September 10-15, 2017; Lisbon, Portugal; Full Report – Award Lectures and Additional Topics – Draft

Executive Highlights

This chapter of our EASD 2017 full report covers outstanding award lectures and additional topics. Hypoglycemia was a major focus of this year’s meeting, as you’ll see in our themes section near the top of this page, and further down, we share learnings from the International Hypoglycemia Study Group, from the great Dr. Brian Frier on long-term consequences of hypoglycemia (Dr. Frier delivered the prestigious Camilo Golgi lecture), and from Drs. Bart Van der Schueren and Stephanie Amiel on a new classification scheme for hypoglycemia. This chapter also includes applications of PCSK9 inhibitors in diabetes (see how Sanofi/Regeneron’s Praluent performed in patients with type 1), as well as thoughts from CDC’s Dr. Edward Gregg on the US diabetes epidemic.

As you scroll through this document, you’ll see our summaries of award lectures, symposia, oral presentations, corporate symposia, and posters (in that order). Talk titles highlighted in yellow were some of the most notable from this meeting (in our view), while talk titles highlighted in blue are new full report additions, and were not part of our daily highlights coverage during the conference in Lisbon.

Themes

Hypoglycemia Takes Center Stage – Regulatory + Biology – Plus New DEVOTE Analysis

• We were delighted to attend two fantastic symposia and the Camillo Golgi lecture, all dedicated to hypoglycemia, from the regulatory to the biological. How fantastic to hear from such world experts. In the first symposium, CHMP member Dr. Bart Van der Schueren (University of Leuven) provided an EMA perspective on measuring hypoglycemia in trials. In the draft diabetes drug guideline (open for comment soon), EMA is leveraging recommendations from the International Hypoglycemia Study Group (IHSG) – “clinically important hypoglycemia” will be defined as <54 mg/dl, while a “glucose alert level” will be <70 mg/dl (but does not have to measured routinely in trials). Dr. Van der Schueren acknowledged that use of the “less than or equal to” will likely be a source of public comment, and we hope it is changed to “less than” so it aligns with the consensus from the Outcomes Beyond A1c meeting in August: <54 mg/dl and <70 mg/dl. In his packed Golgi award lecture that we write much more about below, IHSG member and notable global hypoglycemia expert Prof. Brian Frier (University of Edinburgh) referred to 70 mg/dl as “alert level,” in alignment with Dr. Van der Schueren, but his slide also referenced 54 mg/dl as “significant hypoglycemia,” a bit different from the terminology Dr. Van der Schueren used. Still, we’re elated that tiny points, such as “or equal to” and terminology are all that’s left – the field has come so far to reach consensus in so short a time!
  
  • King’s College London’s Prof. Stephanie Amiel provided a compelling snapshot of why <54 mg/dl (<3 mmol/l) is an evidence-based cutoff for serious/clinically important hypoglycemia. As she did at the August 29 outcomes beyond A1c meeting, Prof. Amiel shared study after study showing the link between negative health outcomes and glucose levels <54 mg/dl – impaired cognitive function (e.g., Gonder-Frederick Diabetes Care 2009), strong correlation with severe hypoglycemia (e.g., DAFNE data), and evidence for CV harm and arrhythmias (e.g., ACCORD, Pistrosch et al., Acta Diabetol 2015). Much of the evidence is summarized in the International Hypoglycemia Study Group paper, published in Diabetologia and Diabetes Care earlier this year (see the reference section for many of the studies she covered). Of note, in many of the studies Dr. Amiel reviewed, <70 mg/dl was NOT linked to the host of adverse outcomes like <54 mg/dl. We wonder how FDA will view the <54 mg/dl data, and how much more validation, if any, it will need to see before considering it when evaluating diabetes therapies.
  • A fascinating IHSG Symposium featured alarming data on the prevalence of hypoglycemia, an explanation for why the correlation between A1c and hypoglycemia is weak, an in-depth look at nocturnal hypoglycemia, therapeutic research in hypoglycemia unawareness, and more. It’s excellent to see this group of clinicians and researchers advocating for more recognition of hypoglycemia!
• New analyses from DEVOTE presented by Drs. Bernard Zinman and Thomas Pieber established the strong correlation between glycemic variability/all-cause mortality, and between severe hypoglycemia/all-cause mortality. This CVOT for Novo Nordisk’s basal insulin degludec (Tresiba) found a remarkable 40% risk reduction for severe hypoglycemia with the next-gen product vs. standard of care insulin glargine (Sanofi’s Lantus). Dr. Zinman showed how day-to-day glycemic variability in the trial was significantly associated with all-cause death (HR=1.58, 95% CI: 1.23-2.03, p=0.0004) across both treatment groups. Dr. Pieber discussed a possible temporal relationship between severe hypoglycemia and all-cause death, with a greater risk for mortality in the first 15 days post-hypoglycemia episode (a whopping HR=4.20, 95% CI: 1.35-13.09) compared to the 365 days post-event (HR=2.78, 95% CI: 1.92-4.04). It’s great to have this hard evidence linking glycemic variability and hypoglycemia to outcomes – as if we didn’t already know the value of these metrics beyond A1c, we now see their association with an outcome everyone cares about: death.
  
  • Notably, Professor Brian Frier’s highly-praised Golgi Lecture warned that recurrent hypoglycemia may be more than a “minor inconvenience” with respect to CV disease. He alluded to a number of studies that suggest links between hypoglycemia and micro- and macrovascular complications, but recent evidence has gone in the opposite direction. In DEVOTE, for example, Tresiba was non-inferior to Lantus on CV outcomes, while reducing hypoglycemia by 40% (53% overnight). However, Prof. Frier pointed out that that conclusions are limited by the facts that the number of severe hypoglycemic events was low and the study was not powered to examine an effect of hypoglycemia on cardiovascular events. Even in the absence of solid evidence at present, hypoglycemia is a huge driver of diabetes quality of life at the very least, so interventions should aim to reduce it, regardless of CV effects.  

