ATTD (Advanced Technologies and Treatments in Diabetes) 2020

February 19-22, 2020; Madrid, Spain; Day #2 Highlights - Draft

Executive Highlights

  • Thursday whizzed by at ATTD as our team blazed their way through oral presentations, parallel sessions, and corporate symposia to bring you the latest in diabetes. See all our top highlights below and make sure to check out day #1, where the formal opening to the meeting was a tour de force keynote by Dr. Jay Skyler on technology, past and present, and where we also saw lots of fascinating FreeStyle Libre real-world data across multiple European countries and learned more on what could be expected from “CGM Pro” data, with Dr. Fiona Campbell using Medtronic’s technology as examples.  

  • Day #2 continued to be an exciting day for CGM trials as we continue to learn more about this incredibly popular and fast-growing technology. Dr. Kellee Miller presented 12-month data from the WISDM trial of CGM in older adults showing improvements in every outcome measured as the BGM group crossed over to CGM in the final six-month extension period – striking six-month data was shown at ADA last June. Dexcom made a splash in the morning with announcement of CE-Marking for G6 in pregnancy with availability in the UK “starting spring 2020.” This is incredibly exciting as it has the potential to improve so many lives and to reflect a very positive and rapid ROI. At Dexcom’s afternoon symposium, Mt. Sinai’s Dr. Carol Levy showed striking data on pregnancy and CGM for both the mom and baby.

  • Not to be outdone, automated insulin delivery had its day, headlined by readout of the Control-IQ trial in pediatrics (6-13 years). The results were similar and also very impressive, just like the adult pivotal trial was (presented ADA 2019, published NEJM), with Time in Range increasing from 53% to 67% after 16 weeks in the Control-IQ group. Like the adult trial, the vast majority of Time in Range improvement came at night, with the closed loop group reaching an astounding 80% Time in Range. Tandem appears to be on track for a Control-IQ pediatric submission to the FDA in 1Q20. We continue to hear raves from patients who have upgraded from Basal-IQ. Medtronic’s symposium featured strong real-world AID data from 12 countries in Europe. Time in Range with Auto Mode enabled (not necessarily on) was very similar across countries: ATTD host country Spain had the highest Time in Range at 74% (n=625), while the UK came in last with a Time in Range of 69% (n=766) – while these sound very similar, the Spaniards had an extra hour “in range,” on average, which most any patient would take from any baseline, in a heartbeat.

  • DreaMed’s Advice4U study, comparing glycemic outcomes with AI-generated Advisor Pro pump settings recommendations vs. expert physician advice. The study showed non-inferiority of Advisor Pro vs. physicians and in fact, the glycemic outcomes are incredibly similar. The implication is that this automated “expert” system can be scaled to settings where diabetes experience is lower (e.g., primary care), to provide more frequent patient interactions, or to improve clinic visits by reducing the time spent analyzing data and more time discussing diabetes management. Less numeric work for HCPs is something they’ll take any day – in addition to prompting more time to spend on more challenging problems with the same patients, it is also exciting since it enables more time to be spent with other patients.

  • The day in diabetes therapy was headlined by a heavyweight debate between Profs. Thomas Danne and Stephanie Amiel over SGLTs in type 1. Prof. Danne argued in favor while Prof. Amiel took the opposite stance – unsurprising! Following the debate, moderators asked the audience whether they would use SGLTs in type 1s without established CVD and whether they would use the class in type 1s with established CVD. On the first point, the room was split 40% yes and 60% no. On the second question, the room was overwhelmingly in favor, 95% yes to 5% no. We continue to hope to see enough data from people with type 1 with heart disease in various outcomes trials – while most CVOTs have not enrolled people with type 1, BI/Lilly is an exception. There are people with type 1 in both their heart failure and kidney disease outcomes trials – we don’t know what the powering will look like, etc., and if anyone can give us a lead on this, please be in touch!

  • JDRF’s Dr. Jessica Dunne and University of Pittsburgh’s Dr. Mark Sperling led a packed-to-the-brim session on type 1 screening and early intervention. Dr. Marian Rewers presented updated data from the Autoimmunity Screening for Kids (ASK) program, up through January 2020 with n=23,423 children (!). In addition, we got a look into future plans for IM Therapeutics from co-founder and CMO Dr. Peter Gottlieb, including upcoming IND filing and phase 1a dates for the company’s lead candidate D-methyldopa.

What a day at in Madrid, Spain, where ATTD Day #2 just finished up! See all of our top highlights in CGM, AID, Decision Support, Drugs, and Big Picture below.

ATTD Day #1 HighlightsDr. Battelino: put DCCT in “history part” of your brain, Dr. Bergenstal: FNIR; Medtronic cost-savings data with iPro 2 CGM; opening ceremony

Table of Contents 

CGM Highlights

1. 12-Month WISDM RCT Extension in Type 1s ≥60 Years Shows CGM Improves Every Outcomes Measured Compared to Baseline: -51 Minutes/Day Below 70 mg/dl, +1.4 Hours/Day Time in Range

Jaeb Center’s Kellee Miller read out primary outcomes from the extension arm of Helmsley- and JDRF-funded WISDM (Wireless Innovations for Seniors with Diabetes Mellitus) study of Dexcom G5 CGM in older adults (≥60 years) with type 1 diabetes. Results from the 6-month, multi-center randomized control trial (n=203) read out at ADA 2019, with 100 of the 103 participants from the CGM arm electing to continue on CGM through 12 months. 94 of the 100 participants randomized to the BGM group also elected to crossover to CGM in the 6-month extension phase. At 12 months, CGM conferred a significant advantage over baseline in every outcome measured. To be included in the study, participants had to have a baseline A1c ≤10%, be pump- or MDI-treated, and could not have worn CGM in the last three months. Patients were excluded if they spent at least 10% of the time with glucose <54 mg/dl during the screening phase and experienced a severe hypoglycemic event in the past six months. At baseline, median age was 68 years, 92% of participants were non-Hispanic white, and 53% used insulin pumps. The primary outcome, percentage of time <70 mg/dl, was reduced from 6.6% at baseline to 2.9% at 12 months in the CGM group (-49 minutes/day; p<0.001); improvements were slightly greater in the BGM/CGM crossover group: time <70 mg/dl decreased from 6.6% at baseline to 6% at 6 months (time of crossover), decreasing to 2.9% at 12 months (-53 minutes vs. baseline; p<0.001). Similarly, time <54 mg/dl was reduced from 2.5% to 0.7% at 12 months (-26 minutes/day; p<0.001) in both the CGM group and BGM/CGM crossover group. In the CGM group, Time in Range increased from 56% at baseline to 64% after 12 months (+1.9 hours/day; p<0.001) and A1c decreased from 7.6% to 7.4% (p=0.01). In the BGM/CGM group, Time in Range increased from 56% at baseline and six months to 60% after 12 months (+58 minutes/day; p=0.007) and A1c decreased from 7.5% at baseline and six months to 7.3% (p=0.02). While not necessarily surprising, the sustained results at 12 months are encouraging to see. The evidence base that CGM is effective in many different populations is building (e.g., COMISAIR, DIAMOND, GOLD) and we strongly hope that the WISDM study can help reduce preconceptions surrounding use of technology and CGM in the elderly – some of the assumptions that they “can’t handle it” or the “caregivers will be very confused” have been downright insulting. While it certainly is true that some technology will not work for some patients, given the incredible heterogeneous patient population, to generalize so negatively is very disappointing.  

 

Baseline

6 Months

12 Months

 

CGM/CGM

BGM/CGM

 

 

 

 

Time <54 mg/dl

2.5%

2.5%

0.6%

2.3%

0.7%

0.7%

Time <70 mg/dl

6.6%

6.6%

2%

6%

3.2%

2.9%

Time in Range

56%

56%

64%

56%

64%

60%

Time >180 mg/dl

37%

37%

34%

38%

33%

37%

Time >250 mg/dl

14%

15%

10%

14%

10%

12%

A1c

7.6%

7.5%

7.2%

7.5%

7.4%

7.3%

Coefficient of Variation

41%

42%

36%

40%

36%

36%

  • During the original study, one severe hypoglycemic event was recorded in the CGM group. After the 6-month extension, the CGM group recorded a total of 5 events across the twelve-month period. By comparison, the BGM arm totaled eleven severe hypo events in the first six months, reduced to just two in the second six-month period (after crossover). Overall, of course, those on BGM did much better in a clinical trial than they would “in real life” – we were very impressed that  12-month time under 54 mg/dL stayed at less than 1% (0.7%), and that time < 70 mg/dL increased only to 3.2%.

