American Diabetes Association 80th Scientific Sessions

June 12-16, 2020; Virtual; Day #2 Highlights

Executive Highlights

  • The first-ever virtual ADA has smoothly rolled into jam-packed day #2. Our team is checking in from over ten states across the US to access the immense learnings at this year’s ADA. If you missed, it be sure to catch up on our Day #1 report before diving into Day #2 below.

  • Diabetes technology:

    • Two study extension phases were presented on day #2, demonstrating sustained improvements from CGM vs. SMBG in two different populations. SILVER, the shrewdly-named 12-month extension phase for the Swedish GOLD study, showed a 0.35% A1c reduction and +2.1 hours/day Time in Range with Dexcom G4 vs. SMBG in MDI users out to ~2.5 years. Meanwhile, the SENCE 12-month extension showed sustained CGM use (Dexcom G5) and reductions in hypoglycemia in young children (ages 2-7). On a less positive note, even with CGM, the study participants still spent over half of the day in hyperglycemia (>180 mg/dl) and just ~40% of Time in Range.

    • A number of studies from today related use of CGM to reductions in acute diabetes events. Looking at insurance claims, IDC’s Dr. Rich Bergenstal presented striking reductions in acute diabetes events (-60%) and all-cause hospitalizations (-33%) among 2,463 adults with type 2 diabetes on short- or rapid-acting insulin who began using FreeStyle Libre. Later on, a large French observational study showed rates of DKA cut in half following FreeStyle Libre initiation. In a particularly memorable talk from the day, Dr. Irl Hirsch, self-admittedly not a healthcare economist, shared his back-of-a-napkin math estimating use of CGM could generate a potential $4.6 billion in hospitalizations related to DKA in the US alone.

    • CGM in type 2s was another hot topic during the day. Early in the morning, Onduo’s Dr. Ron Dixon presented retrospective data from the company’s virtual clinic, suggesting that CGM-use drove ~two-fold greater reductions in A1cs compared to SMBG across all baseline A1c levels. IDC’s Dr. Rich Bergenstal (who has been very busy through the first two days of ADA) presented some valuable tips and hints for using CGM in type 2s. Later in the day, Drs. Philis-Tsimikas and Elbert Huang held a debate on the value of CGM in type 2s.

    • See below for more, including Medtronic’s Analyst Day and diabetes technology and COVID-19.

  • Diabetes therapy:

    • An important new analysis of the DAPA-HF trial highlighted the potential of dapagliflozin in diabetes prevention, finding a 32% RRR in diabetes incidence with dapa vs. placebo in the sub-population of participants in the trial who did not have diabetes at baseline. This is the first evidence pointing the efficacy of SGLT-2 inhibitors in prediabetes, and the first to show possible use in diabetes prevention.

    • J&J’s immunotherapy golimumab showed very positive results in the phase 2 T1GER trial in type 1 intervention. The therapy showed significant and clinically meaningful effects on preserving beta cell function and reducing exogenous insulin use with a very favorable safety profile (golimumab is already FDA approved for multiple autoimmune conditions and marketed by J&J under brand name Simponi).

    • A late-breaking poster on vTv’s oral glucokinase activator TTP399 in type 1 diabetes detailed promising potential. Important benefits were seen on A1c and time in range – albeit at a lower level than part 1 of this same trial demonstrated – with an overall clean safety profile.

Table of Contents 

Diabetes Technology Highlights

1. Swedish GOLD Study Extension (n=107) Shows Sustained Effects with Dexcom G4 vs. SMBG Out to 2.5 Years: 0.35% A1c Reduction, +2.1 Hours/Day TIR, Satisfaction and Hypo Confidence Improvements

University of Gothenburg’s Dr. Marcus Lind presented strong results from the 12-month, SILVER extension phase of GOLD, comparing SMBG vs. CGM. GOLD was a 16-month Swedish trial, that enrolled 161 type 1s on MDI; after a 1.5-month run-in, participants were randomized to either SMBG or CGM (Dexcom G4) for six months, followed by four months of wash-out, and six-months of crossover. GOLD showed strong advantages for CGM vs. SMBG on every glycemic outcome, including a 0.4% A1c improvement and ~30 minutes per day less time <70 mg/dl (4.8% vs. 2.8%) – and this was with the G4, which was less accurate and less easy to use. Of the 141 GOLD trial completers, 107 were enrolled in the 12-month SILVER extension phase. In SILVER, all participants received CGM and had “brief consultations with a diabetes nurse” every three months. Compared to SMBG users at the end of the GOLD trial, switching to CGM produced a 0.35% A1c reduction (8.3% vs. 8.0%; p<0.001), 2.1 more hours/day time in range (51% vs. 43%; p<0.001 – this is a big deal), and significant reductions in hypoglycemia (falling from 7.5% time total to 3.7% total). As shown in the line graph below, A1c remained relatively steady through the entire 12-month extension, demonstrating the benefits of CGM were sustained beyond the initial 1.5-year trial. That said, getting to 53% time in zone means that 47% of their time was not in zone – it turns out most of it was above 180 but below 250, and although a 25% reduction in time over 250 is impressive, still being at 17% or four hours above 250 per day, is not nearly good enough – and, a bit shocking for Sweden. So, again – relatively speaking, yes it’s better, but in absolute terms, it’s not nearly good enough. The fact that this is consistent with an 8% (or 8.3%) A1c is also shocking since those are generally assumed to be “about the same.”

 

SMBG GOLD

CGM SILVER

Difference

A1c

8.3%

8.0%

-0.35%

Time <54 mg/dl

2.1%

0.6%

-1.4%

Time <72 mg/dl

5.4%

2.9%

-2.3%

Time in Range

43%

51%

+9%

Time >180 mg/dl

52%

46%

-5%

Time >250 mg/dl

24%

17%

-6%

Standard deviation

4.2 mg/dl

3.6 mg/dl

-0.6 mg/dl

  • Compared to run-in, CGM showed even stronger improvements compared to SMBG. The end of the SILVER extension study represents ~2.5 years from run-in, providing compelling evidence for the long-term sustainability of CGM benefits. Compared to run-in, CGM improved A1c by 0.5% (baseline: 8.5%) and boosted Time in Range by 2.7 hours/day (!), from 40% to 51%. Again – 51% is not close to being okay, this is nearly 12 hours time out of range. Hypoglycemia, while being significantly lowered, from 2.1% to 0.6% (-22 min/day; p<0.001) for time <54 mg/dl and 5.5% to 2.9% (-36 min/day; p<0.001) for time <70 mg/dl, was already pretty low, leading us to focus on the higher percentages of time that people are way off base.

  • As noted, the 51% Time in Range, even with CGM, is strikingly low. At ATTD 2020, we saw a post-hoc analysis of the GOLD study demonstrating how difficult it is to achieve the new consensus CGM metrics guidelines. In the study, just 3 out of the 137 participants analyzed met both A1c <7% and Time in Range >70% goals when using CGM, and only one participant met both goals on SMBG. 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.

  • The SILVER study showed sustained benefits with Dexcom G4 vs. SMBG on nearly all behavioral and satisfaction outcomes. Diabetes Treatment Satisfaction Questionnaire scores jumped from ~25 to 31 with CGM. Well-being, measured by WHO-5’s Well-Being Index, rose 11% from 60 to 66. The Swedish-Hypoglycemia Fear Scale showed significant improvements around worry and a reduction in hypoglycemia avoidance behaviors, though this second reduction was not statistically significant (p=0.07). Hypoglycemia confidence scores rose from 3.2 on SMBG to 3.45 with CGM (p<0.001).

  • Through the 12-month extension, there were 5 incidents (between 4 patients) of severe hypoglycemia and no DKA. None of these events were deemed to be related to CGM-use. In the original GOLD trial, there was a non-significant trend towards fewer severe hypo events with CGM: there were five events of severe hypoglycemia during SMBG (0.19 per 1,000 patient-years) vs. one event with CGM (0.04 per 1,000 patient-years).

2. SENCE RCT (CGM in Young T1s) 12-Month Extension: Sustained CGM Utilization and Hypo Reduction, but Still Over Half of Day >180 mg/dl

Yale’s Dr. Michelle Van Name presented 12-month follow-up data from the SENCE RCT of CGM in children ages 2-7, showing sustained CGM use and hypoglycemia reduction but no/minimal improvement in Time in Range or hyperglycemia. Positive primary outcomes from the six-month study were presented at ADA 2019. As a reminder, the 14-site trial randomized participants to three groups: CGM + a family behavioral intervention (FBI; n=50) vs. CGM with standard education (CGM-only; n=44) vs. SMBG (n=49). FBI consisted of five visits (weeks 1, 3, 6 13, 19) with additional training on using and living with CGM, using CGM away from home, CGM burnout, and more. The CGM groups used the Dexcom G5 non-adjunctively, with access to Dexcom Share. Participants were not on CGM at enrollment, so baseline metrics were derived from blinded CGM. After the six-month trial portion completed, 131 participants opted to continue using CGM for an additional six months, which is a pretty positive 92%—we’re not sure if G6 was employed during this follow-up phase. For the two CGM groups, the extension period consisted of CGM with no continued educational intervention; members of the SMBG control group who opted to continue were crossed over to receive CGM + FBI.

  • Positive finding #1: CGM usage remained high in both CGM + FBI and CGM-only groups at 12 months. 86% and 95% of children in the respective groups continued to wear CGM ≥6 days per week through the extension phase; compare these figures to 93% and 90% at six months. Overall, we think this is a pretty easy goal with the latest technology in particular, but particularly so with G4 and G5.

  • Positive finding #2: Hypoglycemia reductions observed at six months in both CGM groups were sustained at 12 months. Notably, in both CGM groups, time <70 mg/dl was approximately cut in half at 12 months (CGM+FBI: 69->36 mins/day; CGM-only: 81->39 mins/day). Similarly, percent time <54 mg/dl at 12 months as reduced to ~one-third of baseline levels (CGM+FBI: 30->10 mins/day; CGM-only: 35->12 mins/day – this was very positive, at over two hours per week). In accordance with these findings, the mean hypoglycemic event rate per week was also cut in half in both CGM groups at 12 months (CGM+FBI: 2.3->1.2 events/week; CGM-only: 2.8->1.2 events/week).

    • Those in the SMBG group who crossed over to CGM + FBI for the 6-12 month extension phase saw similar hypoglycemia benefit. From CGM initiation at six months to follow-up at 12 months, notably, although mean time <70 mg/dl fell by 54 minutes per day (6.2% to 2.4%), there was no change in Time in Range.

  • Cautionary reminder: Even after a year of CGM use, young children with type 1 diabetes in a rigorous study treated at top clinical centers are still spending over half of their days with glucose levels >180 mg/dl and just ~40% in-range. Because CGM use did not significantly reduce time >180 mg/dl in either CGM group, time in range hovered at ~40% across all reported measurement periods. This resonates with how hard it is to achieve the outcomes that everyone wants. While it is encouraging that there was no compensatory increase in hyperglycemia as a result of reduced hypoglycemia exposure (we guess), given all we know (and are learning) about the risks of hyperglycemia exposure and the legacy effect, we feel very strongly that future interventions must target the high end. As Drs. Lutz Heinemann and David Klonoff pointed out late last year in the wake of T1D Exchange Registry data showing drastically increased CGM adoption but also increased A1c, “Investment into CGM usage does not result in an automatic improvement in glucose control.” They go on to make the case for better, more comprehensive training programs and comparative studies of such programs. From our view, we hope people do not get too hung up on A1c – we imagine less hypoglcyemia overall and particularly less time in hypo, is increasingly prompting higher A1cs  - higher A1cs that could be higher-quality A1c.