Promise for PCSK9 Inhibitors in Diabetes

• The LDL-lowering PCSK9 inhibitor class made waves at EASD, with new data supporting the efficacy of these agents in diabetes populations specifically. We heard exciting findings pertaining to both PCSK9 inhibitors on the market: A new sub-analysis of the FOURIER CVOT revealed a 17% relative risk reduction in the primary composite CV endpoint and an 18% relative risk reduction in three-point MACE with Amgen’s Repatha (evolocumab) in people with type 2 diabetes (this is on par with the 15% and 20% relative risk reductions seen for the whole participant pool, with or without diabetes). New data from the ODYSSEY DM-INSULIN study showed a mean 52% reduction from baseline LDL with Sanofi/Regeneron’s Praluent (alirocumab) in people with type 1 diabetes. The ODYSSEY DM program presented the first clinical data on PCSK9 inhibitors in diabetes at ADA 2017 (alirocumab was associated with a mean 49% LDL drop in people with type 2, which is on par with the lipid-lowering benefits seen overall). We’re thrilled to see momentum in this area of clinical research, with even more new results on PCSK9 in diabetes shared at EASD. Effective lipid-lowering is critical for best practice diabetes management, and given that CV disease is the leading cause of death in this patient population, we’re hopeful that people with diabetes will also reap the benefits from this advanced therapy class (provided the issues of high cost and poor reimbursement are eventually settled). As Dr. Bertrand Cariou noted in one session at this meeting, there were some earlier concerns that PCSK9 inhibitor products wouldn’t be as efficacious in people with diabetes, given the correlation between higher A1c and elevated levels of circulating PCSK9 (meaning the drugs would have more substrate to overcome). Dr. Cariou asserted that this hasn’t played out in the clinical data so far, which is great news.

Detailed Discussion and Commentary

Award Lectures

Recurrent Hypoglycemia in Diabetes: The Long-Term Complications

Brian Frier, MD (University of Edinburgh, UK)

In the very prestigious (and absolutely packed) Camilo Golgi lecture, University of Edinburgh’s Professor Brian Frier gave a whirlwind overview of everything hypoglycemia, arguing that “while there’s no definitive proof that recurrent hypoglycemia causes cardiovascular disease, aggregating evidence suggests that it may be more than a minor inconvenience.” His hypothesis is that as the natural history of diabetes progresses, hyperglycemia underlies a steady increase in the prevalence of vascular complications. Then, after 10 years or so, the effects of hypoglycemia kick in and cause a rapid uptake in complication rate. The data supporting the impact of hypoglycemia on microvascular complications in type 1 diabetes is circumstantial – rapid improvement of glycemic control has been shown to cause acute worsening of retinopathy, and severe hypoglycemia coupled with a surge in blood pressure can leave patients more susceptible to renal disease than those who had severe hypoglycemia without a blood pressure surge. On the other hand, an analysis of DCCT data found no link between severe hypoglycemia frequency and retinopathy/nephropathy risk (of course severe hypoglycemia is not the only concern, so is “regular” hypo – to say nothing of retinopathy/nephropathy risk not being the only concern related to severe hypoglycemia). On the macrovascular side, there is correlational data suggesting that arteries may thicken, lose elasticity, and fill with calcium, and a retrospective cohort study (Zhao et al., 2012) indicated that patients with higher rates of hypoglycemia develop more micro- and macro-vascular complications. A separate study from a group in Spain suggested that suggests that hypoglycemia may actively promote atherosclerosis – a finding Prof. Frier called "disconcerting." Given the pathophysiology underlying hypoglycemia (which looks spookily similar to that underlying hyperglycemia) and the lasting metabolic effects of a single episode of hypoglycemia – longer than Prof. Frier believes has been realized in the past – we wouldn’t be surprised to eventually find that hypoglycemia (biochemical+severe) contributes to CV disease. That said, in DEVOTE, Tresiba was non-inferior to Lantus on CV outcomes, while reducing hypoglycemia by 40% (53% overnight), though Prof. Frier pointed out that that conclusions are limited by the facts that the number of severe hypoglycemic events was low and the study was not powered to examine an effect of hypoglycemia on cardiovascular events.  Similarly, hypoglycemia was ruled out as a mediating factor between liraglutide and reduced risk for three-point MACE (non-fatal MI, non-fatal stroke, and CV death) in LEADER. There hasn’t been a study inducing recurrent hypoglycemia over the long term and studying outcomes for obvious ethical reasons, but recent secondary outcomes data makes a convincing case against a link. Even in the absence of solid evidence at present, hypoglycemia is a huge driver of diabetes quality of life at the very least, so interventions should aim to reduce it, regardless of CV effects.

• Professor Frier indicated that consensus has been reached on thresholds for clinically relevant hypoglycemia bins – at 3.9 mmol/L (70 mg/dl; “alert level hypoglycemia”) and at 3.0 mmol/L (54 mg/dl; “significant hypoglycemia”). See the slide below for a visual. When we last heard discussion on hypoglycemia “bins” at the diaTribe Foundation’s Glycemic Outcomes Beyond A1c meeting in July, a breakout session moderated by Profs. Frier and Stephanie Amiel at that meeting expressed agreement on the cut-offs of <70 mg/dl and <54 mg/dl to divide the different classes of hypoglycemia, though had less unanimity on terminology. Prof. Frier’s told us that the International Hypoglycemia Study Group has agreed on how to call these bins since then but awaits consensus with other groups. It’s so important for all stakeholders to get on the same page so we can move on with standardizing the measurement and reporting of hypoglycemia in clinical trial and real world data.