 

  • CGM use was very high through the entire twelve months for the CGM group and in last six months for the group randomized to BGM. Participants in the CGM arm showed CGM use 95% of the time during both six-month periods. After the BGM crossed over to CGM, they recorded 94% of time using CGM. Unfortunately, no data on patient-reported outcomes, such as fear of hypoglycemia, diabetes distress, hypoglycemia unawareness, and general measures of quality of life, has been shared yet – we hope to see more of this.

2. Dexcom Announces CE-Mark for G6 in Pregnancy; Available in UK “Starting Spring 2020”

In exciting news, Dexcom just announced that G6 has received a CE Mark for use in pregnancy in Europe. G6 had been previously contraindicated for pregnant women. Rollout of the new pregnancy indication will begin with the UK “starting spring 2020” – a reasonable place to start, considering that NHS has already committed to offer CGM to all pregnant women with type 1 diabetes by 2020/2021, given its robust cost-effectiveness in this population (more on this below). Of course, we’re hoping other countries follow the lead of the UK and offer CGM to all pregnant women with diabetes. G6 joins Abbott’s FreeStyle Libre in garnering a pregnancy indication in Europe, with Abbott received CE-Marking in 2017. No CGM (Abbott’s FreeStyle Libre, Dexcom’s G5/G6, or Medtronic’s Guardian Sensor 3) has yet to be approved for pregnancy use in the US, and while off-label use has become much more common, this should help massively with awareness and education and reimbursement.

  • This morning, we spoke with Dexcom CEO Kevin Sayer about the indication:As you look at pregnancy in women who have diabetes, I don’t know you could get [good] outcomes without [CGM]. I think it’s that critical. Patients who’ve been on CGM haven’t been taking it off in pregnancy. I’d give a lot of credit to the CE Mark. It’s good that we’ve made this progress here. This needs to be a tool adopted by everybody. There is no excuse not to provide someone with a baby the best possible treatment and this is the best.”

  • At Dexcom’s afternoon symposium, Dr. Carol Levy (Mt. Sinai) was given ~15 minutes to discuss CGM in pregnancy – we wish she would’ve had longer as she is so fascinating and this is such important news that could have a massive impact on this often high-risk population of women, who are pregnant with diabetes. Dr. Levy shared a very compelling graph based on T1D Exchange data from 2010-2013 vs. 2016-2018. From 2010-2013 to 2016-2018, self-reported CGM use in pregnant women increased from ~35% to 65%; over the same time period, mean A1c in pregnant women dropped from ~6.9% to ~6.6% - we imagine variability is also much lower. Of course, that is Dr. Levy noted that the two trends are not necessarily directly linked, but she suggested CGM use could certainly be a contributing factor. Dr. Levy also pointed at a poster at ATTD 2020 of Dexcom CGM in 50 women from 2012-2019. The pregnant women used CGM (varied from Dexcom G4, G5, to G6) 93% of the time and recorded no DKA or severe hypoglycemia events. Fetal outcomes were also relatively strong: there were just six cases of preeclampsia and six cases of high birthweight (>4 kg). For context, the prevalence of preeclampsia and large gestational age in women with type 1 is 15%-20% 51%, respectively.

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  • As a reminder, data supporting pregnancy CGM use are overwhelmingly positive. Results from the JDRF-funded CONCEPTT RCT testing Medtronic’s older Guardian CGM in pregnant women (n=125) were presented at EASD 2017 and showed that CGM use drove a significant reduction in the incidence of large for large for gestational age (OR=0.51, p=0.02), fewer NICU admissions lasting 24+ hours (OR=0.48, p=0.02), fewer incidences of neonatal hypoglycemia (OR=0.45, p=0.03), and one-day shorter length of hospital stay (p=0.01). The numbers needed to treat (NNT) were compelling – NNTs of just 6-8 women with CGM to prevent one of those negative outcomes. The primary A1c endpoint showed a small -0.2% A1c advantage for CGM at 34 weeks (p=0.02). However, mothers on CGM spent a significant 100 more minutes/day in range (68% vs. 61%; p=0.003), 72 fewer minutes/day in hyperglycemia (27% vs. 32%; p=0.03), and a non-significant ~14 fewer minutes per day in hypoglycemia (3% vs. 4%; p=0.1). Excitingly, many believe that results from CONCEPTT actually underestimate the efficacy of CGM in driving positive outcomes in pregnancy, given the improvements with G6 when compared to Medtronic’s older Guardian system.  
    • Cost-effectiveness analysis of CONCEPTT have further underscored the need for CGM in this population. At ADA 2019, Dr. Helen Murphy asserted that “for publicly funded health systems like the NHS, they cannot afford not to provide CGM to pregnancy women with diabetes.” Results back up the claim: The unpublished, retrospective evaluation used individual-level data to estimate cost-effectiveness of CGM vs. SMBG in addition to standard antenatal care. Direct costs associated with CGM, including sensors/transmitter and education, were estimated to be £2,046. Although CGM was associated with an additional £330, it was found to be more effective for maternal outcomes, resulting in 61.33 QALYs (quality-adjusted life-years) as compared to 61.27 QALYs. This translates to a fantastic incremental cost-effectiveness ration (ICER) of £5,509/QALY, far under the NICE threshold of £20,000-30,000/QALY. For neonatal outcomes, the results were even more dramatic: not only was CGM found to be more cost-effective, it was also found to be cost-saving. CGM use led to cost-savings of £2,612, resulting in 75.43 QALYs vs. 73.77 QALYs and an ICER of £1,571/QALY. Results were translatable across geographies as well, with a similar study in Canada providing similar results regarding cost-effectiveness. 

  • Broadly speaking, pregnancy can introduce a host of disruptions to glycemic control and diabetes management that CGM can help ease. Early in pregnancy, patients experience increased glucose variability with progressively increasing insulin resistance, requiring intensification of therapy. The risk of severe hypoglycemia also dramatically rises, occurring up to five times more frequently in women with type 1 diabetes during their early stages of pregnancy as compared to the period before pregnancy. 

3. GOLD Study Data (n=137) Shows Just 27% of Participants with A1c <7% Also Meet Consensus Time in Hypoglycemia Goals Even With CGM

University of Gothenburg’s Dr. Shilan Seyed Ahmadi presented an analysis of the Swedish GOLD CGM trial (n=137), focusing on the new consensus CGM goals which are now included in the ADA Standards of Care. The cross-over study took place over ~6 months comparing CGM (Dexcom G4) and SMBG in adult type 1 MDI users (mean age 45 years). Dr. Ahmadi’s sub-analysis of the participants with A1c <7% highlighted the difficulty of achieving both A1c <7% and the time in hypoglycemia goals, even with CGM. For participants in the study with A1c <7%, mean time below 70 mg/dl was 5.4% (consensus goal is <4%) and mean time below 54 mg/dl was 1.5% (consensus goal is <1%) on CGM. Though these values do not meet the consensus targets, they are a notable improvement from the outcomes seen on SMBG: for participants with A1c <7%, mean time below 70 mg/dl and 54 mg/dl were 9.2% and 3.5%, respectively, on SMBG. During the CGM use period, only ~one-quarter (27%) of individuals with A1c <7% also met the <4% time below 70 mg/dl and <1% time below 54 mg/dl goals. The graph below really underscores the difficulty – the green box was added by us and highlights the areas where both A1c and time below 70 mg/dl targets are met. Only three (!) participants (out of 137) met both goals when using CGM and just one participant met both goals on SMBG.

  • The full GOLD study showed an A1c of 7.9% during the CGM period vs. 8.4% during SMBG use. Percent time below 70 mg/dl was 2.8% on CGM, compared to 4.8% on SMBG; percent time below 54 mg/dl was 0.8% on CGM, compared to 1.9% on SMBG. See all the key results here.

