Hello from ENDO 2019! We’re back with our second round of highlights from the meeting, starting with baseline (blinded) data from the WISDM trial evaluating real-time CGM in older adults (≥60 years) with type 1 diabetes. Participants (n=203) wore blinded CGM for up to three weeks prior to the intervention, spending 57% in range, 35% >180 mg/dl, and 5% time <70 mg/dl.
A study of Yale medical records found 21 episodes of SGLT-2 inhibitor associated DKA in 17 patients (one with type 1 diabetes) – of which 52% occurred with euglycemic blood glucose (<300 mg/dl). Importantly, the average hospital stay was seven days, and presenter Dr. George Stamatiades noted that many of these patients were in the hospital for “a couple of days” without knowing that they were in DKA – reflecting the importance of educating hospitalists on euglycemic DKA.
An interesting analysis of T1D Exchange data presented by Dr. Carol Wysham found that the combination of high mean A1c and high A1c variability was associated with worse outcomes, including severe hypoglycemia, DKA, peripheral neuropathy, nephropathy, and renal disease, compared to low A1c (high or low variability) and even high A1c with low variability – further linking glycemic variability to worse outcomes, though the study is observational.
Dr. Robert Califf gave a powerful presentation on big data and healthcare, exploring how search history can be leveraged for diabetes prevention: Can Google “link up physicians” with search queries relevant to diabetes to reach at-risk individuals more proactively?
In an early-morning session, Dr. Jack Leahy reinforced the importance of insulin, remarking that the new ADA/EASD consensus recommendations (including GLP-1 agonists as first-line injectables) “underrepresent insulin.” We were also glad to hear him highlight the value of next-gen basal insulins, stating that either Tresiba or Toujeo is a great option for those experiencing hypoglycemia. From our view, there is just clearly a trend toward HCPs and patients learning more and seeing more the positive effects of GLP-1 and SGLT-2 inhibitors, particularly on the cardioprotection side and it makes lots of sense to us that patients are not being moved quite as quickly to insulin – they shouldn’t be, with such incredible products available. And! We also believe that earlier intensification (of all good therapy!) is still not happening at nearly the pace that it should be – patients should receive encouragement toward some good therapy far earlier on, particularly cardioprotective therapy, even in the absence of glycemic problems.
Read on below for more, including Dr. Philip Zeitler’s call to treat youth-onset type 2 diabetes more aggressively, Dr. Lee Kaplan’s advocacy for the combination of metabolic surgery with obesity pharmacotherapy, Dr. Margaret Eckert-Norton discussing new obesity pathophysiology and lifestyle intervention for weight loss, and data linking recurrent hypoglycemia to fragmented medical care.
We’re back with our second round of highlights on ENDO 2019! Read on below for our coverage of nine standout presentations from the meeting, and don’t miss our days #1-2 coverage. We’ll be back once more with a final report from the meeting – stay tuned.