  • Dr. Van Name highlighted the relative diversity of the study population (for a diabetes technology study), as ~1/3 were minority, ~1/3 were on a pump, and the mean A1c was 8.2%. More than one-third of study participants did not have private health insurance, and the majority of parents did not have a bachelor’s degree or higher.

3. Pre-/Post- Study Shows FreeStyle Libre is Associated with 60% Reduction in Acute Diabetes Events, 33% Reduction in All-Cause Hospitalization

In a retrospective pre-/post- study leveraging IBM Watson Health’s MarketScan database, presenter Dr. Rich Bergenstal (IDC) and co. found striking reductions in acute diabetes events (-60%) and all-cause hospitalizations (-33%) among 2,463 adults with type 2 diabetes on short- or rapid-acting insulin who began using FreeStyle Libre between November 2017 - September 2018. Though not without limitations (e.g., retrospective; no A1c data available; exclusion of Medicare fee-for-service and Medicaid populations; no access to socioeconomic or educational data), Dr. Bergenstal suggested this study offers “compelling support for the use of flash CGM to both improve clinical outcomes and potentially reduce costs in this patient population.” Notably, in the live chat off to the side of him presenting, this presentation incited optimism for CGM reimbursement as well as calls for researchers to take the next logical step for payers by calculating changes in expenditure. While true calculations of overall cost can be complex, Dr. Barry Ginsberg proposed simplifying by reporting cost-savings from reduced hospital days (~$8,000 each), and Dr. Robert Gabbay suggested extrapolating savings from A1c reductions. In the same chat, Dr. Irl Hirsch, a co-author, alluded to a poster (875-P) from the same group showing that FreeStyle Libre use is associated with reduced acute diabetes events regardless of prior blood test strip usage. He proclaimed, “the SMBG requirement [for Medicare CGM reimbursement] makes no sense.” Dr. Aaron Neinstein aptly responded, “Agree... the SMBG requirement is, in the parlance, bats$&$.”

  • Methods: MarketScan is a research database containing commercial and Medicare supplemental insurance claims for more than 30 million individuals in the US. Because it tracks down to the level of the individual and claims for health care facility utilization and pharmacy, the researchers were able to identify codes for inpatient/emergency outpatient utilization in the six months prior to and after the first use of FreeStyle Libre. Dr. Bergenstal commented that the database appears to hold “a reliable collection of data” due to the study participant characteristics: mean age 54 years, 90% with lipid disorder, 88% with hypertension, 60% with obesity, 48% with neuropathy, etc. 

  • As seen in the Kaplan-Meier plot below, there was clear (!) separation and 60% overall reduction (HR=0.40, 95% CI: 0.31-0.51, p<0.001) in acute diabetes events in the six months after vs. six months prior to first FreeStyle Libre use. Acute diabetes events are defined as a combination of inpatient and outpatient emergency events including hyperglycemia, hypoglycemia, DKA, hypoglycemic coma, and hyperosmolarity. Overall number of events fell from 221 (0.18 per patient-year) in the six months pre-purchase to 84 (0.07 per patient-year) in the six months post-purchase. In sub-analyses, this reduction was significant for both genders and across age (stratified by <50 and 50+ years). We’d love to better understand how it cuts across race and socioeconomic lines.


  • In the secondary outcome, there was a 33% reduction in all-cause hospitalization in the six months post-purchase vs. six months pre-purchase (HR=0.67, 95% CI: 0.58-0.77, p<0.001). Overall hospitalizations fell from 516 (0.42 per patient-year) to 331 (0.28 per patient-year). Dr. Bergenstal pointed out that, as expected, the number of endocrinology-related hospitalizations fell by 59% (6.4 per 100 patient-years to 2.6 per 100 patient-years). Also intriguing, he noted, against the backdrop of a resurgence in diabetes complications in the US, were reductions in hospitalizations for infectious disease, respiratory, renal, and hepatobiliary/pancreatic issues.

4. Use of Dexcom G6 Delivers Two-Times Greater A1c Improvements vs. Connected BGM Across All Baseline A1c Groups in Onduo’s Virtual Diabetes Clinic

Onduo’s Head of Clinical Affairs Dr. Ron Dixon presented data from the company’s Virtual Diabetes Clinic, demonstrating ~2x greater A1c reductions in participants who used CGM (Dexcom G6) vs. those using a connected BGM. The retrospective analysis looked at 612 Onduo participants from February 2018 – April 2019, comparing 213 participants who were initiated on Dexcom G6 with 399 who were not. Participants were well matched at baseline with a mean age of 53 and 54 years, mean BMIs of 35 and 36 kg/m2, and baseline A1cs of 7.8% and 7.7% for the CGM and non-CGM groups, respectively.

  • For the highest baseline A1c group (>9%), the CGM group saw a mean A1c reduction of 3.3% (!), compared to a 1.7% reduction (still massive) for the non-CGM group after six months (p<0.001 for between-group difference). Though less pronounced, the CGM group saw greater A1c reductions vs. non-CGM in every other baseline A1c grouping. For baseline A1c of 8%-9%, A1c reductions were 1.3% and 0.6% for CGM and non-CGM groups, respectively (p=0.004). For baseline A1c of 7%-8%, these reductions were 0.4% and 0.1% (p=0.02). Lastly, for those with baseline A1cs <7%, A1c rose by 0.1% in the CGM group and 0.2% in the non-CGM group.

  • As seen in the graphs below, using CGM as part of Onduo’s virtual clinic had a “flattening out” effect on participants’ A1cs across the initial A1c cohorts. While initial A1c in the groups ranged from <7% all the way to ~11%, after six months, mean A1c across all groups was between ~6%-8%. This reminded us of Dr. Rich Bergenstal’s (International Diabetes Center) presentation yesterday in which participants on MDI+SMBG were brought onto Medtronic’s Advanced Hybrid Closed Loop and saw their time in range shoot up from 45% to 65% (+4.8 hours/day). So often, clinicians and researchers seem to exclude participants who are CGM- and pump-naïve, and those with poor baseline A1cs, when in fact, they may have the most to gain from using technology like CGM.

At an Abbott-sponsored symposium, Dr. Irl Hirsch (University of Washington) shared his quick math estimating that in the US alone, the healthcare system could see an astounding $4.6 billion in DKA-related cost savings by using CGM in all people with diabetes.  Note that the following calculations come with Dr. Hirsch’s disclosure that he is not a healthcare economist. Dr. Hirsch’s math hinges on two recent studies from the UK (one from ADA 2019 and another published in Diabetologia in 2019) showing that the use of Freestyle Libre reduces DKA events and hospitalizations by 80%. Using an average cost of $26,556 per DKA-related hospitalization and 188,965 DKA-related hospitalizations recorded in 2014 (Diabetes Care, 2018), Dr. Hirsch calculated the cost of DKA in 2014 at ~$5.0 billion. Then turning to a medical inflation calculator, Dr. Hirsch estimated the cost of DKA hospitalizations in the US in 2019 at $5.73 billion. Using the 80% reduction in DKA hospitalizations using FreeStyle Libre from above, the total potential hospitalization cost savings comes out at $4.6 billion. This simple back-of-a-napkin calculation from Dr. Hirsch is pretty compelling evidence for, at the very least, expanding access to CGM to people with diabetes and cost-savings analyses will become increasingly important as the field continues to move into new populations, particularly basal-only or non-insulin type 2s.

  • Dr. Hirsch’s estimate for annual DKA-related hospital spending (~$6 billion) is a shocking number, but less than 2% of the CDC’s most recent estimate of $327 billion for the total cost of diagnosed diabetes in the US. Additionally, undiagnosed diabetes, prediabetes, and gestational diabetes has been estimated to cost another $77 billion. In classic Dr. Hirsch fashion, he tried to put some of these massive numbers into context, this time using three examples: (i) one billion seconds is equal to ~31.5 years; (ii) one billion pennies stacked on top of each other would make an 870-mile high tower; and (iii) if you saved $100,000 every year, it would take you 10,000 years to save $1 billion.

  • Dr. Hirsch also highlighted findings from a retrospective, observational analysis which showed immediate reductions of adverse events among patients with type 2 diabetes after initiating FreeStyle Libre. Additionally, there was a less significant, but still notable drop in all-cause inpatient hospitalizations with FreeStyle Libre. 

 

  • The real-world, prospective FUTURE study from Belgium showed reductions in adverse diabetes event hospitalizations, hypoglycemic comas, work absenteeism, and in days spent in the hospital due to diabetes events following nationwide reimbursement for FreeStyle Libre in type 1s. Dr. Hirsch pointed to the reduction in work absenteeism as being particularly notable, because it is an often-forgotten economic benefit from using continuous glucose monitoring systems.

  • Lastly, cost-effectiveness analysis of the 2017 2017 DIaMonD study (6-months of Dexcom G4 in type 1s) projected a reduced risk of long-term complications and a quality-adjusted life-year (QALY) increase of 0.54. Incremental cost-effectiveness ratio (ICER) for Dexcom G4 was $98,108/QALY with a 7-day sensor and $35,459 with a 10-day sensor. As Dr. Hirsch noted, US payers are open to paying for interventions <$100,000/QALY and most payers will cover interventions lower than <$50,000/QALY. UK’s NICE generally considers products conferring ~$30,000-$40,000 per QALY worth covering. We would anticipate the newer and improved CGMs would show even more promising long-term benefits. Dr. Hirsch focused these studies as providing strong evidence that CGM is a powerful, and underutilized, tool for bending the massive and quickly rising cost curve of diabetes. Many other clinicians have expressed similar sentiments, perhaps most eloquently written in a powerful commentary published last year in DT&T, calling current eligibility requirements for CGM insurance coverage “clinically irresponsible” and “penny wise and pound foolish.”

6. Medtronic’s ADA Analyst Day: $337 Million R&D Investment from Blackstone; No Publicly Shared Pipeline Timings Under New Leadership

On Friday evening, Medtronic hosted its annual one-hour Diabetes investor briefing, the first under new Diabetes Group head Sean Salmon – download the slides here and watch the webcast here. Obviously, a lot of airtime was dedicated to MiniMed 780G, which was really the star of the day on Friday (see read-outs from the US pivotal study, FLAIR trial comparing 670G with 780G, and a New Zealand study). Diabetes CMO Dr. Robert Vigersky gave most of the company’s remarks around MiniMed 780G, focusing on the system’s ability to increase Time in Range without increasing hypoglycemia, the system’s versatility across various populations (including teens and young adults), and ease of use (44%-46% fewer fingersticks vs. 670G, 95%-96% time in closed loop). Both Mr. Salmon and Dr. Vigersky also highlighted MiniMed 780G’s automatic correction bolus feature (which makes the system more forgiving of mistimed, miscalculated, or altogether missed meal boluses) and the ability to use a glucose set point of 100 mg/dl. Dr. Vigersky’s slides are on pages 15-22 and do a good job of highlighting key points from yesterday’s readouts – we’ve put a few down below, but you can get the full slide deck here.

  • Yesterday, Medtronic Diabetes announced a $337 million investment from Blackstone Life Sciences. That $337 million figure certainly jumps off the page and the funding will be used to “pull forward specific programs in [Medtronic’s] pump and CGM pipeline … beyond PCL [Personalized Closed Loop] and Synergy.” The funding will be used for “four identified Diabetes R&D programs”; when we had a chance to talk with Medtronic’s team this morning, we didn’t get many more details. If successfully commercialized, Medtronic expects to pay royalties in the “low- to mid-single digit range.”

