Endo Fellows 2019

March 19-21, 2019; New Orleans, LA; Days #1-2 Highlights – Draft

Executive Highlights

  • Greetings from New Orleans, where the second day of Endo Fellows 2019 just wrapped up. Adding an interesting twist to the type 1 adjunct conversation, Dr. David Harlan detailed his non-binary approach to treating diabetes (challenging the type 1 vs. type 2 distinction), which enables more personalized diabetes care. Notably, he uses GLP-1s in type 1s with detectable C-peptide with good success and is also positive on selective use of SGLTs – he recommended daily urine ketone monitoring.

  • Dr. Roy Beck gave a valuable master class on clinical trial interpretation, emphasizing the value of confidence intervals over p-values, the need to consider confounding and bias, and wariness around subgroup analyses – including “on-treatment” analysis. Read on below for our thoughts on how these apply to key recent trials in diabetes therapy.

  • On the insulin front, Dr. Elizabeth Seaquist gave an updated talk on hypoglycemia, endorsing insulin degludec (Novo Nordisk’s Tresiba) and CGM for patients experiencing lows. Additionally, Dr. Irl Hirsch gave a practical presentation on how to use human insulin – NPH or regular – in those with type 1, a practice that be characterized as less-than-ideal but sometimes necessary, and even not too bad if you know how to do it (though many don’t – a key point of his talk).

  • In tech, Dr. Irl Hirsch reviewed the latest time-in-range recommendations that arose from ATTD’s consensus meeting earlier this year in Berlin. Dr. Hirsch underscored a goal of <4% time <70 mg/dl, amounting to just under one hour spent in hypoglycemia every day – “still too much” but “as good as we can do with the current technology. While consensus surrounding coefficient of variation (CV) has yet to be reached, we were interested to hear that Dr. Hirsch’s goal for his own patients is CV <33 mg/dl.”

  • We also enjoyed a presentation by Yale’s Dr. Jennifer Sherr, who shared insights on how to optimize MDI therapy, including four benefits of smart pens. Also below are presentations from Dr. Janet McGill and Dr. Luisa Duran on implementing pump and CGM therapy into daily practice, respectively.

Endo Fellows is in full swing, and an impressive series of talks took place today in New Orleans. Read on below for our top highlights in diabetes therapy and technology, and check out our preview for a look at what’s coming tomorrow as the meeting wraps up.

Table of Contents 

Therapy Highlights

1. Dr. David Harlan on Going Beyond Insulin: Doesn’t Classify Patients as Type 1 or 2; Uses GLP-1 in Many Patients (Particularly Those with Measurable C-Peptide); Prefers Daily Urine Over Blood Ketone Tests with SGLTs

Dr. David Harlan delivered a very valuable talk on options beyond insulin therapy in diabetes, peppered with incisive and insightful commentary on diabetes classification and using GLP-1s and SGLTs in “type 1” diabetes. Most notably, Dr. Harlan urged his audience to think beyond the rigid framework of classifying patients as either type 1 or type 2 – he called upon Fellows to “question every patient that you see come in with a type 1 diabetes diagnosis” and recognize that physiology can and does vary significantly. On this point, he put forth a unique paradigm in thinking about diabetes along four axes (instead of the binary type 1 vs. type 2 classification): (i) considering whether the patient is insulin deficient vs. has residual pancreatic insulin production; (ii) whether or not the patient has evidence of anti-pancreatic islet autoimmunity; (iii) whether the patient is overweight or not (i.e., has insulin resistance); and (iv) considering special circumstances (e.g. pregnancy, nursing, renal insufficiency, chronic heart failure) that warrant consideration for individuals not doing well with diabetes management. Dr. Harlan explained that when he sees a patient with diabetes, he strives to avoid documenting type 1 or type 2 diabetes in health records – both for the purpose of providing better care and for the reason of “not wanting anybody to tell me that I can’t use a specific type of therapy because of the type 1 vs. type 2 classification.” We salute this thinking in that it pushes the community to think critically about the complexity of diabetes as a disease and even move past the framework of type 1 and type 2 classifications that can often contribute to stigma and be detrimental to personalization of patient care.

  • Dr. Harlan strongly advocated for SGLT inhibitor use in certain type 1 individuals, noting that he “loves these agents for my properly selected patients.” He highlighted the impressive cardioprotective effects these agents have shown in type 2 diabetes (“SGLTs have taken the diabetes field by storm, so much so that cardiologists want to now start prescribing these”) but did not comment on whether these effects might also translate to traditional type 1 patients (presumably he wouldn’t be able to tell just yet). However, he did highlight that in his personal experience, patients who take SGLT inhibitors immediately experience a time in range benefit, within the first day of initiating the therapy (ed. note - we can definitely vouch for this personally - kc). In reviewing the multiple phase 3 programs that have been conducted for various SGLTs in type 1 (DEPICT for dapagliflozin, inTandem for sotagliflozin, and EASE for empagliflozin), Dr. Harlan emphasized the now well-documented, significantly increased risk of DKA observed with these agents. On this front, he asserted that patient selection is key in ensuring DKA risk mitigation. He insisted that “with properly motivated and selected patients, we can come up with an algorithm for them to carry with them every day, and these therapies can be very safe and effective.” On patient selection, Dr. Harlan only noted that he uses SGLTs in “properly motivated and educated individuals” but did not offer further granularity on selection criteria. After his talk, Dr. Harlan shared with us that he disagrees with the BMI cutoffs of >27 kg/m2 that were recently put forward by CHMP in its recommendation of approval for both dapagliflozin and sotagliflozin in type 1 adults. That is, he finds many patients under the 27 kg/m2 threshold who absolutely benefit from the therapy.

