration into EMRs. The investment in this overhead, along with the time it takes to download, pays off in a big way. Dr. Hirsch called AGP the “gold standard” for displaying data, and said “you’ll all be using it, if you’re not now.” He also said that standard deviation is “good enough” when it comes to measuring glycemic variability, giving an easy answer to a point that people spend a lot of time debating. He uses a simple algorithm: Three times the standard deviation should be less than the mean glucose – if it’s not, then the patient is likely to present with highly variable blood sugars.

• Average glucose varies greatly with by A1c, so to determine the magnitude of a patient’s glycation gap, Dr. Hirsch recommends “at least 14 days of CGM.” A patient doesn’t have to wear a CGM all the time, but this short spell, done just once, could inform how a provider approaches a patient’s treatment. For example, if a patient’s two-week mean glucose (and therefore eA1c) is a lot lower than his 8.0% A1c would suggest, then increasing insulin dose may not be the right thing to do. [We would note, however, that meter calibration drives this too – if a meter is biased low, is will only throw off CGM-measured glucose.]
• A late-breaking abstract submitted for presentation at ADA reveals how much time Dr. Hirsch and colleagues spend managing their diabetes patients. Hint: It’s a lot. We hope it gets accepted so we can advance the discussion surrounding this monumental issue. Diabetes patients are the most time-intensive patients to manage, he said, and it gets worse every year. We look forward to seeing this data, even though we know the answer will be incredibly grim. We have overheard a few attendees here saying that they “love it” when a thyroid case comes in, as it is so easy and frees up their time to spend on diabetes. Oy.
  
  • In a following talk, Dr. Hirsch asked for better advocacy on behalf of providers. “Clinical endocrinologists have failed miserably to get the point across that we need more time with patients, and we need to be reimbursed for that time. Even psychologically, we get beat up by these visits! AACE, ENDO, ADA, all need to be advocates for us, not just for patients. That’s our Achilles heel.”
• Dr. Hirsch mentioned that Roche will reportedly start pivotal trials for the Accu-Chek Insight CGM this summer. We have not verified this with the company, but we assume this refers to a US pivotal trial. The Insight CGM is currently rolling out in Europe at specialized diabetes centers. A US commercialization would be strategically smart for Roche, shoring up the US Diabetes business in a much higher growth area (especially given the recent discontinuation of insulin pump sales and decimation in BGM). Assuming Roche does bring Insight to the US, we’ll be interested to see what happens with the Senseonics partnership. In most of the world, Roche is Senseonics’ distribution partner, though Senseonics plans to launch on its own in the US.

6. Dr. Anne Peters: “Technology is great, but don’t oversell it. It’s still type 1 diabetes”

In her fifth appearance of the morning, USC’s indefatigable Dr. Anne Peters offered her insights on diabetes tech topics ranging from access, to education, expectation management, physician burnout, and more. Along the way, she threw in her belief that Medtronic is actively pursuing Medicare coverage for 670G, and news that the field is now working on obtaining Medicaid and Medi-Cal coverage for CGM. See below for a list of elegant quotes.

• “Technology is great, but don’t oversell it. It’s still type 1 diabetes. 670G is a great option for certain patients, but not for someone who’s not interested in working with the devices. We need to describe the limits of tech. Currently, tech means external devices, site issues, infusion set issues, skin issues. There are challenges with devices, but they hugely help patients, so I advocate for using devices and using them well.”
• “Finally we got CMS to approve therapeutic CGM. A huge win. Now we’re working on Medicaid and Medi-Cal…Also, I believe that Medtronic is working really hard to get approval for Medicare coverage for the whole 670G system. It’s nice how it works, and it really does work.” [Presumably, Medtronic would need a non-adjunctive (insulin dosing) claim for the paired Guardian Sensor 3 CGM, which would require a new FDA submission. We’re not positive on this, however.]
• “I’m not a huge fan of blinded CGM, but patients in under-served communities who are less able to do SMBG do well with it. Libre Pro is very easy to use and look at data from.  It opens up a world of information that we never had before.”
• “Every time a study is published in tech, there’s a newer device on the market. REPLACE-BG just reported with the G4 (with an updated algorithm), and now we’re on to G5, and G6 is on the horizon. We need a different pathway for approving devices which currently require no big RCTs, but rather much smaller studies.” This question was debated heavily at the recent Digital Diabetes Congress, where many panelists felt that both large RCTs and real-world data collection are needed.
• “I received a Helmsley Charitable Trust grant for creating low-literacy teaching tools for patients. It’ll be unbranded. 150-page pump manuals written at an 11^th grade reading level are incomprehensible for many people. We’re focused on making tools to help patients and physicians use technology.”
• “We need to couple device use with interpretation. Educate patients on how to interpret data. Provide them the ability to self-analyze, even though most won’t. Empower people to use the tools appropriately.”
• “When I first had to use Tidepool I was swearing and hated it because I hate change. But I learned how to use it and it became second nature. Now I use it all the time. It’s very useful to look at all the data with a patient.”
• “All of us need free time to avoid burnout, so ideally we won’t spend time at home analyzing data. Don’t do as I do...unless your family is incredibly understanding.” [In the end, Dr. Peters gave six talks in 24 hours at ENDO before jetting home to see patients.]

7. Exhibit Hall – Diabetes Technology

In the tech portion of the exhibit hall, we learned that the ongoing Medtronic customer access phase consists of >710 patients (bigger than we expected; 110 are employees with diabetes!), and Companion Medical’s InPen made its exhibit hall debut. We also visited Abbott’s, Dexcom’s, Insulet’s, and Tandem’s booths.

Top ENDO 2017 Highlights – Diabetes Therapy

1. Drs. David Nathan and Daniel Drucker Debate the Value of New Type 2 Diabetes Drugs

In a showdown that rivaled the Wrestlemania convention occurring next door at the same time, the highly respected Drs. David Nathan and Daniel Drucker engaged in a heated debate over the value of new diabetes drugs in type 2 diabetes care. The debate was a big one, with attendees listening with bated breath. We note our view that from a high level perspective, Dr. Drucker's presentation relied heavily on randomized controlled clinical trial data -- this is, of course, high level evidence that doesn't incorporate "real world" experience or patient preferences that may impact adherence or side effects like weight or hypoglycemia. It was somewhat surprising that someone typically as evidence-based and data-driven as Dr. Nathan had a presentation without nearly as much real clinical trial data although as he pointed out in a conversation afterwards, both speakers had just 20 minutes to present their views (followed by rebuttal time). He also pointed out that they were assigned their “side” though he feels both presenters believe most of what they said. Overall, we felt Dr. Nathan’s part of the debate relied somewhat more heavily on anecdotes, innuendo, what some would term secondary manipulated analyses, and what we would characterize as opinion in some cases devoid of patients. To boot, his analysis included generalizations about finance that are somewhat time-consuming to source - but we are on it!  We think it’s great that he brought those in, as long as the generalizations are apt, and as noted, we’ll be working on some analysis around that!

While the dialogue between the two speakers was biting at times – particularly during the Q&A session following the presentations (full transcript below) – the session ended with a handshake and a hug between the two “titans of diabetes.” Overall, the audience left the session with lots of learnings from both viewpoints, with a side of afternoon entertainment. And, boy, have we heard a lot from the field about this debate! Our full coverage of both viewpoints, followed by a complete transcript of very heated rebuttals and Q&A, can be found in our detailed discussion and commentary below. This one’s a can’t miss!

2. Steno-2 Finds Mortality, MACE Benefit for Intensive Multifactorial Treatment at 21 Years

Dr. Jens Øligaard presented 21-year data from the Novo Nordisk-sponsored Steno-2 trial, which randomized 160 participants with type 2 diabetes/microalbuminuria to either intensive multifactorial treatment vs. standard of care for eight years (at which point both groups began to receive intensive treatment for ethical reasons, since patients in the intensive group were at significantly lower risk for microvascular and macrovascular disease). Results at 21-years follow-up further corroborated the benefits of intensive multifactorial therapy – glucose-lowering, blood pressure-lowering, and lipid-lowering simultaneously. The hazard ratio for all-cause mortality was 0.55 in favor of intensified treatment (p=0.005), with a median increase in survival of 7.9 years. Non-CV death was actually similar between the two study arms, and Dr. Øligaard emphasized that the effect on mortality was driven by a 65% risk reduction for CV death (p=0.003). The hazard ratio for four-point MACE (MI, stroke, cardiac revascularization, or CV death) was 0.36 in favor of intensified treatment (p<0.001). Here, Dr. Øligaard pointed out that fewer than half the participants in the intensive therapy group experienced a CV event, so there’s no way to calculate difference in median time to a component of four-point MACE. He also underscored that this risk reduction persisted for all individual components of MACE and through all pre-specified subgroup analyses, including analyses based on age and sex. Dr. Øligaard concluded that 7.8 years of intensified multifactorial treatment can extend CV disease-free life for patients with type 2 diabetes – it’s tremendously valuable to have data supporting early, aggressive treatment as we strive for reduced clinical inertia in intensifying diabetes therapy through personalized care plans (a recent AACE survey found that patients are often more willing to intensify A1c-lowering efforts than their HCPs think). Further, the data appears to support a legacy effect for early, aggressive treatment – after all, those that were initially in the aggressive treatment arm experienced greater risk reductions that the original standard of care group, even though intensive treatment became the standard of care after eight years. Indeed, Dr. Øligaard suggested that an important takeaway from the Steno-2 study is “the earlier the better,” and while quality of life metrics were not collected, he argued that these results hint at a correlation between earlier intervention and improved quality of life given the intrinsic advantages in living a longer, CV disease-free life. CV complications remain the leading cause of death for people with diabetes, so we’re particularly happy about the impressive risk reduction for CV death and four-point MACE in Steno-2 over 21 years. This was admittedly a small study, but we hope it may kick-start larger investigations and more consideration of multifactorial glucose-lowering, blood pressure-lowering, and lipid-lowering where appropriate. For a transcript of the Q&A following this presentation, see our detailed discussion and commentary below.

3. Dr. Lawrence Blonde Favors Combination vs. Sequential Treatments

Dr. Lawrence Blonde discussed the advantages of combination therapy, suggesting that while we wait for a long-term clinical trial comparing simultaneous vs. sequential approaches, the data we have right now hints at the superiority of combinations. Co-administration of agents results in greater A1c-lowering alongside a milder side effect profile – Dr. Blonde shared data to show this for SGLT-2/metformin, SGLT-2/DPP-4, GLP-1/basal insulin, and SGLT-2/GLP-1 combinations. He also highlighted how reduced pill burden improves medication adherence. In a study comparing co-administration of glyburide/metformin as two separate pills vs. a fixed-dose combination (FDC) of both agents, participants taking the FDC experienced a greater magnitude of A1c-lowering and reported 84% adherence vs. 76% for the two-pill regimen (p<0.0001). We expect this advantage to medication adherence would be even greater when looking at the burden associated with one vs. two injections. Moreover, combination therapies could help HCPs overcome clinical inertia, which is a prominent issue in diabetes care according to Dr. Blonde. No matter where you stand in the simultaneous vs. sequential debate, he argued unequivocally that early intervention leads to better health outcomes. Thus, if combination approaches counteract clinical inertial and get patients on effective therapies sooner, then they’re something to seriously consider in optimal diabetes care. We’ve heard similar advocacy for early intervention with combination therapy from other thought leaders in the field, including Drs. Bernie Zinman and Tina Vilsbøll at EASD 2016. We’d love to see a well-powered clinical trial that provides a clear answer on the differential benefits of simultaneous vs. sequential treatment, but we’re also aware that this will be a massive undertaking and investment – in the meantime, we so appreciate commentary from Dr. Blonde and others on the importance of at least considering combination therapy. Fixed-dose and fixed-ratio combinations are some of the most advanced products for diabetes on the market, and it’s a shame for these effective medicines to be available but not incorporated into treatment regimens. Cost is a key issue on this front, and we have our fingers very crossed that payers will recognize the value and long-term cost savings. On that note, we’re happy that Sanofi’s recently-launched Soliqua (lixisenatide/insulin glargine) is priced on par with standalone GLP-1 agonists.

4. Dr. Anne Peters on How to Be an Agent for Change

In an absolutely incredible talk – that she termed the “most bizarre I’ve been asked to give” – Dr. Anne Peters offered practical tips for endocrinologists and physicians to advocate for broader public health changes in their communities. She provided a series of examples for how she personally has engaged in efforts to create (i) community based change; and (ii) systems/clinic based change. Within the first category of change, Dr. Peters impressed on the importance of engaging the community. Looking to broader systems based change, incredible persistence was the common theme of Dr. Peters efforts. The session ended with Dr. Peter offering advice to a young endocrine fellow on how to advocate for change over a career of decades without burning out: Don’t give up. Create an environment that doesn’t burn you out. Make sure you have time for yourself and have the capacity to refer patients out for mental health. Keep on persisting. See our detailed coverage below for a closer look at Dr. Peters inspiring and practical tips.

5. Afrezza and Fiasp – Leading the Foray of Ultra-Fast Insulins?

A MannKind-sponsored dinner symposium featured three diabetes experts on inhaled insulin Afrezza – Drs. Bruce Bode, Jeremy Pettus, and Janet McGill positioned the product as the only available faster-acting insulin in the US (as Novo Nordisk’s faster-acting aspart is still under FDA review). They described how Afrezza’s quicker onset, quicker offset, and shorter duration of action lowers risk for hypoglycemia and offers better postprandial control. Approximately 67% of diabetes patients express fear of hypoglycemia, and 74% of HCPs say this fear is a barrier to their ability treat-to-target –hypoglycemia and fear of hypoglycemia are far too common. Afrezza addresses both: Insulin action peaks between 10-14 minutes and a majority of activity occurs within 30 minutes, as opposed to the longer 4-5 hour duration of other prandial insulins. The very rapid onset allows patients to bolus at the start of the meal rather than many minutes before, at which point they have a clearer idea of meal content and can dose insulin more accurately to avoid hypoglycemia. Dr. McGill underscored that frequency of hypoglycemia and fear of lows went down measurably in her patients who started using Afrezza, conferring a huge benefit not only on glycemic control but on quality of life. Dr. Bode spoke to the weight gain commonly associated with mealtime insulin, especially when over-bolusing leads to defensive eating. He discussed how Afrezza addresses this issue, again by offering greater potential titration accuracy. Dr. Pettus encouraged providers to use Afrezza alongside CGM whenever possible. With CGM, patients can easily see how the faster-acting insulin acutely affects their blood sugar and can figure out how to adjust their dose, which promotes engagement, enhances self-efficacy, and ultimately contributes to better outcomes. The theme of this MannKind-sponsored symposium falls very much in line with the company’s strategy to push the “faster-acting” aspect to Afrezza instead of the inhaled aspect. Understandably, there’s some reluctance from the field to try inhaled insulin following the discontinuation of Pfizer’s Exubera (though arguably, the Afrezza inhalation device is smaller, more discrete, and much more user-friendly) and lingering, though unsubstantiated, concerns about safety, so we think it smart that MannKind is highlighting the rapid onset/offset feature and its link to reduced hypoglycemia. The company has filed with the FDA for an “ultra-rapid-acting” label claim for Afrezza, which would allow for more direct marketing on this front – a regulatory decision is expected in 3Q17. For more, including Dr. Bode on the promise of faster-acting insulin aspart (branded as Fiasp in Europe and Canada), plus an engaging panel discussion, see below in detailed discussion and commentary.

6. Normal glycemia as Goal for Diabetes Prevention in Prediabetes

Dr. Leigh Perreault advocated for the attainment of normal glycemia – by any means – as a method of diabetes prevention in people with prediabetes. She emphasized numerous studies, including the Diabetes Prevention Program (DPP), have demonstrated that the attainment of normal glycemia just once following prediabetes diagnosis cuts 10-year risk of incident diabetes by 56%. She suggested that this allows us to present people with prediabetes with a set benchmark glycemic target to attain, rather than just telling people they have prediabetes and sending them home. She highlighted lifestyle interventions as an effective method of reaching this normal glycemic goal, as demonstrate by DPP. However, Dr. Perreault also advocated for the use of diabetes and obesity drugs as therapies for prediabetes. Among diabetes drugs, she particularly highlighted TZDs like pioglitazone as promising, though she noted that metformin, insulin glargine, and acarbose have all demonstrated benefits in delaying and preventing diabetes as well. Further, she pointed out that several obesity drugs have been specifically studied for diabetes prevention as well, including orlistat, lorcaserin (Belviq), topiramate/phentermine (Qsymia) and, most promising of all, liraglutide 3.0 mg (Saxenda). Uptake is still low for diabetes and obesity drugs for prediabetes and for diabetes prevention – like obesity just a few years ago, there is still significant resistance in the field to classifying prediabetes as a disease and widespread concerns about over-diagnosing prediabetes, and thereby causing unnecessary alarm in people with prediabetes who might never progress to type 2 diabetes. Some of this resistance is reflected in the pushback (here and here) against the PSA campaign on prediabetes created by the ADA, CDC, AMA, and Ad Council. That said, we agree with Dr. Perreault’s point that while it’s true not all patients with prediabetes will progress to type 2 diabetes, a significant number do. As a result, we applaud her for advocating for clear goals for patients to reach to reduce their risk and for medical therapies with demonstrated efficacy in reaching these goals.

