Keystone 2014 – Practical Ways to Achieve Targets in Diabetes Care

July 17-20, 2014; Keystone, CO – Day #2 Highlights – Draft

Executive Highlights

The second day of the Barbara Davis Center’s 2014 Practical Ways to Achieve Targets in Diabetes Care was filled with animated discussion, as attendees and speakers expressed frustration about certain aspects of the healthcare system while remaining optimistic about the new therapies of the future. The day’s plenary topics were varied and included discussion of the artificial pancreas, immune and cell-based therapies for type 1 diabetes, and a grab-bag of miscellaneous controversies. Our report contains the following ten highlights from the day, followed by detailed discussion and commentary.

1. Dr. Irl Hirsch (University of Washington, Seattle, WA) stirred up attendees by sharing numbers and frank opinions on the rising costs of managing type 1 diabetes in the US.

2. Dr. Hirsch’s frustration over costs spilled over into a highly energized panel discussion, in which he speculated that the coming wave of biosimilars might be driving the rapid increases in insulin costs.

3. Dr. Ed Damiano (Boston University, Boston, MA) outlined tentative plans for four new bionic pancreas studies in 2015, including a chronic glucagon exposure study, that will lay the groundwork for pivotal trials in 2016.

4. Dr. Kenneth Ward (OHSU, Portland, OR) expressed excitement about a new curcumic-ferulic acid glucagon formulation that has demonstrated stability for at least seven days (originally presented at ADA 2014).

5. Dr. Jay Skyler (University of Miami, Miami, FL) suggested that the FDA’s current regulatory paradigm might be incompatible with the need for combination therapies to slow or reverse the progression of type 1 diabetes.

6. Dr. Matthew Riddle (OHSU, Portland, OR) explained that the highest risk of cardiovascular death following severe hypoglycemia is likely in patients with intermittent adherence, rather than those with consistently poor adherence – he also dived deep into the results from ACCORD.

7. The “Meet the Peers” session for adult providers touched upon hot topics such as obesity medications, the challenges posed by single-source formularies, and low-cost test strips.

8. Attendees jointly voiced frustration over the lack of Medicare coverage for CGM during the Meet the Peers session for adult diabetes educators – said one attendee, “We all feel like we’re screaming at the wall.”

9. Pediatric providers engaged in a heated debate over the revised ADA A1c target of 7.5% for all pediatric type 1 diabetes patients – the room was split between those who were satisfied with the change, and those who felt that it might hamper individualization of therapy.

10) Later in the same session, attendees observed that they frequently run into legal obstacles when trying to use social media or mobile devices to reach patients.

Top Ten Highlights

1. In a presentation on more affordable ways to treat type 1 diabetes, Dr. Irl Hirsch (University of Washington, Seattle, WA) expressed frustration with the rising costs of insulin, which have restricted access among some of his uninsured patients – “This does really need to become a national outcry.” The high and rapidly rising costs of insulin, he suggested, make the investment in insulin analogs on the part of payers a much less attractive proposition – he estimated the yearly cash cost of insulin analogs at ~$5,000 per year (~$417 per month). To help clinicians in the audience, the vast majority of whom seemed quite sympathetic to his points, Dr. Hirsch listed several tips on how to help patients manage type 1 diabetes in a more affordable manner. He strongly recommended some ideas, including purchasing strips from Amazon, while others (including the use of CGM sensors or pen needles for longer than recommended or reducing the frequency of SMBG) were advisable only in more extreme circumstances. To conclude, he predicted that if insulin remains unaffordable, it is only a matter of time before the government must intervene. More detail is below.

2. The discussion (and frustration) about the cost of insulin spilled over into the subsequent panel discussion. Dr. Hirsch suggested that approaching patent expirations and the launch of biosimilars might be contributing to the rapid rise in insulin analog prices. (We would also add that the rising cost of developing drugs, mostly due to the FDA’s CVOT requirement, has likely played a role in higher pricing as well.) He shared news of a rumor about a possible upcoming letter to The New York Times on the issue from a set of former ADA presidents. Conference chair Dr. Satish Garg (Barbara Davis Center, Aurora, CO) suggested that 1,000 units of insulin can be produced for next to nothing, while Dr. Philip Home (Newcastle University, Newcastle upon Tyne, UK) emphasized that nothing will change if nobody finds a way to apply the right pressure. There was certainly understanding of the nuances of this debate – the following day, an audience member pointed out that companies are the ones that sponsor research and scientific meetings like Keystone. Still, it was rather striking to see the level of frustration that emerged during this session. The panel discussion is enclosed below.

3. In his presentation on the progress of the bihormonal bionic pancreas, Dr. Ed Damiano (Boston University, Boston, MA) announced plans for four new studies planned for 2015: (i) a chronic glucagon exposure study; (ii) a study testing different glycemic set points; (iii) an alcohol tolerance clamp study; and (iv) an additional pediatric camp study next summer. The studies are currently unfunded, but given Dr. Damiano’s drive and the significant level of interest in the group’s recent NEJM publication, we imagine it will materialize over time. As a reminder from our CWD FFL coverage earlier this month, Dr. Damiano’s team is currently seeking to raise ~$5 million to build the final integrated bionic pancreas device by September  1 – the fundraising time crunch to build the pivotal device stems from federal funding opportunities over the next nine months – this could support all of the clinical costs of the pivotal study, but for the reviewers to take it seriously, the final pivotal study device will need to be completely built by then. The team’s timeline calls for the final pivotal study to happen throughout 2016 (n=100s, several months) assuming the device is ready (lots still has to happen on this front), and the team would, if all goes right, submit the PMA to the FDA in 1H17. More commentary is below.