  • Dr. Harlan also provided his DKA risk mitigation strategy in using SGLT inhibitors. See slide below. Describing his personal strategy with patients, Dr. Harlan said that he asks his patients to check urine (not blood) ketone levels every day. This is notable on two fronts – both on the recommendation of using urine testing and the daily testing frequency. Dr. Harlan explained that he prefers urine over blood ketone testing in terms of convenience and cost considerations, which are more important when one is checking on a daily basis. Urine ketone strips are “20 cents apiece at Walmart” while blood ketone strips are often $2-3 per strip (they are $6/strip for Kelly – Aetna covers this 100% - Abbott ketone strips overseas cost far less and can be used in Libre meters) and also require the use of a separate meter in the US. Of course, urine testing is also significantly less sensitive and specific in indicating ketone levels. Nonetheless, the cost savings would add to >$700 per year with daily testing using Dr. Harlan’s more conservative price estimate. The reasoning behind this testing frequency? Dr. Harlan uses this recommendation partly as a mechanism to remind patients that they are taking “a potentially serious agent.” Daily ketone testing will undoubtedly reduce DKA risk, and although some may believe there is also a risk of exhausting patients who feel ask if they are checking constantly for no reason, we can vouch for the sentiment that urine strips are easy and cheap. While there is no solid evidence that daily ketone monitoring prevents DKA, and no clinical trial of SGLTs in type 1 to date has recommended daily ketone monitoring, we believe it’s only a matter of time. Of course, this entire space still needs ample further study; we believe it’s very possible that in the right patient population, daily ketone monitoring will yield the most positive results.

    • Beyond this point, Dr. Harlan’s DKA risk mitigation protocol greatly aligns with those put forward by Dr. Satish Garg (namely his STICH protocol) and by Prof. Thomas Danne and others in recently published consensus guidelines.

  • In terms of GLP-1, Dr. Harlan explained that he uses these agents in his type 1 patients with detectable C-peptide levels. In reviewing data from the ADJUNCT ONE and ADJUNCT TWO studies of liraglutide in type 1, he pointed out improvements in glycemia, weight, and insulin dose associated with GLP-1 use (however, these were balanced against risk of DKA, and Novo Nordisk chose not to pursue an indication in type 1). For patient selection, he considers using GLP-1s in type 1 patients who have some residual pancreatic insulin production. This consideration is based on a post hoc analysis of ADJUNCT showing that individuals with detectable C-peptide showed improved treatment effect with liraglutide, particularly in terms of A1c lowering (see figure below). Notably, at ADA 2018, Dr. Paresh Dandona presented new data based on an independent, year-long study in which liraglutide showed renewed promise in the type 1 population; nonetheless, Novo Nordisk has stated that it’s still unlikely that it will revive the program for Victoza in type 1.

2. How to Interpret Diabetes RCT Data with Dr. Roy Beck: Favor Confidence Interval over P-Value, Intent-to-Treat over Per-Protocol Analysis

Dr. Roy Beck had a few key messages for the endocrinology fellows as they absorb and evaluate clinical trial literature throughout their careers: (i) confidence intervals are more informative than p-values; (ii) pay attention to possible confounding and bias; and (iii) beware of subgroup analyses, including “on-treatment” analyses. Most published studies report a point estimate (e.g. the hazard ratio for MACE events with a diabetes drug vs. placebo), p-value, and 95% confidence interval. Dr. Beck suggested that the last of these three is most important. A p-value below 0.05 can rule out the explanation that results appeared by chance, but a confidence interval offers much more than that. What is the likely range of values for the hazard ratio? Does this range include the null (a CVOT hazard ratio of 1, for instance, would imply no significant difference in cardiovascular outcomes with treatment vs. placebo)? Does it exclude clinically-meaningful effects (i.e. if study results are negative, are we confident that there was no potential for benefit)? How wide is this range (a larger sample size allows for a narrower confidence interval, offering more precision around the point estimate)? Throughout Dr. Beck’s discussion of confidence intervals, we couldn’t help thinking about EXSCEL, AZ’s CVOT for GLP-1 agonist Bydureon (exenatide once-weekly). EXSCEL was technically neutral, with a hazard ratio for three-point MACE of 0.91 (p=0.06 for superiority), but the 95% confidence interval (0.83, 1.00) tells a different story. For one, this interval is quite narrow/precise, reflecting the study’s impressively large sample size (n=14,752), and the interval almost excludes the null value of 1. Dr. Beck shared a helpful interpretation of confidence intervals that applies here: If EXSCEL was repeated 100 times, 95 of those trials would find a hazard ratio between 0.83 and 1.00. That means far more often than not, patients on Bydureon would fare better than their counterparts on placebo, implying real cardioprotection with weekly exenatide. You’d be hard-pressed to find someone with diabetes who wouldn’t take those odds for CV risk reduction. Dr. Beck presented his own example to illustrate the value of confidence intervals, reviewing two similarly-designed studies of metformin in type 1 diabetes. Nwosu et al. enrolled 28 adolescents with type 1 and overweight/obesity, while Libman et al. enrolled 140 adolescents with type 1 and comorbid overweight/obesity; both papers were published in 2015. The Nwosu study yielded a wide confidence interval – given the small sample size – but estimated the placebo-adjusted A1c reduction with metformin at 0.4%, which is absolutely clinically-meaningful. Libman’s larger trial found similar A1c-lowering with metformin vs. placebo (i.e. no difference), with a narrower confidence interval offering more precision, and therefore more certainty about the neutral glycemic effects of metformin for this patient population.