7. Nephrologist Dr. Robert Stanton Expresses Reservations about Renal Benefits of SGLT-2 Inhibitor Empagliflozin

Nephrologist Dr. Robert Stanton expressed some reservations about the renal benefit of SGLT-2 inhibitor empagliflozin demonstrated in the EMPA-REG OUTCOME trial. He acknowledged that the data in the trial indicates an intriguing potential renal-protective benefit for the drug, but emphasized that many questions remain. Echoing the questions that continue to surround the cardiovascular benefit, Dr. Stanton noted that it’s still unknown whether the renal benefit is a class effect and what the mechanism of benefit is. Further, Dr. Stanton pointed out that there is a normal rate of eGFR decline associated with aging, separate from diabetes-related decline, and empagliflozin appeared to stop even that normal decline in its tracks. He characterized this finding as “puzzling” and expressed skepticism – after all, eGFR is a composite measure of renal function and, according to Dr. Stanton, it’s difficult to get a clear picture from eGFR what is happening at the nephron level. That said, he acknowledged that there are several plausible mechanisms for the benefit, ranging from decreasing plasma glucose and body weight to altering ketone metabolism. Despite the apparent benefit in the trial, Dr. Stanton cautioned that, as a new class, the long-term (10+ years) impact of SGLT-2 inhibition is unknown and he remains wary of the effect of continuous high levels of glucose excretion in the kidneys over that time frame. Dr. Stanton noted that these questions are unlikely to be answered for empagliflozin directly, as no dedicated renal outcomes trial is currently planned for the candidate. That said, he expressed optimism that the CREDENCE trial of J&J’s Invokana (canagliflozin) may be able to lend more clarity to the renal impact of SGLT-2 inhibitors – the trial is currently recruiting and has an expected primary completion date of February 2019 (full completion expected January 2020).

8. Dr. Kasia Lipska Recommends Less Intensive Therapy for Certain, More Frail, Elderly Patients with Diabetes

The prolific Dr. Kasia Lipska framed diabetes care for the elderly in terms of three main goals: (i) Improve symptoms, when present; (ii) Reduce the risk of acute and chronic complications, when pertinent; and (iii) Minimize the harm and burden of therapy, always. She emphasized that age is just a surrogate biomarker for health status and individual patients should be assessed for their level of health, comorbidities, and functional impairments. Among the most frail elderly patients, Dr. Lipska repeatedly emphasized the importance of addressing acute complications (hyperglycemia symptoms, ketoacidosis) and minimizing treatment-related complications (hypoglycemia), while noting that the benefits of preventing long-term microvascular and macrovascular complications may not be relevant for some patients with shorter life expectancy. To that end, she pointed out the 10-year lag-time to microvascular benefit observed in UKPDS and suggested that tight glycemic control is thus only potentially helpful in those with 10+ years life expectancy. In those with a life expectancy less than five years, she characterized tight glycemic control as not helpful and in those with a life expectancy between five and ten years, she suggested that tight control is unlikely to be helpful. As a result, she advocated for less stringent A1c targets in the frailest elderly patients, noting that both the VA and the American Geriatrics Society call for targets of 8%-9% in this population, while the ADA recommends a target of 8.5%. Further, she emphasized that hypoglycemia especially is particularly worrisome for older adults, as they are less likely to experience symptoms (though we’ve heard that impaired awareness is more correlated with duration of diabetes than age), and particularly emphasized the need to reduce hypoglycemia. As one strategy to reduce hypoglycemia risk, Dr. Lipska called for simplification of treatment for these more frail, elderly adults, particularly for those with cognitive impairments. She highlighted a study in which elderly patients on MDI were simplified to once-daily insulin glargine plus non-insulin agents (metformin, sulfonylureas, DPP-4 inhibitors, and GLP-1 agonists) – results demonstrated reduced duration of hypoglycemia with no A1c change. Dr. Lipska further pointed out that there are no guidelines for when or how to “de-intensify” treatment in elderly patients with diabetes; as such, she recommended considering de-intensification when adverse effects or a lack of benefit is observed with a regimen, the regimen exceeds the capacity of patients and caregivers to manage, or when patients prefer a simpler regimen. We certainly agree that simpler regimens that minimize risk of hypoglycemia can be more appropriate for elderly patients – we think the use of newer agents like GLP-1 agonists, SGLT-2 inhibitors, and DPP-4 inhibitors along with tech like CGMs can effectively reduce hypoglycemia without requiring an increase in A1c.

9. Exhibit Hall - Diabetes Therapy

Diabetes therapy companies were out in full force at ENDO 2017. Most notably, Lilly’s booth featured a patient affordability and access section for the first time, highlighting the company’s direct-to-patient discount insulin program. Very excitingly, we learned for the first time about Lilly efforts to engage health plans to create new benefit structures for insulin – ideally, the company hopes to convince health plans to exempt insulin from patients’ deductibles and eliminate co-pays for insulin. We also visited engaging booths from Amgen, AstraZeneca, Janssen, Merck, Novo Nordisk, Rhythm, and Sanofi.

Top ENDO 2017 Highlights – Obesity

1. New Therapeutic Target for Obesity: Synergistic Effects of Three Gut Hormones (GLP-1, OXM, and PYY) in Supressing Appetite

Dr. Tricia Tan presented results from a three-day study (n=18 patients with obesity) in which a 10.5-hour subcutaneous infusion was able to replicate the relative concentrations of three gut hormones – GLP-1, oxyntomodulin (OXM), and PYY – following Roux-en-Y gastric bypass (RYGB) surgery. On day #1, all participants were given low-dose GLP-1/OXM/PYY (GOP) to acclimate. Then, on days #2-3, 10 participants were given the full-dose cocktail of hormones or a saline infusion in a randomized crossover design (allowing for within-participant comparisons). Eight participants who had recently undergone RYGB surgery served as the placebo group to ensure that gut hormone levels with subcutaneous infusion did in fact match post-surgery levels – they did. Food intake declined significantly when individuals were on GOP vs. saline infusion both at lunch (p=0.04) and at dinner (p=0.005) – meals were served as ad libitum buffets, so people could eat as much or as little as they wanted. Caloric intake dropped a mean 32% across both meals (p=0.0005). Previous studies have revealed overlapping function of these gut hormones, in that activating any one of them individually is insufficient to suppress appetite because the others will compensate. We heard trial results at EASD 2016 pointing to synergistic effects of GLP-1 and PYY in suppressing appetite in post-RYGB surgery patients. In light of this redundancy and synergy, Dr. Tan suggested that it’s quite remarkable to see such powerful decrease in food consumption using much smaller doses of each hormone than would be necessary if any one of them individually was used as an appetite suppressor. The implications of this research on obesity therapy are tremendous – high-dose GLP-1 agonists are already being prescribed for weight loss (Novo Nordisk’s Saxenda), but perhaps a GLP-1 agonist in combination with PYY and/or OXM agonists would be even more effective with fewer side effects. “Two hormones are better than one,” Dr. Tan explained, and three could be better still. Moreover, she underscored there were no significant safety/tolerability concerns related to subcutaneous GOP infusion during the trial. Novo Nordisk’s PYY candidate recently completed a phase 1 study for obesity, and we’re incredibly eager to see where the company will go with this. Management has shared that a co-formulation of this PYY candidate with once-weekly GLP-1 agonist semaglutide is also in phase 1 – another exciting early-stage obesity therapy, one we’ll be watching quite closely. We’ve also been following the developmental progress of a number of oxyntomodulin-based therapies with both GLP-1 and glucagon agonism action – OPKO Health in particular is investing these therapies for obesity. Novo Nordisk also has its own GLP-1/glucagon dual agonist in phase 1 for obesity – we’re curious if the company will consider eventually co-formulating this candidate with the PYY candidate.

2. Obesity in America Study reveals Misconceptions Regarding Obesity and its Treatments

Dr. Stacy Brethauer, a top bariatric surgeon at the Cleveland Clinic, detailed fascinating insights from the Obesity in the America survey, revealing widespread misconceptions in public knowledge of obesity. Conducted by the American Society for Metabolic and Bariatric Surgery in collaboration with researchers from the University of Chicago, the survey (n=1,509) reveals two overarching paradoxes in the way Americans think about obesity: (i) Obesity is strongly recognized as a serious health problem with many adverse consequences, but people do not consider it a true disease; and (ii) People overestimate the effectiveness of diet and exercise for long-term weight loss and underestimate the effectiveness (and safety) of medical and surgical treatments. On the first issue, a majority of Americans (81%) consider obesity to be the most serious health problem facing the nation (tying cancer as the top issue ahead of diabetes [72%], heart disease [72%], mental illness [65%], and HIV/AIDS [46%]) and yet only 38% consider obesity to be a disease. This misperception of obesity’s disease status was accompanied by misperception in what actually constitutes obesity: 89% of survey respondents whose BMI placed them in the obese range did not consider themselves to be obese. On the second issue, 78% of people considered diet and exercise to be the most effective weight loss method, with weight loss surgery (59%) and prescription obesity medications (26%) far behind. Dr. Brethauer noted that major goal of this study was to inspire national dialogue on obesity and learn the areas in which education is needed most so that obesity can finally be considered in the same chronic disease paradigm as other serious conditions. The need for greater education on obesity is a major challenge in addressing the obesity epidemic, and this study represents very important groundwork in defining the scope of our misconceptions. While the results of this study certainly underscore the continuing challenges of the obesity market and the uphill battle for widespread patient, provider, and public acceptance of pharmaceutical interventions for obesity, we’re not entirely surprised. Even among medical circles, obesity has only been recognized as a disease in the last handful of year – AACE was one of the organizations to pave the way in 2011, followed by the AMA’s recognition two years later in 2013. Despite the intervening years since those declarations, it’s clear that there’s much more progress to be made. Check out our detailed discussion and commentary section below for a much deeper dive on these fascinating findings. The full survey results are available here. 

3. Uncovering the Mechanism of FGF21

Dr. Steven Kliewer (University of Texas Southwestern Medical Center, Dallas, TX) described his pioneering work uncovering the mechanism of action for FGF21, an obesity drug candidate of growing interest. His studies suggest that FGF21 targets brown adipose tissue by two separate pathways – a direct route and an indirect route via the brain – thereby providing “both the fire and the fuel” to increase energy expenditure and promote weight loss. FGF21 has been hailed as a therapeutic target with vast potential, but the initial enthusiasm for the target as a type 2 diabetes medication has diminished somewhat in recent years as candidates from Pfizer and Lilly failed to demonstrate significant glucose lowering. Despite the lackluster results for type 2 diabetes, FGF21 is promising as an obesity treatment, given that it increases energy expenditure and possibly even causes “browning” of white adipose tissue – though the mechanism by which this occurs is not well understood. Dr. Kliewer discovered the “direct pathway” first, after finding that insulin sensitivity in response to FGF21 (via osmotic mini-pump) increased in adipose tissues selectively in obese mice. However, paradoxically, mice genetically engineered to lack functional FGF21 receptors in adipose tissue still exhibited a marked reduction in body weight (15%), decrease in insulin secretion, and decrease in blood glucose when administered the drug, leading the researchers to suspect that FGF21’s direct action on adipose tissue may not be the whole story. FGF21 receptors are additionally expressed in the hypothalamus and hind brain, important areas for hunger regulation, and Dr. Kliewer’s laboratory discovered that selective ablation of these make mice unresponsive to the weight loss and other metabolic effects of treatment with FGF21 analogue. Together this body of work demonstrates that FGF21’s direct action on adipose tissue (“the fire”) is complemented by indirect action in the hypothalamus and hind brain, which triggers a cascade downstream effects to support increased energy expenditure in adipose tissue (“the fuel”). Noting the pharmaceutical interest in this molecule, Dr. Kliewer issued the caveat that FGF21 analogues may carry some risk of adverse side effects, including bone loss, increases in blood pressure, and depression – important considerations especially in light of the fact that hypertension and depression are often comorbid with obesity to begin with. That said, the overall verdict, according to Dr. Kliewer, is that FGF21 therapy is “promising, but not without challenges.”

• Dr. Kliewer’s research is funded in part by Novo Nordisk, which is developing an FGF21 analog of its own. In fact, Novo Nordisk shared in its recent 4Q16 update that it has initiated a phase 1 trial of a new once-daily FGF21 analog (NN9499) in obesity. The trial will enroll 56 male participants with overweight or obesity and has an expected completion date of August 2017, according to ClinicalTrials.gov. Novo Nordisk is usually very, very smart about its product pipeline and this addition to its pipeline is a strong vote of confidence in FGF21 as a therapeutic target (though Dr. Kliewer’s work involves the discontinued Pfizer FGF21 analogue, and not Novo Nordisk’s FGF21 candidate). We will be watching this very closely in the months to come!

4. Dr. Ken Fujioka Offers “Clinical Practice Pearls” on Obesity Pharmacotherapy

At the pre-conference Obesity Management Workshop, Dr. Ken Fujioka (Scripps Clinic, La Jolla, CA) reviewed the major obesity drugs, offering pearls of wisdom on the clinical use of each one. Dr. Fujioka opened with the caveat “don’t expect one drug to work in every patient” because the causes and pathophysiology of obesity are heterogeneous. The response rate for the majority of obesity drugs is around 50%, so it is important to education patients that it may take multiple tries to find the right medication (or combination of medications). That said, he summarized the pros and cons of each drug as follows:

• Arena/Eisai’s Belviq (lorcaserin) has a low side effect profile, but interacts negatively with SSRIs and may increase hypoglycemia risk in patients with diabetes on insulin or a sulfonylurea;
• Vivus’ Qsymia (phentermine/topiramate) works by multiple mechanisms since it contains two drugs, translating to slightly greater efficacy in terms of weight loss (10% on average), but also a greater side effect profile, including depression and cognitive impairment;
• Orexigen’s Contrave (naltrexone/buproprion) is an excellent option for patients with existing depression (buproprion is an antidepressant) or those who experience food cravings (naltrexone is a therapy for addiction), but this is a very “tough drug” in terms of nausea side effects, so dosing must be titrated very slowly;
• Novo Nordisk’s Saxenda (liraglutide 3.0mg) works for a remarkable 77% and is a particularly good option for patients with diabetes or prediabetes (given its status as a diabetes drug, Victoza as a lower dose), as well as those with cardiovascular disease because of its ability to improve blood pressure and lipids. The main caveat is GI side effects.

On obesity pharmacotherapy in general, Dr. Fujioka further noted that these drugs are indicated for individuals with a BMI over 30 kg/m2 (or 27 kg/m2 with complications) despite the fact that the metabolic consequences of obesity begin at a lower BMI in many minority populations – a very important consideration that is, unfortunately, nowhere to be found on any of the drugs’ labels. We hope that these pearls of wisdom could one day be elaborated in the form of evidence-based guidance on which drugs are most effective in which patients, but for now obesity care is in a state of complete trial-and-error. See our detailed discussion and commentary section below for more.

5. Presidential Plenary Discusses the Role of the Microbiome in Diseases Ranging from Obesity to Type 1 Diabetes

The official ENDO program kicked off with a Presidential Plenary on the microbiome, a clear reflection of the microbiome’s growing status as not only one of the hottest topics in obesity research, but an area of keen interest in metabolism and endocrinology on a wider scale. Esteemed microbiology expert Dr. Martin Blaser (New York University, New York, NY) led the symposium with a compelling argument that population-wide reductions in microbiome diversity – what he calls the “disappearing microbiome hypothesis” – may be underlying the global rise of diseases like type 1 diabetes and obesity. In particular he pointed to antibiotics as a ubiquitously present environmental exposure that has major consequences for the microbiome (which is, after all, composed of bacteria). Consistent with observational studies in the literature reporting an association between antibiotic exposure and type 2 diabetes incidence (Mikkelsen et al., 2015), Dr. Blaser’s team has reported that antibiotic exposure in mice increases adiposity and alters the regulation of hepatic lipogenesis genes, an effect that is exacerbated when mice are exposed to a high-fat diet in addition to antibiotics. The effects of antibiotics on physiology are not limited to obesity; additional studies in the Blaser lab found a similar effect for type 1 diabetes: early life antibiotic exposure led to an increase in insulitis and a decrease in T-Regs in the spleen and small intestine. This body of work supports the notion that microbiota act during a critical developmental period in early life to set the stage for long-term physiology. Disruption during this phase (by antibiotics or other environmental influences) can thus have lasting detrimental effects on metabolism. So fundamental is the microbiome, he argued, that microbiome assessment may one day become standard medical practice. See our Detailed Discussion and Commentary section below for a much deeper dive into this exciting science.