4. Dr. Kenneth Ward (Oregon Health & Science University, Portland, OR) provided an overview of both the promise and the challenges of using glucagon in closed loop systems – two possible obstacles include diminishing glucagon efficacy at high plasma insulin levels and the depletion of liver glycogen. While data from his research group appears to indicate that glucagon does start to lose its effectiveness when plasma insulin concentrations rise above 40 μU/mL, the depletion of liver glycogen is unlikely in type 1 patients who are eating normally. (We imagine both of these concerns could be addressed with smart labeling, should such a device be approved.) Dr. Ward also covered a number of options for developing a stable liquid glucagon formulations, noting that a novel curcumin-ferulic acid formulation that his group is working on is currently his favorite candidate to date, as it has been shown to prevent fibrillation for seven days while maintaining a consistent pharmacodynamic profile – data was first shared on this at ADA 2014. He also shared that a company he is affiliated with, Pacific Diabetes Technologies, is developing a combined sensor and infusion set that would involve only one skin penetration – preclinical data on this project was also shared at ADA in late-breaking poster 69-LB. Further details are included below.

5. Dr. Jay Skyler (University of Miami, Miami, FL) stressed the need to “think out of the box” when designing regulatory paradigms for novel type 1 diabetes cell-based therapies. From the current regulatory standpoint, pursuing a combination of two compounds is difficult unless each component has demonstrated an effect as monotherapy. The growing consensus, however, is that a combination of therapies will be needed to effectively slow or reverse the progression of type 1 diabetes, and that in some cases a combination of two agents may demonstrate efficacy where each component cannot (for example, ATG and GCSF were both ineffective on their own but have shown promise as a combination in clinical trials to date). Dr. Skyler acknowledged that sweeping changes to regulatory paradigms will not come easily, as current regulatory agencies are “pretty rigid,” but expressed hope that “regulators can undergo education,” a hope we certainly share.

6. Dr. Matthew Riddle (Oregon Health & Science University, Portland, OR) concluded his in-depth analysis of the ACCORD results with a hypothesis regarding the connection between severe hypoglycemia and cardiovascular death. One current theory is that cardiovascular death following severe hypoglycemia is mediated by catecholamine secretion and resultant arrhythmias. If true, then non-severe hypoglycemia might actually be protective in a sense (at least with regards to later CV death due to severe hypoglycemia), as it blunts the catecholamine response. Dr. Riddle suggested that it is isolated events of severe hypoglycemia that provoke the maximal catecholamine response, and therefore that the individuals at the highest risk are not those with consistently excellent or poor control, but rather those with intermittent adherence to treatment – another clear reminder that adherence remains one of the most critical problems to solve in diabetes care. We continue to wonder who is doing the most exciting next-gen thinking on adherence, as improvements stand to benefit all stakeholders in diabetes (patients, payers, industry, government, etc.). That said, these trials are very hard to design and execute. We share more on this talk below.

7. The day ended with a series of Meet the Peers discussion sessions – the adult provider session covered a number of hot topics, including payer-mandated insulin switching, low-cost test strips, GLP-1 agonists in type 1 diabetes, and obesity medications. Regarding payers’ assumptions that insulins are interchangeable, conference chair Dr. Satish Garg (Barbara Davis Center, Aurora, CO) noted that basal insulin analogs (such as Sanofi’s Lantus and Novo Nordisk’s Levemir) cannot always be dosed equivalently, and that forced switches are a waste of valuable provider time. We assume it is quite challenging for payers to weigh that negative against the savings of single-source supply on a more macroscale. While the ramifications may not be immediately apparent, we have little doubt that single-source drug suppliers will only increase in the coming years. Meanwhile, Dr. Irl Hirsch suggested that the low-cost Nipro TrueTrack and TrueTest strips are to be avoided – he prefers the Agamatrix Presto brand. The Meet the Peers sessions are summarized below.

8. The adult diabetes educator Meet the Peers session covered the urgent need for Medicare to reimburse CGM. Educator after educator recounted stories of elderly patients who found diabetes incredibly difficult to manage without CGM – the frustration was palpable in the room as attendees described repeated futile attempts to persuade Medicare of the necessity of changing this policy. Several potential avenues were suggested, including lobbying efforts by companies like Medtronic and Dexcom (this is ongoing with JDRF, as we understand it), as well as patient letter-writing campaigns. The consensus appeared to be that a huge amount of public pressure, preferably combined with a concrete demonstration of the cost-effectiveness of CGM, will be necessary to obtain coverage.

9. The pediatric providers Meet the Peers session featured a heated discussion regarding the recently revised ADA A1c target of 7.5% for pediatric type 1 diabetes patients. Notably, a poll of the 60-person audience demonstrated that only 50% were satisfied with the new recommendations. The well-respected Dr. Fran Kaufman (Chief Medical Officer, Medtronic Diabetes, Los Angeles, CA), speaking on behalf of those with reservations, stressed that A1c targets often need to be adjusted based on the individual patient. Dr. Tadej Battelino (University Children's Hospital, Ljubljana, Slovenia) took the opposite tack, calling for an even lower target closer to 7.0%.