  • Dr. Beck went on to discuss differential bias in RCTs, focusing especially on unbalanced attrition, when more participants are lost to follow-up from the treatment arm than the placebo arm. Ideally, researchers will keep people in the study for data collection even after they cease treatment, Dr. Beck explained, as this allows for a proper intent-to-treat analysis. He was critical of per-protocol or “on treatment” analysis because of differential bias, and again, we were reminded of a recent diabetes clinical trial. In reporting results from the PIONEER program for oral semaglutide, which was just (!) submitted to FDA, Novo Nordisk often emphasized the on treatment analysis over the intent-to-treat analysis, excluding the ~2%-15% of patients who stopped taking the GLP-1. Presumably, these individuals dropped out of the treatment group because of unpleasant GI symptoms associated with oral semaglutide, and leaving them out of the analysis may inflate our sense of the drug’s efficacy – in the real world, if patients can’t take their therapy because of side-effects, they’re not going to benefit from that therapy. Novo Nordisk management has defended their decision to highlight on treatment findings by pointing out that more people in the placebo group required rescue therapy; these individuals were also excluded from per-protocol analysis. To be clear, we are extremely excited about Novo Nordisk bringing the first oral GLP-1 agonist to market and we see tremendous potential for this therapy to improve real-world type 2 diabetes care. That aside, we are more convinced than ever after Dr. Beck’s talk that it’s essential to differentiate between intent-to-treat and on treatment analyses, even if they both offer interesting insights.

  • In response to an audience question, Dr. Beck addressed the dilemma of conducting pilot studies – these trials can establish proof-of-concept to justify more intensive, more expensive research, but they’re often too small to be meaningful. “There’s no good answer to this,” Dr. Beck started. “Large studies cost a lot of money, and you need to have good preliminary data to support doing the larger studies. Ideally, the preliminary data would be compelling biological data that suggests there should be a therapeutic effect. Otherwise, more often than not, you’ll have a small study hinting at benefit, but the larger study won’t replicate that finding. You’ll find out there wasn’t any benefit, and then you’ve wasted a lot of money and resources.” He acknowledged, of course, that we have to do research to propel scientific and clinical advances. Moreover, the diabetes field has often discovered clinical benefit before underlying mechanism; there’s ongoing debate over exactly how SGLT-2 inhibitors reduce heart failure, but there’s consensus that this heart failure benefit exists. “Again,” said Dr. Beck, “there’s no good answer to this.”

3. Dr. Seaquist Promotes Next-Gen Basals & CGM to Address Hypoglycemia, Highlights Especially Troubling Cases of Recurrent Hypo and High A1c

Dr. Elizabeth Seaquist reprised her hypoglycemia talk from last year’s Endo Fellows meeting, reviewing the latest definitions and strategies for prevention and treatment. She recommended next-gen basal insulin degludec (Novo Nordisk’s Tresiba – and presumably Sanofi’s Toujeo) over first-generation glargine U100 (Sanofi’s Lantus) for patients struggling with hypoglycemia, which by now is well-accepted “best practice” given results from SWITCH and DEVOTE. Dr. Seaquist strongly endorsed CGM to give patients more insight into their own glucose readings and what causes lows. She supported the use of insulin pumps with threshold suspend for hypo-prone patients, and briefly touched on islet transplantation (Rickels et al., 2016) as an option for type 1s experiencing problematic hypoglycemia. Of course, all these “best practices” come at a nontrivial cost, but Dr. Seaquist also encouraged fellows not to overlook the power of education. She pointed to the DAFNE structured education program as one example. Diabetes educators should be leveraged to help people understand how to anticipate, recognize, and treat hypoglycemia, Dr. Seaquist explained; she paused on the last part and warned that patients tend to over-treat lows with food which leads to hyperglycemia spikes later.