• According to Prof. Frier, the Clark and Gold surveys are sensitive to IAH, but have a number of limitations, so an expert committee (including Profs. Frier and Simon Heller) developed the HypoA-Q for use in the HYPO-COMPaSS trial. The HypoQ-A is a 33-item (seven-minute) questionnaire that has undergone psychometric validation, performing with sensitivity and predictive ability for IAH. “It looks like this is the way moving forward, but we need a longitudinal prospective validation study now.” It would be excellent to see consensus develop around an IAH detection instrument, because as Prof. Frier pointed out, there isn’t even an internationally-recognized definition at this point – IAH means different things to different people and is ignored in many studies of new insulins.
• The detrimental effects of hypoglycemia on the individual are notable, and notably, Prof. Frier reminded attendees that caregivers of patients with impaired hypoglycemia awareness also require support. This was extraordinary to hear so much attention paid to this area in such a prestigious lecture – as well, we would note that although he didn’t name patient-reported outcomes, the impact on the family is critical for most individuals. Caregiver support is important across the spectrum of diabetes, but extremely crucial when the patient has impaired awareness. Caregivers often feel that their lives are restricted because they always have to treat lows, that their loved one has a sort of “Jekyll and Hyde” syndrome, that they have difficulty treating some events, that they too have fear of hypoglycemia, and that there is a major unmet need for information and support.

Rising Star Symposium (Sponsored by Novo Nordisk)

Gustaf Cristoffersson, MD (Uppsala University, Sweden); Teresa Mezza, PhD (Cattolica University, Rome, Italy); Andrew Wood, MD (University of Exeter, UK); Hanieh Yaghootkar, MD (University of Exeter, UK)

It was an absolute pleasure to attend the Novo Nordisk-sponsored Rising Star Symposium, which featured some of the best and brightest young minds in diabetes research today. As one of the very last sessions of the week, we cannot think of a more fitting end to the conference than learning from the newest generation of diabetes scientists. This year’s brilliant recipients were Drs. Gustaf Cristoffersson (Uppsala University, Sweden), Teresa Mezza (Cattolica University, Rome, Italy), Andrew Wood (University of Exeter, UK), and Hanieh Yaghootkar (University of Exeter Medical School, UK) who discussed their work in immunology, islet plasticity, genetic and environmental interactions on BMI, and favorable adiposity respectively. See below for some of our major takeaways from this fascinating symposium.

• Dr. Christoffersson detailed his work leveraging video microscopy to examine the cell to cell immune response in type 1 diabetes. He found that only 1%-2% of the CD8+ T-cells shown to cluster around beta cells in a diabetes mouse model are actually specific for islet antigens. By tagging islet-specific T-cells red and non-islet-specific T-cells green, Dr. Cristofferson discovered that these non-islet-specific T-cells can actually suppress the immune response, potentially by limiting trafficking or proliferation. These findings hint at a new avenue for developing immunotherapies combatting diabetes closer to the source.
• Dr. Mezza presented her work investigating the relationship between beta cell function and islet morphology in hopes of identifying new therapeutic targets to preserve beta cell mass in diabetes patients and prevent beta cell degeneration in those at risk. She found that islet size is inversely correlated with glucose uptake – the more insulin resistant a patient is, the larger the islet. Not surprisingly, insulin sensitivity is inversely related with alpha cell area, with five-times greater alpha cell mass in insulin resistant patients indicating a decrease in beta cells. Additionally, she found an increase in small islets in insulin resistant patients, suggesting that insulin resistance prompts the production of new islets as part of a compensatory mechanism. This is further supported by the observation that insulin sensitivity is inversely correlated with the proportion of double cells (cells that include markers for alpha and beta function), indicating proliferation. Importantly, duct cells in particular were found to secrete both insulin and glucagon, suggesting that they may be progenitors for endocrine cells. Dr. Mezza hopes to investigate potential regulators of duct and alpha cell trans-differentiation to identify how to intercept the conversion from duct to alpha cell and potentially redirect the process to generate more beta cells.
• Next up was Dr. Wood, who sought to determine whether genetic effects on BMI are accentuated given specific behaviors. It’s important to investigate this area, because it’s possible that we’re underestimating the contribution of genetics to obesity risk, which is currently estimated at 40%-70%. Dr. Wood described a Gene x Behavior interaction study (GxB) recently published by Tyrrell et al. in the International Journal of Epidemiology demonstrating that watching TV and self-reported activity exhibit an interaction between genetics and the environment. We know that watching more TV is associated with a greater BMI, but Tyrrell et al. were able to find that this difference in BMI actually increases by 35% as the genetic risk increases, showing that the environment is able to enhance genetic risk. Likewise, self-reported low activity exacerbates genetic susceptibility to a high BMI. Dr. Wood is currently conducting a GxB study examining interactions due to sleep patterns and physical activity data derived from wearable accelerometers. The researchers haven’t been able to identify evidence of interactions with interrupted sleep patterns, although self-reported data suggest it is a significant factor. This area of research could be critical in curbing the global obesity epidemic, as it may serve to identify which environmental factors have the greatest impact on BMI.
• Wrapping up the symposium, Dr. Yaghootkar discussed her research examining the physiological and molecular basis for why some people with obesity never develop type 2 diabetes, a condition which is termed “favorable adiposity.” Using data from the UK Biobank, Dr. Yaghootkar identified genetic variants associated with body fat percentage and then tested the genetic variance against multivariable metabolic outcomes using summary statistics from published GWASs (genome-wide association studies). These analyses revealed 620 independent genetic loci associated with body fat percentage and 24 alleles associated with favorable adiposity. These favorable adiposity alleles were shown to be associated with reduced risk of type 2 diabetes, heart disease, and hypertension. Interestingly, favorable alleles are associated with more lower body fat in women (corresponding to a pear body-type) and fat all over in men (corresponding to an apple body-type). Still, when looking at individual alleles, Dr. Yaghootkar noted heterogeneous effects in body shape, clouding the pciture. Dr. Yaghootkar hopes to use the genetic variance to understand the role of favorable adiposity on non-metabolic disease outcomes. As a parting teaser, she mentioned that favorable adiposity is associated with a higher risk of depression in women – which we find surprising at first glance because people with diabetes are more susceptible to depression, but then again, that certainly has a lot to do with the environment (stigma, etc.).