10. In the same Meet the Peers session, pediatric providers expressed great frustration regarding the legal and reimbursement challenges that have handcuffed their ability to use social media to interact with patients. Although the entire audience (60 persons) felt that social media and telemedicine would improve patient outcomes, only two clinicians were currently using such technology. Multiple clinicians reported running into legal trouble upon attempting to use Facebook and Twitter to distribute information to patients. Audience members also stressed the need for restructured reimbursement policies that recompense more than visits to the clinic – calls for this have only increased in recent years, and we believe it’s only a matter of time until payers realize that remote e-visits are more efficient, equally effective, and likely meaningfully cost-saving.

Detailed Discussion & Commentary

Plenary: Diabetes Management Issues

How to Well Manage T1DM in the Cheapest Way Possible?

Irl Hirsch, MD (University of Washington, Seattle, WA)

Dr. Irl Hirsch opened a provocative talk on the skyrocketing cost of insulin by warning anyone in the audience from an insulin company to “stand back!” The numbers as he presented them were stark – the cost of a vial of Lantus (insulin glargine) has increased 243% over the past nine years and 84% over the past two. The majority of attendees responded with an emphatic “yes” when asked if they were aware of the rising cost of insulin. Much of the presentation was devoted to a set of tips to help clinicians safely reduce costs for their patients. The list included buying test strips from Amazon (most attendees were not aware that this was possible) to using Goodrx.com to look for the best prices in your zip code. Though Dr. Hirsch praised the impact of insulin analogs (“the single biggest advance in type 1 diabetes in the 1990s”) on reducing hypoglycemia, he was blunt about the mindset of payers, who might not feel sufficient pressure to invest in better insulins to reduce hypoglycemia when the cost of those products is so high (almost $5,000 per year per patient by Dr. Hirsch’s back of the envelope calculation). He predicted that if insulin remains unaffordable to this extent, it is “only a matter of time” before government will intervene, and he suggested that an act of Congress might be the only realistic way to bring prices down. Dr. Hirsch’s presentation fell upon very receptive ears, and it stimulated an energetic discussion during the subsequent panel discussion (see below). 

  • Over the past seven years, the cost of insulin products has increased from 84%-547% compared to an overall inflation rate of 11%-15%. Dr. Hirsch said that “these numbers are difficult to really appreciate unless you’re buying them yourself,” but there was no lack of appreciation among the audience members, as demonstrated through a show of hands. He did not speculate in detail about industry’s reasons for elevating prices, but he did suggest that the approaching wave of biosimilars might be a cause. We would also assume the rising cost of developing diabetes drugs – particularly the requirement for CVOTs following 2008 – has contributed as well.
  • Dr. Hirsch shared a few compelling patient examples to illustrate the real life consequences of skyrocketing insulin costs. Dr. Hirsch told the story of a patient who faced an amputation of her dominant arm due to cancer that made operating a syringe impossible; she was unable to convince Medicaid to cover the cost of an insulin pen. Dr. Hirsch also mentioned that several of his patients use regular insulin or a mixture of regular and analog insulin in their pumps due to rising copays for analogs. He described an insurance company that would only dispense a new vial of insulin within 48 hours of the end of the previous vial, even if the patient would be traveling; almost 100% of the audience raised their hands when asked if they had encountered a similar experience.
  • Dr. Hirsch suggested several “workarounds” that HCPs can use to reduce costs for their patients. He encouraged providers to shop around for the best prices on insulin and other equipment – insulin at Walmart and Costco is significantly cheaper than elsewhere, and it is possible to order test strips on Amazon.com (only 25% of the audience was aware of that). Alongside his recommended strategies, he listed some cost-saving tactics that should be avoided, like using infusion sets for longer than recommended or reducing the frequency of blood glucose testing.
    • Dr. Hirsch provided a list of “OK places to try to save money”– use of CGM sensors past their label date, repeated use of pen needles, syringe needles, and lancets, reducing physician visits as much as possible, use of NPH insulin for obese and insulin resistant patients, and a reduction in the frequency of certain tests (retinal exams and albumin-creatinine ratio labs). He made it clear that he did not necessarily support the strategies in this list, but that the extremes of patients’ inability to pay might merit their consideration.
  • Dr. Hirsch presented some back of the envelope calculations to explain why payers might not currently be incentivized to invest in insulin analogs. He suggested that it may simply be more expensive to cover insulin analogs (cost differential of ~$4,920 per patient per year compared to human insulin) than to pay for the increase in emergency room visits for hypoglycemia (~$102 per patient per year). In Dr. Hirsch’s view, government intervention is inevitable if insulin remains unaffordable for many patients.
    • We would note that the data on the costs of hypoglycemia is quite variable, and that many estimates would place the per-episode cost of hypoglycemia hospitalization much higher than the value Dr. Hirsch used ($1,186 per visit) – as an extreme example, a study presented at last year’s ADA estimated the cost at over $46,000 per hospitalization, while Quilliam et al., AJMC 2011 estimated it at ~$17,654. For more on this topic, see our coverage of a JAMA Internal Medicine’s paper on hypoglycemia-related emergency department visits.

Explanation for the ACCORD Outcomes?