  • Turning to type 2 diabetes for a moment, Dr. Seaquist noted that the consequences of hypoglycemia tend to be worse in patients with high A1c vs. low A1c. She insinuated that a similar interaction between A1c and hypoglycemia likely exists for type 1s as well. Dr. Seaquist suggested that this relationship needs to be explored through further research. Intuitively, we imagine that individuals with high A1c and frequent hypoglycemia face substantial glucose variability, and those fluctuations are associated with depreciated quality of life as well as increased all-cause mortality. High A1c + frequent hypo could also mean less time-in-range, and we know from Dr. Roy Beck’s post-hoc analysis of the DCCT (presented at ADA 2018, published in Diabetes Care) that time-in-range is significantly associated with microvascular complications: Greater time-in-range decreased a patient’s risk for development/progression of retinopathy and microalbuminuria.

    • Above all, these comments underscored the important point that hypoglycemia is not correlated with A1c. All too often, fear of hypoglycemia leads HCPs to raise glucose targets for their patients, and while patients/providers should have an open dialogue about an appropriate A1c goal, Dr. Seaquist challenged the assumption that we have to relax glucose control to resolve hypoglycemia. This is an enormously valuable message for endocrinology fellows to hear, and we’re glad to see an emphasis on hypoglycemia at this meeting each year (it makes us optimistic for the future of type 1 diabetes care).

  • Part of Dr. Seaquist’s presentation was dedicated to the cognitive effects of severe hypoglycemia, and on a positive note, she shared that 18-year data from the DCCT shows no evidence of accelerated cognitive decline in type 1s experiencing severe hypo. At ATTD last month, Dr. Pratik Choudhary (King’s College London) reviewed these findings with more granularity – recurrent severe lows had no significant impact on patients’ problem-solving ability, learning, memory/recall, attention, motor skills, etc. – and argued that prolonged hyperglycemia poses the greater threat to cognitive function in the long term. He still acknowledged the acute cognitive impairment associated with hypoglycemia, and Dr. Seaquist picked up on this theme, explaining how people perform worse on word recall tasks during and shortly after a hypo episode (this applies even to individuals without diabetes). Moreover, she cautioned that baseline age in the DCCT was quite young (mean 27 years-old), meaning it may take longer for signs of accelerated cognitive decline to show up. To this end, she mentioned that 30-year DCCT follow-up will include an analysis of participants’ cognitive function and structure (via brain imaging).

  • Finally, we appreciated Dr. Seaquist’s reminder of how hypoglycemia affects patient quality of life, which at the end of the day is the most important takeaway for diabetes care providers. She displayed the slide below, which features Tweets from people with type 1 diabetes responding to a Beyond Type 1 inquiry on living through severe hypoglycemia.

Select Questions and Answers

Q: You mentioned switching to degludec instead of glargine. Is there any evidence for splitting Lantus dose or moving the timing of that dose?

Dr. Seaquist: I don’t know of any randomized trials that have looked at that. We do know that Lantus has an onset time around 4-6 hours, so moving it earlier may help, but I don’t know of any clinical trial data comparing BID vs. single. Of course, we do have published evidence showing the advantages of insulin degludec (Novo Nordisk’s Tresiba) over insulin glargine U100 in terms of hypoglycemia (SWITCH, DEVOTE).

Dr. Hirsch: We’ve seen letters in Diabetes Care claiming improvements with glargine BID vs. once-a-day dosing in C-peptide negative type 1s. The problem with using Lantus once-daily is that if you’re on a reasonable dose of the glargine, between 3-4 AM that dose is gone and you see a real spike. When you get into high doses, you can prolong the glucose-lowering effects of Lantus, but then you’re on way too much basal insulin – and that’s another theme of today, that we’re using too much basal insulin as is. As a rule of thumb, I would say that the vast majority of our type 1 patients need glargine twice-a-day. Type 2s do fine with Lantus once-a-day. Echoing Dr. Seaquist, we know that insulin degludec – and for that matter, glargine U300 (Sanofi’s Toujeo) – also pretty much takes care of the problem.

4. Dr. Hirsch Offers Clinical Pearls on How to Best Use Human Insulin in Type 1 Diabetes: “We Don’t Like Using It … But Sometimes We Have To”

Conference chair Dr. Irl Hirsch offered clinical pearls on insulin therapy, interestingly focusing on the use of human and NPH insulin for type 1 – clarifying that, “we don’t like using it in type 1 diabetes – I don’t like using it in type 2 – but sometimes we have to.” Dr. Hirsch began by outlining the circumstances that led to this talk: he said that a devasting number of patients cannot afford their insulin (~20% of his patients drive to Canada to buy insulin, and he said that one in four intentionally rations insulin because of cost), but programs don’t educate upcoming physicians on how to use cheaper alternatives – only about half of the fellows in the room said their programs had formal training on NPH insulin. He opened the conversation with the case of a 45 year old man who had Humalog and a few leftover CGMs on hand but also had a $4,000 deductible and couldn’t afford Lantus – so he used NPH instead, achieving an A1c of 6.9% with very little hypoglycemia. Said Dr. Hirsch, “NPH isn’t bad if you know how to use it,” referencing the need to understand the drug’s peak and to be very proactive about hypoglycemia, while also decrying the fact that so many patients are able to access state of the art technology more easily than drugs developed decades ago. Without further ado, Dr. Hirsch offered his clinical pearls for human insulin (regular and NPH) use in type 1 diabetes:

  • Location of injection is important. From fastest to slowest absorption, injection areas go abdomen > arms > thigh > buttocks; regular insulin is best in the abdomen as fast absorption is desired, while NPH needs to be given in the same location consistently and thigh or buttocks is best.