- Top Nine Highlights
- 1. WISDM Baseline Blinded CGM Data in Older Adults (≥60 Years) Without Recent CGM Use: 57% Time-In-Range, 35% >180 mg/dl, 5% Time <70 mg/dl,
- 2. Medical Records Study (n=21 episodes) Finds Half of SGLT-2 Associated DKA Events are Euglycemic (<300 mg/dl), Leading to Delayed Diagnoses and Prolonged Hospital Stays
- 3. T1D Exchange Data Link Variability in A1c to Acute and Long-Term Diabetes Complications
- 4. Dr. Robert Califf on Harnessing Google Search History for Suicide, Diabetes Prevention; PCORnet “Open for Business”
- 5. Dr. Jack Leahy Reinforces Importance of Insulin in Type 2 Treatment in Light of Newest ADA/EASD Consensus Guidelines Promoting GLP-1 as First-Line Injectable
- 6. Dr. Philip Zeitler Challenges Therapeutic Inertia in Youth-Onset Type 2 Diabetes: “We Shouldn’t Be Waiting Long to Treat This”
- 7. “Your Gut Might Just Be an Obesity-Promoting Gut” – Dr. Eckert-Norton Elucidates Pathophysiology of Obesity, Discusses Challenges to Weight Loss via Lifestyle Change
- 8. Dr. Lee Kaplan Touts Potential for Synergistic Weight Loss with Drugs + Surgery; Offers General Algorithm for Pharmacotherapy, Focused on Avoiding Inertia
- 9. Significant Association Between Recurrent Hypoglycemia and Care Fragmentation Shown in Chicago
Top Nine Highlights
International Diabetes Center’s Dr. Anders Carlson shared baseline data from the Helmsley- and JDRF-funded WISDM study (n=203) evaluating the effect of CGM in older adults ≥60 years with type 1 diabetes. While Dr. Carlson expects full results from real-time wear to be released later this year (ClinicalTrials.gov slates completion for October 2019), he was able to present blinded Dexcom G4 CGM data collected for up to three weeks (minimum 10 days) prior to the real-time CGM intervention. Similar to the CITY young adult CGM study, participants could not have used real-time CGM in the past three months and had to have a baseline A1c <10%. During this blinded baseline period, participants:
Spent 57% time-in-range (~14 hours/day)
Spent 35% time >180 mg/dl (~8 hours/day) and 12% time >250 mg/dl (~3 hours/day)
Spent 5% time <70 mg/dl (72 min/day) and 1.6% time <54 mg/dl (24 min/day)
Had mean coefficient of variation (CV) of 42% (While consensus has not yet been reached on the optimal CV, many thought leaders, including Dr. Irl Hirsch, recommend ≤33%.)
Fairly high hyperglycemia figures may be do to participant age ≥60; regimens may have been purposefully skewed to protect against hypoglycemia. Dr. Carlson added that the hypoglycemia metrics are close to the newly agreed upon targets aiming for <4% time <70 mg/dl and <1% time <54 mg/dl. The only measurement found to be associated with hypoglycemia was (not surprisingly) hypoglycemia unawareness – those with unawareness spent twice as much time <54 mg/dl (19 mins/day vs. 39 mins/day; p=0.03). There were no differences in overall daytime and nocturnal hypoglycemia. However, among those with hypoglycemia unawareness, time <70 mg/dl and <54 mg/dl was significantly greater during the day than at night.
Interestingly, retirement and lower total daily dose of insulin were associated with higher time-in-range. Household income between $35,000-$75,000 was shown to be associated with lower time-in-range. We’re eager to see the full results of the CGM intervention.
The contrast between these data and that seen in the CITY (ages 14-25) baseline phase is stark: In that group, median time-in-range was just 35%, with median time >180 mg/dl up to 60%. Which group will benefit from real-time CGM to a greater extent?
Dr. George Stamatiades (Yale New Haven Health) presented clinical and biochemical characteristics from 21 SGLT-2 inhibitor related DKA events, highlighting the prevalence of euglycemic DKA and its impact on delaying diagnosis of DKA in hospital settings. Seventeen total patients who were taking an SGLT-2 inhibitor and had a documented DKA episode were identified through medical record examination; of note, only one of these patients had type 1 diabetes. Eleven episodes were observed with canagliflozin, six with empagliflozin and four with dapagliflozin. At diagnosis, all patients had ketones in their urine, and on average had a beta-hydroxybutyrate reading of 6.4 mmol/l (well above the >3 mmol/l threshold for “probable DKA” established in recent consensus guidelines). Very notably, 52% of these cases were euglycemic DKA episodes with blood glucose levels <300 mg/dl (admittedly, a high threshold), and 47% were <250 mg/dl. On average, blood glucose levels at presentation were 329 mg/dl, with a range of 154-777 mg/dl. The average hospital stay was 7 days (!) for those admitted with DKA – much higher than the average stay of ~2 days normally associated with DKA events – and the median was 5 days (average duration of insulin infusion 3.7 days and median 3 days). On this point, Dr. Stamatiades noted that many of these patients were in the hospital for “a couple of days” without knowing that they were in DKA because of otherwise normal blood glucose levels at presentation. This led to delayed diagnoses and progression to more severe DKA, necessitating longer and more intensive hospital stays. Of course, data like these represent one of the greatest fears with SGLT-2 inhibitor use, as the paradoxical nature of euglycemic DKA (most patients, providers, and emergency room staff are used to only checking for DKA with elevated blood sugar levels) may cause many DKA events to be missed and progress to more severe episodes that endanger the patient and result in elevated costs for the entire healthcare system. It’s clear that as usage of SGLT-2 inhibitors continues to grow – especially among type 1s – increased education and awareness (especially in emergency rooms, where early diagnosis of euglycemic DKA will be key) is paramount in ensuring safe use of these nephro-and cardioprotective agents.