DNA Switches, Beta Cells, and Diabetes

Jorge Ferrer, PhD (Imperial College London, UK)

The brilliant Dr. Jorge Ferrer delivered the 11th Albert Renold Lecture, detailing the complex and largely unchartered territory of regulatory genomics as it relates to diabetes. Consider Dr. Ferrer’s metaphor: Diabetes genetics is like the London coliseum theater – there’s wonderful engineering, and when something fails, the regulatory switchboard is likely the culprit. Such is the case with diabetes. Dr. Ferrer was motivated to enter the field of regulatory genomics because he finds current type 2 drugs inefficient. By cultivating a better understanding of the molecular causes of type 2 diabetes, he hopes to eventually develop precision medicine therapies intercepting specific pathways, promising a completely new class of treatment. With recent advances in genome and epigenome sequencing, as well enhanced manipulation via CRISPR/Cas9, this goal seems within reach, but will require enormous effort, given that the number of mapped regulatory elements is on the order of one million. Regulatory elements such as enhancers (locations on the genome where transcription factors can bind to upregulate expression of nearby genes) can be mapped using Chip-Seq. Dr. Ferrer and his team generated a map of human enhancers contributing to early pancreas development and were able to identify enriched sequence motifs. Through this process, they determined that the well-known transcription factor TEAD, which was previously not associated with pancreas development, is essential for the proliferation of pancreatic progenitors. They also conducted GWAS and identified >100 loci that influence the risk for developing type 2. Interestingly, they found blocks of associated variants, most of which did not affect proteins, hinting at a regulatory role. Indeed, Dr. Ferrer found that tissue-specific activity in pancreatic islets is driven by clusters of regulatory elements known as super-enhancers. This fascinating research is still in its earliest stages and several questions: What role do the enhancers play? Which genes do they regulate? Are the variants responsible for activating and/or inhibiting genes? Ideally, Dr. Ferrer would like to be able to track the impact of regulators on beta cell pathways for type 2 diabetes, which would allow for a more targeted molecular therapy.

• Dr. Ferrer discussed several ongoing research projects aimed at better understanding the genetics of diabetes. Several groups are investigating the role of long, non-coding RNAs (lncRNAs) in diabetes. Currently, we know that there are lncRNAs highly specific to pancreatic islets, and that they are abnormally regulated in type 2. Some efforts are now focused on determining whether lncRNAs are involved in islet gene regulation. In one example, a team of investigators used RNAi and CRISPRi to identify a critical structural interaction between PLUTO, a lncRNA, and PDX1, a transcription factor, both of which are downregulated in type 2. When PLUTO is knocked down, nearby enhancers are prevented from appropriate interaction with PDX1, clogging the regulatory network. Another group identified a cross-regulatory feedback circuit contributing to appropriate islet proliferation involving genes known to be associated with monogenic diabetes. Another ongoing project, which has enrolled >1,000 patients to-date, is screening for the presence of penetrant islet enhancer mutations in “mutation negative” diabetes patients. Causal genetic variants can be found in only about half of the population with diabetes, suggesting a pool of patients likely to harbor regulatory mutations. The researchers hope to identify new nodes of defects underlying diabetes and to distinguish connections in the regulatory network. These nodes could potentially be prime targets for developing therapeutics.
• We appreciated that Dr. Ferrer closed his lecture with a slide depicting the reality of diabetes in refugee camps. While cutting-edge research is undoubtedly thrilling, it’s important to remember and respect the urgent need that is happening right now (especially in areas with deplete resources).

EASD/Novo Nordisk Foundation Diabetes Prize for Excellence

Philipp Scherer, PhD (UT Southwestern Medical Center, Dallas, TX)

Dr. Philipp Scherer detailed his impressive work investigating two main questions: (i) What goes wrong in adipose tissue when we gain weight? (ii) How can we pharmacologically intervene? While the field is still a long way from being able to fully answer these questions, Dr. Scherer shared exciting updates regarding the role of adiponectin and ceramides in type 2 diabetes, articulating how further exploration into these topics will yield major ground for pharmacological intervention. At a basic level, vasculature is responsible for maintaining appropriate oxygenation and nutrient supply of adipose tissue. When fat is gained quickly, vascularization sometimes struggles to keep up, and hypoxia can occur, resulting in what Dr. Scherer referred to as the “ominous triad of adipose tissue dysfunction” – inflammation, fibrosis, and impaired angiogenesis. Eventually, this dysfunction amounts to insulin resistance. Interestingly, Dr. Scherer noticed that adiponectin, a peptide produced by adipose tissue, is the only hormone secreted from adipocytes with levels inversely related to fat mass (more hormone correlates with less fat mass). Adiponectin is also associated with remodeling of the extracellular matrix, which has been shown to be instrumental for the metabolic health of fat tissue. Dr. Scherer’s interest in adiponectin led him to investigate ceramides, a group of lipids known to be elevated in those with diabetes, contributing to cell death, insulin resistance, and inflammation, and correlating with non-alcoholic fatty liver disease (NAFLD). In a major win for the field, Dr. Scherer found that adiponectin decreases ceramide levels in the liver, and that when adiponectin is eliminated in mice, insulin resistance develops. Additionally, an overexpression of adiponectin receptors in mice clears up ceramides and improves glucose tolerance. Further supporting the role of adiponectin in lowering ceramides, treatment with TZD pioglitazone improves insulin sensitivity and is known to depend on the presence of adiponectin – in fact, it’s the most potent inducer of adiponectin that we’re aware of. In patients treated with pioglitazone, ceramide levels are lowered. These results could be incredibly clinically relevant, as Dr. Scherer believes anyone with type 2 diabetes will have increased levels of ceramides, although he noted that further tests are needed. We’ll keep an eye out, as we’re very intrigued by this area of research.

• Huge congratulations to Dr. Scherer for winning this prestigious prize! This was a fascinating lecture overall, and we appreciated the deep dive into basic science.

A Glucose-Centric View on Diabetes Pathogenesis: From Islet Biology to Integrated Physiology and Precision Medicine

Bernard Thorens, PhD (University of Lausanne, Switzerland)

Although we think of glucose regulation as a primarily hormonal phenomenon, Dr. Bernard Thorens – honored with this year’s prestigious Claude Bernard lecture – provided a fascinating reminder of the neurological side of glucose sensing and regulation. Dr. Thorens participated in some of the foundational work in cloning beta cell GLP-1 and Glut2 receptors. His work in rodent models demonstrates that neurons in key parts of the body and brain can sense glucose directly via the Glut2 receptor, and in turn modulate beta cell activity, release of gluco-regulatory hormones, and glucose-seeking behavior. Interestingly, knocking out the Glut2 receptor in these glucose sensing pathways essentially causes a prediabetic state in mouse models. Better understanding of the body’s complex glucose sensing neural network – and the ways it is impacted by genetic variations – could contribute to precision medicine in diabetes.