  • NPH needs to be mixed well. It’s in suspension, so failing to mix means getting far more or less insulin than desired. Dr. Hirsch emphasizes this at every visit for those on NPH.

  • When using regular insulin as prandial insulin, “lag time” is tremendously important – dosing 20-30 minutes premeal is necessary to prevent large postprandial spikes. Dr. Hirsch also emphasized the importance of dosing analog insulin sufficiently pre-meal. Conversely, snacking is often necessary (particularly at bedtime) to prevent nocturnal hypoglycemia with the former.

  • Use CGM to assist if possible! Occasional, personal, or professional CGM can all help improve success (and safety) with human insulin.

  • To minimize risk of hypoglycemia, increasing glycemic targets may be advisable; consistent timing and size of meals is also helpful with regular and NPH insulin. This is the real crux of the issue with non-analog insulin, in our view: There’s no doubt that regular and NPH insulin lower glucose, but can they minimize variability and hypoglycemia as well as analogs? Surely, it’s the HCP’s and patient’s prerogative to balance the risks and benefits (i.e., cost savings), but it’s hard not to be upset by affordability driving patients to a less desirable treatment option.

5. Dr. Carla Greenbaum: “If This Disease Were Discovered Today, Would We Be Satisfied with Our Current State of Care?”

Dr. Carla Greenbaum framed the need for disease modifying therapies in type 1 treatment, urging the room to not be complacent and comfortable with current standards of care. She noted that “we are missing some of the big picture of type 1 treatment with all of our tools in terms of treating hypoglycemia and hyperglycemia” and wondered “if this disease were discovered today, would we be satisfied with our current state of care?” Continuing on: “if you were looking at this disease today and said to a patient ‘you’ll probably have a 10-year loss of life,’ you would probably think we need to do a lot better in terms of treatment.” On this front, Dr. Greenbaum listed the several reasons that disease modifying therapies are needed in this space: significant hyperglycemia and hypoglycemia are still common, life expectancy and complication rates remain at a level that (while improved) are still unacceptable, and the day-to-day emotional burden of the disease is still significant.

  • Dr. Greenbaum stressed that immunotherapy does work in changing the disease course of type 1 diabetes – just like in other autoimmune diseases. Dr. Greenbaum explained that five different studies have now shown the effectiveness of various immunotherapies in preserving insulin secretion in type 1 patients, and she stressed that these treatments truly change the course of disease when administered. Notably, they all act on different spots in the immune system, but all share a commonality in targeting the adaptive immune system (rather than the innate immune system). As a result, these findings have furthered the idea that the adaptive immune system is an important component of what type 1 diabetes progression and a driving factor in beta cell destruction. Closing off this section of her talk, Dr. Greenbaum asserted that “there’s no debate” that type 1 patients do better when they preserve more insulin secretion; on this front, immunotherapies may yield important advances in helping to preserve this function and should be adequately considered by endocrinologists when treating the type 1 population.   

6. Dr. Michael Riddell on Life as a Researcher and Recreational Trekker with Type 1 Diabetes; Advocates for SGLT in Type 1 Use; VO2 Max as a Better Marker for Diabetes Management than A1c?

Dr. Michael Riddell – who Dr. Irl Hirsch deemed the “world expert on exercise, glucose metabolism, and type 1 diabetes” – gave a fascinating keynote address detailing his life experiences with type 1 diabetes, which includes his work as a researcher, as a patient, and as a father to a son with type 1. Dr. Riddell recounted how he started down his path as a researcher, spurred by a diagnosis of type 1 diabetes at a young age and coupled with a love of physical activity (specifically basketball). His talk was very well received from the room and was filled with several important insights:

  • Dr. Riddell notably said that he “thinks an SGLT inhibitor really, really helps people with type 1 diabetes.” He explained his three pillars of type 1 management (at least until a cure is found): (i) intensive insulin therapy with CGM; (ii) a healthy diet, meaning a reasonable carb diet (not exactly a keto diet); and (iii) regular exercise. On point number two, he added in that an SGLT inhibitor along with proper diet can help with glucose control for patients. Dr. Riddell disclosed that he was a study participant in the EASE program for empagliflozin in type 1 diabetes and enjoyed his experience taking empagliflozin as a type 1 patient – and continues to do so. Of course, he noted that SGLT inhibitors are “not a risk-free drug” and that ketone surveillance is necessary for its proper application in this population.