6. Time for a Paradigm Change in Obesity Research and Treatment?

Leading obesity researcher Dr. Rachel Batterham (University College London, London, UK) issued a provocative call for a change in the way in which obesity is both treated and researched. On the treatment front, Dr. Batterham discussed a paradox: dieting actually worsens the abnormal biology underlying obesity, rarely leading to long-term weight loss. In her clinical experience, patients are able to lose weight with dieting, but often end up regaining it back, sometimes weighing more at the end of the diet than before. She attributes this to metabolic adaptation: dieting produces an increase in appetite-stimulating ghrelin and a decrease in satiety hormones, leading to a challenging combination of reduced energy expenditure and increased hunger.  In terms of obesity research, Dr. Batterham pointed out a litany of roadblocks that have hindered the translation of science into therapeutic strategies, including:

• Fixation on proving a natural physiological role in regulating body weight for an individual hormone or peptide. Too often, explained Dr. Batterham, the scientific potential of a hormone hinges solely on its ability to cause significant weight loss or gain when “knocked out” in isolation in rodent experiments. This is what dissipated interest in PYY a decade ago, even though it is now being re-recognized as a very exciting drug target in combination with other hormones.
• Central versus peripheral action of hormones, and the difficulty of measuring hormone levels. The majority of gut hormones are expressed in both the brain and the rest of the body, and their actions can be vastly different depending on the tissue type.
• And perhaps most importantly, mouse models of obesity only superficially resemble human obesity. Obesity researchers typically study diet-induced obesity in mice as a starting point to understanding human obesity. Dr. Batterham pointed out that this oversimplifies and misrepresents the obesity that patients experience, which is characterized by several previous weight loss attempts, comorbidities, psychological factors, environmental sabotage (in the form of bombardment with food cues and external constraints like cost driving food choice), and – above all – heterogeneity.

Dr. Batterham’s compelling argument reinforces what we have long hoped for in obesity – a precision medicine-based approach that takes into consideration each patient’s unique genetics and pathophysiology with treatments tailored to the distinct type of obesity. Of course, this future also depends on better diagnostic tools to understand each patient’s manifestation of diabetes, a difficult challenge given the early state of obesity science and the challenges in its translation. Clearly there is a lot of work to do.

Top Endo Fellows Highlights

1. Dr. Bill Polonsky to Endocrinology Fellows: Manage Diabetes Distress with Concerted Efforts to Empower Patients

New to Endo Fellows, Dr. Bill Polonsky provided an excellent primer for endocrinology fellows on assessing and managing diabetes distress, which he described as the much more common psychological phenomenon in diabetes vs. major depressive disorder. Earlier studies overestimated the prevalence of clinical depression in diabetes – which is actually close to 5% in a type 1 population and 4% in a type 2 population – because of reliance on self-report questionnaires. Dr. Polonsky established the PHQ-9 (a 10-question survey) as a useful instrument for busy endos, with the caveat that it results in 57% false positives for a clinical depression diagnosis even at a high threshold (score >15) and thus isn’t a sufficient basis to prescribe antidepressants. Many of these false positives are really cases of diabetes distress, which occurs at much higher rates of 39% in type 1 and 35% in type 2. The overlap is understandable, Dr. Polonsky explained, because a key characteristic of both depression and diabetes distress is a sense of powerlessness. “I will end up with serious long-term complications, no matter what I do” is the most common thinking trap in diabetes distress, according to Dr. Polonsky, which led him to a very interesting and important point about patient motivation: It is well-known in psychology that people respond best to short-term positive reinforcement. In contrast, diabetes asks people to respond to long-term results, and the “fondest hope” for patients is that nothing will go wrong. To address this, Dr. Polonsky underscored the value of empowering patients and reframing diabetes management with “evidence-based hope” (also a theme he discussed at AADE 2016). It’s possible to live a long and healthy life with type 1 diabetes (rates of amputation, blindness, and nephropathy are down with the advent of advanced medicines), and HCPs who treat this chronic disease must recognize the signs of diabetes distress and intervene swiftly to help patient motivation. We were so glad to hear psychology-focused discussion at Endo Fellows, with an expert like Dr. Polonsky no less. We love these endocrinologists-in-training will enter the field with an acute awareness of distress, burnout, and depression in diabetes and will be armed to tackle these challenges in providing optimal diabetes care. As we understand it, this training is sometimes lacking in medical education, which only makes meetings like Endo Fellows and sessions on psychology all the more valuable. Dr. Polonsky shared several specific ideas on how to successfully assess and manage diabetes distress, which we elaborate on in our detailed discussion and commentary section below.

2. Dr. Irl Hirsch’s “Pearls” for Insulin Use in Type 1 Diabetes

In a brand-new addition to the Endo Fellows lineup, Dr. Irl Hirsch gave practical tips on how to use human and analog insulins in type 1 diabetes. Highlighting his now-signature statistics on the rising cost of insulin over the last few decades, Dr. Hirsch emphasized the importance of learning how to use human insulin to the endocrine fellows in the room, as he predicts more and more patients will be forced to resort to human insulin due to financial barriers. While acknowledging that NPH is certainly not ideal for the treatment of type 1 diabetes, Dr. Hirsch underscored that it’s possible to achieve reasonably good glycemic control with NPH, as long as you know how to use it correctly and are very disciplined. Since many young endocrinologists-in-training are not explicitly trained on the nuances of using human insulin, Dr. Hirsch provided several “pearls” of wisdom:

• (i) Location of injection matters for human insulin. In general, regular insulin is best injected in the abdomen. NPH should be injected in the same location each time, either in the thighs or buttocks.
• (ii) NPH needs to be mixed well prior to injection. Dr. Hirsch suggested that some patients and providers who are used to analogs can forget this.
• (iii) “Lag times” for mealtime regular insulin are critical. Regular insulin should be taken at least 20-30 minutes before or meal (or even an hour before) to prevent a large postprandial glucose spike, since regular insulin has a slower onset than rapid-acting analogs.
• (iv) Snacking is often required, especially at bedtime, to prevent nocturnal hypoglycemia.
• (v) Some, but not all, patients may require a small dose of NPH in the morning in addition to the daily evening dose if they are using regular insulin as their prandial insulin. If the patient is using a rapid-acting analog and NPH as their basal, they will definitely want to take this morning dose.
• (vi) It’s okay to use 2017 technology for a 1980s insulin. In addition to personal CGM, Dr. Hirsch suggested that the Abbott Libre Pro and professional CGM can be incredible tools to help patients optimize their insulin therapy.
• (vii) Due to higher hypoglycemia risk, it may be advisable to set higher glycemic targets. Dr. Hirsch acknowledged that insulin analogs have demonstrated a hypoglycemia benefit compared to human insulin in type 1 diabetes. Notably, however, insulin analogs have not demonstrated a benefit on hypoglycemia in type 2 diabetes.
• (viii) Consistency in timing and size of meals (particularly regarding amount of carbs) is beneficial. Dr. Hirsch noted that this is also extremely helpful even in patients using analog insulin. He acknowledged that achieving perfect consistency in meals is very, very challenging, especially among adolescents, but pointed out that those living with 70 years of diabetes had no choice but to live their life this way for decades in order to survive, so it is possible.

In addition to these pearls, on the opposite end of the insulin spectrum, Dr. Hirsch touched on some of the considerations related to next-generation basal insulin therapy. In particular, he pointed out that the unprecedented half-life of Novo Nordisk Tresiba (insulin degludec) means that certain aspects of diabetes care are uncharted territory – for instance, how early should patients stop Tresiba if they’re switching to an insulin pump? He concluded by pointing out that new insulins may create challenges not even thought of previously. We greatly appreciated Dr. Hirsch’s extremely practical “how-to guide” to insulin therapy. While we hope that all the major players can work together to ensure that modern insulin analogs – as well as other non-insulin therapies – remain accessible to patients, but we’re glad that these endocrine fellows are learning how to use this human insulin should they need to.

3. How to Encourage Safe Exercise for Type 1 Patients: A New App?

Dr. Michael Riddell walked the endo fellows through his recently-published consensus statement on exercise and type 1 diabetes. In exciting news, he shared that various industry partners and researchers are interested in supporting the translation of the exercise decision-making tree outlined in the paper (which he admitted is a bit bulky for real-world patients/providers to use regularly) into a decision-making app (much more user-friendly!). Sanofi is supporting a revamp of the related www.excarbs.com website that Dr. Riddell developed alongside Drs. David Kerr and Helen Partridge. We imagine this could help many type 1 patients manage exercise with appropriate insulin dose and timing. It could even empower more people to exercise by reducing fear of hypoglycemia, which according to Dr. Riddell is the no. 1 barrier to physical activity among type 1 patients – an interactive app that facilitates decisions surrounding exercise/diabetes management would offer greater control and would help minimize errors. Tackling barriers to exercise is especially important given the multifaceted health benefits to physical activity, from weight management to insulin sensitivity to better glycemic control in the long run. The ADA’s 2016 guidelines recommend both aerobic exercise and resistance training for optimal glycemic control and health outcomes in both type 1 and type 2 diabetes. Dr. Riddell affirmed this in his recent Lancet paper as well. In writing and during his talk, he advocated for a mix of aerobic and anaerobic exercise, since the former promotes heightened insulin sensitivity in the muscles (and poses the greatest risk for a later hypoglycemia episode) while the latter causes post-activity hyperglycemia. In anchoring his discussion on how to make type 1 diabetes patients feel confident exercising, he pointed to CGM as a valuable safety net, and to SGLT-2 inhibitors which may boost the glucagon response (alpha cells express the SGLT-2 receptor, though Dr. Riddell also underscored that these agents are currently off-label for type 1). Looking ahead, Dr. Riddell predicted that glucagon in the artificial pancreas down the road will make exercise a lot safer.

 

4. The Value of Medical Nutrition Therapy: More Accurate Insulin Titration and More Personalized Diabetes Care

Dietitian expert Ms. Alison Evert framed medical nutrition therapy as an ideal opportunity for personalization of treatment, and as an essential factor in helping patients titrate their insulin accurately. She pointed to a glaring gap in diabetes education when it comes to carb counting, bolusing, and the general interplay between insulin and food. In her personal experience working with diabetes patients, Ms. Evert has found that 90% understand that onset time for a prandial insulin is ~10-15 minutes, but only 50% know the peak action will come ~1-2 hours after bolusing, and only 10%-20% are aware of the ~4-5 hour duration of action of current mealtime insulin products. Many patients are surprised at first that a dietician would want to see their glucose meter – when in reality, “what’s the one thing that makes your blood sugar go up the most? Food!” – and few are comfortable with the all the math that goes into carb counting and insulin titration. To show her patients the value of nutrition education, Ms. Evert highlights how much smoother insulin titration could be with a little practice in carb counting (at home before trying it in restaurants), and the improved quality of life that would result. She made quite a compelling case for the nutritionist’s role in diabetes care to endo fellows in the room as well, describing how dieticians are often able to spend more time personalizing treatment strategies. The ADA’s 2013 nutrition recommendations state that there is no “most effective” mix of carbohydrates, proteins, and fats that applies broadly in managing hyperglycemia. Rather, macronutrient proportions should be adjusted to meet individual goals and preferences. Per the guidelines, individuals on fixed insulin doses should follow a rigid daily diet, but Ms. Evert argued that this is very difficult for most people. She aims to create a dietary plan that people will be able to follow for a long time, which replaces strict diets with food libraries – 3-4 meals a patient could eat for breakfast, 5-7 for lunch, and 7-10 for dinner. Best practice in dietary interventions for diabetes is moving away from a scripted, standard process to an individualized, collaborative process that maintains the joy of eating for people with diabetes. All of this was music to our ears. We know all too well that insulin titration is complicated for most patients, even the highly-engaged. Knowing that endocrinologists are already overwhelmed, we’d love for HCPs to seize any opportunity for personalized care, especially for something as critical and ubiquitous as diet. Ms. Evert suggested that the important role of medical nutrition therapy will continue despite advances in diabetes medicine – even with Medtronic’s MiniMed 670G hybrid closed loop, for instance, patients still have to announce meals and there will still be tremendous benefit in training patients on accurate carb counting.

5. Drs. Robert Eckel and Janet McGill on Macrovascular and Microvascular Disease

In back-to-back sessions, Dr. Robert Eckel, former president of the American Heart Association, provided a comprehensive update of the current state of knowledge of macrovascular disease prevention in type 1 diabetes.  While dedicated clinical trials of lipid-lowering have not been done in this population, observational studies of long-term outcomes and mechanistic studies have been published lately.  Mortality is increased in type 1 diabetes, but has improved over the past decades. Dr. Eckel commented on the use of coronary calcium scores to help determine people at highest risk of large vessel disease who have type 1.  Dr. Janet McGill discussed retinopathy, nephropathy, and neuropathy.  The newer treatments for macular edema and advanced pre-proliferative and proliferative retinopathy, in particular the anti-VEGF intra-ocular injections, prevent vision loss and in many cases can improve vision that is impaired from macular edema. Prevention of nephropathy with glucose and blood pressure control are the mainstays, but careful attention to problems encountered in stage 3 CKD such as anemia, elevated PTH, episodes of acute kidney injury, vaccinations, and management of electrolytes and uric acid are within the purview of endocrinologists.  Neuropathy assessment should include multimodal sensor testing, strength testing, and balance testing if the other tests are positive.  Use of B-vitamins and/or alpha lipoic acid may have disease modifying effects.  Documentation and follow-up are key elements of comprehensive diabetes management.

Detailed Discussion and Commentary

ENDO 2017

Diabetes Diagnosis & Management 2017

Where CGM Is and Where It’s Going

Richard Bergenstal, MD (International Diabetes Center, Minneapolis, MN)

Just before hopping on a Chicago-bound flight to see Hamilton with his family, IDC’s Dr. Rich Bergenstal kicked off ENDO pre-conference proceedings with a talk on the rise of CGM – “the dawn of a new era” and the “setting of old traditions” in diabetes care. He broke his talk down into six main themes – outcomes beyond A1c, report standardization, SMBG, CGM in MDI, improved reimbursement for providers, and “pumps with brains” – along with four book recommendations scattered throughout. On devices, Dr. Bergenstal joked that BGMs will “look awful antiquated pretty soon,” that we are moving toward a system where CGM can be used effectively in both MDIs and pumpers (he advocated for intermittent CGM for type 2s), and that “pumps without brains” are a thing of the past. In Q&A, Dr. Bergenstal expanded on his experiences with the 670G. At his clinic, the mantra for hybrid closed loop is “Let it work, let it work, let it work” – the automated basal insulin delivery system works best when patients let go, which some type A users understandably find challenging. He also urged one questioner to think of the MiniMed 670G as the first computer or the first cellphone; it’s just the first generation, and it is safe, but iterative steps will result in more physiological performance (especially faster insulin). On outcomes beyond A1c, Dr. Bergenstal had a memorable gem: “No patient is average. When you start to treat patients as average you get into trouble. Why not use all of the data [i.e., CGM] and treat them with their life in front of you?” Regarding data reports, he continued his push for standardization (many companies have now adopted his group’s Ambulatory Glucose Profile), and made a strong case for reimbursing providers for remote analysis –  he is optimistic that reimbursement is coming. Dr. Bergenstal also recommended four non-diabetes books to attendees: The Gene: An Intimate History by Siddhartha Mukherjee; The End of Average by Todd Rose; The Undoing Project by Michael Lewis; and Reclaiming Conversation: The Power of Talk in a Digital Age by Sherry Turkle.

• Dr. Bergenstal called for young clinicians in the room to move beyond straight, average thinking (A1c) to metrics such as time in range and hypoglycemia. The issues with A1c-centricity are well-established; chief amongst them, it does not reflect the daily experience of diabetes, and the correlation to mean glucose has significant individual differences (see T1D Exchange data from ADA 2016). Dr. Bergenstal put it plainly and simply: “No patient is average. When you start to treat patients as average, you can get into trouble. Why not use all of the data and treat them with their life in front of you?” A patient with an A1c of 8.0% can feasibly have an average glucose of 120 or 220 mg/dl – how can safe treatment decisions be made off of that huge range? FDA hosted an outstanding workshop on outcomes beyond A1c in August, and we know that discussions on next steps are ongoing.
• “We need an ECG for glucose patterns” – a standard output regardless of the input device. This is another common cause championed by Dr. Bergenstal, whose IDC developed the one-page, standard Ambulatory Glucose Profile (AGP) – Abbott jumped on board early with FreeStyle Libre, and we’ve since seen it incorporated into Glooko/Diasend and Roche’s . Not only should providers be comfortable looking at data reports, but Dr. Bergenstal added that patients can often look at their profiles and tell you why it looks the way it does – “they were just never given the chance to tell their stories.”
• “We will not be throwing away glucose meters tomorrow, but I think they’ll look awful antiquated pretty soon.” Dr. Bergenstal pointed to the real-world FreeStyle Libre data presented at ATTD from over 55,000 users (more scanning=lower A1c (8% vs. 6.7%); up to 49% less hypoglycemia; average of 16 scans per day) and the recent Medicare decision to cover therapeutic CGM as evidence that we are moving away from an SMBG-centric world. He shared that if he personally had a real-time FreeStyle Libre, he would swipe 50 times per day (some patients in the real-world database actually did this!), and compared the discretion level of the “swipe” to looking at a smartphone app.
• The field is moving away from the model of CGM only being used with pumps. “Of course CGM can help guide MDIs.” He pointed to the recently published DIaMonD trial, showing benefits of CGM in MDI for both type 1s (JAMA 2017) and type 2s (ATTD 2017). On the latter, he raised two interesting points: (i) he believes that A1c reductions would’ve been more significant if investigators had been instructed to give patients guidance, as opposed to simply putting a CGM on them; and (ii) will type 2 patients really wear 24/7 CGM? The next era of CGM development must focus on these two areas: (i) patient decision support and real-time education to enhance CGM’s effectiveness (e.g., insulin dosing titration); and (ii) improved product form factors that make CGM much smaller on the body, easier to use, factory calibrated, and lower cost.
• Providers need to be reimbursed for looking at glycemic profiles remotely. Dr. Timothy Bailey shared similar sentiments on Day #2 of Endo Fellows. There’s no reason for patients to have to take time off from work and go into the office. Remote analysis is great for the patient already, but the doctor needs to get paid. Plus, this would free up providers so they can spend time with patients who actually require in-person meetings. He is optimistic that reimbursement is coming. We continue to wonder if CGM will open up new scalable business models for companies, who could provide clinicians/payers with a remote CGM data interpretation service.
• According to Dr. Bergenstal, pumps “without brains” are a thing of the past. He emphasized the overnight improvements offered by the Medtronic MiniMed 670G hybrid closed loop system, particularly with regards to the unpredictable “dawn phenomenon.” This was a very consistent finding in the pivotal study and in anecdotal experiences on the system – as with all hybrid closed loop systems.
• Dr. Bergenstal recommended four non-diabetes books for the audience: (i) The Gene: An Intimate History by Siddhartha Mukherjee – the quote “between races, diversity is slight; within them, it is enormous” sounds a lot like A1c!; (ii) The End of Average by Todd Rose – “as I listened to it, I just kept thinking ‘A1c, A1c, A1c’ because every example was about the danger of thinking in averages; (iii) The Undoing Project by Michael Lewis – “people do not respond to a number; they need a story”: and (iv) Reclaiming Conversation: The Power of Talk in a Digital Age by Sherry Turkle – patient/provider communication becomes even more important with the rise of connected diabetes technology.