Matthew Riddle, MD (Oregon Health & Science University, Portland, OR)

Dr. Matthew Riddle explored different explanations for the cardiovascular death signal that led to the termination of the ACCORD study, ultimately proposing a unifying hypothesis regarding hypoglycemia and CVD. Dr. Riddle spent a majority of the presentation exploring the complexities of the available data, also touched on by Dr. Mark Feinglos (Duke University, Durham, NC) at this year’s ADA. The evidence suggests that CVD risk is associated with severe hypoglycemia, but the association may not be causative. Although it is hard to make specific conclusions on the results of ACCORD (follow-up analyses are still ongoing), Dr. Riddle did put forth a more general hypothesis on the connection between hypoglycemia and CV death. Evidence suggests that CV events following severe hypoglycemia are mediated by catecholamine secretion and resultant arrhythmias. An isolated severe event provokes maximal response to catecholamines, while prior mild hypoglycemia is protective since these events blunt the catecholamine response. If true, postulated Dr. Riddle, the greatest risk of CVD is in those with intermittent adherence to treatment, who experience isolated severe hypoglycemic events following prolonged periods of hyperglycemia.

  • Explanations for the safety signal observed in ACCORD include the high-risk population, the rapid reductions in A1c, and the increase in severe hypoglycemia seen with intensive treatment. Dr. Riddle demonstrated support for the vulnerable, high-risk population hypothesis, but data does not support the rapid-A1c-lowering hypothesis – the opposite is actually true, as risk was highest for those that saw little reduction in A1c.
  • Dr. Riddle presented on the various benefits and risks seen in ACCORD, pointing out that the study population consisted of people at very high risk for CVD. Some benefits included reduction of non-fatal myocardial infarction, albuminuria, retinopathy, and decline of brain volume. However, he highlighted that CVD developed over time, with the increased all-cause mortality seen at 3.4 years leading to the trial’s cessation.
  • Dr. Riddle presented evidence suggesting that the high-risk population contributed to the mortality signal. A subgroup analysis (Calles-Escandon et al, Diabetes Care 2010) showed an association between the high baseline A1c characteristics and complications.
  • Discussing severe hypoglycemia as a possible factor mediating the connection between intensive therapy in ACCORD and an increase in all-cause mortality, Dr. Riddle discussed the somewhat contradictory results from the trial. For example, although the intensive arm had more hypoglycemic events, the association between hypoglycemia and death was much stronger in the standard arm compared to the intensive arm (which was also seen in ORIGIN). Furthermore, mortality risk and severe hypoglycemia were both greater at higher A1c levels. Non-severe hypoglycemic events also showed to be a somewhat protective factor against mortality.

Panel Discussion

Q: Dr. Hirsch, has anyone ever given you an explanation for the dramatic cost of increase for insulin analogs?

Dr. Irl Hirsch: The short answer is no. The usual response is R&D and so forth. I personally don’t think it’s a coincidence that biosimilars are around the corner. Looking at the real reasons, when looking at inflation and looking at the bigger denominator in type 1 and 2 diabetes using insulin, this brings up that we know that it’s $10 a vial in India. I don’t have a good explanation. To be fair to insulin companies, almost every person I’ve talked to, they’re on our side. Many of them are physicians or patients themselves, so they understand it.

Q: Are any of the professional societies taking this on?

Dr. Hirsch: I have heard a rumor that a letter is going to The New York Times from the former ADA presidents. This does really need to become a national outcry.

Dr. Riddle: This is a distinctively American problem. In other parts of world, there’s less of a differential over time. It’s our problem, and we have to figure out what can possibly be done. It’s not just insulin for type 1, but medications for type 2 as well.

Dr. Hirsch: Don’t get me started on that.

Dr. Riddle: It takes me back to one of my personal rants that we shouldn’t be throwing old well-tested drugs under the bus. NPH, regular insulin, metformin, SFUs, and TZDs look pretty good when you look at price, and you can get good control even in type 1 with NPH and regular insulin.

Dr. Hirsch: I agree, especially with the issue of starting insulin using human insulin. If you look critically at the data for prandial insulin in type 2, there’s not much difference at all. You do see a difference with type 1 but not type 2.

Dr. Philip Home: Think about the components of price. If you take aspart or glargine, the development costs were written off a long time ago. Now companies are only faced with production costs, and those are no different for analogs than for NPH – it’s the same process to produce them. What determines price is what the market will bear, and the market has been prepared to bear it. Screaming is important; pressure has to be applied. It’s not going to change otherwise.

Dr. Satish Garg: What’s the real cost of making insulin?

Dr. Hirsch: I honestly don’t know, but I know you know, so why don’t you tell us?

Dr. Garg: So I recently looked into this. These are actual facts because I’m involved with companies that make insulin. They can make 1,000 units of insulin for 25 cents. Now, let’s give companies the benefit of the doubt. Their cost is probably five times that. That’s why anywhere in the world, it costs $1-4 per vial. By 2018, the market that Irl showed was going to be less than a billion dollars. It was going to swell up to $8 billion just for insulin worldwide. It’s unbelievable numbers.

Q: I have two short questions. For Irl, do you feel that everyone with type 1 should have an unexpired vial of glucagon?

Dr. Hirsch: Let’s first talk about type 2. I do prescribe glucagon if there’s any history of severe hypoglycemia and go through the same stuff with the family. In type 1 patients, everyone gets a vial of glucagon. I don’t know what it costs anymore, but there are huge, huge issues and it’s gone up in price. Decades ago, you could take a kit in when it expired and replace it for no charge. Those days are long gone. It is a significant cost, and we want everyone to obviously have it. Look it up and let us know.

Comment: I looked up the price of glucagon. At pharmacies in this area, it’s $195-$201 with a discount or coupon.

Q: Dr. Riddle, in your review of ACCORD and increased death with intensive treatment, you didn’t go into different medications and increased doses. What are your thoughts on that as a cause?