    • Q: Dr. Hirsch: I have a question on SGLT-2 inhibitors and exercise. We know about the paradoxical effect on glucagon, and we know that exercise leads to higher betahydroxybutyrate levels, which are actually better used for energy in the myocardium, muscle, and brain. For pump patients turning down their insulin, they might get very high levels of BHB, which can be potentially very dangerous. I haven’t seen data on exercise and SGLT-2 inhibitors in C-peptide negative patients, unless I’ve missed it. I could see some really interesting physiology arising there.

    • A: Dr. Riddell: We actually have tried to get some funding on this but now we have a little side funding from a Canadian granting agency (CIHR/JDRF). We are trying to do this study in adolescents with type 1 diabetes who will be doing some lab-based exercise on either a placebo or on the SGLT-2 inhibitor. We have done some rat studies as well. The rats are pretty hypoinsulinemic when they exercise on an SGLT-2 inhibitor. But, they seem to be doing fine. However, when they stop exercising, ketones build up. The thing is, when you physically move, you’re oxidizing the ketone very efficiently in the muscle. When you stop, if you don’t get insulin levels up, it can become a problem.

    Dr. Riddell touted the utility of using VO2 max as a long-term marker of health. He presented data indicating how VO2 max (maximal oxygen uptake) can predict long-term outcomes better than almost any other metric. In a Q&A following Dr. Riddell’s talk, Dr. Hirsh expressed considerable enthusiasm over the use of VO2 in diabetes management, commenting that “I’m almost thinking now that VO2 max may be a better long-term predictor of outcomes than A1c.” Dr. Riddell noted that research is still being done in the space and that the mechanisms of how VO2 max may be associated with long term outcomes is still unknown. More interestingly, VO2 max as a predictor of long term outcomes appears to be independent of A1c levels. We would love to see further analysis on how VO2 max in people with diabetes may correlate with long term complications (both microvascular and macrovascular) along with mortality.

Quotable Quotes

  • “We all have handicaps – it’s what you do with your handicap that matters.”

  • “We have to believe in our patients. They too can make their dreams come true, if they have some semblance of control of their diabetes.”

  • “For those of you trying to publish, you have to be able to take rejection. Stand up tall to rejection, and don’t take no for an answer.”

  • “If you surround yourself with friends with type 1 who are motivated, that lifts you up.”

  • “Exercise will make us live longer, even if it doesn’t necessarily improve our A1c’s.”

7. Dr. Robert and Mrs. Margaret Eckel Reflect on Decades of Living and Raising Kids with T1D

Dr. Robert Eckel and his wife Margaret Eckel, in conversation with Dr. Irl Hirsch, offered stories and perspectives on what it’s like to live with and raise children with type 1 diabetes. This is always an enormously insightful and often entertaining part of Endo Fellows – read on below for the most quotable quotes from the session.

  • “Barbara Davis Center is just a wonderful facility – they really educate these parents. When children are diagnosed with type 1 diabetes, the parents are terrified. The kids don’t know, but their parents are over-the-top terrified. They’re almost in tears waiting for their appointment, and the child just knows something terrible has happened and ‘I’m the problem.’ We’d sit there and I’d talk to the parents and tell them, you can do this, this is a great facility.” – Margaret Eckel

  • “Dr. Hirsch deserves a tremendous amount of credit for the insulin pricing issue: He presented to the ADA Board a few years ago, and there was a lot of disagreement about what the ADA’s role should be but the momentum changed very quickly.” – Bob Eckel

  • “I was in Paris for a meeting at Christmas…and both my boys are struggling to pay for their insulin. So in Paris one Sunday, I found one of the pharmacies that was open and was able to communicate that I wanted to buy all the insulin she had. I purchased $385 American dollars’ worth of insulin; when I got back and priced it out, it was over $5,000 of insulin. Each of my boys got $200 of insulin for Christmas, but it was worth almost $5,000 here.” – Bob Eckel

    • “I was in Spain in April of last year and found out a box of Tresiba, if you’re a Spanish citizen, was €5 – here it’s over $500. You can’t make this stuff up.” – Irl Hirsch

  • “Diabetes is not a disease, it’s a life. From the beginning of life, my only recollection is having diabetes. I was five at diagnosis. I feel fortunate to be alive. Nearly 70% of those diagnosed in the 1950s are dead now.” – Bob Eckel

  • “Forty percent of my life was without any glucose monitoring. All we had was urine testing. The way we did this test, I can’t imagine the FDA ever approving that testing method today. We have to keep in mind the crudeness of urine testing to monitor glycemic control.” – Bob Eckel

  • “I remember thinking that I had to get life insurance when I was younger, because I didn’t think I was going to live that long. I’m alive because of the science that’s delved into diabetes pathophysiology and treatment.” – Bob Eckel