3. T1D Exchange Data Link Variability in A1c to Acute and Long-Term Diabetes Complications
Dr. Carol Wysham presented results from a cross-sectional, observational study on A1c variability and diabetes complications using data from the T1D Exchange. To measure A1c variability, intrapersonal mean and standard deviation (SD) of available A1c values were calculated and the 50th percentiles of mean A1c and SD were used to categorize patients four groups (“Mean A1c” x “A1c variability” matrix). Those in the high mean/high SD group, compared to the other three groups, were significantly younger (30 vs. 37-44 years old) and had a shorter duration of type 1 diabetes (16 vs. 21-26 years); they also had a lower BMI and lower usage rate of CGM (24% vs. 27-44%). Most importantly, patients with a high mean/high SD were also significantly more likely to experience diabetes-related severe hypoglycemia, DKA, peripheral neuropathy, nephropathy, and renal disease. Rates of DKA were particularly elevated in this group when compared to those with a low mean/low SD (HR=13.32, 95% CI: 2.95-62.05). While these results are not necessarily surprising, they do further support the probable link of glycemic variability with severe hypoglycemia, DKA, and long-term outcomes and complications. Dr. Wysham noted that application of these results to clinical settings is possible, as high A1c variability may help identify patients at a particularly high risk for complications.
In a tour de force presentation on the impact of big data on healthcare, Duke University School of Medicine/Verily’s Dr. Robert Califf used diabetes as an example of how people’s search history can be harnessed towards prevention. For context, he described how when people currently search for depression on Google, a pop-up appears asking if they’d like to take a questionnaire. If they choose to do so, they are directed to take the PHQ-9, a depression screening and diagnostic tool. According to Dr. Califf, “the very large number of Americans who have filled out the questionnaire and have been shown to be seriously and significantly depressed” are then referred to a patient advocacy group. He acknowledged that the ideal next step would be referring these respondents to a psychotherapist; however, it then becomes very complicated to determine which psychotherapists are worthy of referral and how to match patients appropriately. Dr. Califf pointed to diabetes as a disease state posing similar, yet complex promise. He posited that many individuals likely search for topics related to diabetes prior to seeking medical attention – some of the one billion Google health queries made every day. If Google can figure out how “to link up physicians” with patients’ search history accordingly, patients may be reached proactively. Dr. Califf acknowledged the obvious privacy concerns, though stipulated that “the majority” of people would be willing to let their search history be used to improve their health (we already do it to improve our entertainment and online purchasing experiences, after all).
While it may be too extreme for physicians or health systems to reach out to individuals based on their search history at the moment, we think the current middle ground in which patients searching prediabetes are offered the CDC’s “one-minute” prediabetes risk test is still immensely valuable. Perhaps eventually the test can pop up from other related searches beyond the most obvious terms.
Dr. Califf provided an updated on PCORnet, the “network of networks,” which aims to combined data across health systems to accelerate research. To date, the database accounts for one-third of the US population and comprises 30 health systems and two health plans. Combined, more than 100 million patients who have had a medical encounter in the past five years are represented. Dr. Califf announced that the system is “now open for business.” We’ll be very eager to see the kind of innovative research that arises from this massive undertaking.