Dr. Matthew Riddle: I didn’t mention it because we haven’t published analyses. It’s difficult to do analyses of on-treatment drug prescriptive records, let alone what people actually were taking because the database is less secure. There was lots of confounding between arms of the study and in other ways related to physician preferences and strategies and beliefs, so it’s a difficult analysis. That said, there’s no smoking gun in the data we have. For example, it doesn’t look like TZDs frequently cause lots of heart failure. There’s an analysis that was reported as an abstract but not published – a sophisticated analysis, the best we have at the moment – looking at the risks of insulin use. The short version of the conclusion was that there was no relationship between use, dosage, or time of insulin to a difference between outcomes. That was particularly true for basal; it was less secure for prandial, where there might be weak signal but not statistically strong. That’s where we are, it’s hard to know what to make of it, but it’s an important question.

Q: What about just the people who died, there was no difference?

Dr. Riddle: We haven’t done a subgroup analysis of those who died. That’s even more difficult and confounded. It’s the right question; we just don’t have the answer.

Q: Regarding prevalence of hypoglycemia unawareness, you said numbers between 20-25%. I’ve had experience asking people with type 1 if they recognize when they have low blood sugar. And they say, “yeah, I do all the time.” But when I download their data, I sometimes see some real lows like in the 30s. Do you think we are overestimating some peoples’ abilities?

Dr. Home: Yeah, there is a nighttime problem. People also do go down in the daytime. Even you and I, we sometimes go down to surprisingly low levels without noticing it. So it does occur. The phenomenon that you have to watch out for is if you’re unaware, you can destroy your short-term memory. So you end up not even remembering going low. That’s what makes it really hard.

Plenary: Closed Loop Therapy – State of the Art

Bihormonal Bionic Pancreas

Ed Damiano, PhD (Boston University, Boston, MA)

Dr. Ed Damiano presented on the recent progress of his team’s work on the bihormonal bionic pancreas, providing new guidance on plans for the final pre-pivotal studies in 2015. Most notably, Dr. Damiano revealed plans for four 2015 studies under development that will take place before the planned pivotal studies in 2016. These include a chronic glucagon exposure study (which Dr. Damiano stated will likely occupy much of 2015), a bionic pancreas set point study (which he hopes will take place in 1H15), an alcohol tolerance clamp study (which could take place as early as 4Q14), and an additional pediatric study (which will take place in summer of 2015). These studies are not funded at this time, and he and his clinical collaborator, Dr. Steven Russell (Massachusetts General Hospital, Boston, MA) will be seeking funding over the coming months from various foundations to support these studies. The remainder of his presentation was similar to his talk a few weeks ago at CWD/FFL, including a discussion of the Beacon Hill/Summer Camp Studies (covered in detail in our ADA 2014 report and published on June 15, 2014 in NEJM), results from the first two patients in the multicenter study (consistent with Beacon Hill/Summer Camp), and a reminder of the 2014 summer camp study, which began on July 20 – this is a similar study to last year’s summer camp study, but with much less monitoring and much younger participants (ages 6 to 11).

  • Dr. Damiano showed results from the first two participants in the team’s recently started 11-day multicenter home study of the bionic pancreas (n=40 at four centers). The first patient had an average glucose level (over 11 days) of 133 mg/dl with <1% of the time <60 mg/dl. The second patient had similar results – an 11-day average of 132 mg/dl and 0% of the time spent <60 mg/dl. These encouraging results are consistent with those observed in the Beacon Hill and Summer Camp studies.
  • Dr. Damiano did not mention the Bionic Challenge fundraising campaign, first announced at the Children with Diabetes Friends for Life conference earlier this month. The team is currently looking to raise ~$5 million in the next 60 days to fund development of the Bionic Pancreas final pivotal device. The fundraising time crunch to build the pivotal device stems from federal funding opportunities over the next nine months – this could support all of the clinical costs of the pivotal study, but for the reviewers to take it seriously, the final pivotal study device will need to be completely built by then. For more details, see our detailed coverage of Friends for Life 2014.

The Role of Glucagon in Closed Loop Treatment for T1D

Kenneth Ward, MD (Oregon Health & Science University, Portland, OR)

Dr. Kenneth Ward discussed the challenges associated with developing a glucagon formulation that could be used for the closed loop (he touched upon this subject during a broader presentation at last year’s ADA. His presentation sought to address concerns that high circulating insulin levels and the depletion of liver glycogen may be associated with glucagon ineffectiveness. He shared data illustrating that, in fasting persons with type 1 diabetes, glucagon doses lose their effectiveness only when plasma insulin concentrations rise above 40 μU/mL. Encouragingly, the depletion of liver glycogen appears to be unlikely in type 1 diabetes patients who are eating “normally” (we’re not clear how this is being defined, since diets among patients with type 1 vary considerably). Based on these findings, Dr. Ward expressed confidence that glucagon dosing can be administered in a consistent and effective manner. However, he stressed that developing a stable, pumpable glucagon remains the biggest challenge to the practicality of a bi-hormonal system. He presented his group’s findings from animal studies with a novel curcumin-ferulic acid stabilized glucagon formulation – Dr. Ward’s “favorite” formulation to date – that prevents fibrillation for seven days while maintaining a consistent pharmacodynamic profile (data was first shared on this at ADA 2014). In closing, Dr. Ward piqued our curiosity with a hint at “sensing catheter” technology in development at his company, Pacific Diabetes Technologies, Inc., that seeks to combine a sensor and infusion set into a single skin penetration preclinical data on this project was also shared at ADA in late-breaking poster 69-LB.