• Dr. Thorens’ presentation focused on three key glucose sensing networks:
  
  • Hepato-portal glucose sensing: Sensory neurons in the hepatic portal vein – which carries freshly absorbed glucose and nutrients from the intestine to the liver – plays a key role in the body’s adaptation to incoming glucose. Signals from these neurons help stimulate the first phase of insulin secretion, playing a bigger role in the first phase than the beta cells’ direct sensing of glucose (at least in mice). It also increases muscle glucose uptake and decreases feeding behavior.
  • Pre-autonomic neurons: Another glucose-sensing network of neurons, this one in the brain, modulates activity of the autonomic nervous system. This in turn stimulates beta cell proliferation and glucagon secretion. We appreciated that some of Claude Bernard’s seminal work involved stimulation of these brain areas. 
  • Dopaminergic reward system: Glut2 receptors found in the brain’s reward pathway – which plays a role in addiction – stimulates sugar-seeking behavior. Interestingly, this system is unable to sense artificial sweeteners and fructose, which may play a role in overeating or sugar craving associated with consumption of beverages sweetened with these substances.
• Dr. Thorens is a coordinator of the RHAPSODY public-private partnership that aims to better understand the progression from prediabetes to type 2 diabetes. The Innovative Medicines Initiative (IMI) supports the project and Sanofi is a co-leader. RHAPSODY hopes to define “disease trajectories” for type 2 diabetes and build a database of biosamples that can help identify biomarkers for assessing risk of diabetes progression.

Targeting Therapy in Diabetes: Insights from Genetics

Ewan Pearson, PhD (University of Dundee, UK)

Dundee’s Dr. Ewan Pearson provided optimism and pragmatism in equal doses as he delivered his prestigious Minkowski Lecture on the role of genetics in diabetes management. He shared the story of patient diagnosed with type 1 diabetes at age 18, only for it to be discovered at age 87 that she had robust C-peptide and in fact had MODY. He argued that C-peptide measurements should become standard of care for type 1 diabetes, as genetic diagnoses of diabetes can change lives (the patient in his story switched off of insulin to a sulfonylurea and is doing well). Genetics plays an important role in type 2 diabetes as well, and Dr. Pearson believes that in ten years, patients’ genetic sequences will be a part of their electronic health records, allowing for the creation of response prediction calculators that would factor in demographics, genotype, and biomarkers to predict a given patient’s likelihood of response and risk of side-effects with different therapeutic options (i.e. an output like “Patient A is X% likely to respond and Y% likely to have an adverse reaction to an SGLT-2 inhibitor”). That strikes us as a fantastic way to make PCPs’ jobs more manageable and make targeted therapy in type 2 diabetes a reality, instead of expecting already-overwhelmed PCPs and endos to process these vast amounts of data singlehandedly.

Symposium: Hypoglycemia Revisited

The Case for a New Classification of Hypoglycemia in Clinical Trials: A Regulator's View

Bart Van der Schueren, MD (University of Leuven, Belgium)

Dr. Bart Van der Schueren (University of Leuven) provided an EMA perspective on measuring hypoglycemia in trials. Notably, the Agency’s updated diabetes drug guideline will be open for public comment soon, confirming his remarks at the Outcomes Beyond A1c meeting in August. In the draft guideline (no timeline on release), EMA is leveraging recommendations from the International Hypoglycemia Study Group – “clinically important hypoglycemia” will be defined as <54 mg/dl, while a “glucose alert level” will be <70 mg/dl (but does not have to measured routinely in trials). Dr. Van der Schueren admitted that use of the “less than or equal to” will likely be a source of public comment: “I don’t know why we did that, but we might get comments on that!” We hope it is changed to simply “less than” so that it aligns with the consensus achieved at the Outcomes Beyond A1c meeting in August: <54 mg/dl and <70 mg/dl. (This may seem small, but it is very critical for the field to agree on.) Dr. Van der Schueren mentioned that if a drug shows less of these non-severe hypoglycemia events, it “will be taken into account” in the review – we assume such CGM data would be reported in the label, just like severe hypoglycemia for products like Tresiba. He echoed his August comments that “better analytic tools have changed what we can measure” – his slide showed a picture of time-in-range on FreeStyle Libre and the FDA press release approving Dexcom’s G5 for non-adjunctive use. We love seeing this CGM enthusiasm from EMA and we seriously hope FDA gets the message. Dr. Van der Schueren highlighted patient-reported outcomes as an area where more consensus is needed, since “a lot of questionnaires are not sufficiently validated.” The upcoming EMA guideline will not recommend a specific PRO, though EMA did include the hypoglycemia fear survey and diabetes therapy-related quality of life questionnaire in the Trulicity label (see page 16 here). Last, he reprised his comments from August on composite/co-primary endpoints, which are difficult for regulators – they typically mix efficacy and safety endpoints within the same statement (e.g., achieving A1c <7% without episodes of severe hypoglycemia or DKA). “It becomes difficult to disentangle that into a primary indication,” said Dr. Van der Schueren. The EMA is seeing more of these outcomes proposed for adjunctive therapies in type 1 diabetes (e.g., SGLT-2s), and we’ll be interested to see how companies and regulators cope with them for benefit-risk decisions and product labels. 