Questions and Answers

Q: I would argue that it will take more work to train providers in new technology paradigms, and less so patients. It won’t be hard for patients to get excited about less finger-pricking and better blood sugars, etc. How do you get there?

Dr. Bergenstal: Most of the patients in the 670G study were high-intensity patients, but some had never used CGM. So who did better? Turns out they did the same. But with the lower technology people, it was better for us. Same with A1c, average glucose, hypoglycemia, but a lot less hassle for us because they went with the program. Our mantra with closed loop is “Let it work, let it work, let it work” because people just want to correct it. Providers definitely need some instruction on this. Come to Minneapolis on May 5^th for the first national training program. How often should you contact patients? What are the two things you can adjust? What’s an ideal basal-bolus ratio for MDI? 50/50. What about here? More 75-80% bolus, and 25% basal. Cover meals better than you used to, and the basal will just shut off if you need to, go up if you undercounted. Sometimes I think the basal rate is too low, but just let it go. CDEs will be a big part of this. [We’d note that for patients eating fewer carbohydrates, basal/bolus can easily be in the other direction – 80% basal and 20% bolus – since a hybrid closed loop can take care of most low-carb meals with basal alone.]

Q: I hate the conversation about average basal vs bolus ratio. There’s enormous variability. The big excitement for me is that Medicare finally approved CGM so seniors can monitor glucose. It won’t be long before the world sees that average ratios and general settings are sub-optimal.

Dr. Bergenstal: I agree. Let the numbers tell you what you need, not the textbook.

Q: The MiniMed 670G doesn’t give boluses; it seems like that’s what you need to fix as a provider?

Dr. Bergenstal: This is gen one. Think first computer, first cellphone. Fixing the basal (microboluses) is just a start. Right now, you have to interact with the system, give a bolus before the meal. I can show year-old examples of people who don’t do that, and they struggle. We won’t have bolus capabilities until we have faster insulins, or better algorithms that detect rising sugar and give a bolus, which is still too late unless we have a faster insulin. The first system can’t be as aggressive as we want it to be because it’s about safety first. In 124 patients, we had no severe hypoglycemia and no DKA, and that was the primary outcome in the pivotal study.

Q: How does it work with exercise?

Dr. Bergenstal: Instead of a temporary basal rate, now the concept is a temporary target. The system usually aims for 120 mg/dl. Some wish it was 110 mg/dl. Alright, alright. But before you exercise, hopefully you set to 150 mg/dl. That’s all we have, and it helps, but you still have to educate on when you need carbs, when you don’t, some go up when they exercise, etc.

Q: Fingersticks to CGM, is that at a higher cost?

Dr. Bergenstal: For FreeStyle Libre, the cost in Europe is about equivalent of six SMBGs per day. So it’s fairly similar, and you don’t need SMBG along with it. Should every type 2 have this? 30 million people, and wear continually? I don’t think so. If someone is on metformin, SGLT-2, do you need continual monitoring? No. Would it be nice to reinforce learning habits, just for two weeks, and see what exercise, pizza, and pasta are doing? I’d rather type 2s not bring in 47 fasting blood glucoses, but bring in two weeks of continuous data three times per year. We need to be cost-conscious, but also have data that helps make a personalized decision.

Q: How do we change corrections in the era of CGM? Same formulas, or altered basal rate? Size for tilted arrow, one arrow, two arrows?

Rich: Read the article by Edelman and Pettus. It’s a little complicated to do in your head, but the goal was to get it in a bolus calc. Machines know which way you’re going. If we got one we agreed on, put it in the formula. I’m a little more conservative than their algorithm, I’m more on one unit more, or if more than 10 units, 2 units more, 4 units more. But just that start makes a big difference and people get it. I start conservative, one more unit, and then the next visit, another unit. I think we can build a conservative model into a bolus calculator.

Debate: The Diabetes Dilemma: How to Treat Type 2 Diabetes?

In a showdown that rivaled the Wrestlemania convention occurring next door at the same time, the highly respected Drs. David Nathan and Daniel Drucker engaged in a heated debate over the value of new diabetes drugs in type 2 diabetes care. While the dialogue between the two speakers was biting at times – particularly during the Q&A session following the presentations (full transcript below) – the session ended with a handshake and a hug between the two “titans of diabetes.” Overall, the audience left the session with lots of learnings from both viewpoints, with a side of afternoon entertainment. And, boy, have we heard a lot from the field about this debate!

The New Drugs: Are We Benefitting Anyone Other Than Pharma?

David Nathan, MD (Massachusetts General Hospital, Boston, MA)

Dr. David Nathan argued provocatively that, overall, the use of new diabetes drugs (GLP-1 agonists, SGLT-2 inhibitors, DPP-4 inhibitors, and modern insulin analogs), do not benefit anyone other than pharma companies. If this is actually true that he believes this, we would be very surprised, but we do think this is accurate reporting (and he has approved this transcript). One of the things we admire about Dr. Nathan is how data-driven he is – he is an incredible clinical trialist, for example, and a very highly-regarded thinker (he has come up consistently in all discussions we’ve had on the smartest researchers in the field). However, to actually say and believe that glycemic-dependent drugs are not significantly better for at least some part of the diabetes population is very surprising, particularly at this time when it’s recognized that some patients careen more quickly toward diagnosis from pre-diabetes and some develop complications more quickly or more slowly. He argued that these newer drugs, despite costing 10 to 100 times more than older agents (metformin, human insulin, sulfonylureas, and TZDs), produce more modest A1c lowering and do not necessarily offer benefits beyond the older, cheaper drugs. He did not say whether he would suggest to patients that it may be worthwhile to use these drugs once they become generic – we have asked him this question and are awaiting an answer on whether some of these compounds could be effective in some patients as we do acknowledge his point that 20 minutes isn’t a long time to speak. Overall, Dr. Nathan suggested that the long-term benefits on microvascular risk reduction and primary prevention of cardiovascular events has been demonstrated with metformin, insulin, and sulfonylureas, whereas the microvascular benefits of newer drugs are merely extrapolated from their A1c efficacy and the demonstrated macrovascular benefits are all in secondary prevention populations. We have asked him about cardioprotection shown in Victoza and Jardiance and await an answer. He further suggested that greater utilization of newer drugs has not translated to population level improvements in A1c and hypoglycemia – to make his point he highlighted a study from Yale’s Dr. Kasia Lipska that we’ve written about extensively before – in our view, the study has major limitations because there is no sub-group analysis. (She didn’t even report on GLP-1, DPP-4 inhibitor, or SGLT-2 inhibitor results separately, which we can’t believe got by the reviewers, since that would’ve been easy analysis to do –but, we think many reviewers are tired these days!) He also suggested that the newfound adverse effects associated with GLP-1 agonists and SGLT-2 inhibitors are comparable to those associated with older drugs – all drugs are “tainted” in his view, but newer drugs just offer a different set of issues. He did not mention any benefits associated with hypoglycemia or less time in hyperglycemia or higher quality of life or emotional well-being or other aspects of the therapies that may be tied to better adherence. Granted, adherence studies are notoriously hard to do and we acknowledge there is little data here, but this must be easier with new tools available. Finally, Dr. Nathan pointed to the high advertising spend and high profits of pharmaceutical companies to conclude that new diabetes drugs only benefit the bottom line of industry. We point out that although we also believe the business models could use examination, drugs associated with lower hypoglycemia, weight loss rather than weight gain, no beta cell burnout, etc. will never be generic unless they have a commercial market first. Given the advantages a much higher number of patients will have once these compounds are generic, we disagree with Dr. Nathan’s view that there are no benefits (presumably absolute or relative) to these therapies for patients or doctors. We also wonder what Dr. Nathan’s view is that so few medical school students pursue helping people with diabetes – from our view, they appear to find it hard to be successful and we doubt taking away therapies will help in this regard. We’d like to see far more support for various HCPs (including nurses and community health workers) to spend with patients – and for peer support to be better researched and supported. As always, Dr. Nathan was a charismatic and engaging speaker and we highly respect his work. Although his arguments from our view missed critical elements, particularly related to hypoglycemia, weight gain, and patient experiences, we also point out that debate speakers are often necessarily one-sided. Further, Dr. Nathan has a long history of scientific investment in GLP-1 agonist and artificial pancreas development and we greatly respect his leadership, as does the diabetes field as a whole. We detail his arguments and our thoughts below.

• In terms of preventing long-term complications, Dr. Nathan pointed out that the drugs that have direct data indicating a microvascular or primary cardiovascular benefit are metformin, sulfonylureas, and human insulin, as these were the drugs used in older landmark outcomes studies like UKPDS, DCCT, etc. On the other hand, the microvascular benefit for newer agents is largely extrapolated from their effect on A1c, a surrogate marker, though Dr. Nathan did affirm that he does believe that lower A1c from treatment with these drugs is associated with lower microvascular risk (this was not very evident in his remarks, or he assigns no value to this). He also briefly acknowledged that SGLT-2 inhibitor empagliflozin has demonstrated a beneficial reduction in late-stage nephropathy in EMPA-REG OUTCOME. In terms of macrovascular risk, he emphasized that empagliflozin and GLP-1 agonists liraglutide and semaglutide have only demonstrated a benefit in a secondary prevention population. We are not sure whether he assigns no value to reduction of CV risk unless this applies to all patients – clearly, secondary prevention populations are still pretty large! We may have misinterpreted this and are checking with him.
• Dr. Nathan further suggested that newer drugs do not necessarily produce A1c or hypoglycemia benefits. He highlighted a paper by Dr. Kasia Lipska, published online last October, that found that population-level A1cs increased and hypoglycemia rates were flat between 2006 and 2013 as utilization of GLP-1 agonists, DPP-4 inhibitors, and modern insulin analogs increased. We’ve written extensively about the limitations of this paper, which were never addressed by Dr. Lipska beyond noting she couldn’t look at sub-population data. For example, only 5% of patients in the study took GLP-1 agonists in this study and none were on SGLT-2 inhibitors; so, overall, if only 20% of the population studied were on “new drugs,” we’re not too surprised by the population-level results and we can hardly believe either Dr. Lipska or Dr. Nathan was. The author, Dr. Lipska, did acknowledge in personal correspondence with us that she wasn’t responsible for the headlines (or presumably future mentions by leaders noting that her study proved modern drugs could not help any patients). We think it’s incredibly important that the diabetes field conveys information about this study accurately – at the time of the publication, the study prompted media headlines that did not address the sub-population problem and implied proof that “expensive” drugs were not of any use. We asked Dr. Lipska specifically if she could look at A1c and hypoglycemia rate associated with GLP-1 and DPP-4 inhibitors and modern analogs separately and she declined. 
• Newer drugs also do not offer an improved safety and tolerability profile so much as present a whole new host of adverse effects, according to Dr. Nathan. He asserted that all drugs have adverse effects and suggested that newer drugs just bring up a whole different spectrum of adverse effects not seen in older drugs – as he put it, all drugs are “tainted” in some way or another. While acknowledging that insulins and sulfonylureas are associated with hypoglycemia and weight gain, he pointed out that GLP-1 agonists are associated with GI side effects and SGLT-2 inhibitors are associated with increased UTIs and yeast infections. We do not see these latter side effects as remotely comparable to the hypoglycemia and weight gain in terms of impact on quality of life and mental and emotional health for patients because if patients experience these side effects, they can easily go off the drugs. We’ve seen data from diabetes market research firm dQ&A indicating that time in range (of which hypoglycemia is a key component) is the number one contributor to a positive frame of mind for patients with diabetes. As well, the adverse events are very addressable; the GLP-1 side effects improve substantially when dosed correctly and the small percentage (~10%) that have UTIs and yeast infections can obviously go off SGLT-2s (it’s sad the drugs won’t work for them, but hardly a reason for them not to be developed for anyone).
• Dr. Anne Peter’s patients have spoken compellingly about the enormous burden of hypoglycemia and the JDRF recently convened a full day workshop on the topic. In our view, it’s quite a disservice to equate GI side effects – which, as we understand it, can be managed through slower titration of the GLP-1 agonist at initiation in HCPs that are experienced in using them – with hypoglycemia. In terms of serious adverse events, Dr. Nathan emphasized that GLP-1 agonists have been associated with pancreatitis and pancreatic cancer and SGLT-2 inhibitors have been associated with DKA. On the first point, several pieces of clinical evidence have suggested a reassuring lack of association between incretins and pancreatitis – most recently, a 1.53 million patient multicenter, retrospective, observational, population-based case-controlled cohort study published in JAMA last August that led even the infamous Dr. Peter Butler – one of the initial individuals to cast doubt on the safety of incretins – to advocate for GLP-1 agonists as the “logical choice” for second-line therapy! While the DKA risk with SGLT-2 inhibitors is obviously “real,” the risk is low in patients with type 2 diabetes as we understand it and we do believe that the risk is manageable even in patients with type 1 diabetes with careful patient and provider education (which, to date, has been largely absent according to conversations we have heard – again, not a reason for the drugs not to be developed) – Dr. Anne Peters has anecdotally had great success with her personal protocol for treating type 1 patients with SGLT-2 inhibitors and we’d love to see news of this spread.  
• Dr. Nathan took aim at pharmaceutical companies, suggesting that manufacturers spend exorbitantly on advertising for “me-too” drugs with little added benefit and pass high costs onto consumers. He noted that the marketing budget for pharma is typically 1.1 to 2 times that of their R&D budget and that spending has only increased – reaching $5.2 billion in 2015. We’ve requested his source for this; typically marketing, sales, and distribution costs are consolidated. We don’t know enough about this area to comment at this stage and we suspect that public information is very limited. Further, Dr. Nathan pointed out that only three countries in the world – the US, New Zealand, and Brazil – allow direct-to-consumer (DTC) advertising. We aren’t sure how successful DTC is – we also note a lot of lawyer advertising in the field although not for any generic drugs that have hurt patients. In Q&A, Dr. Nathan suggested that patients are inundated with DTC advertising and, even more so, primary care providers’ prescribing habits are primarily influenced by extensive marketing from sales reps – debate opponent Dr. Drucker expressed disappointment at this opinion, which he found disrespectful to his primary care colleagues. We would agree, though we also agree with Dr. Nathan that DTC ads are not necessarily good sources of spending – we think HCPs need better education but they are also extremely limited in terms of time so that is not easily addressed though we have asked Dr. Drucker and Dr. Nathan for their views. Additionally, Dr. Nathan suggested that insulin prices have been rising in lock-step – “the opposite of how I understand a competitive market should be” – and noted that several insulin manufacturers (and PBMs) are defending against lawsuits on this issue. We agree that increasing prices were going on for some time though we don’t think base prices have increased in some time; we also note the “PBM” middlemen continue to be a black box that few write about or understand. Nothing has happened at the ADA’s recent appearance at Congress on this pricing issue that we are aware though the ADA has prompted much social media note. Further, Dr. Nathan pointed to a 2014 Forbes report indicating that pharmaceutical companies (and banks) have the highest return on investment – the report actually only discussed the top ten pharma companies, which average a profit margin of 19%, a number inflated by Pfizer’s 42% profit margin, a company that doesn’t market any diabetes products currently. Dr. Nathan did not give any details on the companies with diabetes drugs in their portfolio; we point out their lower than average profit margins compared to the rest of the field – AZ (10%), Merck (10%), Sanofi (11%), Novartis (16%), and Lilly (20%) – this is probably why Genentech, BMS, Amgen, Gilead, and others have stopped developing diabetes therapies.
• In Q&A, Dr. Nathan implied that we’ve already seen data indicating cardiovascular neutrality for J&J’s SGLT-2 inhibitor Invokana (canagliflozin). Topline results from the CANVAS and CANVAS-R cardiovascular outcomes trials have not been publicly reported and full results are expected at ADA 2017. It’s unclear if Dr. Nathan was referring to these largescale CVOTs and it appears we’ll have to wait and see to gain more clarity on his comments. It’s possible that Dr. Nathan was referring to the interim safety analysis of CANVAS conducted for FDA approval of Invokana. That all said, Dr. Drucker expressed strong optimism that the cardiovascular benefit observed in EMPA-REG OUTCOME will be shown to be a class effect for SGLT-2 inhibitors. [Editor’s note: In a separate discussion with us following the debate, Dr. Nathan acknowledged that he may have misspoke regarding canagliflozin’s CV potential and emphasized that he has no advance knowledge of ongoing studies.]
• Dr. Nathan also suggested in Q&A that some companies like BMS and Genentech/Roche have moved out of diabetes because they realized older drugs are better and “they can’t do anything to improve upon them” – he didn’t cite any patient data to back up these views and didn’t talk about whether the older drugs were easier for HCPs to use.