  • Dr. Ward stressed the tighter glycemic control enabled by a bihormonal system relative to an insulin-only system. He emphasized that present insulin formulations are unable to mimic the rapid pharmacodynamic and pharmacokinetic profile of physiological insulin. Not only does glucagon counteract the effects of insulin, but its more rapid pharmacodynamic profile enables much more accurate dosing. During the panel discussion, Dr. Ed Damiano (Boston University, Boston, MA) unsurprisingly agreed with the bihormonal approach, while Dr. Boris Kovatchev (University of Virginia, Charlottesville, VA) noted that the second compound in a bihormonal system does not necessarily need to be glucagon.  
  • Though glucagon loses its effectiveness at high circulating insulin levels, Dr. Ward asserted that there is a significant range of “optimal” insulin levels within which glucagon maintains its efficacy. His group has carried out studies in which single doses of glucagon were administered to patients (n=10) at steady state insulin levels under fasting conditions. These results have demonstrated that plasma insulin concentrations less than 40 μU/mL tend to maximize glucagon effectiveness, while glucagon is likely to be less effective when insulin concentrations exceed that level. Noting that glucagon should remain effective at even higher insulin concentrations in the postprandial state, Ward expressed confidence that glucagon can be administered in a consistently effective manner.
  • Depletion of liver glycogen is not a concern in type 1 patients who are eating “normally.” Dr. Ward shared unpublished data from his group, in which patients with type 1 diabetes (n=7) were given eight small doses of glucagon (2 ug/kg) in succession under fasting conditions. Even after the eighth dose, patients still seemed to have a good supply of glycogen, and their blood glucose still rose in response to glucagon delivery. This finding is certainly encouraging, but given the potential for inter-individual variability in liver glycogen storage, more data on this front from a larger sample size would certainly be welcome. We also wonder how the results would change in type 1 patients who tend to eat lower carb.
  • Commercially available glucagon is too unstable to be used in pumps, though a number of new formulations (including a curcumin-ferulic acid stabilized formulation) hold promise. Dr. Ward reviewed that when glucagon is in solution, it rapidly forms fibril aggregates. However, the Oregon researchers are experimenting with the combination of the polyphenolic compound, curcumin, and ferulic acid. This formulation has shown much lower levels of fibrillation than regular glucagon at seven days and still demonstrates the same rapid kinetics as fresh glucagon, leading Dr. Ward to label it his “favorite” compound to date.
  • Consolidation of artificial pancreas platforms will represent the next generation of closed-loop technological improvements. Dr. Ward’s company, Pacific Diabetes Technology, Inc., is in the process of combining a sensor and infusion set into a “sensing catheter.” As opposed to options like the Medtronic MiniMed Duo that involve two skin penetrations, Pacific’s “sensing catheter” appears to wrap the sensor element around the infusion set channel for only one single skin penetration. The slide stated that the “sensing catheter” is currently for research only. Preclinical data on this project was also shared at ADA in late-breaking poster 69-LB.

Plenary: Type 1 Diabetes – Immunology and Cell Therapy

Knowledge Gains in Type 1 Diabetes Pathogenesis – New Opportunities for the Next Generation of Disease Biomarkers

Mark Atkinson, PhD (University of Florida, Gainesville, FL)

Dr. Mark Atkinson expressed optimism about the potential of using new biomarkers to more effectively diagnose and treat type 1 diabetes.  He began by acknowledging that type 1 diabetes biomarkers face a significant implementation gap – out of every 100 biomarkers discovered, only a very few make it through clinical validation. He believes that the areas of greatest unmet need are: (i) prediction of who is at highest risk of developing type 1 diabetes, (ii) stratification of patients’ response to treatments (both conventional insulin therapy as well as experimental attempts to reverse the disease), and (iii) more broadly accounting for the heterogeneity of the disease. He identified five approaches that could potentially lead to the discovery of useful biomarkers: (i) finding direct markers of beta cell health (rather than relying on insulitis, which is turning out to be less pronounced in humans than once thought), (ii) examining other pancreatic abnormalities, such as size, exocrine insufficiency, or leaky vasculature, (iii) more accurate staging of type 1 diabetes based on evaluating test results in the context of genetic markers for disease risk, (iv) quantifying beta cell mass, which is variable between individuals and may be related to the risk of developing diabetes, and (v) evaluating the clinical significance of residual C-peptide production in long-standing type 1 diabetes, as recently suggested with improved C-peptide assays. Dr. Atkinson said that the NIH and other entities are increasingly aware of the need for better biomarkers in type 1 diabetes and are working to improve the process; indeed, the recently launched second phase of the European Innovative Medicines Initiative (IMI2) has listed biomarker development as a priority for diabetes research, and we hope that other organizations will follow suit. In addition, we’d note a recent publication (Feldman et al., Nature Medicine 2014) that demonstrated potential to diagnose type 1 diabetes using a microchip.

Is Primary Prevention a Realistic Expectation?