  • Noticeably absent from this year’s presentation were anticipated regulatory submission and launch timelines for Medtronic’s pipeline products. See last year’s slides for comparison. On our call with Medtronic this morning, Sean Salmon noted that the company doesn’t want to “overpromise” to its patient and provider users. This seems like a prudent approach, as Medtronic, and many other diabetes device companies, have often failed to deliver on publicly announced products and timelines. “Reinvigorating” the CGM pipeline remains a priority for Medtronic, first with its “Zeus” sensor, which will bring calibrations to day 1-only in the US and zero calibrations outside the US. Synergy will bring a new, slimmer and fully-disposable design, along with an easier insertion process. An extended-wear infusion set remains in a US pivotal trial; CE-Marking was announced at ATTD 2020.

7. Drs. Philis-Tsimikas and Huang Debate Value of CGM in T2D; Clear Clinical Utility, but Case for Cost-Effectiveness Needs More Research and to Take the Who, What, and Where into Account

Drs. Athena Philis-Tsimikas (Scripps Whittier Diabetes Institute) and Elbert Huang (University of Chicago) debated the value of CGM in type 2 diabetes. Dr. Philis-Tsimikas bolstered the “pro” argument while Dr. Huang—admitting that he was assigned the more challenging side to defend—argued the “con.” Even as Dr. Huang made a strong economic-based case against the use of CGM in type 2 diabetes, he was primarily arguing that CGM shouldn’t be worn by all type 2s all of the time: “Should it be used for the whole population or are there subpopulations or moments for using CGM? As a technology for the entire type 2 diabetes population, the answer is probably that, no it’s not valuable to be deployed widely.” Both speakers were intrigued by the concept of “rental” (intermittent) CGM use and noted that the expected decline in cost in the coming years will tip the scale in the direction of value.

  • Wearing her clinician hat, Dr. Philis-Tsimikas wondered aloud: “Do we have to wait until someone who has type 2 diabetes for many years is on a complex medical insulin regimen and potentially has significant complications before providing them with a CGM to manage their disease?” She cited a handful of the early evidence of CGM benefit in non-MDI/CSII-treated type 2 diabetes: Erhardt et al (JDST 2011); Vigersky et al. (Diabetes Care 2012); Yoo et al. (Diabetes Res Clin Prac 2008); Lensing et al. (Diabetes Spectrum 2019); Allen et al. (Diabetes Res Clin Prac 2008); Cox et al. (Diabetes Care 2016); and Bailey et al. (DT&T 2016). These studies are all encouraging and range from prediabetes to basal-insulin-treated diabetes, but we’re in the early innings of building the evidence base for CGM in this population as many of them were small and short-term. Still, there is certainly enough evidence that both patients and providers can use CGM to improve clinical and behavioral outcomes to warrant further investigation. Dr. Philis-Tsimikas proposed that the value of can be improved (i.e., made more cost efficient) by integrating it into DSMES, leveraging AI tools to aid in data interpretation, using it intermittently and integrating with coaching, and by reducing/removing medications due to improvements from CGM.

  • Dr. Huang wore his economist hat (he’s also a physician), pointing out that not everything in health care can be “valuable” and there are budget constraints in the US health system. How then, given budget constraints, do we decide between spending money on CGM and spending money on other cost-effective interventions? While that question remains in the air, he did propose that CGM could be more valuable if it were used intermittently, the price were to decline, it were incorporated into the DPP without increasing programmatic costs (we’re not sure how this could work), improved glucose control while reducing need for medicines, and—most provocative—if we could show that it produces clinical benefits beyond glucose control, such as allowing people to social distance during the COVID-19 pandemic. We love this last idea of identifying positive externalities of CGM use and presenting them as opportunities for reducing cost! Dr. Huang also made the case that CGM use in type 2 diabetes hospitalizations and the long-term care setting is likely cost-effective, though that has not yet been studied.

    • The US is “famous” for spending >$10,000 per capita on healthcare annually (the highest in the world), for healthcare share of GDP that approaches 18%, for high obesity/diabetes rates and subsequent costs, and for high prices of services and products (insulin, for example). In this setting—exacerbated by COVID-19 and the likely coming depression—Dr. Huang explored whether CGM in type 2 diabetes is where we should be spending our marginal dollar. In type 1 diabetes, a lifetime of Dexcom CGM use was determined to be cost-effective in the DIaMonD trial, with an incremental cost-effectiveness ratio (ICER) of ~$98,000/quality-adjusted life-year (QALY). CGM is costly, but it’s A1c reductions are modeled to lower incidence of amputations, stroke, heart failure, renal disease, and other costly complications, resulting in a substantial QALY increase of ~0.5 years. Notably, with real-world use (e.g., extended sensor wear), ICER was reduced to ~$34,000/QALY—this shows that ICER for CGM in type 1 diabetes is highly sensitive to cost. In cost-effectiveness for type 2 diabetes, Dr. Huang pointed to two studies that have “wildly” different results: (1) Garcia-Lorenzo et al (J eval clin pract 2018) calculated an ICER of $198,453/QALY based on a meta-analysis of 5 studies; and (2) Fonda et al. (JDST 2016) calculated an ICER of $13,030/QALY. [Editor’s note: The cost of CGM use in Fonda et al. was significantly lower—$631.72—because it was used intermittently over the span of 3 months.] Fonda et al. point to the possibility of very cost-effective CGM, but there are many cost-effective interventions in diabetes, e.g., lifestyle, statin use for secondary prevention of CVD. How do we decide where to spend the marginal dollar? “Should a patient spend money on CGM over fresh food or medications?”, Dr. Huang posited. He also put forth that more data might not be better for mental health, and people might not share their data with their doctor, both of which could decrease the utility of CGM.

8. The “Frontline of Diabetes Care”: Dr. Richard Bergenstal Demonstrates Practical CGM Use in Type 2 and Hints at Further Uptake with COVID-19 Telehealth

“Is there anyone more grounding than Dr. Richard Bergenstal?” is a question we often ask ourselves while watching presentations from the Executive Director of Park Nicolett’s International Diabetes Center – today’s fantastic session on practical ways to personalize and optimize care using CGM was no exception. During the session, which came as part of Abbott’s industry symposium entitled “Translating Clinical Evidence for Sensor-Based Glucose Monitoring and Technological Innovations to the Front Line of Diabetes Practice,” Dr. Bergenstal treated us to one of his favorite rules-of-thumb: treat patients by both “thinking fast and slow” – “Fast” referring to in-the-moment therapeutic or behavioral changes based on real-time CGM numbers or trends, and “slow” meaning deliberative analyses of AGPs (many may also know the famous and Nobel-prize winning book by this name). To exemplify “slow” thinking, Dr. Bergenstal walked the virtual audience through a number of clinical examples, in which CGM led to practical, actionable changes in care.

  • For Jean, a 72-year-old woman with type 2, Dr. Bergenstal began by recommending HCPs ask the patient themselves to look at their ambulatory glucose profile (AGP) and self-identify areas that could be improved – although seemingly obvious, we found this tip to be quite useful in a time when both HCPs and patients may be rushed through in-person appointments or still trying to familiarize themselves with telehealth platforms. In Jean’s case, Dr. Bergenstal honed-in on her history of heart disease, and with a Time in Range of just 65%, recommended a long-acting GLP-1 to provide further cardio-protection and glucose management. Removal of Jean’s sulfonylurea further improved care by reducing time below 70 mg/dl.

 

  • Next, a man with type 2 diabetes exhibited what Dr. Bergenstal referred to as a “classic stair-step” AGP, in which glucose levels rise after each meal. The patient had previously tried and failed to tolerate a GLP-1 and had already worked up to 70U of insulin glargine at bedtime, with only 51% Time in Range and a worrisome amount of time in hypoglycemia . Dr. Bergenstal noted that he would recommend starting meal-time insulin, subsequently reducing glargine, and dropping the sulfonylurea. Dr. Bergenstal surmised that even one dose of prandial insulin at breakfast could improve the entire day’s outlook by preventing time above 180 mg/dL straight away.

  • In terms of “fast thinking,” Dr. Bergenstal shared a classic example of using trend arrows to better calculate insulin dose at mealtime. Patients can require vastly different doses depending on current glucose trends. Here, a patient with an “up” trend arrow, would need to add 3.5 units, while the same patient with a “down” arrow would need to reduce by 3.5 units, despite using the same insulin-to-carb ratio and correction factor calculation in each example.

  • Overall, Dr. Bergenstal’s very easy-to-understand clinical applications in patients with type 2 further highlight Abbott’s commitment to expanding into this patient population. During the company’s 1Q20 update, we estimated ~one million Freestyle Libre users with type 2, demonstrating Abbott’s undeniable headway into the field. Of course, Abbott’s low-cost CGM, in addition to its accessibility through the pharmacy, make it a very appealing option for payers, patients, and providers alike at a cost of $109/month, which is only $34/day.

  • Closing out his presentation, Dr. Bergenstal emphasized that the process of slowly working with patients through their AGPs “visit after visit, phone call after phone call” does seem to be translating well to telehealth during current stay-at-home advisories. As we imagine a healthcare system “after” COVID-19, we wonder if HCPs who have had to rely on CGM data during the pandemic will continue to prioritize the technology even when in-person visits are more of a possibility, and the CMS likely rolls back temporary exceptions for the treatment. From our view, they are likely to be much more enthusiastic about CGM following this work.

9. DKA Rates Among PWDs on Pump/MDI Cut in Half Following FreeStyle Libre Initiation in Large French Observational Study

Bichat Hospital’s Dr. Ronan Roussel presented compelling data from a nationwide cohort study (n=74,076 people with diabetes), showing that DKA rates were cut in half in the year following vs. preceding initiation of FreeStyle Libre. The analysis was performed using the SNDS database (the French reimbursement claims database), including type 1s and 2s on pump therapy or ≥3 injections/day (French reimbursement criteria) who had at least a year of follow-up. This cohort is made of 45% type 1s and 55% type 2s. As seen in the chart below, hospitalization rates fell by 52% for type 1 and 47% for type 2s (albeit from a lower base).  Improvements were observed in both pumpers and MDIers. And, while the improvement was seen across baseline strip usage, the most marked reduction was in the group who was registered as using zero strips per day. We’re noticing a greater push to generate evidence that baseline strip usage has little to no bearing on outcomes with CGM (see 875-P)—Medicare requires records of 4+ daily fingersticks before it will cover.

  • Remarkably, pharmacy claims show that ~1/4 of type 2s and type 1s on pump/MDI are using zero strips per day. Only roughly half are using at least four strips per day. It’s possible that they are obtaining strips through some other method (e.g., subscription bundle, black/gray market), but on its face, it is very striking that people who are dosing insulin multiple times per day are performing fingersticks so infrequently. Then again, this is one of the powerful forces underlying CGM adoption in this population.

  • Belgium has also reported very strong results from nationwide reimbursement of FreeStyle Libre. Their one-year follow-up report documents higher treatment satisfaction, less severe hypoglycemia (including coma), maintained A1c, and less work absenteeism.