4. CITY Sub-Analysis Shows High Utilization of Dexcom CGM Features in Teens and Young Adults: 91% Use Low Alerts, 81% Use Mobile App, 62% Use Share

The wonderful Dr. Laurel Messer (Barbara Davis Center) showcased data from the Continuous Glucose Monitoring Intervention in Teens and Young Adults (CITY) trial, showing that teens and adolescents have fairly levels of engagement and usage of CGM and CGM features. Primary results for CITY (n=153) read out at ADA 2019, demonstrating efficacy and safety of CGM vs. SMBG in type 1 adolescents (14-24 years). Seventy-four participants were randomized to the CGM (Dexcom G5) group, receiving instruction on how CGM works, optimizing alerts and features, and troubleshooting. As a reminder, Dexcom G5 has non-adjunctive indication, seven-day wear, and requires two fingersticks/day. The CGM group had a mean age of 18, A1c of 8.9% at baseline, and was 65% white. During the study period, 50 of the 74 participants (68%) wore Dexcom G5 for more than 5 days/week. The top reasons for not wearing CGM were wanting a break from daily use, forgetting to use it, and hesitancy/discomfort wearing the device. On average, CGM was used 6.4 days/week with a median of 2 fingersticks/day. Impressively, 98% of participants regularly used CGM without a confirmatory fingerstick before dosing.

  • The vast majority of participants (81%) used the mobile app with their CGM. Slightly more than half of mobile app users (62%) used Dexcom’s Share feature, with 91% of Share users sharing their data with parents/guardians. 13% of the participants shared data with their siblings, while 9% shared with a significant other. The most cited reason for not wanting to use Share was not wanting others to see their glucose values or receive alerts.

  • Nearly all of the participants (91%) surveyed used low alerts, while 84% had high alerts enabled. The median setting for low alerts was 70 mg/dl, while the median setting for high alerts was 270 mg/dl.

  • About half of participants (55%) reported reviewing Clarity reports more than once per month. Another 11% said they reviewed the reports less than once per month, while one-third said they never reviewed their Clarity reports. At AADE, we heard that the open rate for Dexcom Clarity app’s weekly summary report was 80%, though this was across a broader population of Dexcom users. Given the immense learning that can come from retrospectively looking at CGM data (see Dr. Rich Bergenstal’s tips from ATTD Day #1), we wonder how this number could be improved, particularly in the more challenging teen/young adult population.

AID Highlights

1. DCLP5: Control-IQ in Children Ages 6-13 Drives Significant Time in Range Improvements (67% vs. 55%); Massive Improvements at Night (80% vs. 54%); 93% Time in Closed Loop

On the heels of the recent launch of Tandem’s Control-IQ for patients age 14 and up, Dr. R. Paul Wadwa (Barbara Davis Center for Diabetes) presented highly anticipated results from the DCLP-5 trial of Control-IQ in children ages 6-13 years old. The 101 participants were randomized 3:1 to Control-IQ or SAP (i.e., open loop Dexcom G6 + Tandem t:slim X2). Over 16 weeks, Time in Range in the Control-IQ group increased from 53% at baseline to 67%, compared to those in the SAP group, who increased Time in Range from 51% to 55% (p<0.001). Like the adult trial, the vast majority of Time in Range improvement came at night, with the closed loop group reaching an astounding 80% Time in Range compared to 54% in the SAP group. Overall, time spent above 180 mg/dl was 31% for closed loop and 43% in SAP group (p<.001). Time below 70 mg/dl was not changed in either group. Only 8% of the patients were sensor naive at the start of the trial and time below 70 mg/dl was less than 2% in both groups at the start of the trial. Again, similar to the adult study, treatment effect on Time in Range emerged during the first month of the trial and persisted consistently over the course of the four month study.

  • Control-IQ was approved in December for ages 14+ and a specific black box warning against use in patients under 6 years old. It appears pediatric submission is on track for filing in 1Q20. Since the pediatric indication is the same algorithm (to our knowledge), it should be a 510(k) filing claiming substantial equivalence to today’s submission.

  • Regarding adverse events, there were no DKA or severe hypoglycemia events in the trial.

  • At baseline, 40% of patients had A1C >8%, 20% were new to pump, 92% used CGM, and A1C ranged from 5.7-10.1%. 

2. Real-World MiniMed 670G Data in Europe (n=3,139) Shows Time in Range Increase from 62% to 71% Before and After Auto Mode

Medtronic’s Dr. Ohad Cohen presented MiniMed 670G data uploaded to CareLink from 7,847 patients across 12 countries in Europe. The data was uploaded between October 2018 and January 2020. For the entire cohort, after Auto Mode was enabled, mean Time in Range was 71% and mean GMI was 7%. Impressively, users spent just 1.8% of time <70 mg/dl and 0.6% of time <54 mg/dl. On the hyperglycemia side, users spent 20% of time >180 mg/dl and 6% of time >250 mg/dl. Note that the “post-Auto Mode enabling” data includes time spent in and out of Auto Mode due to Auto Mode exits. In an email with Medtronic, we learned that time in Auto Mode in the cohort was 87% – in the US, this has typically been around 70%-75%. Time using the Guardian Sensor 3 was an impressive 90%. Time in glycemic ranges did not vary too much from country to country in Europe: ATTD host country Spain had the highest Time in Range at 74% (n=625), while the UK came in last with a Time in Range of 69% (n=766). Again for comparison, Medtronic’s last batch of real-world data shared in the US showed a mean Time in Range of 71%.

  • In 3,139 users with pre- and post-Auto Mode enabling data, Time in Range increased from ~62% to 71% after enabling Auto Mode (+2.3 hours/day; p<0.001). Mean sensor glucose dropped from 164 mg/dl to 153 mg/dl after Auto Mode enabling, and GMI fell from 7.2% to 7%. Notably, the decrease in mean glucose and GMI actually came with a decrease in time spent in hypoglycemia: time <70 mg/dl and <54 mg/dl both decreased slightly, from 2% to 1.8% and 0.6% to 0.5%, respectively. This made us think of Dr. Tadej Battelino’s comments at an Abbott-symposium yesterday that we should put the DCCT idea of lower A1c requiring more hypoglycemia exposure in the “history drawer” part of our minds. Time above 180 mg/dl and 250 mg/dl decreased from 26% to 21% and 10% to 6%, respectively.

  • Looking at nine-month data that was available in 237 users, Time in Range improvements were seen one month after Auto Mode enabling and sustained for at least nine months. The pattern of improved glycemic control appearing just weeks or months into starting closed loop is not a surprise, as we’ve seen similar trends with other systems. We’d be curious to know how percentage of time in Auto Mode changed over the nine-month period, as many view the calibration requirements and various Auto Mode exits in 670G as quite burdensome. Time spent in Auto Mode is correlated with improved glycemic outcomes, so the sustained Time in Range results are an encouraging signal.

  • As Medtronic’s Dr. Bob Vigersky compared MiniMed 670G with the upcoming 780G, the excitement in the audience was palpable. On Medtronic’s earnings call earlier this week, we learned that the system is planned for a launch after April 2020, though the system has already been submitted for CE-Marking. US pivotal trial data will read out at ADA this year. Of note, Medtronic’s slide (below) notes “fingerstick is optional” for meal bolusing. This assumes that Guardian Sensor 3 would have non-adjunctive labeling (submitted to FDA in June) allowing users to forego a confirmatory fingerstick before bolusing. Of course, 780G will also launch with Guardian Sensor 3, which does require two fingerstick calibrations/day. Much to the crowd’s delight, Dr. Tadej Battelino brought a patient, Ana, from his center enrolled in the 780G trial to share some of her experiences with the system. When Dr. Battelino showed Ana’s glucose profile, the audience saw 92% Time in Range with a GMI of 5.8%. On a stage with renowned KOLs like Drs. Battelino and Vigersky, the audience asked 16-year old Ana to field many questions. Ana summed up her experience so far, saying, “I was so happy to achieve a better daily Time in Range with considerably less effort.” Of course, this was one select patient and we eagerly await details from several 780 studies once the overall data is analyzed and presented in June at the ADA.