  • “I’m on my third pump now – just changed to the Tandem t:slimX2. I love the software on the pump. One thing I think can be improved is that I have numbness in my fingertips, which makes dealing with the clips and tubing hard for me. I can rarely do this by myself, and Margaret has to help me. Otherwise, I love the pump, and I love the programming on it.” – Bob Eckel

    • “They are not making these systems for people our age. You have to remember that 70% of people with type 1 his [Dr. Eckel’s] age are dead. They are making these systems for young people who haven’t lost feeling in their fingers.” – Margaret Eckel

  • “What’s the future going to be like? It’s going to be different. In terms of cures, it ain’t around the corner. A cure for type 1 is currently unrealistic. It’s wonderful that we want to do this, but the reality is that it’s not in the near future. I think in terms of the future, everyone has to be on closed loop. Islet transplantation is also appealing.” – Bob Eckel

Technology Highlights

1. Dr. Irl Hirsch on The Latest Consensus for Time-In-Range; Personal Recommendation of CV <33 mg/dl; “Tweaking” the 670G

University of Washington’s Dr. Irl Hirsch underscored the latest recommendations for time-in-range outcomes. Referencing the recent international consensus meeting on time-in-range in Berlin, Dr. Hirsch detailed nuances such as a recommended adjusted target range of 63-140 mg/dl for pregnant women with diabetes. He also explained that the goal for patients is to reach <4% time <70 mg/dl, amounting to just under an hour spent daily in hypoglycemia. While he acknowledged that this is “still too much,” he believes it is “as good as we can do with the current technology,” pointing to patients currently on the Medtronic MiniMed 670G achieving similar outcomes. According to Dr. Hirsch, “most patients playing mostly by the rules” on the 670G can get to 4% time <70 mg/dl. Dr. Hirsch’s goal for his own patients is to get them to an average blood glucose of 140 mg/dl. Any lower than this threshold, he believes, requires “a lot of fake carbs.” Dr. Hirsch was careful not to express any official perspective on the practice of fake carbs – last year at Endo Fellows, he admitted to having reservations to the practice of falsely adding carbs to the bolus calculator to artificially make the 670G more aggressive, though he recognized that many patients are doing it anyway. The closest Dr. Hirsch came to straying into more contentious territory was when he estimated that the patients “doing the best” override or underride the 670G about 15%-20% of the time. As he explained, the bolus calculator is unaware of glucose trends, exercise, and other factors such as menstruation. The lowdown? “The most sophisticated patients are always tweaking.” We imagine this presentation is going to change a lot once Tandem’s Control-IQ comes to market later this year.

  • Although Dr. Hirsch noted that consensus regarding coefficient of variation (CV) has not yet been reached, his personal recommendation is a CV <33 mg/dl. He explained that this threshold will drive a time <70 mg/dl of 3.5%, which was achieved in the 670G pivotal trial. As a reminder, key takeaways from the consensus meeting include a time-in-range target of ≥70% (range: 70-180 mg/dl) and a time below range target of <4% time below 70 mg/dl and <1% time below 54 mg/dl for people with diabetes. Note that the recommendations have not yet been finalized. The writing committee aims to to refine and publish before ADA in June. See our report for more detail.

  • In discussing the impetus to move away from A1c as an indicator of an individual’s glycemic control, Dr. Hirsch reiterated his previous estimate that in a “typical diabetes practice” ~14%-25% of A1c measurements are misleading. He emphasized that each A1c comprises a wide mean glucose range, and that for this reason it should not be used as a metric by which to compare two people. However, he maintained that this “does not take away” from the use of A1c as an outcome in clinical trials. Dr. Hirsch explained that “we’ve been so focused on A1c that we’ve sort of forgot who the enemy is here ­– glucose.” To this end, Dr. Hirsch detailed the rebranded Glucose Management Indicator (GMI), which will replace the term estimated A1c. Currently, GMI is only provided on the Tidepool download, but Dr. Hirsch expects it to be a part of “every download” next year. For now, physicians can go to the Jaeb site to enter a patient’s mean glucose (ideally 14 days, but 10 days is acceptable) and generate the patient’s GMI.

2. Dr. Sherr’s Tips and Tricks for Optimizing MDI; Four Benefits of Smart Pens: Accuracy, Tracking, Shared Decision Making, Affordability

Yale’s Dr. Jennifer Sherr offered practical advice on how to optimize MDI therapy in type 1, assuming the goal is to approximate physiologic insulin action as closely as possible. In reality, Dr. Sherr explained, every patient’s personal goal for their diabetes care regimen will be slightly different – reach target A1c, increase time-in-range, reduce hypoglycemia, enhance quality of life, minimize daily diabetes burden, prevent DKA (a more common goal in pediatric T1D management), etc. However, since the best-case scenario for people with type 1 diabetes would be healthy, functioning beta cells, physiologic insulin action is a logical target. While Dr. Sherr suggested that this goal is more likely to be achieved with pump therapy, which is why ~80% of her patients are on insulin pumps, she assured that when implemented carefully and creatively, a basal-bolus regimen can come close. To this end, Dr. Sherr shared several insights for clinicians to keep in mind, including: (i) Young children tend to snack between meals, which therefore should be accounted for in dosing prandial insulin; and (ii) Adolescents are more likely to skip breakfast and eat a large after-school, pre-dinner snack, which should be a key consideration in developing an overall insulin schedule.