Marian Rewers, MD, PhD (Barbara Davis Center, University of Colorado, Aurora, CO)

Dr. Marian Rewers asserted that primary prevention of type 1 diabetes is still a realistic expectation, despite the inconclusiveness of much recent research in this area. An important goal is to identify the environmental triggers responsible for the increasing incidence of type 1 diabetes (a rise of 3-5% per year in children under 15 since the 1960s) so that it will be possible to prevent islet autoimmunity from developing. Because islet autoimmunity typically begins very early in life, many primary prevention studies have focused on potential triggers in the infant diet. However, the large number of trials in this area has not led to a consensus in the field about the best approaches; Dr. Rewers noted that every expert would come up with a different list of likely environmental triggers if asked. A review of several of the larger studies, including TEDDY, TRIGR, and BABYDIET, served to emphasize the level of uncertainty in this area and the difficulty of identifying one trigger that significantly increases a child’s risk of developing diabetes. In Dr. Rewers’ view, there is little evidence that childhood obesity, cow’s milk formula, or routine immunizations are risk factors for type 1 diabetes. Evidence is slightly stronger (though far for conclusive) for the introduction of cereal outside of the ideal age range (four to six months) or exposure to enteroviruses. Additionally, there is evidence that omega three fatty acids may be somewhat protective against developing islet autoantibodies. These conclusions are far from definitive, and Dr. Rewers stressed that much more work will be needed to identify environmental triggers and translate findings into clinical practice.

Immunomodulatory Trials: What Will Work?

Peter Gottlieb, MD (Barbara Davis Center, Aurora, CO)

The highly regarded Dr. Peter Gottlieb provided an overview of the state of the science on immunomodulation as a therapy for type 1 diabetes. Three years ago, Dr. Gottlieb presented on the same topic (read our coverage) – it was somewhat sobering to see the relatively modest updates from that presentation to his current one, although he did give us some reasons to be optimistic. The two main immunomodulatory strategies for type 1 diabetes involve changing the balance of harmful autoreactive T cells vs. more protective regulatory T cells. Moving through time from 1980 to the present, Dr. Gottlieb compiled a massive list of the immunomodulatory therapies that have been tried, marking those that showed promise and those that did not yield positive results. He expressed reservations about myeloablation with stem cells (the “Voltarelli cocktail”), which in his view effectively constitutes a bone marrow transplant and comes with a very high level of risk. He shared a more positive outlook on the ATG/GCSF combination therapy presented at this past ADA (read our coverage), which showed preservation of C-peptide and improvements in T cell balance. A common theme over the course of the presentation was the need to identify responders to particular therapies and to use better biomarkers to tailor a package of therapies for different patients.

  • Dr. Gottlieb touched upon his own group’s work investigating alpha-1 antitrypsin (AAT), an anti-inflammatory serum protein. In a recently published study of 12 newly diagnosed type 1 diabetes patients, AAT was shown to preserve or increase C-peptide levels in four of the patients. Dr. Gottlieb interpreted the results with a glass-half-empty/glass-half-full mentality – the improvements seen in the four patients were certainly intriguing, and potentially merit further study in a larger randomized trials, but as he tells patients frequently in response to their phone calls, there is not enough data yet to support the use of AAT off-label.

Targeting the Trimolecular Complex for Immune Intervention

Aaron Michels, MD (Barbara Davis Center, University of Colorado, Aurora, CO)

Dr. Aaron Michels outlined two immunologic approaches – small-molecule pharmacotherapy and an insulin vaccine – that he believes could eventually lead to prevention of type 1 diabetes. He used the analogy of a hot dog to describe the trimolecular complex that stimulates the autoimmune attack in type 1 diabetes: if the insulin peptide is the hot dog, the T cell receptor and the antigen presenting cell are the bun and condiments that surround it. Dr. Michels believes that the right small molecule may be able to separate the “hot dog” from the “bun” by inserting itself into crucial binding sites. He highlighted the hypertension drug methyldopa (Aldomet) as a candidate that has been shown to block the immune response to insulin in preclinical studies; a phase 1b clinical trial investigating the compound in patients with recent onset type 1 diabetes is currently enrolling (ClinicalTrial.gov Identifier: NCT01883804). Another approach, based on an insulin vaccine, aims to alter the balance of helpful vs. harmful immune cells and stimulate a protective immune response. Dr. Michels’ lab has developed a novel insulin peptide with a mutation in the B chain, which successfully induced a protective immune response and delayed the development of islet autoantibodies and type 1 diabetes in non-obese diabetic (NOD) mice. Early clinical studies have demonstrated that both patients with recent onset type 1 diabetes and healthy control subjects have a similar protective response to this peptide. Although the project is still at a relatively early stage, Dr. Michels is hopeful that by exposing immune cells to a constant, low concentration of the peptide, it may be possible to alter the balance of helpful and harmful immune responses and prevent progression to type 1 diabetes.

Meet the Peers

Adult Providers

This informal discussion among adult providers (conference faculty and attendees) covered a number of topics, including comparisons between the US and UK healthcare systems, the best agents to achieve weight loss, frustration with payer-mandated switching between insulin brands, and how to obtain more affordable glucose testing strips.