3. Regulators, Manufacturers, DIYers, and People with Diabetes Express Hope for an Interoperable, Open-Protocol AID Ecosystem

An afternoon session brought together regulators, people with diabetes, manufacturers, and members of the DIY artificial pancreas community to discuss the implications of an interoperable, open-protocol AID ecosystem. JDRF led the charge toward an “open protocol” system with a 2017 initiative encouraging pump and CGM manufacturers to apply with proposals to provide seamless, secure, interoperable connectivity with other devices and smartphone apps. JDRF’s Dr. Daniel Finan elaborated that the vision behind this initiative is to both promote innovation and to ease the regulatory burden for CGM, pump, and algorithm developers such that they are responsible for developing and perfecting only one part of this system, as opposed to the entire multi-component AID platform. The wider goal is to improve patient choice for people with diabetes who use AID systems, giving them the opportunity to “mix and match” pumps, CGMs, and algorithms according to their unique needs. This point was underscored by patient advocate Ryan Gutzmer, a professional figure skater and hockey player who has lived with type 1 diabetes for 29 of his 32 years. He pointed out that the current rather limited range of FDA-approved AID devices encourages patients to venture into the DIY space, where they often receive little direction and support from HCPs: “We’ve come so far with DIY systems, but at the end of the day the result is that you can’t discuss one of the most effective diabetes management strategies with your most trusted people.” He emphasized that much better outcomes would result “if patients are allowed to combine what CGM they like, what pump they like, have an algorithm that allows both to communicate, and be able to be educated on all of these systems by trusted HCPs.” Stanford behavioral psychologist Dr. Jessie Wong echoed this. Pointing out the vastly different preferences that govern the preference of pump and CGM in children (device use in social situations) vs. adolescents (physical features, wear-ability, and comfort) vs. adults (device reliability and safety). In step with this, the FDA has been incredibly active to create the pathways to fully interoperable AID ecosystems. In contrast to the “dark ages” of the past, where algorithm developers had to partner with hardware companies and fix a system with specific components before gaining FDA approval, Dr. Courtney Lias elaborated that these changes will incentivize additional technology development, allowing companies (particularly small companies) to develop and take ownership of CGMs, pumps, and algorithms separately, without a need to have exclusive partnerships or take responsibility for the development of devices or software that aren’t their area of expertise. With this vision in mind, from 2018 to the end of 2019, the FDA created three new regulatory classifications in iCGM (March 2018), ACE pump (February 2019), and iController (December 2019). With dual partnership announcements between Insulet’s Omnipod Horizon with Dexcom’s and Abbott’s CGMs, we could see the first hybrid closed loop system with multiple CGM options as soon as the end of this year.

  • The session closed with a panel discussion including independent innovators in the DIY artificial pancreas space. Adrian Tappe, a developer for Android APS, praised the new open-protocol system, noting that the new environment incentivizes startups to “develop a very innovative product, do it well, and then connect to others working on other aspects of an AID system without having to take care of everything themselves.” Loop’s Katie DiSimone agreed, and posited that the open-protocol initiative frees manufacturers to be more innovative in the domain of training users and HCPs on how to use these new products – a domain that currently has great room for improvement from the current standard of long documents that few people have the motivation to read. As she pointed out, AID systems represent a huge opportunity to engage people and “light a fire” to motivate them to manage their diabetes in new ways, and it is critical to find ways of “de-burdening” patients when it comes to learning these new systems.

  • On the manufacturer side, Diabloop CEO Erik Hunecker discussed the fundamental differences in companies that focus on hardware vs. software, praising the open protocol initiative for allowing these domains to undergo development separately. Extending upon this, Medtronic’s Patrick Weydt urged that at this juncture toward open protocols, the AID community should acknowledge that it is “not the first industry to undergo interoperability,” and should take the opportunity to learn from the wins and losses of other industries that have entered this domain.

  • An ongoing theme during this session was regulatory differences between the US and the EU. In contrast to these progressive moves to facilitate AID development by the FDA, the EMA has made the regulatory pathway for AID more difficult in recent years, going as far as to move closed loop systems from class II to the stricter class IIIb. This is surprising. During Q&A, many Europe-based attendees argued that AID systems approved in the US should be available to people in the EU because, after all, “if it’s safe for someone in the US it should also be safe on the other side of the Atlantic.” We’ve heard the same thing for other approvals, the other way around (SGLT-2 for type 1 inhibitors). We urge regulators at the FDA to share their thinking with their counterparts at the EMA.

4. Control-IQ Use in Pediatrics and in Adult Populations Deliver Similar Time in Range Improvements of ~2.5 Hours/Day; Comparisons Between MiniMed 670G and Control-IQ Pivotal Trials

The renowned Dr. Boris Kovatchev (University of Virginia) compared two Control-IQ trials, demonstrating similar Time in Range improvements and A1c reductions when comparing pediatric patients (ages 6-13) and adults (14+) using Control-IQ. In a 16-week study assessing the efficacy of Control-IQ in pediatric populations (iDCL Protocol 5), patients (n=100, 6-13 years of age) were randomized 3:1 to Control-IQ vs. sensor-augmented pump treatment (i.e., open-loop G6 with t:slim X2). The Jaeb-coordinated study, took place across four clinical sites over four months with an extension phase of three months. Preliminary results demonstrate almost identical results when compared to iDCL Protocol 3 (the Control-IQ pivotal trial in adults), with improvements in Time in Range of 2.5 hours/day, driven by decreases in hyperglycemia: time spent >180 mg/dl was reduced by 10%. A1c reductions in iDCL3 and iDCL 5 were 0.3% and 0.4% and time spent in closed-loop were 92% and 93%, respectively. Approximately 20% of these participants in the iDCL5 were new to pump therapy with the majority already using a CGM. Dr. Kovatchev began his talk by demonstrating the exponential growth in artificial pancreas publications from approximately one in 1950 to almost 240 in 2019. As of today, there are ~30 recruiting or active, non-recruiting artificial pancreas clinical trials on ClinicalTrials.gov - a real testament to how much traction the field has gained in the last few years.

  • The second metanalysis Dr. Kovatchev displayed compared results of the pivotal trials from the Medtronic 670G and Control-IQ, finding a much greater Time in Range improvement with Control-IQ after adjustments for study type and baseline characteristics. Dr. Kovatchev noted that this analysis was challenging to perform because baseline Time in Range for populations in both trials were different. Additionally, MiniMed 670G’s pivotal trial was not a randomized controlled trial and did not have an equivalent control group seen in Control-IQ’s trial. (670G’s pivotal was single-arm.) Nonetheless, after utilizing three distinct statistical methods to match the baseline Time in Range distribution in the Control-IQ study to the same distribution in the 670G study, the data found a Time in Range improvement during active treatment of 5.5% in the 670G trial vs. 10.7% in the Control-IQ trial.

  • Dr. Kovatchev also displayed metanalysis data from DTM 2019 which made comparisons from iDCL protocol 1 (smartphone-embedded inControl algorithm, Roche Spirit Combo pump, Dexcom G4 or G5) and iDCL Protocol 3 (algorithm embedded in Tandem t:slim X2, Dexcom G6). The results indicated that the Control-IQ/G6 (embedded closed-loop system) delivered an additional 1.5 hours/day of Time in Range. According to Dr. Kovatchev, these results indicate that closed-loop design, form factor, and user-friendliness are also important to consider beyond results as future technology is developed. According to Dr. Kovatchev, these direct comparisons are valid because both studies’ control group received the same treatment of sensor-augmented pump therapy.