The Case for a New Classification of Hypoglycemia in Clinical Trials: A Researcher’s View

Stephanie Amiel, MD (King’s College London, UK)

Dr. Stephanie Amiel (King’s College London) provided a compelling snapshot of why <54 mg/dl (<3 mmol/l) is an evidence-based cutoff for serious/clinically important hypoglycemia. As she did at the August 29 outcomes beyond A1c meeting, Dr. Amiel shared study after study showing the link between negative health outcomes and glucose levels <54 mg/dl – impaired cognitive function (e.g., Gonder-Frederick Diabetes Care 2009), strong correlation with severe hypoglycemia (e.g., DAFNE data), and evidence for CV harm and arrhythmias (e.g., ACCORD, Pistrosch et al., Acta Diabetol 2015). Much of the evidence is summarized in the International Hypoglycemia Study Group paper, published in Diabetologia and Diabetes Care earlier this year (see the reference section for many of the studies she covered). The paper has already been cited 20 times! Dr. Amiel again noted that 70 mg/dl is an “alert level,” meaning it is the lower limit of the target range (Dr. Amiel said this level was “usually asymptomatic”) and alerts patients that they need to do something. Interestingly, in many of the studies Dr. Amiel covered, <70 mg/dl was NOT linked to the host of adverse outcomes like <54 mg/dl. We thought her summary of the data was compelling and wonder how FDA will interpret all the evidence linking <54 mg/dl to meaningfully negative outcomes. Will further validation be needed? Hopefully, the field will start to use CGM widely to capture the occurrence of hypoglycemia in trials, further building a case. Ultimately, we hope non-severe hypoglycemia data (e.g., <54 mg/dl) makes it into product labels, changes incentives for drug development, and even redefines the bar for reimbursement.

Symposium: Diabetic Hypoglycemia: New Thinking, New Tools (Sponsored by the International Hypoglycemia Study Group)

Summary

Ulrik Pedersen-Bjergaard, MD (Diabetes Research Foundation, Copenhagen, Denmark); Bastiaan de Galan, MD (Radboud University Medical Center, The Netherlands); Rory McCrimmon, MD (University of Dundee, UK)

The International Hypoglycemia Study Group hosted an information-packed symposium at EASD, imparting some of their endless knowledge on hypoglycemia prevalence, pathogenesis, therapeutic pipeline, and more.

• Hypoglycemia is certainly recognized to be a huge problem, but statistics presented by Dr. Ulrik Pedersen-Bjergaard were still alarming. These figures demonstrate how, even though hyperglycemia hospitalizations have gone down and overall A1c has decreased, hypoglycemia remains a big limitation to better therapy. As CGM use rises further, we expect a lot more hypoglycemia that has traditionally gone undetected will surface, hopefully adding more urgency to the discussion. Could we ever see a day where drugs are indicated for the reduction of hypoglycemia (independent of A1c)?

• Denmark’s Dr. Pedersen-Bjergaard emphasized that the correlation between hypoglycemia and A1c is not strong, likely due to differential glycemic variability from patient-to-patient. In the DCCT, intensive control did increase the risk of severe hypoglycemia relative to the control arm, but people with recurrent hypoglycemia or impaired awareness of hypoglycemia were excluded from the study. Recently, the HAT study demonstrated that the association between A1c and severe hypoglycemia is actually much less significant in the broader population – there is a slightly significant relationship (with a small effect size) between A1c and any hypoglycemia in type 1, but not in type 2. Nocturnal and severe hypoglycemia were not associated with A1c at all. 2017 data from EDIC, the DCCT follow-up, now shows that the relationship between lower A1c and increased rate of severe hypoglycemia is blunted, even though in the same cohort of patients. Why? Dr. Pedersen-Bjergaard suggested that treatment improvements may underlie the differences, though patients outside of the intensive arm may have developed impaired hypoglycemia awareness or other risk factors.
  
  • Audience members seemed confused by this counterintuitive tenet, as one asked for clarification during Q&A. The panel dismissed explanations including glycemic variability, a “disengagement with one’s own self-management,” and a clustering of risk factors in a few individuals. We believe the evidence against a solid relationship between A1c and hypoglycemia should be preached from the mountain tops, as it is the best argument against relaxing glycemic control in hypoglycemia-prone individuals.
• Nocturnal hypoglycemia actually reduces sleep efficiency, increasing delta power and slow wave sleep at the cost of decreased REM sleep, increased wakes, and increased sleep latency (time to sleep) once awoken. This is why people with diabetes often feel exhausted when they wake in the morning, and why morning exhaustion is a possible indicator of prior hypoglycemia. Belgium’s Dr. Bastiaan de Galan also contested the “myth” of the Somogyi effect (elevated blood glucose in the morning as an indication of nocturnal hypoglycemia, or “posthypoglycemic hyperglycemia”). Low fasting glucose in the morning is still an accepted possible sign of nocturnal hypoglycemia, but the morning glucose rebound is no longer widely accepted.
• Scotland’s Dr. Rory McCrimmon showed data demonstrating that impaired awareness of hypoglycemia prevalence hasn’t changed in the last 30 years (~25%), and skimmed the surface of ongoing mechanistic and therapeutic research. The field hasn’t yet determined the main biological culprit(s) behind IAH, but it may involve glucose transport, alternate fuels (glycogen/lactate), glucose sensing (GK/AMPK/KATP), peripheral signals (opiates/steroids/cytokines), and/or neurotransmitter release. Whatever the mechanism, the net result is an increase in GABAergic (inhibitory) tone and a decrease in glutamatergic (excitatory) tone from glucose-sensing neurons. He showed preliminary evidence that IAH is a product of habituation to some repeated stimulus (a logical hypothesis): in a rodent model, his group was able to dis-habituate and restore physiological response to recurrent hypoglycemia with high-intensity exercise. There are countless other novel approaches to restore hypoglycemia awareness currently under investigation: (i) oral dehydroepiandrosterone; (ii) inhaled formoterol; (iii) opioid receptor blockade; (iv) naltrexone; (v) somatostatin type 2 antagonism; and (vi) oral diazoxide (K+ channel activator). Having a toolkit of agents that improve hypoglycemia awareness, and a pharmacogenomics approach that dictates which work best in which patients, would be a true game-changer. Of course, we also hope to see CGM and automated insulin delivery better studied in those with impaired hypoglycemia and high risk of severe hypoglycemia.
• Dr. Pedersen-Bjergaard introduced the IHSG patient and provider hypoglycemia risk stratification infographic tool, which will be available here soon. The tool separates patients by low, moderate, and high risk, offers solutions for each risk range, describes acute and long-term outcomes and risk factors, and providers risk-reduction strategies. This could be a very helpful resource, especially for those who aren’t seen after by one of the luminaries of the IHSG.
• Two days prior, IHSG member Prof. Brian Frier was given the honor of delivering the Camilo Golgi lecture, in which he indicated that consensus has been reached on thresholds for clinically relevant hypoglycemia bins – at 3.9 mmol/L (70 mg/dl; “alert level hypoglycemia”) and at 3.0 mmol/L (54 mg/dl; “significant hypoglycemia”). When we last heard discussion on hypoglycemia “bins” at the diaTribe Foundation’s Glycemic Outcomes Beyond A1c meeting in July, a breakout session moderated by Profs. Frier and Stephanie Amiel at that meeting expressed agreement on the cut-offs of <70 mg/dl and <54 mg/dl to divide the different classes of hypoglycemia, though had less unanimity on terminology. Prof. Frier told us that the International Hypoglycemia Study Group has agreed on how to call these bins since then but awaits consensus with other groups.
• Dr. McCrimmon explained why hypoglycemia may only be deleterious in the context of hyperglycemia, not on its own. Chronic hyperglycemia is an inflammatory stimulus that depletes the anti-oxidative response. When hypoglycemia comes along, it causes tremendous oxidative stress, but there are fewer reserves of anti-oxidants to restore homeostasis. This makes sense in theory, and was supported in a rodent study: Control mice performed fine on novel object recognition task (testing memory) after intermittent hypoglycemia, while STZ mice (who have chronic hyperglycemia) struggled immensely following the same intervention (while STZ mice not exposed to hypoglycemia did fine). At a molecular level, the STZ mice who had undergone the hypoglycemia treatment had significantly higher protein carbonylation, a biomarker of oxidative activity. Might eating a diet rich in anti-oxidants help to dampen the deleterious effects of hypoglycemia? The idea that the recovery from hypoglycemia and the control leading into it could be just as important as the event itself is fascinating.