  • On SMBG and test strips: Dr. Irl Hirsch (University of Washington, Seattle, WA) started his answer to an audience question on “offshore strips” by drawing a distinction between US-produced low-cost strips and strips that are produced internationally, generally in Asia. Quality issues plague the latter category of strips, and Dr. Hirsch pointed out that the FDA does not police these strips once they have been approved. Regarding the lower cost domestic options, Dr. Hirsch suggested that Nipro’s TrueTrack and TrueTest strips are to be avoided, and shared that he prefers the Agametrix Presto brand. Dr. Satish Garg (Barbara Davis Center, Aurora, CO) pointed out that competitive bidding has brought down prices significantly, and that testing strips are in the process of becoming more of a commodity than before.
  • On HMO-mandated switches from one insulin brand to another: Dr. Garg suggested that these changes, such as payer-mandated switches from Lantus to Levemir (or vice versa), are a waste of providers’ valuable time. Dr. Hirsch followed by noting that sometimes the switches are between products that are not clinically identical – he cited the example that patients generally need a higher dose of Levemir than Lantus – and that continued switching stands to cause problems in the community.
  • On the use of GLP-1 agonists in type 1 diabetes: Dr. Hirsch shared the story of a type 1 diabetes patient who was placed on a GLP-1 agonist four years ago due to an incorrect diagnosis, and who has since not seen a drop of insulin. He is interested to see more clinical trials on this application of the GLP-1 class, as he cannot recommend the option on-label to his type 1 diabetes patients at the moment. As a reminder, Novo Nordisk’s phase 3 trials testing liraglutide in type 1 diabetes began in 4Q13, and management is “hoping” for a 2015 launch.
  • On weight loss medications: Regarding the newest generation of obesity therapeutics, Dr. Sarit Polsky (Barbara Davis Center, Aurora, CO) expressed a strong preference for Vivus’ Qsymia (phentermine/topiramate) over Arena/Eisai’s Belviq (lorcaserin). She stated that she never prescribes Belviq due to a “huge” side effect profile and very modest weight loss. Although she acknowledged that Qsymia is also associated with some risks and (like Belviq) can be expensive, she expressed satisfaction with the 10% weight loss possible with the agent.
  • On differences in diabetes care between the US and UK: UK representative Dr. Philip Home (Newcastle University, Newcastle upon Tyne, UK) noted that more patients are seen in primary care in the UK, and that sulfonylureas and NPH are used to a greater extent. Dr. Matthew Riddle (OHSU, Portland, OR) suggested that the UK treatment paradigm does a good job of doing a lot with old tools, but Dr. Hirsch countered that the patients he sees who have come from the UK have a higher prevalence of retinopathy and other complications.

Adult Educators

This open-ended session with a panel of adult diabetes educators quickly turned into a passionate discussion of the need for Medicare coverage of CGM. The consensus opinion in the room was well articulated by one panelist: “we all feel like we’re screaming at the wall.” Many of the educators had written numerous letters to their senators or to the Center for Medicare & Medicaid Services (CMS) telling stories of patients who had successfully managed their diabetes for years with CGM only to rack up ER visits after transitioning to Medicare and losing CGM reimbursement (“my patient has a stack of ambulance bills this high”). Disappointingly, none could cite a single case in which the government was willing to provide coverage. Much of the discussion centered on the most effective tactics for changing the current policy; a Medtronic representative in the room mentioned the company’s joint lobbying effort with Dexcom but cautioned that industry “can only fight one end” of the battle. Many participants agreed that personal letters from patients would be the most effective way to convince CMS of the importance of CGM coverage, though one educator described a conversation she had with a CMS official that convinced her that proving cost effectiveness is ultimately the best solution.

Pediatric Providers

The Meet the Peers Session for pediatric providers featured a heated discussion regarding the recently revised ADA A1c target of 7.5% for pediatric type 1 diabetes patients (read our report on the Position Statement presented at ADA 2014). Notably, a poll of the 60-person audience demonstrated that only 50% were satisfied with the new recommendations. The well-respected Dr. Fran Kauffman (Medtronic Diabetes, Northridge, CA), speaking on behalf of those with reservations, acknowledged the importance of the new Position Statement, but stressed that there are too many “caveats” in the real-world to apply a single target for all patients. In order to personalize care, she emphasized that recommendations need to be adjusted based on the patient, such that appropriate A1c targets could range a great deal. Dr. Tadej Battelino (University Children's Hospital, Ljubljana, Slovenia) suggested that the ADA recommendations were not strict enough, although he did acknowledge that hyperglycemia is relatively unlikely to lead to permanent brain damage in most pediatric patients. Later in the session, pediatric providers also expressed great frustration regarding the legal and reimbursement challenges that have handcuffed their ability to use social media to interact with patients. Although the entire audience (60 persons) felt that social media would improve patient outcomes, only two clinicians reported using such technology. Multiple attendees reported running into legal trouble upon attempting to use Facebook, Twitter or mobile technology to distribute information. However, providers stressed that these policies could not prevent third-party sources from attempting to provide information – often misleading –and insisted that there must be a way to communicate with and monitor patients outside the clinic.

  • Dr. Battelino on hyperglycemia and brain damage: “Who is really afraid of hyperglycemia? Parents. It’s the worst fear they can get.”
  • Dr. Battelino on the power of social media: “I had a patient with an A1c of 6.7%. She asked me if she can have a piece of chocolate. I said, ‘Sure!’ Within minutes, this was on Facebook. ‘Battelino allows chocolate.’ I had everyone asking me for chocolate. This never could have happened without social media. This is the power of social media. We need to do something – I just don’t know how.”
  • An attendee speaking on social media and reimbursement: “Insurance companies would love it if we interacted with patients over Facebook. But we still have to be paid.”
  • Dr. Battelino on reimbursement in Europe: “What I want you to say is that physicians are cheap in Europe all over. That’s why we can afford more nurses and more physicians. It’s a social system. How else would a heart surgeon or brain surgeon make exactly the same salary as me. We’re cheap. For me, a young physician costs me approximately $45,000. It’s cheap labor.”

 

-- by Melissa An, Varun Iyengar, Emily Regier, Manu Venkat, Adam Brown, and Kelly Close