5. Pregnancy in Diabetes Draws Crowds: Dr. Helen Murphy on What’s New in AID, Dr. Yariv Yogev’s Call-To-Action on Research Standards

In an aptly timed session with the recent CE-Mark for Dexcom in pregnancy, the venerable Dr. Helen Murphy (King’s College London) provided audience members with a brief update on the ongoing AiDAPT closed loop trial (n=124 type 1s) in women with diabetes. We first caught wind of AiDAPT at Diabetes UK 2018, where Dr. Murphy presented on the study’s predecessors CLIP_03 (n=16) and CLIP_04 (n=16). As a reminder, CLIP_03 demonstrated that overnight closed loop reduces hyperglycemia without increases in hypoglycemia or insulin dose, and CLIP_04 showed that day-and-night closed loop reduces hypoglycemia. AiDAPT is a parallel-arm, randomized controlled trial comparing the new CamAPS FX closed loop system (Dexcom G6, Dana RS pump, Samsung S7 phone) developed by Cambridge’s Dr. Roman Hovorka with open loop (Dexcom G6, pump or MDI). Excitingly, we got a first look at one of the trial participants’ closed-loop stats, showing an impressive 84% Time in Range. While these results of course are only meant to illustrate the type of data AiDAPT will be collecting, we so look forward to seeing the full results in the future.   

  • Israel’s Dr. Yariv Yogev jumpstarted the session with an impassioned request to improve standards for the study of gestational diabetes, directed towards researchers and journal reviewers. To illustrate this issue, Dr. Yogev walked audience members through a 2018 publication in JAMA, entitled “Effects of Glyburide vs. Subcutaneous Insulin on Perinatal Complications Among Women with Gestinational Diabetes: A Randomized Clinical Trial,” which concluded that its findings do not justify use of glyburide as a first-line treatment. Dr. Yogev critiqued the study for categorizing study participants into those with good, moderate, or poor glycemic control, rather than giving actual glycemic values. In addition, the study’s primary outcome was set to have a non-inferiority margin of 7% “based on a group of clinicians’ point of view,” rather than any sort of specific criteria. Dr. Yogev called the study’s findings “ambivalent” overall and urged journals to only publish data with glucose values (vs. “well-controlled,” “poorly controlled,” etc.), define disease-related outcomes, and use outcome-based rather than statistics-based measures. In his purview, articles must be held to a higher standard, as HCPs often do not have time to “read the fine print.” Although we were somewhat surprised that Dr. Yogev would dedicate so much of his presentation to criticizing one publication, his call-to-action was undoubtedly compelling. 

6. On-Body iAPS Data (n=18) Reveals Time in Range Improvement from 57% to 62% After 48 Hours; Reduction in Time Spent <70 mg/dl in Outpatient Settings (n=10) From 3.5% to 2.3% After Two Weeks

Dr. Eyal Dassau (Harvard) presented positive initial data from two studies highlighting outcomes of the Interoperable Artificial Pancreas System (iAPS) smartphone app under two conditions: one where exercise was not announced and there were no restrictions on meals and another in the context of prescribed meals. As a reminder, the application is capable of interfacing with CGMs (Dexcom G5 and G6), pumps (Insulet Omnipod and Tandem t:slim X2), and algorithms while running on an unlocked smartphone. Patients can use iAPS to bolus insulin, log activities, and view glucose. The app even provides alarms for system malfunctions and synchronizes data with a server to enable remote monitoring. As he often does, Dr. Dassau situated his talk with an emphasis on human-centric design in closed loop therapy.

  • The first study was a single-arm, 48-hour study (n=18, type 1s) of iAPS use in a semi-supervised environment among children 2-18 years old. Participants consumed three meals per day and were not restricted in what they could consume. Unsurprisingly, most subjects consumed more carbohydrates on closed loop compared to open loop. Participants also took part in one unannounced group exercise activity such as escape rooms, trampoline, and ropes courses. After 48 hours, mean glucose had decreased from 173 mg/dl to 167 mg/dl, while Time in Range improved from 57% to 62%. Impressively, participants on average had CGM active 99.9% of the time and spent 92% of time in closed loop. Despite the improvements in both metrics as a whole, not all participants reaped the benefits. Were there any unique characteristics of these patients that led to these outcomes? We also wonder how these outcomes would hold under longer periods of time.

  • The second study was a two-week randomized crossover study comparing iAPS use at home on an unlocked Google Pixel 2 smartphone vs. predictive low glucose suspend in the context of prescribed meals. More specifically, participants alternated between eating pasta and rice with the same carbohydrate content. Meals were blinded during analysis. While there were no statistically significant improvements in mean glucose or Time in Range, time below 70 mg/dl decreased from 3.5% to 2.3%. Participants spent 85% of time in closed-loop. Participants also described positive experiences with the iAPS platform during follow-up interviews. Dr. Dassau mentioned at ATTD 2019 that he had received “excellent feedback” from users in this study – it’s nice to put some numbers now behind these qualitative insights!

7. Real World Study of Omnipod Users: Pumpers Who More Frequently Bolus Have Improved Glycemic Outcomes

In a very intriguing real-world study, the indomitable Dr. Irl Hirsch demonstrated that pumpers who bolus more have better glycemic outcomes, making the point by using a large dataset of Omnipod users sourced from Glooko. A cohort of 1,159 adult, type 1, Omnipod users who also submitted CGM data were selected from a large (~26,000) set of Omnipod system users in the Glooko diabetes management system. The most common bolus frequency was in the four to six times a day range. However, Time in Range increased smoothly with increasing bolus frequency up to eight times per day, after which it remained constant at 73%. People who bolused <4 times per day averaged 57% Time in Range. Impressively, time <70 mg/dl was below the consensus target (4%) for all groups. Those bolusing eight or more times a day had a GMI of 6.8%, compared to 7.6% in the <4 boluses/day group. The takeaway from these data are clear: remembering to bolus for food or hyperglycemia corrections can have a big payoff in improved treatment outcomes.

Decision Support Highlights

1. DreaMed Advice4U Study: Advisor Pro Pump Setting Decision Support System Non-Inferior to Expert Physician Advice; Dr. Revital Nimri Says “Equal is Perfect”

The much awaited readout of DreaMed’s Advice4U trial showed that use of the Advisor Pro yielded non-inferior results (p<0.0001) to expert physician advice in n=122 young people with poorly controlled type 1 diabetes. DreaMed Advisor Pro is a decision support system for pump setting recommendations. In this trial, it obtained pump and CGM data from the Glooko diabetes management platform and provided advice on various pump parameters (i.e., pump basal rates, insulin:carb ratios (ICR), and correction factors (CF)). In the Helmsley-funded trial, participants were randomized to either receive physician advice or Advisor Pro advice delivered seven times during a 24-week study. The two groups yielded almost perfectly identical Time in Range across the various cutoff points, establishing statistically significant non-inferiority. Average Time in Range was 55% in the Advisor Pro group and 54% in the physician arm. The secondary outcome, A1c, declined from a baseline of 8.4% to 8.1% in the physician group and 8% in the Advisor Pro group. DreaMed’s Dr. Revital Nimri commented, “Equal is perfect. If we put all our experience into an algorithm [that works], then we have done what we need to do.” The implication is that this automated “expert” system can be scaled to settings where diabetes experience is lower (e.g., primary care), to provide more frequent patient interactions, or to improve clinic visits by reducing the time spent analyzing data and more time discussing diabetes management. The potential for decision support systems is only growing as physicians and other providers become increasingly flooded with data-creating devices, such as CGMs, pumps, and smart pens.