In reviewing the new ADA/EASD consensus recommendation of GLP-1 agonists as first-line injectable therapy, Dr. Jack Leahy remarked that insulin is “a little under respected” and emphasized that “insulin is an important part of what we do in type 2 diabetes.” Although he understands the reasons behind the recommendation, Dr. Leahy does feel a “general sense that insulin has been underrepresented on these guidelines.” This sentiment is surely understandable, as basal insulin is placed near the bottom of each specific part of the treatment algorithm. Nonetheless, the evidence supporting the recommendation of GLP-1s over basal insulin as the first line injectable in type 2 treatment (save specific circumstances of severe insulin deficiency) is strong; we particularly note the mass of evidence showing similar A1c lowering and superior effects on weight with GLP-1s compared to insulin. Generally, we remain thrilled to see GLP-1s promoted over basal insulin for most patients, given preferable effects on weight, the option of once-weekly dosing, little to no hypoglycemia risk, and long-term beta cell preservation; we’ve also seen this recommendation received with notable enthusiasm among thought leaders. Still, Dr. Leahy’s general point does stand, and the community should not disregard the role of insulin in treating type 2 diabetes.
Discussing next-gen basal insulins, Dr. Leahy emphasized that the defining clinical benefit of these agents is a lower risk of hypoglycemia, rather than superior A1c reductions. Dr. Leahy reviewed clinical trials for both Sanofi’s Toujeo (insulin glargine U300) and Novo Nordisk’s Tresiba (insulin degludec), showing that although significant A1c differences were not observed between these next-gen agents and their predecessors, significantly lower rates of hypoglycemia (especially nocturnal) were seen. On this front, Dr. Leahy argued that next-gen basals should be targeted to people “doing okay with A1c but having trouble with lows, especially at night.” In discussing which next-gen to pick for a patient, Dr. Leahy emphasized that there are more similarities than differences between Toujeo and Tresiba (we couldn’t agree more) and that as a provider “you choose what you want to choose or what your insurance company forces you to choose. There’s not much of a difference either way.” We agree with Dr. Leahy’s thinking here, and maintain that while comparisons between Toujeo and Tresiba are interesting and inevitable, the focus should be on getting as many patients as possible on one of these next-gen agents rather than older insulins.
As part of a “Meet the Professor” session on youth onset type 2 diabetes, Dr. Philip Zeitler advocated for more aggressive treatment of this population. Dr. Zeitler emphasized that with youth onset type 2 diabetes, “the problem is that you [the provider] really can’t wait. A big problem we have is therapeutic inertia. The rise in A1c in these kids is not linear, but really exponential. You’ll see them for a few visits, and their A1c is in the fives, and then it will suddenly jump all the way up to nine. We shouldn’t wait long to be treating these kids.” We’re glad to see Dr. Zeitler shine a light on therapeutic inertia in the youth population, as this specific sub-population was not directly addressed in ADA’s recent Summit on Therapeutic Inertia.
During Q&A, some questioned whether such intense pharmacotherapy is appropriate in this population, especially considering the young age of many. Shouldn’t we first focus on improving lifestyle choices in these young children, the audience wondered? Dr. Zeitler provided the following response on balancing lifestyle intervention and pharmacotherapy or surgery: “This is a serious lifestyle disease, but you have to remember that these are also children with serious health risks that we cannot ignore just by thinking that this is a lifestyle disease. You have got to treat what is in front of you. It’s not just their lifestyle, and their lifestyle won’t change right away. You have to keep them from getting into trouble [by using other approaches].” Dr. Zeitler continued: “It may seem that they’re only kids and that we should therefore focus on lifestyle interventions. But the fact of the matter is that this is a more aggressive disease in kids than in adults [see RISE peds at ADA 2018]. They are losing beta cell function more quickly and developing complications more quickly than adults. [Treatment] may also include referrals for bariatric surgery. Surgical therapy is much more successful for almost all of these problems that this population faces.”