New Drugs for Diabetes: True Innovation with Real Patient Benefits

Daniel Drucker, MD (Lunenfeld-Tanenbaum Research Institute, Toronto, Canada)

In response to Dr. Nathan, Dr. Daniel Drucker argued passionately, “To diminish the importance of new drugs for diabetes is malfeasance. To advocate for their affordability is our responsibility. To eschew the use of new drugs in treating diabetes is intellectual malpractice.” Dr. Drucker emphasized that patients and providers in the diabetes field face numerous barriers to optimal treatment, including the cost of medication/insurance coverage, cost of SMBG, side effects (hypoglycemia, weight gain), adherence, frequent dosing, injections, and the effectiveness and durability of medications. As a result, Dr. Drucker argued that we need as many tools as possible in our toolbox to address these challenges – yes!

• Dr. Drucker noted that we often focus on the cost of drugs at the pharmacy, without adequately accounting for associated costs (cost of SMBG, increased healthcare utilization, emergency room visits, hospitalizations for hypoglycemia, and time and days off work). That said, Dr. Drucker strongly advocated for an affordable and reasonable cost for drugs, agreeing that it’s absolutely essential that patients are able to afford their medication and that even the best drug is useless unless patients are able to take it. To that end, in the rebuttal portion of his debate, Dr. Drucker called for providers to engage in conversations with other stakeholders to help us, as a society, to get ahold of the cost issue.
• He acknowledged that the newer diabetes agents are associated with their own adverse events, but emphasized that it’s now possible to treat diabetes with medications that offer a low risk of hypoglycemia (avoiding the need to for glucose monitoring and reducing serious hypoglycemia risk) coupled with “extremely robust” A1c lowering. To illustrate his point, Dr. Drucker cited data from a Swedish registry study demonstrating less hypoglycemia and weight gain with DPP-4 inhibitors compared to sulfonylureas and data from the SWITCH 1 and 2 and DEVOTE trials demonstrating a reduction in hypoglycemia risk with Tresiba (insulin degludec) compared to Lantus (insulin glargine). On GLP-1 agonists, Dr. Drucker cited several studies demonstrating comparable or greater A1c reductions for different agents compared to insulin – often accompanied by weight loss. As he put it, “The concept that insulin is superior to GLP-1 agonists as a glucose-lowering drug is simply not borne out by the data. If you want to practice evidence-based medicine, stick to the data.”
  
  • Dr. Drucker was particularly positive about GLP-1 agonist/basal insulin fixed-ratio combinations. He highlighted data demonstrating that these combinations offer great A1c efficacy with less hypoglycemia, almost no nausea and vomiting, and weight loss. He suggested that agents such as these allow providers to be more aggressive about treatment and glycemic goals, when appropriate, without a fear of increased hypoglycemia.
• “It’s hard to argue with death as an outcome.” Dr. Drucker argued that newer diabetes agents allow us to enter an era of reducing diabetes complications beyond microvascular complications. He highlighted the impressive cardiovascular and renal results from EMPA-REG OUTCOME and LEADER, emphasizing that most providers would agree that the ultimate aim is to keep patients healthy and alive – and “new diabetes drugs allow us for the first time to make that commitment to our patients.” He also noted that the number needed to treat to prevent a death with empagliflozin (39 for three years) and liraglutide (98 for three years) is far lower than that of statins (100 for five years), anti-hypertensive agents (125 for five years), or aspirin (333). is Further, he underscored that the cardiovascular benefits demonstrated in these trials are not mere pharma hype – the data have been carefully evaluated by the FDA and supported an expanded label indication for the reduction of cardiovascular death for empagliflozin.

Dr. Nathan’s Rebuttal:

“Individualization of therapy seems to be the argument of the day. Our previous president talked about personalizing therapy… it’s an incredible shame we have no clue how to do it. There’s no business model for pharma to do that. Their model is to sell it everyone and let them figure it out. They haven’t looked at the performance of their drugs in any of the simple demographics – not men vs. women or in African-Americans, etc. – they haven’t designed studies to assess this. There’s currently no data to individualize therapy based on.

Regarding the studies, you showed that GLP-1 agonists reduce A1c more than insulins, there are just as many studies that have showed trivial or no difference in A1c between insulin and GLP-1 agonists. DUAL V just looked at the combination of insulin and GLP-1 agonist – you got a 0.4% reduction in A1c and yes, hypoglycemia was reduced, but severe hypoglycemia was vanishingly rare in either group. In fact, the major difference I saw in the results was that nausea and vomiting occurred in 26% of those on the new drug compared to in 2% of those treated with just insulin. The other major difference was the estimated cost of $10,000 per year with the new drug, for 26% more nausea and vomiting and A1c being lowered by 0.4%.

Also, when you look at the control groups, insulin titration was done with a weak hand. They’re not using insulin aggressively like they say they are in the protocol. Looking at the epidemiological data does not give us any sense of the bias or confounders in terms of why patients may have been put on one therapy over another in the first place.

I will just end by stressing that Daniel seems to be living in an alternative reality.”

Dr. Drucker’s Rebuttal:

“In some of the insulin comparator arms of the trials I showed, our colleagues the investigators did an excellent job with A1c – 6.9%, 7%. I don’t think the argument that they didn’t really try hard to get A1c down holds. I don’t have much new additional data to rebut with, I think the data I showed speaks for itself.

What I’d like to do though is pose a thought experiment as we grapple with drug costs. A drug can have all these wonderful reductions in hard events that we’ve seen, but if patients can’t access the drugs, we’re not going to be able to make the impact we want. Let’s think about this. If you have a new diabetes drug that lowers A1c, reduces heart failure, and all that and we sell it for $100,000 a year, nobody’s going to buy it and it won’t save anyone. But if you sell it at 25 cents per day, you won’t actually recoup the investment and the company will go bankrupt. So we need to figure out as a society how to set the appropriate level of reimbursement.

Dr. Nathan showed you a slide on pharmaceutical return on investment. If diabetes is such a great business though, why did BMS abandon diabetes to work on oncology? Why did Roche stop pharmaceutical drug development for diabetes and refocus on the Genentech oncology pipeline? Why did Abbott labs abandon pharmaceutical diabetes research? It’s a difficult business, risks are taken, innovation is not guaranteed, and return on investment can’t be taken for granted. As a society we need to come to grips with cost and we need to work with pharma.

In order to use these drugs wisely, patients are going to need to be able to afford them and they’re going to look to you, the healthcare providers, to join into that conversation.” (Editor’s note – we would also ask, why did Genentech leave the field? Why are so many companies like Takeda and GSK not continuing to invest in the field?)

Questions and Answers:

Dr. Gordon Weir: Sulfonylureas have been bummed around for years, but the sulfonylureas use now are shorter acting and there are more warnings on the label for higher risk people, like the elderly. So you do think that the older data on sulfonylurea harms might not apply in the present day?

Dr. Nathan: Yes, absolutely using the short acting sulfonylureas that we now routinely teach physicians to use and avoiding their use in high risk groups should make a difference. Are there dangers to sulfonylureas? Absolutely. But wiser use of any of these drugs improves their benefit to risk ratio.

Dr. Drucker: Sulfonylureas are used widely around the world for primarily one reason: they’re cheap. We now have an ongoing randomized controlled trial, an outcomes study, of a DPP-4 inhibitor and a sulfonylurea. We will soon learn from data from over 6,000 patients whether or not there is really harm or benefit or neutrality when one chooses a DPP-4 inhibitor or a sulfonylurea.

Dr. Nathan: Going back to a point Daniel made, he was making us feel sorry for pharma by pointing out all of the companies that have moved away from diabetes. I would suggest that perhaps they moved out of diabetes because they realized older drugs are better and they can’t do anything to improve upon them.

Dr. Drucker: Why are some of the older ones still available? We can’t imagine they would even be approved today? Would any SFU? Clearly for patients not at risk for hypo, some are fine, depending on affordability issues.

Q: Maybe there is a lag for primary care physicians to learn how to use new drugs. Most guidelines recommend a stepwise approach to treatment. It could be that in five years when primary care physicians are more skilled at the stepwise approach, these utilization numbers will change.

Dr. Drucker: David outlined beautifully the challenges primary care physicians have faced in the past with prescribing new drugs that come back and bite them. I respect them for being cautious, for taking time to assess drugs, saying “this drug is only one, two, or five years old” and seeing how it does. You could call it clinical inertia, but you could also respect it as caution from primary care physicians being burned before. Being cautious is the hallmark of a seasoned, experienced physician.

Dr. Nathan: Although specialists are well-versed in the data that comes out, I think primary care physicians are responding more than anything to advertising. It’s kind of sad, really, they’re pulled by people who come in and tell them what to use. Patients’ who’ve seen an ad on TV come into the clinic and ask their doctor if they can try it and the doctor says why not. I wish there were a more thoughtful approach, but a large number of people with diabetes are seen by primary care physicians with an ocean of advertisements around them and there are only a few saying let’s take a step back to look for what the data actually shows.

Dr. Drucker: I have enormous respect for my colleagues in primary care. When I ask my colleagues why they’re using a particular drug, I’ve never once had them respond that they were watching a football came and saw a commercial for it. I think they’re wise, cautious, and respectful in how they practice. I would never malign a single colleague as being influenced primarily by advertising in their prescribing.

Dr. Nathan: I think that’s naïve to think that people wouldn’t be affected by this ocean of advertising. Direct to consumer advertising only accounts for 10%-20% of pharma companies’ advertising budget; the rest goes to physician advertising.

Dr. Drucker: I think it catches their attention but they’re not basing their decision on the advertising.

Q: Dr. Nathan, do you believe in the EMPA-REG OUTCOME study? How do you explain the clear cardiovascular benefit observed within six months in the EMPA-REG OUTCOME trial?

Dr. Nathan: My colleagues and friends ran that study and I think it was a well-done study and I think the results are real. We’ll see if it applies to other SGLT-2 inhibitors. Canagliflozin, as you know, did not show similar results. Shorter study duration may be an explanation for that. But the question is, is it a cardiac medicine or a diabetes medicine? If it’s operating within six months, it’s not likely it has its effect through glycemia, which as I’ve said was only separate by 0.4% at the end of the trial. Now if the company wants to advertise this as a good drug to be used in men, only (because women unfortunately have a higher risk of yeast infections and UTIs), and they want to use it only for cardiovascular disease, I can get behind that. But that’s not the way they’re selling it. They’re selling it as an overall diabetes drug. If we’re going to individualize therapy, that would be a good starting point actually. Use it only in people who have had an MI, but that’s not all people with type 2 diabetes, that’s a small fraction of people. (Editor’s note – we are surprised to hear this, and do not quite understand whether Dr. Nathan is literally saying that the vast majority of women, who do not experience yeast infections and UTIs, should not have access to this drug.)

Dr. Drucker: Three points: (i) We should only extrapolate the data to patients that look like the patients in the outcomes study. I agree that you can’t extrapolate the data beyond that to the general population of people with diabetes at low risk for CVD. (ii) We will get the canagliflozin outcomes results very shortly and we will be able to see if it’s a class effect. At the American College of Cardiology meeting the results from CVD-REAL were presented. It was a huge, hundreds of thousands of patient study of SGLT-2 inhibitor versus other kinds of therapies and demonstrated a marked reduction of mortality and hospitalization for heart failure. So I do personally think that SGLT-2 inhibitors will show a class effect. (iii) And finally, I think your comment about men vs. women on empagliflozin, again, is disrespectful. If you have a conversation with your female patient and you can say “I can give you this SGLT-2 inhibitor, you do have a good chance of having a urogenital infection, but you also have a 38% chance of having a reduced rate of death,” I don’t think you can say you shouldn’t prescribe it.

Dr. Nathan: But that’s not the way they’re being marketed. (Editor’s note – the labels have only recently been changed, so this would not have been possible until recently.)

Dr. Drucker: Well they should be used according to the indication so I agree with you there.

Dr. Nathan: So you agree with me that it should be reserved for people who’ve had a prior MI.

Dr. Drucker: No, they should be reserved for people who fit the entry criteria, which wasn’t just MI.

Q: The supplements at the back of the study publications can tell us a lot about the flaws of the study and I’m surprised neither of you brought up the flaws with EMPA-REG OUTCOME and LEADER. The main question when we see a cardiovascular reduction is what are we comparing these medications to? If we look at the placebo group in EMPA-REG or LEADER, the A1c was at 8% over the three-year period, there were more patients on sulfonylurea, on TZDs, on insulin that could confound the results of the study. In addition, there were silent MIs that were excluded from the EMPA-REG results and the FDA said that if these silent MIs are included, then the superiority that was claimed by the medication is lost. In addition, there was no information whatsoever on whether or not they were ensuring these patients were getting adequate education on lifestyle in a disease that is mostly driven by poor lifestyle.

Dr. Drucker: The FDA held a special hearing to comb through the data and look at all of those issues you highlighted. They are the last agency to give pharma the benefit of the doubt if there was really a serious issue. What did the FDA do? It approved on the label that these drugs are indicated for reduction of cardiovascular death. Today’s FDA looked at all of the data that’s in front of you or I and made that decision in accordance with what the panel recommended. Let me also remind you that all of those other drugs that you talked about that might have confounded the result – insulin and sulfonylurea, etc. – were also used in the comparator arms in the DPP-4 inhibitor trials and there was no difference in cardiovascular benefit, despite much more insulin and much more SU in the major DPP-4 CV outcomes studies. So we can’t just say “oh it’s insulin and SU” again because we didn’t see that asymmetry in the other studies. The data is the data, we’ve had two GLP-1 agonist outcomes studies reduce MACE events. I’m going to predict to you that we’re going to have multiple SGLT-2 inhibitors outcomes studies reduce events. And if not, we’ll have to rethink our approach, but today the data I think speaks loudly as to the outcomes.

Dr. Nathan: I don’t know how loud it is when you have an absolute risk reduction of 1.5% to 2%.

Q: Was it ethical to allow the placebo group to run at an A1c of 8% over three years?

Dr. Drucker: Can you tell me what the A1c difference at the end of the trial was? It was 0.3% - no significant difference. So I would suggest we all go read the outcomes studies before standing up here and talking about them.

Dr. Nathan: I think it was 0.4% actually. But can you remind us what the advisory panel vote was for the FDA approval of the indication?

Dr. Drucker: It was close, but it was in favor of approval.

Dr. Nathan: It was 12 to 11.

Oral Presentations: Clinical Dilemmas and Outcomes in Diabetes

Increased Survival and Reduced Macrovascular Disease with 7.8 Years of Intensified, Multifactorial Intervention in Patients with Type 2 Diabetes and Microalbuminuria in the Steno-2 Study

Jens Øligaard, MD (University of Southern Denmark, Odense, Denmark)

Questions and Answers

Q: Did you do any cognitive assessment? These are exactly the kinds of interventions that might be useful in reducing rate of cognitive decline.

A: Unfortunately, there was no direct measure of cognitive dysfunction. But, the study is so small that we’ve had all patients visit the Steno Diabetes Center and we know them quite well. Our thinking is that patients in the intensified treatment group do better cognitively. Also, note the very large risk reduction in stroke. That could reduce vascular dementia, for example.

Q: When you looked at outcomes at 21 years, did you notice more benefit in people at higher baseline risk?

A: The study was not powered to look at any single risk, whether A1c, blood pressure, or lipid levels. So, we can’t assess with component of multifactorial intervention was most important. It seemed that cholesterol-lowering was key, but we have not been able to stratify participants based on high- or low-risk for these various risk factors.

Q: What was the A1c difference between groups after 21 years?

A: That’s a very good question. After 7.8 years, multifactorial intervention was suggested to participants across both groups. From 7.8 years forward, we haven’t found any differences in mean A1c, blood pressure, cholesterol, or other risk factors. We consider these findings to be more so an effect of early intervention rather than a legacy effect. But it is difficult to discern, because there is concurrence after 7.8 years.