10. Dr. Einhorn Describes the “New Era” of Diabetes Care Enabled by CGM and Telemedicine

During an Abbott product theater, Scripps Whittier’s Dr. Daniel Einhorn spoke excitedly about how the potent combination of CGM and telemedicine is bringing about “a new era” in diabetes care. On the CGM side, Dr. Einhorn provided a slate of Beyond-A1c aphorisms, such as “It’s the difference between having a synopsis vs. the whole short story.” He conveyed that adding telemedicine into the mix helps providers and patients get the most out of CGM: “In the old days we waited months between visits, and it would take years before people would get A1c lower. So those years are now being compressed to days and weeks. The idea of waiting three months between visits becomes silly because you can make decisions much faster [now with CGM]. We’re actually going to change the diabetes guidelines to reflect this possibility. The three-month adjustment cadence is artificial, based on A1c maturation. At the beginning I’ll see a patient a lot; when that person is stable, then I’ll see them less and less and less…If you need me every day, you got me every day. If you need me every six months, you got me every six months.” Dr. Einhorn’s team has the process down: Staff sets up the appointment through a telemedicine platform; the staff then emails/prints the preferred CGM reports for the provider; Dr. Einhorn then has a 25-30 minute discussion with the patient; Finally, the patient and doctor decide on a follow-up plan and set a time to follow up (“Historically, a month, two, or three later, but now, maybe a week or two later. It’s easier now”). This is undoubtedly a much-improved approach for diabetes care, but Scripps Whittier is a well-funded, diabetes-focused center. Even with the availability of codes for remote monitoring and CGM interpretation, reimbursement for more high-touch care (for those who need it, when they need it) is insufficient. CGM and telemedicine provide the technology, but there will likely need to be significant payment reform to encourage reorganization of care teams and delivery models before most clinics are able to offer the Scripps Whittier level of service. This is even more so the case at the primary care level, where the vast majority of people with diabetes are treated. But we’d love to be proven wrong!

 

Diabetes Therapy Highlights

1. Dapagliflozin in Diabetes Prevention? New DAPA-HF Analysis Finds 32% RRR in Diabetes Incidence w/ Dapa in Sub-Population of Patients w/o Diabetes at Baseline

Yale’s Dr. Silvio Inzucchi presented an intriguing analysis of the landmark DAPA-HF trial, suggesting that along with the robust CV mortality/heart failure benefits seen, an additional benefit with decreasing incident diabetes also exists. The analysis of diabetes incidence in the sub-population in DAPA-HF that did not have type 2 at baseline found that dapagliflozin treatment reduced the relative risk of incidence of type 2 diabetes by 32% when compared to placebo. After 18.2 months of median follow-up, 4.9% of the dapa group had been diagnosed with diabetes compared to 7.1% in the placebo arm (HR=0.68; 95% CI: 0.50-0.94; p=0.019). As a reminder, DAPA-HF was a dedicated CVOT (n=4,744) for a HFrEF population that included patients both with and without type 2 diabetes – at trial start, 45% of the population had type 2 and the remaining 55% did not have diabetes (n=2,605). Of these 2,605 without type 2 at baseline, 6% (n=157) developed type 2 during the trial. Of these 157, 96% had prediabetes at baseline (using ADA’s definition of an A1c between 5.7%-6.4%). People that progressed to type 2 diabetes in the trial were more likely to be heavier (BMI 28.5 vs 27.1; p=0.003), have a higher A1c at baseline (6.2% vs. 5.7%; p<0.001), and have a lower eGFR (61.5 vs. 68.2; p<0.0001).

  • How do these results compare to other type 2 prevention trials? Dr. Inzucchi explained that the relative risk reduction seen with dapagliflozin (32%) is on par with metformin treatment as established in past trials. Metformin treatment similarly showed a 31% RRR in decreasing diabetes incidence in the US DPP – however, it’s important to note that this was a dedicated prevention trial, while the results presented here is an analysis of a HFrEF CVOT. Still, we find these results exciting as the first evidence of SGLT-2 usage in prediabetes and normoglycemia, with potential prevention effects seen. Additionally – in DPP – they were trying to prevent diabetes and it was a very long trial – given the speed at which SGLT-2s work, this is interesting to see this DAPA-HF data right up against the other trials.

  • Dr. Inzucchi also reviewed broader metabolic outcomes from DAPA-HF, which were first presented at EASD 2019. A1c effects were minimal in both the type 2 group (~0.2% difference between dapa and placebo) and non-type 2 group (~0.1% difference). [We note that the smaller than usual A1c drop in the diabetes population was due to the decreased renal function at baseline seen in these HFrEF patients]. Within the non-type 2 group, A1c differences between dapa and placebo in the prediabetes and normoglycemic subgroups were also very minimal. Dr. Inzucchi urged the audience to keep this minimal A1c difference in mind when interpreting the effects on diabetes incidence – he noted that there is some debate between true diabetes prevention and simply “masking hyperglycemia.” The key to determining whether true prevention has been reached is whether long-term complication and mortality are impacted.

  • We’re glad to see this important benefit, type 2 diabetes prevention, that may be conveyed to HFrEF patients who can now take dapagliflozin regardless of type 2 status. As a reminder, FDA approved in May this added indication for Farxiga, making it the first SGLT-2 inhibitor to be approved for a non-diabetes specific population. While the larger effects of treatment are undoubtedly the immense CV mortality and heart failure benefits seen in DAPA-HF, our sense is that the community views the benefits of diabetes prevention as an important finding as well as question. How long it lasts is critical and we certainly hope there is funding to do important follow up or at least to monitor the patients.

2. J&J’s Golimumab Delivers Positive Results in Type 1 Intervention Trial; Significant Effects on Beta Cell Preservation + Exogenous Insulin Use at 52 Weeks w/ Favorable Side Effect Profile

In a moderated poster, Dr. Teresa Quattrin presented highly positive phase 2 results of J&J’s golimumab (TNF-alpha targeting immunotherapy) as a type 1 intervention therapy, showing significant and clinically meaningful effects in preserving beta cell function and reducing exogenous insulin use with a very favorable safety profile. The T1GER trial enrolled 84 participants, age six to 21 with newly diagnosed stage 3 type 1, randomized 2:1 to golimumab (subcutaneous injection every two weeks) or placebo for one year. On the primary endpoint of a four-hour MMTT C-peptide AUC at the end of the trial (a measure of beta cell function), golimumab achieved significance vs placebo (0.64 pmol/mL vs. 0.43 pmol/mL; p<0.001). While the placebo arm showed consistent declines on this measure over the course of the trial from baseline, the golimumab arm displayed little decline over time, indicating great promise in the drug’s ability to arrest type 1 progression and protect beta cell function (see figure below).

 

  • Golimumab treatment also conferred a significant reduction in insulin use. The golimumab arm had a significantly lower change from baseline in insulin use compared to placebo (LS mean change 0.07 U/kg/day vs. 0.24; p=0.001). This is a meaningful difference and further supports golimumab’s efficacy in protecting beta cell function. Notably, both groups achieved “good” treat-to-target glycemic control, as A1c change over the course of the trial was not significantly different between treatment and placebo. CGM was not used in the trial, although we would have loved to see if there were any potential time in range benefits with golimumab treatment.

  • About ~40% of participants were responders to golimumab treatment in terms of having a significant effect on C-peptide levels or being deemed in “partial remission,” compared to ~10% in the placebo group. We note that the definition for "responder" was quite strict as used, and that all patients on treatment in the trial saw some sort of positive response. C-peptide responders were those with an increase or ≤5% decrease in C-peptide AUC from baseline, and partial remission was defined as having an insulin dose-adjusted A1c remission score of ≤9 at week 52. 29% of people on golimumab were both C-peptide and partial remission responders, compared to only 4% for placebo. We’d love to see what could be done to identify characteristics of these responders in order to better target treatment to people that could benefit most.

    • People on golimumab treatment did not see a marked increase in the ratio of proinsulin/C-peptide levels over time, while those on placebo did. This measure of proinsulin/C-peptide levels is another marker of beta cell function, with lower levels indicating more efficient proinsulin processing.   

  • Golimumab had a relatively clean safety profile, consistent with the known safety record of the drug. Overall occurrence of adverse events were balanced between treatment and placebo (91% vs. 82%, respectively), and serious adverse events were very uncommon (2% vs. 4%). Adverse events related to study drug were the same in frequency between golimumab and placebo (43%). Most common adverse events were infections, which occurred most frequently in the upper respiratory system – this is expected with immune therapies, and in line with the known safety profile of golimumab. There was a numerically higher rate of hypoglycemia with golimumab treatment (23% vs. 7%); however, this was mainly attributed to higher rates in both treatment and placebo groups at one specific study site.

    • Regarding safety, it’s important to realize that golimumab has a long track record of use with a known safety profile. Golimumab is already FDA approved for the treatment of several autoimmune diseases that include rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, and ulcerative colitis, and is currently marketed by J&J under the brand name Simponi.

  • T1GER’s study design also includes a 52-week off-drug follow-up period. Our understanding is that participants in the trial will be routinely checked on for the year following the initial 52-week treatment period of the trial. We’ll be curious to see if effects with treatment persist in this follow-up period, as this will have important implications for what dosing and long-term treatment may look like for usage of the therapy in real-world settings.

  • In an informative conversation with our team, lead investigator Dr. Teresa Quattrin characterized these results as “extremely positive” and highly clinically significant. Dr. Quattrin explained that the benefits seen with golimumab treatment are very meaningful for patients and their families. She noted that the ability to achieve “partial remission” is extraordinary and may help to reduce the intense trauma that is often underappreciated in terms of what patients and families experience when being informed of a type 1 diagnosis. Any drug that can modify or even arrest type 1 progression can have a huge impact for patients, and it certainly appears that golimumab is able to produce these benefits with a tolerable safety profile. On this point, Dr. Quattrin commented that given the known safety profile of golimumab, she sees no reason why the therapy cannot be considered a long term treatment option past 52 weeks. She hypothesized that benefits with this treatment may also be seen with intervention even earlier on in type 1 progression, namely in people with stage 2.

  • Dr. Quattrin also helped to contextualize these results with those seen for teplizumab in type 1 prevention. While acknowledging important differences in study design and populations, Dr. Quattrin pointed to the unique mechanism of action of golimumab (targeting TNF-alpha vs. anti-CD3 mechanism for teplizumab), the well-known safety profile for golimumab, and the more favorable method of administration for golimumab (subcutaneous injections every two weeks at home vs. two week outpatient IV course of teplizumab). As a reminder, teplizumab’s rights are currently owned by Provention Bio, with the company in the midst of attempting to bring the therapy to market. Provention has initiated a rolling BLA submission review with FDA, with hope of approval as soon as mid-2021. Landmark results from the teplizumab type 1 prevention trial were presented last year at ADA 2019. (We note that J&J was an initial investor (with JDRF) in Provention Bio). We’ve been thrilled to now see multiple positive results emerge in this space since then, including these results with golimumab and results for Novo Nordisk’s combo therapy of liraglutide + anti-IL-21 (also to be presented at ADA 2020).

3. Powerhouse KOLs Talk Challenges in Clinical Trial Design, Lack of Proper Type 2 Screening, and Over Emphasis on “Beta Cell-Centric” Medications at Annual ADA Diabetes Care Symposium

We caught up with the fantastic team at Diabetes Care (and a number of our favorite KOLs in the group chat) at the publication’s annual symposium at ADA. Moderated by Editor-in-Chief Dr. Matthew Riddle (OHSU, Oregon), this year’s symposium took an expansive lens to “Long-Term Perspectives on the Study and Care of Diabetes.” As Dr. Riddle put it, “diabetes is a life-long illness, and the study of outcomes should be a long-term process” – we couldn’t agree more, especially in light of the vigorous debate surrounding FDA guidance on cardiovascular outcomes trials moving into the next decade. In addition to insightful presentations from a star-studded list of speakers – including University of Oxford’s Dr. Amanda Adler, Karolinska Institutet’s Dr. Lars Rydén, and University of Washington’s Dr. Steven Kahn – Dr. Riddle also presented this year’s Profiles in Progress awards, dedicated to researchers and physicians who have made a lasting impact in diabetes. Be sure to check out the very moving profiles on Drs. Robert Henry, Fred Whitehouse, and Daniel Porte Jr before diving into our highlights from the symposium below.