  • Advisor Pro develops recommendations for pump settings based on insulin delivery, glucose, exercise, and food consumption data. The exercise and food consumption data is logged by the user in an app. Advisor Pro is already CE-Marked FDA-cleared to provide pump settings recommendations based on either CGM or SMBG data. In addition to basal rates, correction factor, and carb ratio recommendations, the system also provides some personalized behavioral diabetes management tips. Those tips and recommendations are reviewed by a provider and can be pushed to a patient through a smartphone app.
  • The Advice4U study compared the outcomes of young people aged 10-21 with type 1 diabetes who either used the DreaMed Advisor Pro (Advisor group) or received advice from experts from four specialized academic diabetes centers (physician group). The study was done at seven clinical sites, including four within the US. Six of the centers had at least four experts (one had two experts). The primary outcome was Time in Range and time below 54 mg/dl. At baseline, n=122 young people with an average age of 15.5 and A1c of 8.4% were randomized, but the trial reported a per-protocol result of n=60 – those who had completed at least five out of seven visits.
  • The TIR range results at 24 weeks for the two groups were strikingly similar and met the condition for non-inferiority with high statistical significance (p<0.0001):

Time in Range (Primary Outcome)

Very High

>250mg/dl

High

180-250 mg/dl

In Range

70-180 mg/dl

Low

54-70 mg/dl

Very Low

<54 mg/dl

Physician Arm

17.9%

23.9%

54.7%

2.6%

0.9%

Advisor Pro Arm

17.7%

24.6%

54.3%

2.4%

1.0%

  • A1c decreased in both groups over the course of the trial, declining 0.3% points in the physician group and 0.4% in the Advisor group; the difference between groups (0.2%) at 24 weeks was not statistically significant. The Advisor group used about 10% more insulin, but again it was not significant. Rates of adverse events were also similar.
  • A 50-item post-intervention survey demonstrated satisfaction with Advisor Pro and that it saved time.  Interestingly, physicians implied that there was some variation between the advice they would have given and the automated recommendations. Still, physicians gave the system a 4.5/5 rating for “reliable” and 4.5/5 rating for “useful.” Eleven out of 13 physicians reported that they would keep using the Advisor product. A full breakdown of the physician acceptance data is available in our ISPAD 2019 report.

2. Dr. Bruce Bode Looks Back and Forward at Automated Glucose Control Systems in Hospital Settings

Dr. Bruce Bode summarized decades of experience in delivering automated glucose control in the hospital setting. As background, Dr. Bode co-founded Glytec, a company offering the Glucommander glucose management system, which is currently in use by over 200 hospitals. The system, which covers the ER, ICU, step-down wards, discharge, and the transition to insulin at home, decreases mortality and complications and saves money, regardless of the underlying condition. In his talk, Dr. Bode covered the checkered history of glucose control in the ICU, noting that while normoglycemia radically improves outcomes, hospitals struggle to deliver it without increases in hypoglycemia. Given the practical limitations of the hospital setting, the logical approach to this problem is an automated system that takes glucose from meter readings and provides specific dosing recommendations. A plethora of data established that these systems save nursing time, decrease complications, decrease re-admission rate and complications after surgery. Despite this, only about 10% of hospitals use such a system, although it seems inevitable that they will become the standard of care.

  • In 2001, a seminal paper by Van Den Berghe established that controlling glucose in the ICU leads to dramatic reductions in mortality (about 30-40%) and improvements in a whole range of complications, such as infection. Many hospitals tried to replicate these results, leading to the classic NICE-SUGAR study in 2009, which yielded the frustrating result that attempting to attain normoglycemia across a broad range of ICU settings increased the rate of death. After the fact it became clear that it was hypoglycemia that caused the excess death. Many hospitals simply didn’t have the tools to lower glucose safely. Consequently, this led to the weakening of ADA recommendations for glucose in the ICU. Prior to 2001, average glucose was above 200 mg/dl, but from 2001-2007 the ADA target was 80-110 mg/dl, which was then relaxed after NICE SUGAR to 140-180 mg/dl.
  • In the United States, CMS is on the verge of imposing penalties on hospitals that cause hypoglycemic events. CMS is developing a hypoglycemia measure (<40 mg/dl and five or more minutes before the patient gets back to 80 mg/dl) for which they will require reporting and ultimately will levy a fine.
  • For all these reasons, reducing insulin-induced hypoglycemia is a critical issue. It’s remarkable to note that in a typical hospital, 40% of inpatients require insulin at some point. In the first place, 25% of all inpatient days are people with diabetes. 6% of hospitalized patients experience hypoglycemia, and readmission rates for people with diabetes are 20%. In a study at Florida Hospital, if a patient goes under 40 mg/dl at any point during their stay, it was found to cost an additional $10,000 and add about seven days to the length of stay. Mortality is also about three times higher. In Florida Hospital, severe or moderate hypoglycemia cost an excess of $45.6m over a twelve month period, which was largely eliminated using an automated system.
  • Given the inadequacy of current systems, an automated glycemic management system is the best approach for managing hyperglycemia and avoiding hypoglycemia. Currently, less than 10% of all hospitals are using such a system. Commercial computerized systems include Glytec, EndoTool, GlucoCare and Glucostabilizer. Dr Bode’s company, Glytec offers an extended glucose management system (called an eGMS) that covers the ER, ICU, step down ward, long term acute care (LTAC), skilled nursing facilities (SNF), and the discharge process and enables the transition to insulin at home. The system also integrates tightly with EMR and ICU systems.
  • The Glytec Glucommander system provides strong benefit, including time saved for nurses, cost savings to the hospital, and reduced readmission rates. In a test of the system at Kaweah Delta Medical Center, sliding-scale insulin management was almost completely replaced with eGMS, leading to a reduction in whole-stay average glucose from 204 mg/dl to 165 mg/dl, a 25% reduction in hypoglycemia under 70 mg/dl and a 75% reduction in hypoglycemia under 40 mg/dl. Length of stay was reduced by 25% and cost savings were $10m. In another example of patients admitted for diabetic ketoacidosis, the automated system reduced time spent above 200mg/dl from 17 hours to 14 hours and saved 1.5 days in the hospital per event.
  • Dr. Bode highlighted a study of automated glucose control following coronary artery bypass surgery (CABG) that yielded a 20% improvement in complications and 60% less readmission. Although cardiologists were initially very concerned about insulin induced hypoglycemia, the intervention caused no hypoglycemia at all. Patients ended up with an average glucose of 132 mg/dl versus 154 mg/dl in the standard of care comparator. The cost of hospitalization was 10.3% lower in the intervention group.
  • On discharge, an automated system can determine insulin requirements at home. Controlling glucose at home prevents re-admissions. For the hospital to home transition they system advises on the need for insulin and provides dosing information for basal/bolus.

Selected Questions and Answers

Q: What type of glucose measurements do you make?

A: There are only two point of care meters approved in our hospitals at present - Novo Biomedical and Roche. We are testing some CGM solutions, but we don’t have it in the product at this time

Q: Have you used the technology in an outpatient setting?

A: Yes, we have used it for titration of MDI and it works well. We are conducting a study with Abbott Libre. The system provides feedback by texting to their phone. A CDE also provides support for 500 patients.

Diabetes Drugs Highlights

1. Profs. Thomas Danne and Stephanie Amiel Face Off on Debate Over SGLTs in Type 1

To an absolutely packed room, Profs. Thomas Danne and Stephanie Amiel engaged in a thoroughly riveting debate on SGLTs in type 1, bringing much-appreciated novel perspectives to the often discussed lighting rod topic. Prof. Danne argued in favor of SGLTs in type 1 while Dr. Amiel took the opposite stance for the purposes of the debate. Following the debate, moderators asked the audience whether they would use SGLTs in type 1s without established CVD and whether they would use the class in type 1s with established CVD. On the first point, the room was split 40% yes and 60% no. On the second question, the room was overwhelmingly in favor, 95% yes to 5% no.

Overall, this debate was a tremendous back-and-forth of key points on a topic that we’ve heard from thought leaders extensively over the past few years, with many novel points emphasized throughout. We harken back to a similar debate between Drs. Bruke Perkins and David Nathan at ADA 2019 which was equally strong. Hats off to Profs. Danne and Amiel for an incredible debate – see the table below for a summary of the key points presented by both sides:

Are SGLTs as an Adjunct Therapy in Type 1 Diabetes Worth It?

IN FAVOR: Prof. Thomas Danne

OPPOSED: Prof. Stephanie Amiel

SGLT inhibitors provide clinically meaningful benefits on a host of metabolic and other parameters, including A1c (without increasing risk of hypoglycemia), weight, blood pressure, and time in range.

Dr. Danne summarized the numerous phase 3 trials of SGLTs in type 1, showing that these benefits have been consistently shown across multiple trials.

SGLTs have also been shown to increase patient quality of life

Type 1 diabetes is an insulin deficiency disease, and therefore the treatment of type 1 is insulin replacement. SGLTs do not directly address this fundamental pathological process in type 1.

Dr. Amiel believes that resources would be more properly spent on diabetes education for proper insulin usage vs. spending on SGLTs and ketone monitoring strips. 