Q: Once people have a MACE event, does it help to continue intensive treatment?

A: With regard to survival, yes, it helps to intensify treatment. If you stick to the guidelines, most patients who have a CV event would be recommended to intensified treatment at some point. We can only speculate, because there’s no hard evidence on this question right now. It seems like the earlier you start the better, but it’s never too late.

Comment: That’s a positive message – never too late!

Comment: Thank you for this presentation. I think it’s great to have support for early intervention with diabetes treatments.

Corporate Symposia

Updates on Inhaled Insulin: Reaching for the Stars in PPG Control (Sponsored by MannKind)

Bruce Bode, MD (Atlanta Diabetes Association, GA); Jeremy Pettus, MD (UCSD, La Jolla, CA); Janet McGill, MD (Washington University, St. Louis, MO)

A MannKind-sponsored dinner symposium featured three diabetes experts on inhaled insulin Afrezza – Drs. Bruce Bode, Jeremy Pettus, and Janet McGill positioned the product as the only available faster-acting insulin in the US (as Novo Nordisk’s faster-acting aspart is still under FDA review). They described how Afrezza’s quicker onset, quicker offset, and shorter duration of action lowers risk for hypoglycemia and offers better postprandial control. Approximately 67% of diabetes patients express fear of hypoglycemia, and 74% of HCPs say this fear is a barrier to their ability treat-to-target –hypoglycemia and fear of hypoglycemia are far too common. Afrezza addresses both: Insulin action peaks between 10-14 minutes and a majority of activity occurs within 30 minutes, as opposed to the longer 4-5 hour duration of other prandial insulins. The very rapid onset allows patients to bolus at the start of the meal rather than many minutes before, at which point they have a clearer idea of meal content and can dose insulin more accurately to avoid hypoglycemia. Dr. McGill underscored that frequency of hypoglycemia and fear of lows went down measurably in her patients who started using Afrezza, conferring a huge benefit not only on glycemic control but on quality of life. Dr. Bode spoke to the weight gain commonly associated with mealtime insulin, especially when over-bolusing leads to defensive eating. He discussed how Afrezza addresses this issue, again by offering greater potential titration accuracy. Dr. Pettus encouraged providers to use Afrezza alongside CGM whenever possible. With CGM, patients can easily see how the faster-acting insulin acutely affects their blood sugar and can figure out how to adjust their dose, which promotes engagement, enhances self-efficacy, and ultimately contributes to better outcomes. The theme of this MannKind-sponsored symposium falls very much in line with the company’s strategy to push the “faster-acting” aspect to Afrezza instead of the inhaled aspect. Understandably, there’s some reluctance from the field to try inhaled insulin following the discontinuation of Pfizer’s Exubera (though arguably, the Afrezza inhalation device is smaller, more discrete, and much more user-friendly) and lingering, though unsubstantiated, concerns about safety, so we think it smart that MannKind is highlighting the rapid onset/offset feature and its link to reduced hypoglycemia. The company has filed with the FDA for an “ultra-rapid-acting” label claim for Afrezza, which would allow for more direct marketing on this front – a regulatory decision is expected in 3Q17.

• During his opening remarks, Dr. Pettus polled the audience on several questions that confirmed barriers to uptake for Afrezza. A vast majority of HCPs in the room, 81% to be exact, said they consider inhaled insulin for <10% of their diabetes patients. The no. 1 reason for this was safety concerns, followed by lack of familiarity with the data and with clinical applications of the data. Certainly, education on safety as well as safe titration of Afrezza will be crucial for the franchise, given that most patients aren’t used to inhaling their insulin (a growth hormone) and given past experience with Exubera. Dr. Pettus shared his view that this prandial option is greatly under-utilized, but admitted that he’s not particularly surprised given these lingering barriers to uptake. Hopefully, with widespread education, Afrezza will come to be known as a next-generation, more flexible option for mealtime insulin and will be presented to patients as such – we’re keen to have patients aware of this therapy because feedback from those who have tried it has been decidedly positive.
• Dr. Bode dedicated a portion of his presentation to Novo Nordisk’s next-generation prandial insulin Fiasp (faster-acting aspart), pointing especially to its promise in pumps. We’re intrigued by the implications of Fiasp for insulin pumps, and were glad to hear Dr. Bode’s prediction that the benefits of Fiasp vs. NovoLog (insulin aspart) will be amplified in CSII. We also found it quite interesting that Fiasp and Afrezza were discussed side-by-side, implying the emergence of a new class of ultra-fast insulins. An FDA decision on Fiasp is expected in 4Q17, just after the decision on an ultra-rapid-acting label claim for Afrezza. Without a doubt, these products are much-needed in diabetes care – what we have in terms of mealtime insulin isn’t great, and we’ll take any progress we can get.

Questions and Answers

Q: What are advantages and disadvantages of inhaled insulin vs. MDI?

Dr. Bode: The advantage of inhaled insulin is that if you offer it to anyone to try, especially someone with a short diabetes duration, they will take you up on that and tell you they like it because they don’t go low and they don’t gain weight. The problem is that no one offers inhaled insulin because of concerns over pulmonary safety. But from the opinions of lung biologists, pulmonologists, and oncologists it’s clearly safe.

Dr. McGill: The biggest problem is when patients look at their CGM downloads and it looks like a spaghetti bowl. Where do we start to fix these highs and lows? If we’ve already had the patient in for education and tried to change their habits and it doesn’t work, I think it’s time to change the insulin and have them restart their engines. Inhaled insulin is good for the patient who just isn’t settled – and we have a lot of these. Boy, the distress they have with keeping blood sugars in range, even if their A1c is at goal… These patients where we need to try again and think of something new.

Dr. Bode: You pointed out the roller coaster action of blood sugar throughout the day, especially in type 1 patients. I think you give an FEB to all of these patients and give them a trial of inhaled insulin. This would open the door for many people.

Dr. McGill: We also use inhaled insulin in our exercisers because they really can’t handle the tail effect on their insulin.

Q: What are the barriers that are preventing physicians from prescribing inhaled insulin?

Dr. Pettus: The perceptions about safety. According to the clinical data, inhaled insulin really does appear to be safe, and people should be reassured about that. Getting the required spirometry tests for patients is unfamiliar to endocrinologists, which may also contribute to this. Lastly, the unfamiliarity with inhaled insulin dosing. It’s critical that physicians understand that 4 units of inhaled insulin is more like 2.5 units of subcutaneous insulin. I just want people to understand that inhaled insulin is a reasonable option.

Dr. Bode: It’s about safety. I’ve been around lung biologists and they’ll convince you that it’s safe. The difference found in FEB levels in the clinical trial was very minimal, <1% of overall lung function. But that’s hard to get over. Inhaled insulin goes in and out so quickly. If this was initially on the market back in the 1920s, no one would have ever developed subcutaneous insulin, but now injections is all people know. Another application of inhaled insulin is gestational diabetes.

Dr. Pettus: People should understand the unique features of inhaled insulin’s PK/PD profile. This was initially targeted as a good option for people with needle phobia, but it’s really most remarkable for its fast onset and offset.

Q: Inhaled insulin vs. non-insulin oral anti-hyperglycemic agents?

Dr. Bode: If you need insulin, you either need to take it subcutaneously, or you can go with an injectable GLP-1 agonist in type 2 diabetes. There’s no oral agent that can even come close to this, not even a DPP-4.

Q:  Inhaled insulin vs. short-acting GLP-1 receptor agonists?

Dr. Bode: We played with pramlintide, an amylin analogue. Compulsive patients would take it with every meal, but <1% stayed on it. For some there are quick-acting GLP-1 agonists like lixisenatide and exenatide, but lixisenatide isn’t available in the US and very few people are using exenatide three times a day, and furthermore it is only indicated for twice daily use. Once-day and once-weekly GLP-1 agonists have of course changed all of that.

Dr. McGill: One of the things I’ve done more of is measure C-peptide. I’m not looking for insulin resistance, but we have some type 2 patients who have very low C-peptide levels, and if I’m actually suspicious of the course of their diabetes I’ll test their antibodies also. Of the very low C-peptide patients, some do pretty well with GLP-1 agonists and basal insulin, but it comes down to this and controlling their diet. If you need insulin, you need insulin. And for those who need to go to mealtime insulin, that’s the conversation that you need to have. Clearly we have a lot of options, and I want to make another point: we were brought up through the human insulin, rapid-acting analogs, then to glargine, with everything being a 1:1 conversion. Then we got insulin detemir and that’s not, and neither are Toujeo, Tresiba, and now inhaled insulin. I think this is job insurance for endos, understanding all of these insulins and knowing how to manage them when dosing is a little trickier.

Q: What do you do when a patient doesn’t like Afrezza because of cough?

Dr. Bode: Cough is the most common complaint about inhaled insulin, and there are several ways to combat it – have a glass of water first, and make sure to aim the device correctly.  It’s no different than taking albuterol. After the third or fourth inhalation people learn to tolerate it, but most people quit after the second or third inhalation. Long-term cough dissipates dramatically; these complaints mostly occurred in the first week or so of initiation and this is when people would drop out of the trial. The others figured out what to do. Now you can just go to the diabetes blogs to learn tips about inhalation. It’s not a major issue.

Dr. Pettus: When patients first start to try inhaled insulin they do these dramatic inhalations, and that can induce the cough. It is intended for more of a calm, gentle inhalation. Most people just cough the first or second time, but it does go away as they learn.

Q: The barrier for pediatric endos with inhaled insulin is the age restriction and the high incidence of asthma. Are there trials in pediatric patients?

Dr. Bode: No, but plans are in development. Before Sanofi owned inhaled insulin and was developing these trials, but now the product is in MannKind’s hands. The trials are being developed by experts at Harvard and Yale. Let me say that if you offer inhaled insulin to a kid, they’d do anything to have it, they’ll beg to have it. Unfortunately, it’s not available to them right now.

Q: Is it safe to take inhaled insulin 20 minutes after the meal?

Dr. McGill: It’s not ideal, but patients sometimes inject their insulin 20 minutes after eating, and if you had to pick, you’d be better off inhaling insulin this late than injecting it. 

Dr. Pettus: Yes, although be attentive to macronutrient content of the meal, especially in type 1.

Dr. McGill: The studies of inhaled insulin were done just before CGM became a standard addition to studies. Now patients can watch and see their numbers. It’s quite different than just the finger sticks. We have to speak a different language.

Dr. Pettus: I teach my type 1 patients to be as proactive as possible with subcutaneous injections, but with inhaled insulin they can be more reactive and can wait to dose until they see the blood sugar rise. I think this is a lot easier and more intuitive for people. It changes the conversation.

Dr. Bode: If you just give 4 units patients will say it didn’t work. You might need 8, 12, or even 16 units of inhaled insulin. It’s important to methodically teach them how to logically approach this to see how much insulin they need to cover the meal.

Q: In terms of inhaled insulin, what is Medicare Part D coverage?

Dr. McGill: Medicare Part D will cover anything, but then patients hit the donut hole, because they’re responsible for ~$3,000 of pharmaceutical coverage. It’s interesting in Medicare, because in older type 1 patients pump supplies and CGM are all covered under durable medical equipment, and don’t send patient to this donut hole. Insulin is supposed to be covered as part of this as well, but most won’t do it, because they’re not paying enough to cover rapid-acting analogues, the pricing system was designed for human insulin. That’s tricky, getting the insulin covered. Medicare is not the problem – the problem is the PBMs.

Q: Is there any post marketing data on lung cancer?

Dr. Bode: As far as I know, none has been reported.

Meet the Professor

How to be a Change Agent

Anne Peters, MD (USC, Los Angeles, CA)

In an absolutely incredible talk – that she termed the “most bizarre I’ve been asked to give” – Dr. Anne Peters offered practical tips for endocrinologists and physicians to advocate for broader public health changes in their communities. She provided a series of examples for how she personally has engaged in efforts to create (i) community based change and (ii) systems/clinic based change. Within the first category of change, Dr. Peters impressed on the importance of engaging the community. Looking to broader systems based change, incredible persistence was the common theme of Dr. Peters efforts. The session ended with Dr. Peter offering advice to a young endocrine fellow on how to advocate for change over a career of decades without burning out: Don’t give up. Create an environment that doesn’t burn you out. Make sure you have time for yourself and have the capacity to refer patients out for mental health. Keep on persisting.

• In attempting to foster community based change, Dr. Peters repeatedly emphasized the importance of engaging the community to figure out what it needs and wants and to craft sustainable interventions in close partnership with community members. As she put it, “The worst thing is for us to go in and say we’re the great saviors and say we’re going to do a study for x, y, and z and then just leave afterward.” In order to lay the groundwork for welcomed and lasting change, Dr. Peters recommended devoting substantial time and effort to fully identify and understand the problem, as well as define the baseline structural issues (lack of access to good, quality, nutritious food, food insecurity, and lack of safe places to exercise, for example). Next, she advocated for the convening of community advisory boards to determine the programs that are most wanted, and thus most likely to be successful. She highlighted several successful initiatives that followed this model, including farmers’ markets in low-income areas of LA and church-based exercise groups and children’s summer camps on nutrition. On the other hand, she also presented initiatives that did not work – in particular, a UCLA-driven project that did not sufficiently gather advice from community members before convincing a number of corner stores to devote prime floor space to fresh produce and relegate junk food to the corners of the store. While the program had good intentions, this change was too dramatic in Dr. Peters view and it made these very different-looking corner stores a target of theft and other crimes, leading to store owners wanting to pull out of the effort.
• In advocating for systems- or clinic-based change, persistence is the name of the game, according to Dr. Peters. For instance, Dr. Peters and her colleagues convinced LA country to sign on to create a “quick guide” to help clinics implement better diabetes care strategies – but the county government didn’t fund the project. In response, Dr. Peters emailed key players every Sunday night for two years to make sure it stayed on the radar until it was funded. On an even broader level, Dr. Peters encouraged audience members to “fight formularies” by writing prior authorization after prior authorization – “the more prior authorizations we write, the more it becomes something the insurance companies can’t ignore.” While the challenges on the formulary front have noticeably increased even in the last year (“since I agreed to this talk, the amount of prior authorization work I have to do to get people insulin is like killing me”), Dr. Peters encouraged persistence (“I learned that you have to always fight and if you don’t give up, you can create change.”) Notably, she shared that she was able to get empagliflozin on the formulary for her clinic in East LA by giving some sense of its benefits. On that note, she maintains several form letters with many citations to support the benefits of specific therapies (from a particular insulin to CGM, etc.) that she regularly sends to insurance companies and she’s happy to share this with any provider who asks. Looking to the professional societies and foundations in the diabetes field, Dr. Peters commended them for finally working together to advocate for vitally important issues like pump coverage for Medicare beneficiaries and outcomes beyond A1c. Finally, Dr. Peters argued that patient testimonial videos can be powerful stand-ins for quantitative patient-reported outcomes data (as standardization and consensus still needs to be reached on that front). She showcased a video created by her patients (with patient and videographer Craig Stubing) describing their experience with hypoglycemia that she’s been presenting to at various meetings and advocacy events – we previously saw this video at the JDRF/HCT Hypoglycemia workshop and we think it’s brilliant.

Questions and Answers:

Q: As a young physician just getting out of fellowship and starting my career, what would you say to people who would like to make change, but with the healthcare system changing and things getting more difficult, the administrative burden is increasing. There’s not going to be enough time to care. What would you say to them?

A: I would say don’t give up, we need you to stay in practice. I think about this all the time. It’s getting harder and harder to practice medicine – it’s certainly way harder than when I started – and you need to create an environment that doesn’t burn you out. That may mean having breaks in your schedule or making sure you take all of your vacation days. We don’t tend to stop enough. Also, you need to have time when you’re not working. You need to take time – especially when you’re younger and have a family and kids. Whatever your life is, you cannot work all the time.

It’s also important to have the ability to refer your patients to mental health providers. Patients are getting more and more stressed and you should refer them to a social worker or psychologist or whoever fits into the patient’s insurance plan. I keep a list of providers who can help them with that piece because we can’t also be the psychotherapy – we need to have people to refer patients to who can help with that and help them feel safe.

In creating change, it’s important to keep advocating, even if it’s just continuing to write prior authorizations. The more prior authorizations we write, the more it becomes something the insurance companies can’t ignore. With health insurance changing, we need to do whatever we can to get patients access. You can’t take it all on alone, so you need to figure out what you can do and what other resources there are, like where the free clinic are, etc. Also, figure out how to advocate for your own group of patients and use science and data to support your points – I use the EMR to track everything in the clinic so when they come and try to shut us down, I saw “how can you shut us down? Look at all of the great outcomes we have.”

But the most important thing is don’t burn out. Make sure you have time for yourself and have some capacity to refer for mental health. Keep on persisting.