Dr. Amanda Adler on the Evolution of Clinical Trials

Premier diabetes health policy expert Dr. Amanda Adler led the audience through the “key drivers” of evolution in clinical trials, in what Dr. Julio Rosenstock later referred to as the “best lecture ever” on the topic. Dr. Adler opened her commentary with an enlightening quotation from cancer statistician Dr. Don Berry: “it is ironic that we take the same clinical trial approach to evaluate all manner of potentially amazing transformative experimental therapies and yet we don't experiment with the design of the clinical trial itself.” Dr. Adler emphasized a number of current points of discrepancy – most notably, (i) inconsistent following of regulatory guidelines, despite a push towards “harmonization” between multiple geographies and institutions (we can harken back to the PROactive study for pioglitazone in macrovascular events, which seemed to conjure a secondary end point that reached significance out of thin air); and (ii) insufficient acknowledgement of the risk of false positives during interim analyses. On the latter point, statistician Mr. Ben Goldacre noted, “if you stop a trial early, or late, because you are peaking at the results as it went along, you increase the chances of getting a favorable result.” This same concern can also be applied to “futility” analyses, which halt clinical trials ahead of schedule due to the unlikely achievement of study objectives.

  • These discrepancies are also of great interest when considering the aforementioned 2020 draft guidance on safety trials for type 2 diabetes. Many KOLs have separately voiced concern that the agency seems to be returning to a more “glucose-centric” approach to trial design, and Dr. Adler pointed out that the new guidance no longer mandates CV safety trials, which previously unearthed signals like saxagliptin’s heart failure risk in SAVOR-TIMI and canagliflozin’s amputation risk in CANVAS. At a session yesterday on the guidance, the FDA’s Dr. Lisa Yanoff and Peter Stein however steered audience members to the new longer-term treatment exposure and usage in older patient and patients with comorbidities such as CVD/CKD guidelines. However, whether or not the required patient numbers or patient years will be enough to identify risk signals has yet to be seen.

  • All in all, Dr. Adler assured audience members that she believes clinical trials are “here to say,” despite a push from some drug developers to prioritize real-world clinical evidence. As to how clinical trials can be improved, Dr. Adler highlighted advances in long-term modeling and encouraged the use of underutilized trial designs, such as “basket trials,” which group participants by genetic mutation rather than phenotypic manifestation and “stepped wedge cluster randomized trials,” which can be used when simultaneous rollout is impractical.

Dr. Lars Rydén on Type 2 and Coronary Artery Disease

Sweden’s ever-informative Dr. Lars Rydén gave a compelling argument as to why he does not believe atherosclerotic heart disease is inevitable in patients with type 2 diabetes, given the right screening and management practices. On the diagnostic front, Dr. Rydén noted that often patients who have acute coronary symptoms are unaware that they have diabetes or impaired glucose tolerance (IGT). Numerous studies, including the Euro Heart Survey and China Heart Survey, have uncovered that ~1/3 of patients with acute coronary symptoms have unknown prediabetes and another ~1/3 have unknown type 2 diabetes. Dr. Rydén further emphasized that dysglycemia is harmful even before the onset of diabetes and “having diabetes” or “not having diabetes” should not be treated as a dichotomous variable. Relatedly, most current guidelines only recommend that patients with coronary artery disease are screened using A1c and fasting glucose levels when oral glucose tolerance testing (OGTT) is the only procedure that can truly identify IGT for earlier intervention. Dr. Rydén demonstrated this point using data from n=4,400 patients with unknown glycemic state under the ESC’s European Observational Research Programme (EORP); Without the OGTT, 30% of patients with type 2 and 70% of those with IGT would not have been detected. As such, Dr. Rydén believes every coronary heart disease patient without known dysglycemia should be screened using OGTT.

  • Once diagnosed, a wide array of multifactorial barriers is preventing better outcomes, including persistence of smoking, lack of physical activity, poorly implemented blood pressure and LDL-C control, and slow uptake of glucose-lowering drugs. Looking ahead, Dr. Rydén encouraged greater bridging between cardiology, endocrinology, and primary care, streamlining of guidelines (“we don’t need 10 guidelines of the same thing”), and reinforcement of lifestyle (and addition of a GLP-1) at screening to possibly “save many lives in the future.”

Dr. Steven Kahn on Limiting the Progression of Type 2 in Youth and Adults

With quite the deft hand, Dr. Steven Kahn dissected the distinction between insulin sensitivity and beta cell function in the development of type 2 diabetes, in order to shine a light on possible directions for future therapies. Too often, these two aspects of disease progression are confounded rather than carefully examined as separate factors. A previous NEJM article from Dr. Kahn on why glyburide had the most positive effects compared to rosiglitazone and metformin on the short-term but the worst benefit on the long-term suggested that declining beta cell function may be largely to blame. This finding is however not unique to glyburide, and Dr. Kahn suggested that any medication that works primarily on beta cells will lead to failure over time.

  • Using data from the TODAY study in youth and ADOPT study in adults, Dr. Kahn underscored that while 50% of youth failed on metformin monotherapy by 39 months, only 13% of adults had failed at this same timepoint. Of course, the patient populations and protocols vary slightly between the two studies, however the data seem to suggest that disease progression in youth is much more rapid and severe. This supposition was further corroborated by the RISE study, which found that youth beta cell function deteriorated during metformin or metformin + glargine treatment, while adult beta cell function improved during the intervention (though this benefit was not sustained post-treatment).

  • In terms of next steps, Dr. Kahn recommends further investigation into disease progression between youth and adults with type 2. Whether or not youth will follow a similar disease progression to adults who develop type 2 later in life of if their prognosis will be far worse has yet to be determined. In addition, he pointed to the earlier instigation of metformin therapy as a potential preventative measure. Full results from the GRADE study, a long-term study evaluating glimepiride, sitagliptin, liraglutide, and glargine, is also set to read out at next year’s ADA and will shed some important light onto this arena. We’ll be particularly excited to see how liraglutide performs but lament that SGLT-2 inhibitors were not yet approved at the study’s inception.

  • For his “ideal” glucose-lowering approach to treating type 2 diabetes, Dr. Kahn postulated a medication that (i) improves insulin sensitivity, subsequently reducing beta cell deterioration by decreasing secretory demand; (ii) reduces the loss of beta cells; and (iii) reduces weight or is at least weight neutral. University of Glasgow’s Dr. Naveed Sattar gave ample support in the session’s “chat box” for treatment options that prioritize substantial and sustained weight loss – one of the most difficult frontiers in cardiometabolic medicine today. 

4. Simplici-T1 Part 2 Affirms Strong Safety Profile, Time-in-Range Increase with vTv’s Glucokinase Activator TTP399 in Type 1 Diabetes, but A1c Benefit Less Clear

A late-breaker on vTv’s phase 1b/2 Simplici-T1 trial of once-daily, oral, liver-selective glucokinase activator TTP399 (800 mg) in type 1 diabetes (122-LB) supported the candidate’s positive effects on A1c and time-in-range, albeit at a lower level than Part 1 demonstrated – see table below. As a reminder, full results from Part 1 of the trial (n=19) were presented at EASD 2019 and in a company webcast; all 19 of these participants used both insulin pumps and CGM. Topline Part 2 results were released in February. Importantly, Part 2 was reportedly conducted in a in a larger, “broader” population with type 1 (we’ve yet to see this characterized), over 12 weeks, and study drug was added to an optimized insulin regimen. The poster emphasized that prior oral adjuncts for type 1 have been hampered by hypoglycemia and ketoacidosis, highlighting a key strength of TTP399: so far, the candidate has raised no safety concerns. Additionally, vTv previously reported that the TTP399 group in Part 2 reported fewer symptomatic hypoglycemic episodes vs. placebo (one vs. eight). While the safety profile of TTP399 remains clean, we’re eager to see its efficacy further characterized in phase 3. Reminiscent of SGLTs in type 1, this candidate seems to be stronger on increasing time-in-range than lowering A1c – this drug seems to hold great potential for patients, but remember: FDA guidance states that a 0.3% improvement in A1c is considered clinically meaningful. Read on below for more on vTv’s future plans for TTP399.

 

Part 1 (n=19)*

Part 2 (n=85)

Baseline A1c

7.4%

7.6%

A1c change

-0.7% (p=0.03)

ITT: -0.2% (p=0.03)

Trial product estimand: -0.32% (p<0.01)

TIR (70-180 mg/dl)

+12% or +2.9 hours (p=0.04)

+7.8% or +1.9 hours (daytime only, p<0.05)

Bolus insulin

-23% active vs. -4% placebo

-11% active (p=0.02)

Severe hypoglycemia or DKA

No reports with TTP399

No reports with TTP399

*Note: Part 1 results for time-in-range reported on this poster are slightly different from those previously reported by vTv, which showed a +11% (+2.7 hour, p=0.055) increase in time between 70-180 mg/dl.

A responder analysis of Phase 2 data found 42% of the TTP399 group vs. 12% of the placebo group were “responders”, defined as improved A1c with no severe hypoglycemia, increase in insulin dose, or abnormal beta-hydroxybutyrate or lactic acid.

  • vTv is already is discussion with FDA on a pivotal study for TTP399, and our sense is that the company is very committed to further development of TTP399 for this indication. vTv planned to initiate phase 3 in 2020, but the timeline is now unclear. Of note, Simplici-T1 was sponsored by JDRF – we’ll be interested to see if/how the non-profit remains involved.

  • TTP399 is unique in clinical diabetes drug development: It is the singular glucokinase activator under investigation in type 1 and one of only two clinical-stage glucokinase activators, to our knowledge. China-based Hua Medicine’s dorzagliatin boasts positive 26-week results in a phase 3 type 2 diabetes study, and a phase 1 trial (n=15) in the US combining dorzagliatin with DPP-4 sitagliptin was completed last August. vTv’s agent was also initially investigated in type 2 diabetes, and the phase 2b AGATA trial – which read out back in 2016 – demonstrated A1c lowering comparable to sitagliptin. 

  • The clinical and commercial potential of TTP399 is much stronger in type 1 than type 2 diabetes, and while vTv will have to face the uncertain landscape of adjunct therapies for type 1 diabetes, we are eager to learn more about the side effect profile. The SGLT-2 for type 1 advocacy work was going well (in its infancy) and then when the euglycemia curveball was hit, the type 1 field (not to generalize) was not unified in how to approach – probably because ultimately, safety was hard to determine. By contrast, there does not seem to be a safety issue with TTP339 to date, and all the same “unmet need” arguments are still exactly the same. The failure of insulin and its current delivery systems to effectively manage type 1 diabetes for most people is widely recognized, and yet the field has not been able to bring a safe and effective adjunct therapy to market since the 2005 approval of AZ’s Symlin (pramlintide) – though not for lack of dedicated and diligent effort. A patchwork quilt of adjunct and other therapies, each appropriate for a specific type of patient, has been pieced together (see Dr. David Harlan at ENDO 2020): GLP-1s for those with residual insulin production, SGLT inhibitors for the highly-diligent – or at the provider’s discretion, inhalable mealtime insulin Afrezza for those who can access it (or whose HCPs know what to do). Side effects and major risks have hampered widespread success – most prominently the small (in relative terms though in absolute terms, big, for anyone who experiences it) but serious risk of DKA with SGLT inhibitors. With any new adjunct therapy for type 1, eyes will be on the side effect profile as much, if not more than, the efficacy. We note that previous GKA candidates from Lilly/Yabao (phase 2 trial terminated prior to initiation) and Ligand (preclinical candidate discontinued) have been terminated, and though the reason for these decisions is not clear, one doesn’t have a completely optimistic view with those experiences.