Dr. Danne discussed the evidence pointing to cardio and renal benefits of SGLTs in people with type 2 diabetes and even without diabetes (DAPA-HF). He said that although there is no hard evidence yet that these benefits will translate to type 1, the need is clearly large and he believes that benefit can also be derived in this population.

Dr. Danne also made an impassioned call on this front, noting that in his work in pediatrics, the need for CV risk reduction is even greater, given that data from the Swedish registry shows that young girls with type 1 face 17 years of lost life and 14 years for boys due to CV risk w/ type 1.

Dr. Amiel pointed to real world DKA risk in the US of type 1s on SGLTs, which show rates much higher than in the background type 1 population. She explained that given these higher rates and normal rates of death from DKA, >1,700 people would die each year from DKA who were taking an SGLT in type 1.

Dr. Amiel questioned the applicability of the consensus paper on DKA risk mitigation. She pointed out that a few of the recommendations (such as “do not offer to people with lower BMI” and “do not offer to people on low insulin doses”) are not supported by data. She also questioned the practicality of “regular” ketone monitoring as defined by the paper, given the multiple cases where such monitoring would be needed.

Dr. Amiel also worried that providers in the real world would not actually look into these detailed paper and protocols when prescribing to patients, and therefore significantly elevate risk.

Also on DKA, Dr. Amiel noted that the largest DKA risk is actually in the 25-64 age range, which is the actual population we would actually want to most use this drug class in.

Dr. Danne conceded that there obviously is an increased DKA risk across the clinical trials, but that the numbers on this risk is low, and that this risk can be mitigated with proper education and training.

He pointed to the consensus document published last year on mitigating DKA risk and new educational tools that ATTD has created regarding DKA as important ways to help in educating clinicians/patients.

Dr. Amiel suggested that the weight loss effects may be overstated. Weight loss achieved by SGLTs is only 29% of that estimated from the calorie loss due to glucose excretion, and is actually coupled with a 13% increase in calorie uptake due to increased hunger. More generally, the positive glucose and weight effects seem to not persist past six months.

Dr. Danne emphasized that this is an important situation where it is important that patients have the choice to make an informed decision on whether they should be on this therapy or not, given the risk/benefit profile.

Dr. Amiel also mentioned higher rates of UTIs, especially in women, with SGLTs. She also brought up the reports of Fournier’s gangrene associated with the therapy.

2. Dr. Julio Rosenstock Peers into His Crystal Ball and Envisions Future Treatment Guidelines Focused on Combination Therapy Instead of Sequential Therapy

Dr. Julio Rosenstock provided a powerhouse speed lecture that highlighted his view that the future of type 2 treatment guidelines should move away from sequential treatment to early, aggressive combination therapy. Looking into his “crystal ball,” Dr. Rosenstock gave his hopeful prediction for what this may look like: (i) initial combination therapy with metformin and an SGLT-2 inhibitor/GLP-1 agonist becoming the preferred standard therapy in newly diagnosed type 2; and (ii) when basal insulin is needed, fixed ratio combinations of basal insulin + GLP-1 becoming the preferred option. Dr. Rosenstock’s talk here was an abridged version of a longer and more detailed presentation on a very similar theme at CMHC 2019 – see our coverage of that talk here. He noted in the opening of this talk that he was glad to see so much interest in the type 2 space at ATTD, and we would add that enthusiasm and interest from the audience was very high for this presentation.

  • Dr. Rosenstock detailed the evolution of treatment guidelines over the years, hammering home the point that they have mainly relied on sequential therapy recommendations. Traditionally, therapy has been “stepped-up” based on A1c checks over time for each patient, which has led to significant therapeutic inertia in terms of pursuing more aggressive treatment to successfully combat disease progression. Regarding ADA/EASD consensus guidelines updated in 2018, Dr. Rosenstock noted that although they do represent an important step in the right direction in terms of more seriously considering personalized CV risk, a more aggressive approach is still necessary. He commended session co-chair Dr. Chantal Mathieu for her work on putting together the guidelines as part of the writing committee but explained that “these guidelines are not going to take care of the problem of clinical and treatment inertia. We need to be more aggressive in management.”  In this vein, he harkened back to the famous Albert Einstein quote regarding insanity being “doing the same thing over and over again and expecting different results.” How long can the diabetes community continue to rely on a sequential treatment paradigm in diabetes care when outcomes are not necessarily improving for patients? Dr. Rosenstock firmly believes that it is time to deviate from this frame of thinking and move toward aggressive combination therapy use early on in treatment, especially considering the vast armamentarium of efficacious drugs (SGLT-2s, GLP-1s, fixed-ratio combos, and more) now available to patients.

  • Dr. Rosenstock listed out his principles for effective combination therapies, stressing that these principles simply “make sense” and are not “rocket science.” His six principles are: (i) components should exhibit complementary actions; (ii) glycemic control should be better with the combo than with each individual component; (iii) combined doses may be lower than each individual component alone; (iv) side effects should not be increased and ideally be mitigated with the combo vs. separate therapies; (v) treatment should be simplified as to improve adherence and persistence; and (vi) cost should be lower than the sum of the costs of each individual component.

  • Dr. Rosenstock pointed to results from the VERIFY study as a “proof of concept” regarding further adoption of combination therapies. Results from VERIFY for the first time provided robust evidence of durable glycemic control with initial combo therapy. As a reminder, VERIFY (presented at EASD 2019) showed that early combination therapy of metformin and Novartis’ DDP-4 inhibitor Galvus (vildagliptin) doubled the time to initial treatment failure vs. metformin monotherapy. We imagine that results would have been even more robust with usage of an SGLT-2 or GLP-1.

  • Dr. Rosenstock closed his talk with his own algorithm for simultaneous therapy-centric decision making. See slide below. At diagnosis, combo therapy of metformin + SGLT-2 is used, and thereafter a host of various combo therapies are utilized based off of A1c targets.

Big Picture Highlights

1. Passion for Prevention: Dr. Marian Rewers Gives Updated Type 1 Prevalence Stats from n=23,423 Children in ASK; IM Therapeutics to File IND for D-Methyldopa in March/April 2020

JDRF’s Dr. Jessica Dunne, Senior Director of type 1 prevention, and pediatrics luminary Dr. Mark Sperling led an enthralling, standing room only session on type 1 screening and early intervention. A number of presenters expressed gratitude towards the audience for coming to a session on prevention despite ATTD being a predominately technology-oriented conference. As Dr. Desmond Schatz (University of Florida Health) eloquently stated, “Thank you for being here while we pursue a biological cure and biological prevention, while at the same time, this meeting serves to update us on technology as we pursue an artificial pancreas.” Looking at the enraptured audience throughout the presentations, it was clear to us that screening and prevention both remain huge areas of interest for the broader diabetes community. Read on below for a selection of top highlights from the session.

  • Barbara Davis Center for Diabetes’ Dr. Marian Rewers opened the session with updated statistics from the Autoimmunity Screening for Kids (ASK) program – through January 2020 (!), detailing a substantial 1.0% prevalence of pre-symptomatic type 1 diabetes. As a reminder, ASK aims to identify children early in disease progression, in order to prevent DKA and potentially direct participants to further prevention studies, as well as collect epidemiological data. Thus far, ASK has screened an incredible n= 23,423 children from the Denver Metro area, of which more than 90% had no first-degree relatives with type 1 diabetes. As such, ASK is “truly a general population screening.” Furthermore, 51% of study participants were Hispanic, 35% non-Hispanic white, 8% African American, 2% Asian American, 1% Native American, and 3% Other or Unknown, making ASK one of the most diverse screening studies to date, with the potential to shed light on diabetes prevalence in minority populations.

    • Of the ~23,000 children screened, 796 (3.4%) tested positive at the initial screening, and 143 (1.0%) had persistent confirmation at second screening. Of the 1.0%, 122 (0.5%) tested positive for multiple islet antibodies, predicting a 70% ten-year risk of developing clinical diabetes, and 121 (0.5%) tested positive for a single high-affinity islet antibody by ECL, predicting a 49% ten-year risk of diabetes. Importantly, 90% of children detected did not have a relative with type 1. 