 

  • For patients who can afford it, Dr. Sherr recommended smart insulin pens, listing four benefits: (i) greater dosing accuracy (“before dose calculators, things ended in 3, 5, or 0 for me, and it’s nice to have more precision so we can actually put into practice all the clinical advice we’re learning”); (ii) high-quality tracking enabling HCPs to observe insulin dosing between visits; (iii) data sharing to facilitate shared decision-making between patient and provider; and (iv) lower cost compared to insulin pumps. We’re certainly excited about the smart pen competitive landscape. Companion Medical’s InPen was first-to-market with a US launch in December 2017, and as of JPM early this year, the product had nearly 2,000 users paying a median co-pay of only $50 annually. Right around the corner is Novo Nordisk’s NovoPen 6 (which has been piloting in Sweden), Echo Plus, and reusable Bluetooth pen attachment for FlexTouch; the first two are CE-marked and should be available any day now in Europe, while the latter is slated for a launch later this year. Lilly has also stated that it will submit its smart pen to FDA in 2019. We learned at JPM that Companion will pursue a clinical trial comparing the InPen vs. traditional MDI using Abbott’s FreeStyle Libre, which could bring valuable data further supporting Dr. Sherr’s endorsement of smart pens to optimize MDI.
  • Although not mentioned in Dr. Sherr’s discussion, there are insulin therapies in development that attempt to more closely resemble physiologic insulin delivery (see our insulin competitive landscape here). Diasome has a liver-targeted formulation of rapid-acting insulin lispro (Lilly’s Humalog) in phase 2 (ISLE-1 wrapped up in June 2018 according to ClinicalTrials.gov), and more than 50% of endogenous insulin is typically cleared by the liver. We’ll be curious to see if molecular innovation can push the field closer to optimal MDI therapy as Dr. Sherr defined it – mimicking physiologic insulin action.

3. Any Patient Treated by Intensive Insulin Therapy as The “Ideal Candidate for CGM;” CMS Guidelines for Obtaining Pumps: “So Specific It’s Ridiculous”

In a series of very practical sessions, Washington University in St. Louis’s Dr. Janet McGill and John Muir Health’s Dr. Luisa Duran described the pumps and CGMs on the market, as well as detailed best practices for implementing these technologies into daily practice. On the CGM side, we were pleased to hear Dr. Duran unequivocally state that the “ideal candidate for CGM” is any patient treated by intensive insulin therapy (later during Q&A, Dr. Hirsch pushed the audience to consider CGM for all patients with diabetes, regardless of insulin therapy). Not surprisingly, Dr. Duran emphasized education as “paramount for success with CGM.” Dr. McGill emphasized that physicians no longer assist their patients with choosing an individual pump, but rather a complete diabetes management system – a good point on HCP complexity as technology gets more nuanced. The CGMs that a patient can use with a particular pump, plus the available data downloads, can obviously play a huge role in pump choice – and provide another rationale for interoperable pumps and CGMs that can be mixed and matched. Dr. McGill noted that systems like Tandem’s t:slim X2 Basal-IQ with Dexcom’s G6, which utilize devices from different companies, can be “very confusing” for patients. (Presumably she means for reordering and insurance hassles, as Basal-IQ gets excellent reviews for simplicity – and Net Promotor Score, per dQ&A – relative to the 670G.) Echoing Dr. Duran, Dr. McGill underscored the need for repeated education to set patients up for success with pumps, suggesting that older patients especially will require more sessions to reach competency.

  • Dr. McGill reviewed the highly detailed CMS guidelines for obtaining a pump for Medicare patients. She was careful to note that the stipulation added in April 2018, which called for proof of four fingersticks per day for two months or use of a CMS-approved CGM for two months. As she put it, the requirements are “so specific it’s ridiculous.”

  • Reflecting the complex nature of the field, both Dr. McGill and Dr. Duran made a few inaccurate statements. One of Dr. McGill’s slides incorrectly characterized Roche’s Accu-Chek Solo patch pump as FDA cleared – last we heard at ATTD, the pump is CE Marked and undergoing a limited launch in Europe, but has only just entered into pre-submission with the FDA. It’s remotely possible that FDA clearance was just received and Roche is remaining quiet, though that seems unlikely and there is nothing in the 510(k) database. On another smaller note, Dr. Duran referenced the contraindication for MRI use as a downside to Senseonics’ 90-day Eversense. However, Senseonics actually received an FDA indication for MRI use earlier this year, making the Eversense the only FDA-approved, MRI-safe sensor. The pace and scope of the tech field is enormous and only getting bigger – how can we make it easier for physicians to keep their patients informed?

 

-- by Ann Carracher, Martin Kurian, Payal Marathe, Maeve Serino, Adam Brown, and Kelly Close