Symposium: Role of Alirocumab in Lipid Management of Individuals with Type 1 and Type 2 Diabetes at High CV Risk: ODYSSEY DM Program

PCSK9 and Diabetes: What is Currently Known?

Bertrand Cariou, MD (Institut du Thorax, Nantes, France)

Dr. Bertrand Cariou provided an excellent overview of the connections between PCSK9 and diabetes, and outlined the key questions about PCSK9, lipids, and diabetes that Sanofi/Regeneron’s ODYSSEY DM program for Praluent (alirocumab) set out to answer. Reviewing data that has already been presented on alirocumab and Amgen’s PCSK9 inhibitor Repatha (evolocumab), Dr. Cariou noted no deteriorations in A1c, worsening of other markers of glucose homeostasis, or increase in diabetes incidence with use of PCSK9 inhibitors. Both type 1 and type 2 diabetes patients have been found to have elevated PCSK9 levels on average, with higher A1c predicting higher PCSK9 levels even after adjusting for traditional CV risk factors. This relationship raises an important question: Are PCSK9 inhibitors less effective in diabetes, because they have more substrate to overcome? Dr. Cariou noted that data so far (including from the ODYSSEY DM program) does not suggest that PCSK9 inhibitors are any less effective in diabetes patients.

Overview of the ODYSSEY DM Program

Kausik Ray, MD (Imperial College London, UK)

Before the presentation of results – old and some new – from the ODYSSEY DM-INSULIN and ODYSSEY DM-DYSLIPIDEMIA trials, Dr. Kausik Ray provided an extensive walkthrough of the trials’ design, highlighting the ways in which they were unprecedented. ODYSSEY DM-INSULIN was the first trial to examine PCSK9 inhibitor efficacy specifically in insulin-treated diabetes patients facing high CV risk. ODYSSEY DM-DYSLIPIDEMIA was the first PCSK9 inhibitor trial in diabetes to use non-HDL cholesterol as a primary endpoint (most other PCSK9 inhibitor trials have used LDL as the primary outcome).

Alirocumab in Insulin-Treated Individuals with Type 1 and 2 Diabetes: ODYSSEY DM-INSULIN

Helen Colhoun, MD (University of Edinburgh, UK)

New data from Sanofi/Regeneron’s ODYSSEY DM-INSULIN study demonstrated a 52% reduction in LDL cholesterol with PCSK9 inhibitor Praluent (alirocumab) vs. placebo in people with type 1 diabetes (p<0.0001), comparable to the 49% placebo-adjusted LDL reduction previously reported at ADA 2017 for the subgroup with type 2 diabetes. This double-blind, 24-week study randomized 517 insulin-treated patients (441 with type 2 diabetes, 76 with type 1 diabetes) with starting LDL levels >70 mg/dl despite maximally-tolerated statins to alirocumab 75 mg or to placebo in a 2:1 fashion. Alirocumab dose was titrated up to 150 mg at 12 weeks for patients who did not achieve an LDL cholesterol <70 mg/dl at week 8. University of Edinburgh’s Dr. Helen Colhoun presented the results specific to type 1. The impressive 52% drop from baseline LDL 121 mg/dl translated to a mean 62 mg/dl decline (as we understand it, this is very clinically-meaningful). Notably, 63% of participants achieved this LDL reduction with the lower, 75 mg dose of alirocumab, while 37% of participants were titrated up to 150 mg. In terms of the time course for LDL reduction, a massive drop occurred by week eight, after which point levels largely plateaued. Dr. Colhoun pointed out that 70% of participants with type 1 diabetes achieved LDL goal of <70 mg/dl with Praluent vs. 76% of people with type 2 diabetes (who came in with a lower mean baseline LDL of 110 mg/dl, and a smaller variance). Similarly, high levels of target achievement were seen for the non-HDL cholesterol goal of <100 mg/dl with Praluent – 71% for type 1 participants and 79% for type 2 participants. Overall, we are thrilled to see a dedicated analysis of type 1 diabetes in this clinical trial program, and we’re even more pleased that Praluent’s potent LDL-lowering effect also spans to this often under-studied population (in addition, of course, to type 2 diabetes). Given that CV disease is the main cause of morbidity and mortality in people with diabetes, we see great potential for Praluent as an effective tool for lipid management in this patient population. We are eagerly awaiting results from the ODYSSEY OUTCOMES CVOT of Praluent, expected to complete in December 2017 with results anticipated early 2018, to learn whether this LDL-lowering effect translates to a lower incidence of CV events. In the FOURIER CVOT, Amgen’s Repatha (evolucmab) recently became the first PCSK9 inhibitor to report a cardioprotective effect (demonstrating a 15% risk reduction the composite primary endpoint of CV death, non-fatal MI, non-fatal stroke, hospitalization for unstable angina, or coronary revascularization), and we think this bodes well for Praluent’s CVOT results.