Dr. Zeitler explained that he views prescribing metformin to the youth population with type 2 onset as a “beta cell stress test.” He explained that “if you can’t get them to an A1c of 6.5% with metformin, their chance of going out of control is very much increased.” In terms of next-line therapy, insulin is prescribed (to our understanding, this is a function of label indication more than anything – Victoza has been submitted for youth type 2). However, Dr. Zeitler commented that A1c often doesn’t improve with insulin because “this is a very challenging population with a lot of different barriers affecting treatment” – we imagine he was referring to adherence.
Dr. Margaret Eckert-Norton, former Secretary and Committee Chair for the Endocrine Nurses Society, summarized (i) new concepts in the pathophysiology of obesity and (ii) empirically-tested lifestyle interventions for weight loss. Throughout the first half of her talk, we were intrigued by the idea that a more accurate understanding of what causes obesity might reduce weight-based stigma. For example, Dr. Eckert-Norton distinguished between homeostatic (fulfilling biological need) vs. hedonic (for pleasure) eating. She suggested that food companies have leveraged food science to increase the palatability of what they sell, deliberately targeting the hedonic, reward-sensitive pathway. This gets at the environmental contribution to the obesity epidemic, which needs to be addressed first and foremost, in our view (e.g. by making healthy food more affordable/accessible, or perhaps taxing junk food). Dr. Eckert-Norton explained that ~70% of excess energy consumed is stored as fat, and that greater adiposity lowers the efficiency of energy expenditure (i.e. the same amount of exercise may burn fewer calories). Moreover, obesity is associated with both leptin and insulin resistance. The former phenomenon interferes with satiety, and the latter, of course, becomes type 2 diabetes. After weight gain, any energy deficit – such as the start of a new diet – leads to a hyper-insulinemic state (the body is accustomed to over-producing insulin, and now it’s not being used), which exacerbates insulin resistance and adiposity. With all this pathophysiology in mind, it shouldn’t come as a surprise that dietary modifications don’t always lead to immediate weight loss, Dr. Eckert-Norton argued. Given how frustrating weight loss can be, she urged nurses and other HCPs to go over these concepts with patients, eliminating any blame and setting reasonable expectations for body weight targets. She also shifted blame from individuals to their microbiome: “Your gut might just be an obesity-promoting gut.” Dr. Eckert-Norton discussed one case in which a fecal microbiome transplant led to new-onset obesity in the recipient (the donor was overweight, but otherwise healthy). The obesity that developed in the recipient was unresponsive to all traditional treatments. Dr. Eckert-Norton highlighted how over-prescription of antibiotics has “perturbed” the gut microbiome and may be implicated in the obesity epidemic, lowering the concentration of bacteria thought to protect against obesity.
In the second half of her presentation, Dr. Eckert-Norton echoed a refrain from obesity expert Dr. Donna Ryan – that the best diet for weight loss is the one a person can adhere to. She displayed weight loss data for four diets: (i) DASH; (ii) low-carb; (iii) low-fat; and (iv) Mediterranean. While the last of these has shown greatest adherence out to six years, Dr. Eckert-Norton emphasized that there’s no significant difference in weight loss achieved with each of these methods. Where there is a significant association is between diet adherence and weight loss. Personalizing a diet plan is thus paramount for successful obesity management.
Turning to physical activity, Dr. Eckert-Norton exclaimed that “sitting is the new smoking.” She noted that any exercise is better than none; for people with severe obesity who may not be able to walk long distances, even chair exercises can make a positive difference. Dr. Eckert-Norton framed physical activity as a critical prong in weight maintenance, though she showed how diet is the dominant factor for weight loss.