    • Mechanistically, TTP399 is thought to actually lower ketone levels: It activates the enzyme – glucokinase – that traps glucose inside liver cells, promotes further glucose uptake and breakdown, and keeps the liver in a “fed” state – preventing ketone production. Because glucokinase activity is lowered in people with type 1, TTP399 directly targets some of the pathophysiology associated with the disease – a possible advantage over other adjunct therapies though admittedly we do not really understand the implications.

    • In a huge vote of confidence, Dr. John Buse (during a vTv webinar) called glucokinase activators the most promising of all diabetes drug classes for type 1 diabetes. At the time, he commented: “If [these results] hold up in part 2 of the trial, TTP399 will be the most impressive adjunctive therapy to insulin in type 1 diabetes care.” We’re keen to see how KOLs in type 1 receive these results – while the side effect findings are clearly positive, we’re curious how the efficacy results will be viewed.

5. Lilly and Novo Nordisk Highlight Competing Real-World Data Touting Trulicity and Ozempic, Respectively

  • Lilly promoted a poster that found Trulicity as having a higher adherence and persistence than Novo Nordisk’s Ozempic and AZ’s Bydureon after six-months of follow-up. The real-world observational study compared six-month adherence and persistence rates amount patients initiating one of these GLP-1, using insurance claims from the HealthCore Integrated Research Database. Trulicity users were then propensity matched 1:1 to Ozempic or Bydureon users. After six months, at least according to how data was collected, it was seen that Trulicity users were more likely to be adherent and less likely to discontinue therapy than both Ozempic and Bydureon users (see table below for the full data). Adherence for Trulicity (defined as having a proportion of days covered ≥80%) was 60%, compared to 43% for Ozempic and 40% for Bydureon. Persistence (defined as how long on average patients stayed on treatment) for Trulicity was 144 days, compared to 130 days for Ozempic and 121 days for Bydureon. Treatment discontinuation rates were 31% for Trulicity vs. 41% for Ozempic and 49% for Bydureon. From our point of view, while we’ve heard considerable patient enthusiasm for Trulicity stemming from its friendly once-weekly dosing and IDEO-designed autoinjector pen, which may help to explain these results, we’ve also heard very positive feedback on Ozempic and Bydureon. Nonetheless, we still believe that as a whole, too few patients are on any GLP-1 agonist, and that the field must first focus less on intra-class differences and simply on ensuring that any patient who may benefit from a GLP-1 can get on one.  

  • Novo Nordisk highlighted data from a real-world study, EXPERT, that demonstrated the efficacy of Ozempic in patients with previous GLP-1 exposure. The EXPERT trial used prescription data to examine patients who switched from a GLP-1 to Ozempic. In these patients that switched to Ozempic, significant reductions in both A1c and weight were seen (2.2% drop for those w/ baseline ≥9% and 1.1% for those w/ baseline ≥7%). A similar pattern was seen with weight loss, as an average of 2.2 kg weight loss was seen after six months and 3.5 kg loss at 12 months after switching to Ozempic. These results confirm the impressive efficacy seen in the SUSTAIN program for Ozempic that highlighted the therapy as being leaps and bounds above its competitors in the GLP-1 class in terms of delivering meaningful outcomes on A1c and weight. Importantly, since the SUSTAIN program only employed Ozempic in GLP-1 naïve patients, these data add important new context surrounding the use of Ozempic in patients who may have already tried GLP-1 therapy. Digging deeper, we’re curious to see how the data might reveal differences in outcomes regarding which specific GLP-1 therapy a patient switched from before using Ozempic – were effects consistent across each therapy?

6. Is 54 or 70 mg/dl More Important? Prof. Heller and Dr. Kowalski Discuss the Value of Hypoglycemia Measures to Patients, Providers, and Payers

In a morning symposium on hypoglycemia and new diabetes therapies, Sheffield’s Professor Simon Heller and JDRF President and CEO Dr. Aaron Kowalski discussed the importance of measuring blood glucose ≤54 mg/dl and ≤70 mg/dl, respectively. The argument made for each reflected both the information the measurement provides and these speakers’ personal and professional backgrounds. Prof. Heller is perhaps the foremost scholar on the clinical consequences and pathophysiology of hypoglycemia. He emphasized that a blood glucose of ≤54 mg/dl, more so than ≤70 mg/dl, is associated with cognitive and physiologic dysfunction, a better discriminator of treatment differences, and more likely to persuade regulatory and reimbursement authorities as to the value of new diabetes drugs. Dr. Kowalski – an accomplished research and scientist as well as also a person with diabetes and a prominent patient advocate – focused more on the real-world implications of glucose ≤70 mg/dl for patients. His central thesis was that hypoglycemia, including these mild drops in glucose, remains a major barrier to tight glucose control. From a patient perspective, ≤70 mg/dl generally requires action and can contribute to rebound hyperglycemia or fear of future hypo. The symposium, moderated by King’s College’s highly regarded Professor Stephanie Amiel, was riveting and highly cooperative. While the presentation titles assigned to these speakers seemed in direct opposition, they were ultimately in vehement agreement that both measures are of critical importance. Here’s a bird’s-eye view of each presentation:

  • Professor Heller framed ≤54 mg/dl as a middle ground between ≤70 mg/dl (very common, but less impactful overall) and severe hypoglycemia (rare, but critical to patients and the healthcare system). He explained that the International Hypoglycaemia Study Group (IHSG, a 15-member group formed in 2013) felt that 70 mg/dl was an important alert threshold. However, it is also of unclear health and economic relevance, which makes it difficult to persuade reimbursement authorities to make decisions on clinical trial data that includes only differences in hypoglycemia ≤70 mg/dl. On the other hand, he also highlighted how challenging it is to demonstrate an impact on severe hypoglycemia because the outcome is so rare in clinical trials. This led the IHSG to a strong case for ≤54 mg/dl, a level with more physiologic implications than ≤70 mg/dl but that occurs more frequently than severe hypoglycemia. To support the clinical relevance of ≤54 mg/dl, Prof. Heller presented a handful of studies linking blood glucose of 50-55 mg/dl to impaired cognition, arrhythmias, hypoglycemia unawareness, mortality, and – as a result – economic impact. Additionally, the ≤54 mg/dl threshold enables more meaningful comparisons of diabetes interventions while maintaining confidence in those estimates, demonstrated by an analysis of SWITCH 2 (insulin degludec vs. glargine crossover) data he and others recently published in Diabetes Care:

 

  • In 2017, both ADA and EASD adopted IHSG’s recommendation that trials track and report glucose ≤54 mg/dl in a joint position statement. This led to the currently-held framework of three levels of hypoglycemia classification:

    • Level 1 (≤70 mg/dl): often asymptomatic alert value that requires re-checking and may require insulin dose/type alterations.

    • Level 2 (≤54 mg/dl): denotes cognitive impairment and predicts cardiac arrhythmia and mortality; repeated episodes cause reduced awareness.

    • Level 3 (severe hypoglycemia): severe cognitive impairment, coma, or seizure and requiring external assistance, regardless of blood glucose. Prof. Heller noted this can occur anywhere from ~20-40 mg/dl, depending on the person and other factors.

  • Dr. Kowalski emphasized the importance of a 70 mg/dl threshold to patients and for enabling overall tighter glucose control: Spending time below 70 mg/dl is a barrier to better glucose control (i.e., reduced hyperglycemia and glucose excursions). In his words, “If we want to reduce hyperglycemia, we need to reduce hypoglycemia” – and 70 mg/dl is a critical metric for patients to do so. He immediately reframed the ≤70 mg/dl threshold as part of time-in-range, asserting that we absolutely need to know how much time is spent below 70 mg/dl and that patients and providers need actionable ways to reduce that time. Ultimately, Dr. Kowalski also argued that time-in-range is superior to A1c: TIR offers more insight into hypo- and hyperglycemia, is a better reflection of glycemic “health”, and provides a more actionable target for patients. As time-in-range and glucose variability become more accepted and understood measures of diabetes control, and as CGM becomes more common, 70 mg/dl will only become a more important marker of glucose control and an actionable piece of information for patients

    • Reminding the audience that diabetes is a disease defined by hyperglycemia, Dr. Kowalski characterized hypoglycemia as the main barrier to better glucose control. Historically (e.g., in DCCT), lowering A1c and complication risk was closely linked to higher risk of severe hypoglycemia. He underscored the balancing act of diabetes management: balancing the risks of treatment (“hypoglycemia is iatrogenic”) vs. the long-term risks of diabetes. In all people using insulin or SUs, hypoglycemia, impaired counterregulatory response, and unawareness all make tight glucose control challenging. Dr. Kowalski characterized the threat of hypoglycemia as the main reason most people with type 1 diabetes do not achieve their A1c goals, and he indicated the value of CGM in reducing time spent below 70 mg/dl. Moreover, he both highlighted current technology and called for further development of drugs and devices to keep patients safely above 70 mg/dl, giving a nod to the DIY community for the peace of mind homemade devices have offered people with diabetes. 

  • During Q&A, Prof. Heller explained that, a few years ago, IHSG did not feel that 70 mg/dl was sufficient to persuade reimbursement authorities to fund new treatments for the purpose of reducing hypoglycemia. He made a point to agree that time-in-range is a more meaningful outcome than A1c, and asked Dr. Kowalski if he felt we are now in a position to argue that time-in-range and time ≤70 mg/dl are “enough” to persuade regulatory and reimbursement bodies to spend more on new technology. Dr. Kowalski commented that, in a recent JDRF meeting with a large payer about hybrid-closed loop systems, he was pleased to hear that the payer is seeing cost savings on these systems. Further, he noted, data collected by payers may also help correlate improved time-in-range with cost savings over the long term, via reduced healthcare utilization and productivity losses. To be sure, we’re lucky to have JDRF, Dr. Kowalski, and others working to demonstrate the value of new tech.

  • Professor Heller also offered a useful outline of the history of hypoglycemia classifications, beginning with a 2004 ADA working group that landed on ≤70 mg/dl as the cutoff for “hypoglycemia” and defined “severe hypoglycemia” as requiring the help of another person to recover, independent of plasma glucose. These recommendations were met with criticism, including that glucose commonly falls below 70 mg/dl in healthy individuals and this level overestimates clinically significant hypoglycemia,. ADA’s definition was extended in 2013 to include “pseudo” hypoglycemia (symptomatic >70 mg/dl) and “probable symptomatic” hypoglycemia (symptomatic independent of plasma glucose), but the general glucose level of 70 mg/dl remained unchanged.