    • As one of ASK’s goals is to assess the benefits and cost-effectiveness of universal screening, we were also excited to see a recently submitted cost-effectiveness analysis for screening. The analysis, authored by Dr. R. Brett McQueen, showed that screening for type 1 diabetes will be cost-effective if it decreases the risk of DKA by 1 in 5 and subsequently lowers A1c by 1.0%. So far, of the 18 children who have developed diabetes after confirmation from ASK, only one has experienced DKA compared to the 11 that would be expected, hinting that cost-effectiveness could be feasible using the program’s screening and education program.

  • Co-founder & CMO of ImmunoMolecular Therapeutics (IM Therapeutics) Dr. Peter Gottlieb gave an exciting update on next steps for the company, including an upcoming NIDDK-funded phase 2 study (n=36) with TrialNet in children with pre-stage 1 or stage 1 diabetes for L-methyldopa, a drug traditionally used as an anti-hypertensive. Dr. Gottlieb anticipates that the trial will begin “late this year or early next year” and is anticipated to complete in March 2022, according to ClinicalTrials.gov. An earlier JDRF-funded phase 1b trial of patients with recent-onset type 1 and positive for DQ8 demonstrated that treatment with L-methyldopa successfully blocks HLA-DQ8 and reduces inflammatory T-cell response to insulin. The single-arm, open label dose escalation study (n=20) found that DQ8 presentation was at least 40% inhibited compared to baseline levels, while 85% of patients with inflammatory T-cell responses toward insulin showed reduction with treatment. Interestingly, while the upcoming TrialNet study and past JDRF study are examining L-methyldopa, Dr. Gottlieb confirmed that the company intends to take the drug’s chemical enantiomer D-methyldopa to clinical trial. As the human body does not metabolize D-methyldopa, Dr. Gottlieb anticipates that the drug should have a longer half-life, act more potently, and have fewer side effects, as many of L-methyldopa’s side effects are presumed to come from metabolization. IM Therapeutics plans to file an IND for D-methyldopa around April 2020, and a phase 1a trial is slated to start after June 2020. The company’s $10 million in Series A financing, led by the JDRF T1D fund and Morningside Ventures, will help fund these studies.

2. Dr. Richard Bergenstal Channels James Taylor’s “Fire and Rain”, Calls for Community to Focus on Improving “Rain” (Cascade of Diabetes Care) While Spotting “Fires” of New Diverse Causes of Mortality in Diabetes

On a talk focused on the worrying trend of increasing rates of diabetes complications after decades of progress, IDC’s esteemed Dr. Richard Bergenstal picked out three pieces of literature identifying causes for concern and gave his prescription for the path forward. After reviewing over 100 literature articles in preparation for this talk, Dr. Bergenstal honed in on three papers of note that brought the following problems to focus: (i) a stagnant cascade of diabetes care in the US (as evidenced by this recent JAMA publication); (ii) a resurgence of diabetes complications in recent years (evidenced by this JAMA viewpoint); and (iii) new, diversified causes of diabetes mortality (see this Lancet publication).

  • Dr. Bergenstal underscored that the current cascade of diabetes care in the US is inadequate, with only one in four patients at goal in terms of reaching goals for A1c, blood pressure, cholesterol, and smoking status. Of course, much of this can be attributed to the dismal state of healthcare coverage in the US, which Dr. Bergenstal said must be addressed. Outside of this, he noted that there needs to be innovations in terms of glucose management, seeing as this is often the biggest barrier out of those four factors. On this front, he called for a systematic new type 2 algorithm that he calls the “CKG” algorithm, which stands for CVD, CKD, and Glucose. The CKG moniker comes from the similar “EKG” acronym used in cardiology, and CKG focuses on the three main components that Dr. Bergenstal sees as critical to delivering high-quality diabetes care. Notably, the “G” for glucose can also stand for CGM and AGP, which Dr. Bergenstal importantly stressed as part of going beyond A1c when considering glucose. Invoking Albert Einstein’s famous quote on the definition of insanity, Dr. Bergenstal remarked that “Einstein would say that if you’ve been using A1c measurements to get better A1c’s for over thirty years, then maybe should probably try something different now [such as CGM metrics].” We couldn’t agree more, and as always, are thrilled to hear Dr. Bergenstal hone in on thinking beyond-A1c, especially in regard to type 2 care.

  • Along with focusing on the diabetes cascade of care and reducing complications, Dr. Bergenstal stressed that the field must simultaneously make sure not to miss the new “fires” of diverse causes of mortality. New epidemiological data show that declining rates of vascular disease mortality are leading to a diversification of forms of diabetes-related mortality, with important implications for clinical management, prevention, and disease monitoring. These “new fires” include often-underrecognized causes in diabetes for mortality such as sepsis, cancer chemotherapy, the flu, liver disease/NASH, and amputations. As rates of CVD improve in terms of treatment and mortality rates, clinicians and patients must not forget these other areas.

3. New Epidemiological Evidence Points to Association Between Diabetes and Cognitive Impairment

In a standing-room-only morning session, Johns Hopkins’ Dr. Elizabeth Selvin presented compelling epidemiological evidence for an association between type 2 diabetes and cognitive decline/dementia. Longitudinal results from the ARIC study – a population-based study encompassing the metro areas and surrounding suburbs of Minneapolis, MN, Jackson, MS, Winston-Salem, NC, and Washington, DC – demonstrated that mid-life diabetes is associated with a 19% greater degree of cognitive decline over 20 years (Rawlings et al. 2014; n=13,351) and late-life diabetes is associated with a 23% greater risk of cognitive impairment, the precursor to dementia, over five years (Rawlings et al. 2019; n=5,099). This rose to a 58% increased risk of cognitive impairment for people with longer (>5 years) diabetes duration, and a 73% increased risk for people with an A1c >7%. As discussed in the ensuing Q&A, the extent to which the greater risk of adverse cognitive outcomes with higher A1cs is due to hyperglycemia itself vs. greater glycemic variability remains unclear, and an active area of interest.

  • Diabetes is a well-established risk factor for dementia, conferring approximately double the risk, but the influence of diabetes on the preclinical stages of dementia has been less explored. The ARIC study’s demonstration that diabetes impacts cognitive decline and cognitive impairment strongly suggests that interventions to prevent or reduce the severity of diabetes could also be deployed as early-prevention efforts against dementia, before the first stages of cognitive impairment set in. What a win it would be for public health if two of society’s most costly and burdensome diseases, diabetes and dementia, could be addressed together with the same set of interventions! The idea of exploring glucose and metabolism-related targets for new dementia therapies is already an incredibly hot topic in the dementia world, and there has been increasing buzz about the possibility of repurposing diabetes drugs, particularly GLP-1 agonists, for Alzheimer’s disease. This is a field we’ll continue to watch very closely.

  • Dr. Selvin further underscored that the adverse impact of diabetes on cognitive extends to hypo- and well as hyperglycemia. Another analysis from the ARIC study showed that, over 14 years of follow-up, people with diabetes and a history of severe hypoglycemia had a ~2.5-fold greater risk of developing dementia than people with diabetes alone (Lee et al. 2018). With both hypo- and hyperglycemia implicated in the increased risk of dementia and cognitive impairment, we wonder whether cognitive protection could eventually become another piece of evidence for the importance of time-in-range.

  • On the type 1 diabetes side, Dr. Nelly Mauras (University of Florida) presented evidence of widespread hyperglycemia-related changes in the brain from MRI studies comparing children with vs. without type 1 diabetes.   Specifically, children with type 1 diabetes showed significant differences in gray and white matter growth in several brain regions over time, as well as greater brain activation during memory tasks – interpreted as an indication of compensation for detrimental structural brain changes. Dr. Mauras elaborated that her group is currently exploring whether these changes in the brains of children with type 1 diabetes can be reversed with intensive glycemic control. We remain curious whether these changes are unique to type 1 diabetes, particularly in the developing brain, or are also present in response to the later-life hyperglycemia that characterizes type 2 diabetes.

 

--by John Close, Natalie Bellini, Ani Gururaj, Abigail Dove, Rhea Teng, Martin Kurian, Albert Cai, and Kelly Close