Presidential Plenary Sessions

Perturbing the Early Life Microbiome and Its Metabolic Consequences

Martin Blaser, MD (New York University, New York, NY)

The official ENDO program kicked off with a Presidential Plenary on the microbiome, a clear reflection of the microbiome’s growing status as not only one of the hottest topics in obesity research, but an area of keen interest in metabolism and endocrinology on a wider scale. Esteemed microbiology expert Dr. Martin Blaser (New York University, New York, NY) led the symposium with a compelling argument that population-wide shifts in the microbiome – what he calls the “disappearing microbiome hypothesis” – may be underlying the global rise of diseases like type 1 diabetes and obesity. His research suggests the typical microbiome of today is considerably less diversified from that of generations past (or that of individuals from non-industrialized societies). Dr. Blaser pinpointed factors such as the rise of C-section births and decrease in breast feeding as potential reasons for this, as they alter the normal transfer of microbes between mother and child during critical periods in infancy. Our “massive exposure” to antibiotics, he argued, may be another contributing factor to the alteration of our gut bacteria profiles. Though antibiotics are, of course, revolutionary drugs and one of the great medical discoveries of the 20^th century, they may harbor unintended consequences. The average American is prescribed one course of antibiotics per year, in addition to significant environmental exposure, especially via meat consumption since livestock are typically treated with low doses of antibiotics to encourage growth. Consistent with observational studies in the literature reporting an association between antibiotic exposure and type 2 diabetes incidence (Mikkelsen et al, 2015), Dr. Blaser’s team has reported that antibiotic exposure in mice increases adiposity and alters the regulation of hepatic lipogenesis genes, an effect that is exacerbated when mice are exposed to a high-fat diet in addition to antibiotics. Only four weeks of early-life antibiotic exposure is sufficient to induce this phenotype, and though the microbiome is only transiently influenced by antibiotic exposure, the metabolic consequences are lifelong. The Blaser lab found a similar effect for type 1 diabetes: early life antibiotic exposure led to an increase in insulitis and a decrease in T-Regs in the spleen and small intestine – data he assured the audience would be elaborated in more detail in a subsequent poster presentation later in the conference (we can’t wait!). Dr. Blaser’s body of work supports the notion that microbiota act during a critical developmental period in early life to set the stage for long-term physiology. Disruption during this phase (by antibiotics or other environmental influences) can thus have lasting detrimental effects on metabolism. So fundamental is the microbiome, he argued, that microbiome assessment may one day become standard medical practice. For more details on the role of microbiota in metabolism and the potentially disruptive role of antibiotics, check out the Blaser laboratory’s recent publications in Nature and Cell.

Endocrine Fellow Series: Type 1 Diabetes Care and Management

Depression and T1DM

William Polonsky, MD (Behavioral Diabetes Institute, San Diego, CA)

New to Endo Fellows, Dr. Bill Polonsky provided an excellent primer for endocrinology fellows on assessing and managing diabetes distress, which he described as the much more common psychological phenomenon in diabetes vs. major depressive disorder. Earlier studies overestimated the prevalence of clinical depression in diabetes – which is actually close to 5% in a type 1 population and 4% in a type 2 population – because of reliance on self-report questionnaires. Dr. Polonsky established the PHQ-9 (a 10-question survey) as a useful instrument for busy endos, with the caveat that it results in 57% false positives for a clinical depression diagnosis even at a high threshold (score >15) and thus isn’t a sufficient basis to prescribe antidepressants. Many of these false positives are really cases of diabetes distress, which occurs at much higher rates of 39% in type 1 and 35% in type 2. The overlap is understandable, Dr. Polonsky explained, because a key characteristic of both depression and diabetes distress is a sense of powerlessness. “I will end up with serious long-term complications, no matter what I do” is the most common thinking trap in diabetes distress, according to Dr. Polonsky, which led him to a very interesting and important point about patient motivation: It is well-known in psychology that people respond best to short-term positive reinforcement. In contrast, diabetes asks people to respond to long-term results, and the “fondest hope” for patients is that nothing will go wrong. To address this, Dr. Polonsky underscored the value of empowering patients and reframing diabetes management with “evidence-based hope” (also a theme he discussed at AADE 2016). It’s possible to live a long and healthy life with type 1 diabetes (rates of amputation, blindness, and nephropathy are down with the advent of advanced medicines), and HCPs who treat this chronic disease must recognize the signs of diabetes distress and intervene swiftly to help patient motivation. Dr. Polonsky shared several specific ideas on how to successfully assess and manage diabetes distress:

• “First of all, ask.” A structured interview on depression symptoms is the gold standard for assessment, but Dr. Polonsky acknowledged the time pressure that most endocrinologists and PCPs face. Instead, he suggested that providers can accomplish a lot with one question: “What’s one thing about diabetes that’s driving you crazy?” This singular question honors patients and their real-world experience of living with a hard-to-manage, chronic disease, and it can get at some of the most critical issues surrounding diabetes distress. We’d love to see even informal psychology evaluations like this introduced into diabetes care to catch diabetes distress before it advances to diabetes burnout. Psychology is still too-often overlooked in the field, so we appreciated this reminder from Dr. Polonsky and we hope this lesson can spread far and wide within the diabetes community.
• There are formal ways to quantify diabetes distress – and Dr. Polonsky pointed to the new DDS-T1D scale specifically for people with type 1 released in 2015 – but he highlighted that these measuring schemes were originally developed as conversation starters. These questionnaires are merely a more formal version of “what’s one thing about diabetes that’s driving you crazy?”, but Dr. Polonsky articulated that it’s important for all endocrinologists to know they exist.
• Provide a sense of hope and offer congratulations. Scare tactics might work okay for some patients, according to Dr. Polonsky, but by and large people are better motivated by positive reinforcement. During later Q&A, one fellow in the audience proposed positive cognitive reframing as a means toward conveying “evidence-based hope,” which Dr. Polonsky agreed could be beneficial in practice, especially in breaking the thinking traps that perpetuate diabetes distress and burnout.
• Set reasonable expectations. Dr. Polonsky pointed out that it’s not uncommon to build up an all-or-nothing mentality toward type 1 diabetes management – patients will drive themselves crazy thinking glycemic control has to be “perfect” or they should just “forget the whole thing.” This is where personalized treatment plans are key, in finding the compromise between perfect diabetes care and “having a life,” as Dr. Polonsky put it. He continued, providers must ensure that A1c targets are doable for any particular patient, taking into account the individual’s daily life and personal life preferences/goals. We loved hearing about this strategy to bolster a patient’s sense of self-efficacy while diminishing feelings of failure. This topic of managing expectations is something we’ve been hearing about increasingly in the context of advanced diabetes devices, especially prospects for closed loop. There, too, we see tremendous value in supporting a patient’s self-efficacy with the technology and with reasonable expectations about what that technology can and cannot do.
• Make diabetes less overwhelming by constructing a step-by-step plan for action. Dr. Polonsky again emphasized personalization of care in presenting this diabetes distress management strategy. Dr. Linda Siminerio (University of Pittsburgh, PA), who also provided some commentary throughout this session, chimed in to mention how technology can greatly ease the daily burden of diabetes self-management. She described how the stress of having to make diabetes-related decisions on your own is a major contributing factor to diabetes distress. Technology makes self-management easier and also empowers patients, Dr. Siminerio explained, meaning it feeds directly back into a solution for diabetes distress.

Obesity Management Workshop

Pharmacotherapy for Obesity Management

Ken Fujioka, MD (Scripps Clinic, La Jolla, CA)

At the pre-conference Obesity Management Workshop, Dr. Ken Fujioka overviewed the major obesity drugs, offering pearls of wisdom on the clinical use of each one. Because the causes and pathophysiology of obesity are heterogeneous, Dr. Fujioka opened with the caveat “don’t expect one drug to work in every patient.” The response rate for the majority of obesity drugs is around 50%, so it is important to educate patients that it may take multiple tries to find the right medication (or combination of medications). He further explained that these drugs are indicated for individuals with a BMI over 30 kg/m2 (or 27 kg/m2 with complications) despite the fact that the metabolic consequences of obesity begin at a lower BMI in many minority populations – a very important consideration that is, unfortunately, nowhere to be found on any of the drugs’ labels. We hope that the following “clinical practice pearls,” as Dr. Fujioka calls them, could one day be elaborated in the form of evidence-based guidance on which drugs are most effective in which patients, but for now much of obesity care is in a state of complete trial-and-error. AACE recently published its very first edition of obesity guidelines last May which, together with Dr. Fujioka’s advice, we hope may provide some guidance.

• Arena/Eisai’s Belviq (lorcaserin) targets the 5HT2C serotonin receptor with extreme selectivity, activating the POMC neurons and MC4R pathway to increase satiety. It also has a rapid beneficial effect on blood sugar. Dr. Fujioka highlighted the low side effect profile of lorcaserin (due to its selectivity) in addition to its lack of stimulating effects. For this reason, it is a good candidate for patients with cardiovascular concerns. Lorcaserin is not an ideal drug for patients on SSRIs or other serotonergic medications, and may increase hypoglycemia risk in patients with diabetes on insulin or a sulfonylurea.
• Vivus’ Qsymia (phentermine/topiramate) packs the punch of two different molecules: phentermine, which stimulates norepinephrine and dopamine release to affect the brain’s reward system, and topiramate, which is hypothesized to dampen the drive to eat through its action on GABA activity. Dr. Fujioka highlighted the very high patient response rate to phentermine/topiramate – patients (responders and non-responders alike) lose an average of 10% body weight with the drug, and those who are prone to binge eating are especially responsive. The drug is also distinguished by the unique side effect of dysgusia (altered taste). Dr. Fujioka framed this as a massive benefit: in his experience, patients tend to experience an aversion to carbonated drinks such as beer and soda – very advantageous for patients trying to lose weight! Despite all this, phentermine/topiramate is associated with a significant number of adverse events (because it is two drugs) including depression, myopia, cognitive impairment, and birth defects.
• Orexigen’s Contrave (naltrexone/buproprion) combines the opioid receptor agonist naltrexone (approved for drug and alcohol addiction) with the dopamine and norepinephrine reuptake inhibitor bupropion (approved for depression and smoking cessation). Both of these mechanisms combine to affect both hunger regulation in the hypothalamus and craving in the brain’s reward system. People lose an average of 8% body weight on naltrexone/buproprion, but responders can achieve almost 14%. Dr. Fujioka noted that this is an excellent obesity treatment for people with existing depression or those who experience food cravings, but warned that naltrexone is a “tough drug” associated with nausea, so dosing must be titrated very slowly.
• Novo Nordisk’s Saxenda (liraglutide 3.0 mg) is a GLP-1 agonist that suppresses appetite, delays gastric emptying, and augments glucose-stimulated insulin secretion via both the gut and the brain. A remarkable 77% of patients respond to liraglutide 3.0 mg, and lose an average of 11% body weight on the drug. Dr. Fujioka praised liraglutide as an excellent option for patients with diabetes or prediabetes (given its status as a diabetes drug, Victoza as a lower dose), as well as those with cardiovascular disease because of its abilty to improve blood pressure and lipids. Caveats associated with liraglutide are its GI side effects, and Dr. Fujioka recommended slow titration, especially in elderly patients.

Obesity in America

Dr. Stacy Brethauer (Cleveland Clinic, Cleveland, OH)

Dr. Stacy Brethauer, a top bariatric surgeon at the Cleveland Clinic, detailed fascinating insights from the Obesity in the America survey, revealing widespread misconceptions in public knowledge of obesity. Completed by the American Society for Metabolic and Bariatric Surgery in collaboration with researchers from the University of Chicago, the survey (n=1,509), the survey reveals two overarching paradoxes in the way Americans think about obesity: (i) Obesity is strongly recognized as a serious health problem with many adverse consequences, but people do not consider it a true disease; and (ii) People overestimate the effectiveness of diet and exercise for long-term weight loss and underestimate the effectiveness (and safety) of medical and surgical treatments. These findings are detailed in two separate reports, both available here.  A major goal of this study was to inspire national dialogue on obesity and learn the areas in which education is needed most so that obesity can finally be considered in the same chronic disease paradigm as other serious conditions. The need for greater education on obesity is a major challenge in addressing the obesity epidemic, and this study represents very important groundwork in defining the scope of our misconceptions. While the results of this study certainly underscore the continuing challenges of the obesity market and the uphill battle for widespread patient, provider, and public acceptance of pharmaceutical interventions for obesity, we’re not entirely surprised. Even among medical circles, obesity has only been recognized as a disease in the last handful of year – AACE was one of the organizations to pave the way in 2011, followed by the AMA’s recognition two years later in 2013. Despite the intervening years since those declarations, it’s clear that there’s much more progress to be made.

• The first report, entitled “Obesity Rises to Top Health Concern for Americans, but Misperceptions Persist” reveals that Americans understand the risks of obesity but hold major misperceptions about the causes of the disease. A majority of Americans (81%) consider obesity to be the most serious health problem facing the nation, tying cancer as the top issue ahead of diabetes (72%), heart disease (72%), mental illness (65%), and HIV/AIDS (46%). Furthermore, nearly all (94%) agree that obesity increases a person’s risk of early death. That said, only 38% consider obesity to be a disease. This misperception of obesity’s disease status was accompanied by misperception in what actually constitutes obesity: 89% of survey respondents whose BMI placed them in the obese range did not consider themselves to be obese. Only ~60% of these participants have spoken with a doctor about their weight. Other notable findings:
  
  • Americans disagree on the causes of obesity: 50% view obesity as resulting from a combination of genetic, environmental, and social factors whereas 48% attribute it to a lifestyle choice. Those in the latter group are more likely to say individuals (and not the healthcare system) are responsible for taking action on obesity, yet are also less likely to speak with a doctor about their own weight.
  • Among people who believe something needs to be done to prevent obesity, 58% say that it is up to the individuals themselves whereas 41% want action from the healthcare system.
  • There is bipartisan support for national action to encourage obesity prevention, with the majority of Democrats (95%), independents (95%), and Republicans (78%) indicating that something should be done.
• The second report, entitled “New Insights into Americans’ Perceptions and Misperceptions of Obesity Treatments, and the Struggles Many Face,” centers on Americans’ beliefs about obesity treatment. Three quarters of the population surveyed say they have tried to lose weight at some point in their life. Furthermore, those who are obese are much more likely to describe this weight loss experience as frustrating (52% vs. 27%) and not worthwhile (46% vs. 64%). Despite this, losing weight on one’s own through diet and exercise is considered the most effective weight loss method (78%), followed by formal exercise programs (72%) and dietary counseling (61%). Weight loss surgery (59%) and prescription medications (26%) were considered among the least effective weight loss methods, despite clinical evidence to the contrary. Among obese participants, 25% have looked into whether their insurance covers any of these methods for long-term weight loss. 60% of all respondents indicated that insurance should cover medical obesity therapies (despite widespread skepticism of the efficacy and safety of these).
• The misconceptions about obesity revealed in the ASBMS Obesity in America survey are largely consistent with those shown in the ACTION study. Whereas the Obesity in America survey focuses on how the population at large thinks about obesity, the ACTION study zooms in on the particular differences in perspective between obesity stakeholders (people with obesity, their physicians, and their employers) to identify barriers to obesity management rather than disconnects in public understanding. We certainly need a better understanding on all of these accounts, and we are glad to see obesity perceptions being investigated from so many different angles. Education is certainly a major key to combatting the growing obesity epidemic.

Exhibit Hall

Abbott

Abbott’s booth was entirely dedicated to the FreeStyle Libre Pro (retrospective, blinded) professional CGM, with a tiny sliver calling attention to AGP with the tagline “the more you see, the more you can do.” The product launched in the US last fall, meaning this was the first time Libre Pro was not under glass in the US. While we were visiting the booth, we overheard one woman exclaim “You don’t have to calibrate? Really? That’s huge!” Or our favorite quote from a provider: “it’s like a nanny cam for my patients.” A rep told us that providers also frequently indicated that they love the low cost, convenience (no disinfecting, reusing), and finding “hidden treasures” in profiles. We continue to see very, very high global potential for this product for people not willing/able to wear real-time CGM. As a reminder, the unblinded, real-time FreeStyle Libre consumer version is under FDA review (both for adjunctive and non-adjunctive claims) and Abbott hopes to launch in the US in the second half of this year.

Amgen

Amgen occupied a commanding booth at the very entrance to the exhibit hall. About half of the square footage of the bustling booth was dedicated to the company’s PCSK9 inhibitor Repatha (evolocumab), featuring large wall displays and flat screens highlighting the drug’s safety and efficacy data and Repatha’s ability to “maximize LDL reduction in one move.” A particularly prominent sign on a pedestal in the middle of the booth read “91% of adults covered” – a response, we imagine, to widespread concerns over affordability and accessibility of the PCSK9 inhibitor class. Smaller signs described Amgen’s patient assistance program which offers a $5 copay card to eligible commercially-insured patients such that no prescription refill of Repatha will exceed $5 in cost. This is a great initiative, but we remain concerned about the broader population’s access to Repatha (noting, of course, that payers also need to make moves in recognizing value and improving reimbursement for PCSK9 inhibitors). The booth contained no hints of Repatha’s recently-demonstrated risk reduction for cardiovascular death, which is certainly a differentiating factor for the drug – we imagine that this is due to the fact that the FOURIER CVOT reported only a few short weeks ago and is not yet included on the label for Repatha. The rear-facing side of the booth was much more muted in appearance, featuring solid blue walls, a (very popular) cookie stand, and table where scientific affairs representatives sat eager to answer attendees’ questions. 