Harvard’s Dr. Lee Kaplan shared valuable insight into the obesity pharmacotherapy and metabolic surgery landscapes, highlighting the additive and even synergistic benefits of using these together. Dr. Kaplan began his talk with an interesting hypothetical: It wouldn’t make sense to combine surgical weight loss procedures (~30% weight loss on average) with obesity pharmacotherapy (~3%-7% weight loss on average) if surgery was simply physically restricting food intake. After all, the weight loss seen with pharmacotherapy pales in comparison to the dramatic weight loss with surgical procedures and would not be worth the investment for most patients. However, Dr. Kaplan argued, it’s important to remember that surgical weight loss procedures do affect the fundamental biology of weight and do change the physiology of energy and fat balance regulation. As a result, he underscored that there is a chance for the combination of pharmacotherapy and surgical weight loss to be synergistic in driving down weight. Therefore, it’s important to fully consider pharmacotherapy in patients who are also considering weight loss surgery or have already undergone such a procedure. Indeed, we often hear pharmacotherapy promoted as a means of enhancing or maintaining weight loss post-surgery.
Dr. Kaplan outlined the anti-obesity medication algorithm that he uses in clinical practice. Patients are initiated on a drug therapy (Dr. Kaplan named the four branded therapies: Saxenda, Qsymia, Belviq, and Contrave) and treated for one to three months. After an initial treatment period, patients response is evaluated. If >10% weight loss is achieved, they continue on the therapy indefinitely. If 5-10% weight loss is achieved, therapy is continued but another drug is added. If <5% weight loss is met, the drug is stopped and a new drug is initiated. We appreciate the emphasis on timely progression, something sorely needed in both diabetes and obesity.
Dr. Kaplan noted a unique challenge associated with the current landscape: “With obesity pharmacotherapy, we have a lot of opportunity and a lot of mechanisms to learn about and to choose from. Learning how to use one or two or three of these drugs is inadequate for the task. We don’t have an anchor drug or class like we do for diabetes or hypertension.”
Additionally, Dr. Kaplan predicted that the next big advance will be identifying clinically useful predictors of response to individual therapies. For most treatment options, weight loss greatly varies among patients – this includes lifestyle interventions like low-carb diets, pharmacotherapies such as liraglutide, devices such as duodenal liners, and metabolic surgery. Not all patients react the same way to these interventions, and spectra of weight loss follow standard curves from those who respond with significant weight loss (>50 pounds) to those who do not respond at all or even gain weight. Predicting which patients will respond best to certain treatments is surely no small task, but the potential yield of is tremendous – it would save time, money, energy, and frustration for both patients and HCPs. To our knowledge, both regression models and genetic based prediction models for weight loss in those with obesity remain in their infancy, with much work ahead before such prediction techniques can reliably be used in clinical practice.
9. Significant Association Between Recurrent Hypoglycemia and Care Fragmentation Shown in Chicago
Northwestern University’s Dr. Clare O’Connor presented data demonstrating a significant association between recurrent hypoglycemia and fragmentation of care in Chicago-based people with diabetes. Recurrent hypoglycemia was defined as a patient seen in the emergency department and/or admitted to the hospital for hypoglycemia on more than one encounter, while fragmentation was defined as emergency department visits and/or hospitalization for hypoglycemia at more than one participating site. Data were collected from the Chicago HealthLNK Data Repository during 2006-2012, comprising six institutions across Chicago. To compile patient data, an algorithm sifts through patient records, removes personal health information, and links patient records between institutions into one database. Out of a total of 1,775,069 patients, 187,644 were determine to have diabetes (11%). 9,741 (5%) had at least one hypoglycemia event recorded, and 2,897 (1.5%) were shown to have recurring hypoglycemia. Fragmented care was identified in 10.5% of those with recurrent hypoglycemia – a significant association (IRR: 1.12, p=0.036). Dr. O’Connor concluded that there may be a causative association between the number of hypoglycemia events and fragmentation of care. Given that incidence of hypoglycemia was also shown to be highly associated with mortality as compared to those with diabetes but without hypoglycemia, Dr. O’Connor hopes to conduct further analysis examining the relationship between mortality and fragmentation of care. Hopefully these results generate greater discussion on how to provide continuous, wraparound care without patients resorting to visiting multiple health systems.
--by Ann Carracher, Martin Kurian, Payal Marathe, Maeve Serino, Brian Levine, and Kelly Close