7. Two-Year EndoBarrier Trial Shows Sustained or Partially-Sustained Improvements in A1c and Weight in 78% of Participants

NHS’ Dr. Robert Ryder presented encouraging two-year weight loss and A1c-lowering data for the EndoBarrier device in people with difficult-to-treat type 2 diabetes and obesity. The EndoBarrier is a 60 cm intestinal sleeve that is endoscopically inserted into the intestinal lining for one year in order to mimic the duodenal-jejunal exclusion portion of a gastric bypass procedure without costly and invasive surgery. This study enrolled people with type 2 diabetes and obesity who had already tried lifestyle, diet, and medications (including GLP-1 agonists and SGLT-2 inhibitors) with little success. Participants (n=62; average age 51.5 years, average diabetes duration 14.5 years, average BMI 41.6 kg/m2) were inserted with an EndoBarrier for one year and then followed for one additional year following device removal. After EndoBarrier removal at one year, mean A1c fell by 1.9% (from 9.2% to 7.2%, p<0.001), weight by 17.2 kg/37.9 lbs (from 121.9 to 104.7 kg/268.7 to 230.8 lbs, p<0.001), and median total daily insulin dose among insulin-treated patients (n=31) fell from an average of 104 to 30 units (p<0.001). Remarkably, 32% (n=10) of insulin-treated patients discontinued insulin therapy. At the two year follow-up, 39% of participants showed sustained improvements in A1c reduction and weight loss (i.e. no significant rise in A1c and weight between one year and two year follow-up), 39% showed partially sustained improvement (i.e. A1c and weight loss at two year follow-up were significantly lower than at baseline but significantly higher than at one year follow-up), and 22% reverted to baseline (i.e. A1c and weight at two year follow-up were the same or higher than at baseline). Notably, of these “reverters,” 90% had experienced depression or bereavement, indicating that external factors and unintended lifestyle changes may have had a confounding effect.

  • As for safety, 10 trial participants required early removal of the EndoBarrier device due to adverse events or symptoms. These included gastrointestinal hemorrhage, liver abscess, and GI symptoms. All 10 participants fully recovered and many still showed major improvements in A1c and weight despite not receiving the full one year “dose” of EndoBarrier treatment. Dr. Ryder emphasized that many of these adverse events were avoidable and related to non-adherence to the dietary guidelines associated with EndoBarrier insertion (liquid diet for first week and pureed food for second week after insertion, food should be very thoroughly chewed, mouthfuls should be kept small etc.)

  • These encouraging results for EndoBarrier come on the heels of previous safety and efficacy concerns for the device. The original US pivotal ENDO Trial was terminated early in 2016 based on higher than expected incidence of hepatic abscesses and missed primary efficacy and safety endpoints. That said, the FDA approved a new pivotal trial, STEP-1, in 2018 and the ongoing trial could ultimately enroll up to 240 participants.

  • With the caveat that this is a small trial that requires further replication, the fact that 78% of participants achieved at least partially sustained improvements with this minimally-invasive device is quite encouraging in our view.  In obesity medicine, there is an urgent need for therapeutic options that fill the wide treatment gap between mildly effective lifestyle-based therapies and maximally effective but expensive (and poorly reimbursed), invasive, and side-effect-ridden options like metabolic surgery. EndoBarrier could fit into this niche, given continued reassurance of safety and efficacy in larger trials.

  • Dr. Ryder speculated that the mechanism underlying EndoBarrier’s effectiveness could be due to reductions in hepatic and pancreatic fat. In the previous REVISE trial, MRI imaging after four months of EndoBarrier treatment revealed significant reductions in the percentage of fat in the liver (from 14.9% to 2.9%, p=0.003) and the pancreas (from 6.9% to 1.3%, p=0.02). In Dr. Ryder’s view, these changes target two key pathological features of diabetes and obesity: Reduction in hepatic fat promotes improved hepatic insulin sensitivity, and reduction in pancreatic fat promotes improved insulin secretion.

8. Application of ADA Screening Guidelines to NHANES Data Reveals Racial/Ethnic Disparities in Detection of Prediabetes/Diabetes Among Younger Adults

An analysis of NHANES data presented by UCSF’s Dr. Alexandra Lee indicates that ADA screening guidelines might lead to racial differences in the detection of prediabetes and diabetes and suggests that risk factor and BMI guidance could lead to missed cases of diabetes. This study included NHANES participants 20-44 years old without a reported diabetes diagnosis and with an A1c, FPG, and 2-hr OGTT on file, leading to a sample of 897 non-Hispanic whites, 382 Asians, 432 non-Hispanic Blacks, and 646 Hispanic individuals (n=2,362). Presence of prediabetes or undiagnosed diabetes was defined as A1c ≥5.7%, or fasting glucose ≥100 mg/dl, or 2 hour glucose ≥140 mg/dl (i.e., the criteria for prediabetes). Prevalence of prediabetes and undiagnosed diabetes hovered between 35%-47% for each cohort when all three tests (fasting glucose, A1c, and 2-hr glucose) were considered (blue bars). However, this includes people who might not be screened under current guidelines AND who may have only been screened with one test in a real-world setting, missing their diagnosis. Next, Dr. Lee’s team screened their cohorts according to current BMI and risk factor guidelines recommended by ADA and using only A1c and fasting glucose results (orange bars). Dramatically fewer cases were detected, and the effect was most severe in the white (and closely behind, the Asian) cohort. Finally, BMI criteria were removed so that all racial/ethnic minorities plus whites with one additional risk factor were screened, still only with A1c and fasting glucose. Removing the BMI requirement for screening ameliorated the loss of detection, with the largest improvement in Asians and the smallest in whites – indicating the 23 kg/m2 guideline for screening those of Asian descent may be particularly problematic. A much larger improvement in detection for whites was observed when the requirement of an additional risk factor was removed.

Ultimately, this analysis suggests that current screening recommendations could miss a large proportion of prediabetes and diabetes cases in younger adults. We do think it could be important to differentiate between the two, as the long-term implications of undiagnosed diabetes are likely more serious. However, early detection of prediabetes is also critical to delaying and preventing progression to diabetes. Dr. Lee did note that healthcare provider adherence to the screening guidelines is unknown, and there’s likely an intangible aspect of clinical judgment involved in choosing who to screen. Moreover, Dr. Lee noted, there are also potential harms associated with increased screening.

  • Currently, ADA recommends diabetes screening in all adults ≥45 years old, and younger adults on a race-specific basis: Asian people with a BMI ≥23 kg/m2, Black and Hispanic people with a BMI ≥25 kg/m2, and white people with a BMI ≥25 kg/m2 and at least one additional risk factor (family history of diabetes, CVD, hypertension, low HDL, high triglycerides, PCOS, physical inactivity).

    • Per ADA guidelines, fasting plasma glucose is the best screening test for diabetes/prediabetes, as it is easier, faster, cheaper, and more convenient/acceptable to patients. Specifically, “An FPG ≥126 mg/dl is an indication for retesting, which should be repeated on a different day to confirm a diagnosis. If the FPG is <126 mg/dl and there is a high suspicion for diabetes, an OGTT should be performed. […] A 2-h postload value in the OGTT ≥200 mg/dl is a positive test for diabetes and should be confirmed on an alternate day.”

    • Diagnosis of diabetes, in the absence of unequivocal hyperglycemia, requires two abnormal tests: 2 hr PPG ≥200 mg/dl during 75g OGTT, A1c ≥6.5%, FPG ≥126 mg/dl (≥8 hours fasting), or random glucose ≥200 mg/dl in a patient with symptoms of hyperglycemia.

  • At baseline, mean age in this study population was 31-32 years and ~50% of the sample was female. Overweight and obesity were more common in the Hispanic and Black cohorts (~75%) compared to the white (65%) and Asian (54%) cohorts. Hypertension and family history of diabetes were more common in the Black cohort (20% and 44%) than the other groups (6%-10% and 30%-38%).

9. How Weight Loss Can Impact 20-Year Health: Dr. Knowler Discusses Legacy Effects of Lifestyle Interventions

NIH’s Dr. William Knowler gave a very interesting talk on the so-called “legacy effect” of lifestyle interventions, focusing on the DPP, China’s Da Qing study, and the Finnish Diabetes Prevention Study. The DPP showed remarkable efficacy while the intervention was underway – a 58% risk reduction for new-onset type 2 diabetes relative to the control group. But what happened after the intervention (and all the accompanying support) ceased after year 3? During 10 years after randomization in DPP, the annual incidence rate of new cases of diabetes was  34% (95% confidence interval = 24 to 42%) lower than in the original placebo group that was also offered lifestyle intervention after the first three years. By year 15, cumulative incidence of type 2 diabetes remained 27% lower in the intensive lifestyle arm vs. the control arm (HR=0.73, p<0.001). Dr. Knowler noted that maximum weight loss occurred at the one-year mark, and individuals gradually returned to their baseline weight thereafter (this is common for lifestyle change programs). Nevertheless, there was clear long-term benefit for those enrolled in the DPP. Dr. Knowler summarized similar findings from a long-term look at China’s Da Qing study, the Finnish Diabetes Prevention Study, and Look AHEAD. After 30 years of follow-up on Da Qing participants, those originally treated with intensive lifestyle intervention faced 26% lower risk for CV events compared to the control group (HR=0.74, 95% CI: 0.59-0.92); this impressive benefit appeared even though there was no positive signal on CV risk in the first 20 years of follow-up since the clinical trial began (HR=0.98, 95% CI: 0.71-1.37). Look AHEAD reported a neutral hazard ratio on its primary cardiovascular outcome as well, but Dr. Knowler emphasized that ongoing follow-up has found improved diabetes control with fewer medications, decreased rates of depression, reduced rates of kidney disease, and lower out-of-study health costs – all of these outcomes are important in and of themselves. He also promised forthcoming data from Look AHEAD that will shed more light on legacy effects. In the Finnish DPS, intensive lifestyle intervention gave a 39% relative risk reduction for new-onset type 2 after 13 years (HR=0.61, 95% CI: 0.48-0.79). Reviewing these four studies in rapid succession sent a strong message: lifestyle interventions deliver rewards well beyond the initial weight loss. We hope that as this message spreads, more people with prediabetes and type 2 diabetes have access to lifestyle change support.

  • Dr. Knowler discussed two models for the legacy effect, which provide a useful framework for evaluating the benefits of any intervention. There is either a permanent shift in the slope of the curve, meaning that even after the intervention formally ends, participants face reduced incremental risk for adverse outcomes in every period; or there is a dramatic improvement during the active intervention phase followed by a return to the same slope, meaning that participants’ risk for adverse outcomes begins to climb at the same rate but from a much lower base. The US DPP falls into this latter camp, delivering most of its value by resetting people’s baseline risk for type 2 diabetes. All this said, Dr. Knowler didn’t rule out a possible third model for the legacy effect – a convergence of the curves over time, meaning the benefits of the intervention wear off completely. We suspect different types of interventions, even within the category of lifestyle change, will have varying levels of “legacy effect.” It would be extremely worthwhile to probe for the specific elements of lifestyle interventions that bring about long-term results.

10. Dr. Lundgren Shares S-LITE Data, Pitches GLP-1 Saxenda + Exercise as Ideal Solution to Challenges of Weight Loss Maintenance

Dr. Julie Lundgren (University of Copenhagen) presented detailed results from the S-LITE trial, the headline being that treatment with Novo Nordisk’s Saxenda (liraglutide 3.0 mg) + exercise together promotes the greatest chance of weight loss maintenance. S-LITE enrolled 215 participants, all adults with obesity (baseline weight 237 lbs) but not type 2 diabetes (baseline A1c 5.4%), in a very low calorie diet (VLCD) for two months. Individuals who achieved ≥5% weight loss (n=195) were then randomized for one year to either (i) 150 minutes of exercise per week, (ii) daily Saxenda injection, (iii) both, or (iv) neither. Average weight loss was nearly 29 lbs after the VLCD phase, and impressively, people in the liraglutide + exercise arm lost an additional 7.5 lbs in the year follow-up (p<0.001 vs. placebo). This sums to 36.5 lbs of weight loss, or a ~15% body weight reduction, which is notable since 5%-10% is the threshold to start seeing health benefits. In contrast, people in the placebo + no exercise group gained back 13.4 lbs on average. Individuals on Saxenda alone lost an addition 1.5 lbs after the VLCD, while those on exercise alone gained back 4.4 lbs; Dr. Lundgren emphasized that the combination approach was statistically significantly better on this primary outcome of one-year weight loss than either treatment on its own. She explained how the GLP-1 agonist and exercise each target one of the two main mechanisms that make maintaining weight loss so incredibly difficult. The human body adapts to weight loss by increasing appetite and decreasing energy expenditure. GLP-1s solve the first problem – they are known for their appetite-suppressing effect (it’s no secret that Saxenda is a highly-efficacious obesity therapy) – and exercise stimulates energy expenditure.