AstraZeneca

AstraZeneca highlighted SGLT-2 inhibitor Farxiga (dapagliflozin), fixed-dose combination Xigduo XR (dapagliflozin/metformin extended-release), and GLP-1 agonist Bydureon (exenatide once-weekly). These drugs were featured on three interactive monitors on each side of the exhibit, with two rows mirroring each other. Interestingly, there was no mention anywhere in the booth of recently FDA-approved Qtern (dapagliflozin/saxagliptin) – reps attributed this to the fact that the product has not yet launched in US pharmacies. For our part, we’re curious to see the marketing around Qtern when it does officially launch, as AZ management has expressed high confidence in its SGLT-2 inhibitor franchise which includes the fixed-dose combination with DPP-4 inhibitor saxagliptin (branded by the company as Onglyza). We mirror this confidence in the Farxiga franchise as well, and we note that standalone Farxiga could very well reach $1 billion blockbuster status in 2017. We weren’t particularly surprised about Onglyza’s no-show in the exhibit – management has shown some willingness to let SGLT-2 product sales cannibalize DPP-4 sales, and has outlined a strategy to position Farxiga as the SGLT-2 inhibitor of choice for patients looking to switch off a DPP-4 inhibitor. Moreover, the Farxiga family of products and Bydureon have very much been the focus of AZ’s exhibit hall presence at many conferences of late (see our coverage from ACC 2017 and Diabetes UK 2017). The company’s booth at ENDO 2017 also had informational pamphlets available to take away, including one on Fit2Me, the very cool app that offers customized support to type 2 diabetes patients in the form of meal plans, exercise plans, and medication regimen reminders, among other resources.

Companion Medical

Companion Medical (InPen, Bluetooth enabled, prandial, reusable insulin pen) made its first ever major conference exhibit hall appearance here. CEO Mr. Sean Saint told us that the planned 2017 launch is still on track. The messaging on the company’s website (“We are steps away from making smart insulin delivery available to the public”) is understandably vague – there are a lot of moving parts to launch a new category! Mr. Saint indicated that manufacturing capacity won’t be an issue upon release, which is good to hear – we imagine demand could be significant as the first connected pen in the US. He told us that when he first established Companion, he didn’t fully appreciate how important this device would be for his own diabetes care; now he loves it, and IOB is his favorite feature (in a “mini demo,” he guessed that his current IOB was 1 unit, and then checked…it was 1.7 units). We wonder how reimbursement/cost, potential partnership, and demand will shake out when distribution begins. See our deep dive from last August (upon FDA clearance) for specifics, and check out the company’s updated website. As a reminder, Lilly is an investor in Companion, and we wonder if the insulin company will help Companion launch the product, navigate reimbursement, etc. Companion has just six full-time employees at the moment, meaning launching on its own will be a challenge.

• Companion Medical has launched a nicely redesigned website (www.companion-medical.com). The home page features testimonials from respected Drs. Steven Russell, Steve Edelman, Jeffrey Joseph, and Mr. John Walsh.  

Dexcom

We visited the Dexcom booth just over a week after Medicare’s announcement that it will cover therapeutic CGM for type 1 and type 2 beneficiaries. According to the rep, this news was (unsurprisingly) one of the hot topics – many adult endos were wondering what it takes to get reimbursement for their qualifying patients. It’s still pretty early and we imagine Dexcom will provide a material update on the 1Q17 call soon. Other than that, the booth was business as usual – reps detailed the web-based Clarity data management platform and handed out information sheets about the DIaMonD trial showing the benefits of CGM in MDI.

Eisai

Eisai occupied a decent sized booth toward the edge of the exhibit hall in its pink and blue color scheme. We found virtually no mention of the company’s Arena-partnered obesity drug Belviq (lorcaserin), despite the notable emphasis on obesity in this year’s ENDO agenda. This is disappointing but not entirely surprising; both Arena and Eisai have shifted their attention away from Belviq in light of its weak performance over the past few quarters. Notably, there was also no presence for Orexigen’s Contrave (naltrexone/bupropion extended-release) or Vivus’ Qsymia (phentermine/topiramate extended-release) at the exhibit hall, indicative of the challenges the obesity market is facing as a whole.

Insulet

On a pipeline note, Stanford’s Dr. Bruce Buckingham shared at an Endo Fellows lunch that he could not make the actual ENDO meeting because he had to be in Palo Alto to initiate patients in a new hotel study of the OmniPod Horizon Automated Glucose Control System (OmniPod system + Dexcom G4 Share). The multicentre trial (n=60 between Stanford, Diablo, and Barbara Davis) is designed to evaluate the system’s performance in the context of high-fat meals and exercise. Patients will spend about a week outpatient in open-loop, followed by a 54-hour hybrid closed loop hotel phase with either meal alterations or exercise (participants can choose to do both, but not at the same time). Primary outcome measures are percent below 70 mg/dl and percent over 250 mg/dl. We had our first look at data from the Insulet closed loop system at ATTD in February, and we’re glad to see trials zipping along under Dr. Buckingham’s leadership and Insulet VP & Medical Director Dr. Trang Ly. Insulet’s booth highlighted the benefits of the OmniPod: tubeless, waterproof, auto-insertion, and the powerful Glooko integration. In addition, if attendees put on a demo pod (no needle), then they received a pod-shaped piece of chocolate.

J&J – Janssen

Janssen’s large booth was all about Invokana (canagliflozin), as well as other products in the company’s SGLT-2 inhibitor franchise – Invokamet (canagliflozin/metformin) and Invokamet XR (canagliflozin/metformin extended-release). Outward-facing monitors along the border of plush carpet provided medical information to help providers, and displayed key data from phase 3 clinical studies of Invokana. Deeper inside the exhibit, commercials for Invokana were played on loop. And it was all situated around a popular froyo station!

Lilly

Drawing in attendees with one of the best espresso bars in the ENDO exhibit hall, several new features headlined Lilly’s busy red-and-white booth. We were immediately drawn to a brand-new section devoted to patient affordability and access (tagline: “Helping more patients ge the medicine they need.”) Several representatives were present to introduce healthcare providers to Lilly’s direct-to-patient discount insulin program, offered in partnership with Blink Health. Notably, representatives shared with us that Lilly is actively working to expand the discount insulin program by partnering with other organizations similar to Blink Health or with pharmacies and the like. Lilly reps shared that “several hundred” patients took advantage of the Blink Health program in its first month post-launch in January – updated numbers since then are not yet available. Even more excitingly, we learned that, as of two weeks ago, Lilly has begun to engage in conversations with health plans to modify the benefit structure for insulins. Importantly, the Blink Health discount program functions largely outside of the existing reimbursement system and is directed at cash-pay patients. By engaging health plans directly, Lilly hopes to impact the broader reimbursement process for critical diabetes drugs. Lilly is speaking with commercial health plans as well as employers to hopefully convince them to consider insulins in a separate benefit category from other drugs, and perhaps structure patients’ insulin benefit so that it does not incur copays or is exempt from the deductible. Lilly is drawing on a variety of health economic arguments – described in easy-to-read infographics available at the booth – underscoring the life-saving potential of insulin and the downstream cost savings of preventing hospitalization and complications through effective use of insulin. The analysis, commissioned from actuarial consulting firm Milliman, also found that exempting insulin from deductibles and having a $0 co-pay would save the average patient $434 annually at the cost of just a $0.22 increase in each plan member’s monthly premium – further, this would work within the existing system and thus features a low barrier to implementation. Fingers crossed, Lilly hopes that some alternative benefit structures for insulin will be implemented in some health plans for 2018 – the company has apparently received positive feedback from a number of parties in these discussions. We’re so glad to see Lilly’s continued commitment to real, concrete change to alleviate the burden of insulin costs on patients – the issue has reached a fever pitch in recent years and action from leaders in the field is sorely needed and much welcome. According to Lilly reps, relieving insulin cost concerns for patients is one of the top priorities at the company currently – brand-new CEO Mr. Dave Ricks is actively engaged in these efforts and reportedly requests frequent updates on their progress.

• We also saw promotional materials for the new cardiovascular death indication for SGLT-2 inhibitor Jardiance (empagliflozin) for the very first time, following the indication’s approval in December and launch in January. The materials feature the slogan “CV death has a new opponent” and an animation of a patient’s shadow dressed as a knight, protecting him from three-headed dragon. The screens also highlight, “Despite advances in care, CV disease is still the number one killer of adult patients with type 2 diabetes.” Lilly reps shared that, as expected, the section has drawn enormous interest from ENDO attendees. He noted that endocrinologists in general appeared more familiar with the EMPA-REG OUTCOME data and the specific CV indication, while primary care providers were less clear on the details, though they were vaguely aware of the benefit. Interestingly, he shared that he received many, many more questions about the heart failure impact of empagliflozin at the ACC 2017 meeting last month – of course, booth representatives were unable to discuss the heart failure results as it’s not part of the indication, but this commentary follows on the immense enthusiasm for Jardiance’s heart failure impact that we’ve noticed in the cardiology field. Throughout the Jardiance section, it’s clear that the new CV indication is the centerpiece of Lilly’s promotional efforts for the drug at the moment – while it certainly makes sense given the enormous hype and long journey to this indication, we still found it an interesting choice given that the indicated population of people with type 2 diabetes with established cardiovascular disease is rather small compared to the overall population of people with type 2 diabetes.
• Other big draws with the Lilly booth were sections focused on biosimilar insulin glargine Basaglar and GLP-1 agonist Trulicity (dulaglutide). Less-trafficked sections of the booth included areas devoted to Synjardy (empagliflozin/metformin), Tradjenta (linagliptin), Glyxambi (empagliflozin/linagliptin), Humulin U500, and Humalog U100 and U200. A separate, much smaller booth featured “Lilly for Better Health,” a patient support program featuring recipes, exercise tips, and easy-to-read guides on lifestyle interventions for diabetes and prediabetes.

Medtronic

At Medtronic’s booth, we heard metrics on the 670G launch phases: there are over 700 people in the customer training launch, 110 of whom are Medtronic employees with diabetes. This is the first metric we have heard on the size of the customer training launch, which began last month and sounds bigger than we expected. This early phase will last until June and allow the ~300 trainers on staff (!) to optimize onboarding – how many appointments? How far apart? What are the common sticking points/mistakes? Further, one rep estimated that ~25,000 patients will be awaiting a 630G to 670G upgrade via the Priority Access Program – wowza! That’s more than we would have guessed and will require a pretty careful rollout.  At AACE, there will be a product theater featuring a clinician from the training phase offering actionable information for providers starting patients on the system. Wow is this a big launch with a lot of moving pieces – we’re glad to see it proceeding deliberately, since it will set the pace for the entire field.

Merck

Merck occupied a booth toward the back of the exhibit hall, though the large “Januvia” sign rotating above was quick to catch the eye. Large, bright monitors showcased safety/efficacy data for the DPP-4 inhibitor (sitagliptin) and for fixed-dose combination Janumet (sitagliptin/metformin). Individual patient cases were also featured on interactive screens, and attendees could tap to learn about Manny’s and Dorothy’s experience with Januvia, its glucose-lowering ability, and its favorable safety profile.

Novo Nordisk

Novo Nordisk’s main booth was simple and devoted almost entirely to next-generation basal insulin Tresiba (insulin degludec) and GLP-1 agonist Victoza (liraglutide). Tresiba materials featured a skydiving/parachute motif with the slogan “a proven A1c descent.” Data featured in the booth focused especially on the flexible dosing indication on Tresiba’s label and the fact that it is the only basal insulin pen with a max injection dose up to 160 units – this latter point is clearly part of Novo Nordisk’s efforts to position Tresiba for patients with type 2 diabetes and higher insulin requirements. Victoza materials highlighted the drug’s “3-for-1 benefits” – A1c efficacy, weight loss, and low rate of minor hypoglycemia – and emphasized that it is the #1 prescribed GLP-1 agonist globally. Rapid-acting NovoLog (insulin aspart) was relegated to a single panel on the back wall of the booth and there was nary a mention of Levemir. A separate, smaller booth was devoted entirely to obesity medication Saxenda (liraglutide 3.0 mg), beckoning providers to “help your patients with obesity get the reductions they need.” The booth featured a photo of a women holding a larger pair of jeans – the classic “before and after” weight loss pose – with the phrases “excess weight,” “high cholesterol,” “large waistline,” and “high blood pressure,” emblazoned on the pants. Notably, the promotional materials referred to Saxenda as “the first and only GLP-1 agonist for chronic weight management” – we got the sense that Novo Nordisk is very much trying to drive home the message that obesity, like diabetes, requires chronic therapy rather than the “diet pills” of the past.

Rhythm

Rhythm Pharmaceuticals was present with an exhibit hall table promoting the company’s Genetic Obesity Project. This initiative supports greater genotyping and diagnosis of genetic forms of obesity, particularly POMC and LepR deficiency, which have been responsive to Rhythm’s melanocortin 4 receptor (MC4R) agonist setmelanotide according to a phase 2 study last year. Of course, given setmelanotide’s preclinical status, Rhythm’s booth made no mention of it, instead providing handouts describing the Genetic Obesity Project and resources for physicians for how to enroll their patients in Rhythm’s Genetic Obesity Genotyping Study, GO-ID, to identify individuals with POMC and LepR deficiency. Representatives at the booth informed us that the study has been proceeding very well: whereas only 30 patients with these genetic forms of obesity were known prior to the start of GO-ID, now approximately 170 patients have been identified. There is currently no approved treatment for these genetic obesity conditions, and we will be keeping a close eye on the progress of both the GO-ID study and the ongoing development of setmelanotide. The company recently received $41 million to advance this potential first-in-class drug into phase 3.

Sanofi

Sanofi occupied two commanding booths at the center of the bustling exhibit hall. Sanofi’s main booth was recognizable by its usual sleek white banner and overhead signs for its varied insulin analog offerings. Some signage highlighted flagship Lantus (insulin glargine) and Apidra (insulin glulisine), but the majority of the booth’s floorspace was dedicated to next-generation basal insulin Toujeo (U300 insulin glargine). Several touchscreens provided interactive displays pointing to information on Toujeo’s efficacy in clinical studies and ease of use, touting Toujeo as providing “all day stability with an insulin of today.” We were happy to additionally see a strong presence for recently-approved Soliqua (insulin glargine/lixisenatide). Launched in early January, Soliqua is the first basal insulin/GLP-1 agonist fixed-ratio combination to hit US pharmacies (Novo Nordisk’s Xultophy [insulin degludec/liraglutide] was FDA approved on the same day as Soliqua but has yet to launch). Soliqua occupied about a third of Sanofi’s entire booth, as demarcated by the drug’s signature dark blue, purple, and gold color scheme, largely in the form of information booths where physicians could speak with Sanofi representatives running through a touchscreen display of clinical data on Soliqua and how to initiate this in therapy in patients. This messaging was largely centered on how to initiate for people hoping to intensify existing Lantus therapy. These displays were quite popular, indicating a growing interest among physicians in this long-awaited new drug. Sanofi’s mountain-climbing-themed booth also made a reappearance, dominated by bright red signage and rugged rock walls, beneath large signs reading “Are you a glycemic explorer?” A humming crowd surrounded each of the touchscreens interspersed within the booth, eager to participate in the Glycemic Challenge multiple choice game, which quizzed attendees on lesser-known facts about insulin therapy for type 2 patients. For instance, one question read “How long do physicians typically wait to add insulin to therapy for patients with an A1c above 8%?” – the answer is a startling 6 years! A counter at the center of the booth filled with healthy, outdoorsy snacks like nuts, wasabi peas, and trail mix drew a substantial crowd as well.

Sanofi/Regeneron

Sanofi/Regeneron booth was positioned directly adjacent to Sanofi’s main booth, and PCSK9 inhibitor Praluent (alirocumab) took center stage. Throughout the booth was a motif of blue and green arrows, pointed down toward the ground to parallel Praluent’s LDL cholesterol-lowering action. Signage surrounding the booth’s perimeter emphasized Praluent’s efficacy and ease of use, posting large statistics boasting the drug’s “more than 60% LDL reduction” and the fact that “up to 80% of patients achieved their goal” when taking Praluent. With an eye toward personalization, Regeneron’s advertisements also emphasized the fact that Praluent comes in two different pens, a 75 mg/dl dose and a 150 mg/dl dose for “more power if you need it.”

Tandem

The Tandem booth advertised the Bluetooth-enabled, software-updateable t:slim X2 pump. According to a rep, many providers are not familiar with remote software upgrades, but they like the sound of it when they learn about it. Many clinicians asked when they will see the pump overseas, but that seems off Tandem’s radar at this point – we’ve never heard the company comment on this, since there is a lot to do stateside. Tandem’s pipeline is pretty strong: (i) a possible first-to-market Dexcom G5 integrated pump (under FDA review); (ii) a pivotal trial of the PLGS system expected to wrap up by 3Q17 (per last month’s call); and (iii) the hybrid closed loop system’s pivotal trial with TypeZero is getting underway now (per last month’s call, a launch is expected by the end of 2018).

-- by Abigail Dove, Helen Gao, Brian Levine, Payal Marathe, Adam Brown, and Kelly Close