We appreciated this focus on weight loss maintenance, because that is crucial to improving both individual health outcomes and population-level health. There need to be supports in place to drive weight maintenance, and Saxenda + exercise could be an effective solution. That said, our view of weight maintenance extends well beyond one year; obesity and diabetes are chronic conditions, after all, and people can struggle with the weight loss/regain cycle for their entire lives. Real-world data on Saxenda use could provide this longer-term perspective. Moreover, we’d be remiss if we didn’t acknowledge that Saxenda remains prohibitively expensive for many patients who could benefit. With studies like S-LITE, we hope to see improved reimbursement of the drug so that more people struggling with weight maintenance can access it as a supplement to exercise.

Key Secondary Outcome Results

 

VLCD Phase (8 weeks)

Placebo

Saxenda

Exercise

Saxenda + Exercise

Fat percentage change

(p-value vs. placebo)

-2.3%

+0.4%

 

-1.6%

(p<0.05)

-1.8%

(p<0.05)

-3.5%

(p<0.001)

Fat mass

(p-value vs. placebo)

-15 lbs

+5.5 lbs

-4.4 lbs

(p<0.05)

-3 lbs

(NS)

-10 lbs

(p<0.001)

Lean mass

(p-value vs. placebo)

-11 lbs

+6.4 lbs

0 lbs

(NS)

+4.6 lbs

(p<0.001)

+1.1 lbs

(NS)

11. Presidential Healthcare and Education Address Outlines the Future of DSMES to Include Cooperation Among Sectors, Behavioral Science, and Actively Combatting Boredom

To kick off day two of ADA, CEO Ms. Tracey Brown, President of Healthcare and Education Dr. Mary de Groot, and Outstanding Educator Awardee Dr. William Polonsky discussed the history of the Scientific Sessions and the future of DSMES. Ms. Brown began the first virtual session with a look back at the first ADA in the 1940s – which was attended by 250 people to listen to five presentations. Now, 12,000+ people are in attendance to see over 800 presentations, 1,800 posters, and 2,400 abstracts. She emphasized that the Scientific Sessions’ mission, advancing research, education, prevention, and care, is stronger than ever. This provided a great segue to the presentations in this session, which included Dr. de Groot’s Healthcare and Education Address and Dr. Polonsky’s Outstanding Educator in Diabetes Award Lecture. Both presentations outlined the progress of diabetes care and education, with specific reference to the importance of behavior in both disciplines.

  • In light of COVID-19, during which behavioral change has been integral to curbing the virus’ spread, Dr. de Groot advocated for the future of behavioral science in diabetes care. This future depends on a model of person-based care, in which assessment, clinical recommendations, and treatment options flow from the patient and depend on a strong patient-HCP relationship. Patients at the center of care will also make necessary collaboration between different parts of a care team possible to best support people with diabetes. According to Dr. de Groot, the next golden age of behavioral science in diabetes involves an integrated care team for every person, expanding access to medicine, endocrinologists, care and education specialists, psychologists, social workers, and more. As new systems are enacted, their accessibility to all people with diabetes is of the utmost importance. Dr. de Groot stressed that successful care requires early identification of social determinants of health, interventions that make diabetes care equitable, and the removal of weight, blood glucose, A1c, and TIR stigma. To be actionable, Dr. de Groot pointed the audience to the newest DSMES consensus statement that outlines four critical periods of diabetes education: (i) at diagnosis; (ii) annually and/or when not meeting treatment targets; (iii) when complicating factors develop; and (iv) when transitions in life and care occur. Once people recognize the importance of behavior and its ability to even the playing field, then fully integrated care can leverage scientific advancements to both prevent diabetes and improve the lives of those with the condition. HCPs must screen patients for psychosocial conditions, advocate for multidisciplinary teams at their institutions, supporting funding behavioral science research and programs, and work with large professional organizations like ADA. Dr. de Groot concluded her talk with an important message: “medication and devices only work if we use them, and the time has come to recognize and celebrate the foundational roles of education and behavior in all aspects of diabetes.”

  • Dr. Polonsky cautioned that while diabetes care and education specialists are qualified and well-meaning, all still have to be cognizant of making DSMES exciting for patients. He candidly warned against the danger of boring education sessions, backed by disappointing data from 2018 on attendance of group DSMES sessions. Specifically, in an evaluation of diabetes group visits, only 3.9% of participants attended all four education sessions. Combined with PCPs under referring patients to DSMES services, many people stop going to sessions because of conflicting commitments. Dr. Polonsky wagered that this means that patients don’t think their sessions are worth the inconvenience, leaving it up to educators to change their methods to engage participants. Potential ways to do so are as follows:

    • Cut down content of DSMES sessions. Dr. Polonsky stated that addressing concerns about participants’ specific medications is more effective and important than explaining medication classes broadly. Further, participants can benefit more from dietary changes than learning about carb counting, reading example food labels, and learning about the biochemical pathways involved in diabetes complications.

    • Personalize sessions. Participants are more likely to learn from discussions or Q&A sessions on their specific questions or confusions. It’s beneficial to frame classes as meaningful for each participant to promote interest and learning.

    • Be willing to reflect on sessions in a constructive way. Dr. Polonsky believes that educators have to be aware of their own potential shortcomings when facilitating sessions to become better teachers. He recommends keeping track of no-shows/dropouts, interviewing those individuals to find out what they were looking for, and consistently working to be “less boring.” Only then will DSMES reach the most people and be the most beneficial.

12. Small Renal Outcomes Trial Finds Significant Effects on UACR w/ Twice-Daily Exenatide vs. Insulin Lispro, Adding to Evidence of Modest Class Effect

A small renal-outcomes focused RCT examining GLP-1 exenatide twice-daily (AZ’s Bydureon) in type 2 patients with DKD found significant reductions in UACR levels after 24-weeks. The study enrolled 92 patients across four general hospitals in China between 2016-2019 and randomized participants to either twice-daily exenatide or mealtime lispro. Mean age was 56 years, baseline 24-hr UACR was 1512 mg, mean eGFR was 70, and all patients were on background glargine treatment. After 24 weeks, exenatide treatment was associated with a significant 30% decreased reduction in 24h-UACR percentage change (p=0.02). Consistent with the known profile of exenatide, significant reductions were also seen in body weight at 24 weeks. Mean body weight declined by 1.3 kg after 24 weeks, for a total difference between the insulin lispro add-on group of 2.7 kg (p=0.0001).

  • These outcomes add to the growing body of evidence suggesting modest renal effects with GLP-1 therapy. Consensus among the field has been that GLP-1 provide some benefit in improving renal function, but do not impact the “harder” endpoints assessing renal health such as eGFR. This is more apparent when comparing data from the GLP-1 class with the SGLT-2 class, as SGLT-2s have been consistently shown to robustly impact eGFR and other renal endpoints.

  • For the strongest evidence on GLP-1s and potential renal protection, we’re waiting on results from Novo Nordisk’s FLOW trial of semaglutide in CKD. As a reminder, the FLOW trial was initiated in June 2019 and will enroll 3,160 patients with type 2 diabetes and CKD (eGFR 25-75 ml/min/1.73 m2) for up to five years. Expected completion is August 2024, and the primary endpoint is a composite of persistent eGFR decline of ≥50%, reaching ESRD, and CV or renal death. Traditional MACE endpoints will also be measure. This is a highly notable, first-ever renal outcomes trial among GLP-1s, and it’s clear that enthusiasm is high for the trial’s potential in further informing renal benefits of the GLP-1 class. We’ve sensed optimism from Novo Nordisk that more efficacious GLP-1s (such as semaglutide) may be able to compete in the future with renal outcomes data from the SGLT-2 class, along with providing the additional benefit of not losing their glucose lowering abilities in patients with a lower eGFR. 

13. ACCORD Data Shows Intensive Glucose Control and BP Lowering Reduce Risk of Cardiovascular Autonomic Neuropathy

An analysis of ACCORD data presented by Joslin’s Dr. Yaling Tang demonstrated beneficial effects of intensive glucose lowering and blood pressure control on cardiovascular autonomic neuropathy (CAN), a common and dangerous microvascular complication of type 2 diabetes. After full adjustment, intensive glucose control was associated with a 17% relative risk reduction for CAN (HR=0.83, 95% CI: 0.74-0.93, p=0.001). Additionally, intensive blood pressure control drove a similar risk reduction (HR=0.78, 95% CI: 0.65-0.92, p=0.004) compared to standard BP control. Fenofibrate + statin treatment trended toward benefit compared to placebo + statin, but did not reach significance (HR=0.87, 95% CI: 0.74-1.02, p=0.08). The benefits of intensive glucose control were greater in those without a history of CVD (OR=0.73, 95% CI: 0.63-0.85, p-value for interaction=0.001). Additionally, BP lowering had a greater impact on those ≥65 years old (OR=0.66, 95% CI: 0.49-0.88, p-value for interaction=0.05). Of course, Dr. Tang noted, these benefits must be balanced against the excess mortality associated with intensive glycemic control in ACCORD, which some have suggested was due to increased risk of severe hypoglycemia in that group. Nevertheless, these are interesting findings given outcomes trials have struggled to demonstrate a definitive link between intensive glucose control and reduced cardiovascular risk. However, this benefit would likely be due to a reduction in microvascular rather than macrovascular disease, and tight glycemic control already has a well-established role in reducing microvascular complications.

  • In ACCORD, the presence of CAN at baseline was associated with subsequent all-cause mortality (HR=1.55, 95% CI: 1.09-2.21, p=0.016) and cardiovascular mortality (HR=1.94, 95% CI: 1.20-3.12, p=0.007). Moreover, Dr. Tang emphasized that CAN is very common among those with type 1 and type 2 diabetes, citing prevalence as high as 30% and 60% after 15 years of disease duration, respectively.

    • Dr. Tang characterized two stages of CAN: subclinical, characterized by lower heart rate variability; and symptomatic, characterized by resting tachycardia, exercise intolerance, orthostatic hypotension, syncope, and silent MI.

  • This analysis included 7,275 of the 10,251 ACCORD participants (71%), based on record of valid CAN measures at study entry and at least once during follow-up. Per study protocol, CAN status was examined via 12-lead ECG and obtained at baseline, every two years, and last trial visit. As a reminder, ACCORD enrolled people with type 2 diabetes and high CV risk. All participants were randomized 1:1 to intensive (A1c <6.0%) or standard (A1c between 7.0%-7.9%) glucose control, then further to a 2x2 matrix of intensive vs. standard blood pressure or lipid control. Due to high mortality in the intensive glycemic control arm, all participants were transferred to standard glucose control at a median follow-up of 3.7 years. In this analysis, 32%-35% of participants had a prior CV event at baseline.

 

--by Ursula Biba, Rhea Teng, Ann Carracher, Abigail Dove, Payal Marathe, Martin Kurian, Joseph Bell, Kira Wang, Katie Mahoney, Ani Gururaj, Albert Cai, Brian Levine, and Kelly Close