• Beyond the primary endpoint of superior LDL-lowering with Praluent vs. placebo, the trial’s type 1 diabetes subgroup also met several key secondary endpoints: placebo-adjusted, alirocumab was associated with a 43% reduction in non-HDL cholesterol (p<0.0001), a 29% reduction in total cholesterol (p<0.0001), a 39% reduction in ApoB (p<0.0001), a 19% reduction in Lp(a) (p=0.0039), and a 40% reduction in LDL particle number (p<0.0001). Dr. Colhoun highlighted the Lp(a) reduction as particularly exciting, since this key risk factor for peripheral vascular disease is not affected by statin therapy. Consistent with the rest of the ODYSSEY program, adverse event rates were low, with no appreciable differences between the alirocumab and placebo arms.

Alirocumab Versus Usual Care in Diabetes with Mixed Dyslipidemia: ODYSSEY DM-DYSLIPIDEMIA

Stefano Del Prato, MD (University of Pisa, Italy)

Dr. Stefano Del Prato presented new results from a sub-analysis of the ODYSSEY DM-DYSLIPIDEMIA trial, specifically comparing alirocumab with fenofibrate, another lipid-lowering drug. Results from the whole trial were presented at this year’s ADA so we won’t revisit them again here except to say that alirocumab performed as well as expected in type 2 diabetes patients with mixed dyslipidemia (high triglycerides, low HDL). The high level takeaway from the new analysis was that alirocumab looked great when compared with fenofibrate, one of the existing “usual care” drugs for mixed dyslipidemia. Even setting aside the comparison vs. alirocumab, fenofibrate didn’t really appear to be particularly effective in this trial (9% reduction in non-HDL cholesterol vs. a much more impressive 42% reduction with alirocumab). Fenofibrate trended toward a slightly better reduction in triglycerides (-24% from baseline vs. -15% with alirocumab), but the difference was not statistically significant. No new, specific, or worrying safety signals arose with alirocumab. These new results said more about fenofibrate than alirocumab, since we already saw how alirocumab did in the overall trial. Importantly, neither alirocumab nor fenofibrate disrupted glucose control as measured by A1c, fasting plasma glucose, or a number of glucose-lowering medications.

Symposium: East-West Forum: Diabetes Outcome Trends

The US Experience

Edward Gregg, PhD (CDC, Atlanta, GA)

The CDC’s highly respected Dr. Edward Gregg shared fascinating insights on the changing character of the US diabetes epidemic: A diversification of complications and maintained cumulative incidence and secondary events.

• The first factor that Dr. Gregg believes may be underlying these trends is progress in the treatment of older adults, thanks to improvements in clinical and public health efforts. As a consequence, we are likely seeing greater reductions in macrovascular complication and decreased mortality, which could cause reduced competing risk (i.e. allowing other complications to manifest) and extended exposure (i.e. people have diabetes longer).
• Dr. Gregg suggested that factor #2 contributing to the observed trends is an increase in type 2 diabetes in youth and young adults in virtually all ethnic groups except for non-Hispanic whites. He explained that the improvements we’ve seen in the care of older adults are not apparent in youth (this is probably because research in this demographic is sorely lacking). Millennials (born between 1980-2000) are the most obese generation yet; within this generation, smoking prevalence is higher in people with diabetes than in those without diabetes; these patients are most likely to have very poor glycemic control; and youth have seen the smallest improvements in CVD hospitalization and mortality.
• Taken together, diagnosis at young age plus a lack of quality care leads to extended exposure. We found this analysis to be particularly interesting, and on the whole, a positive outlook. Improved outcomes in adults speaks for itself – our tools and drugs are getting better. While the trends in young people are heading in the wrong directions, we believe that studying this at-risk cohort in greater depth would yield improved preventative and care measures. Dr. Gregg believes the field has hit a tipping point, as everyone in behavioral research and otherwise is talking about behavioral research/intervention and healthy environment design. This is terrific, of course – we’re still wary that most numbers we see on the “most” obese are getting worse.
• Overall diabetes complication incidence in the US has been ~flat since 2010. There hasn’t been much of a decline in the last four years in CV hospitalization rates; over time, as long as they were reimbursed, the advent of cardioprotective diabetes drugs will bend that curve meaningfully. On a quite worrisome note from our view, there has actually been an increase in amputations in the past four years, largely driven by men, and by toe amputations.
• Diabetes appears to take a larger toll on disability-free life than overall life-expectancy. A recent study showed that if a woman has diabetes and is 50 years old, she can expect disability onset (on average) at age 70, and then live to 80 years. Meanwhile, a 50-year-old woman without diabetes can expect to live disability-free until she’s 79, and then live to 86 years. That’s a nine-year difference in disability-free living, and just a six-year gap in life expectancy. It’s clearly not enough to just make patients live longer, because we risk creating a population of elderly unwell who will not only have compromised qualities of life, but also cost the healthcare system boatloads.
• Increased incidence + decreased mortality = increased lifetime risk. The average 60-year-old man spent 15 years with diabetes in the 1990s; 18 years in the 2000s. Put in a population context, the total years spent with diabetes for the average community of 1,000 was 5,463 years in the 1990s; in the 2000s, it was 12,199 years. That’s more than a doubling of exposure to diabetes. Even if diabetes management continues to improve dramatically and complication rates continue to drop, there will still be a huge burden attributable to the sheer size of the epidemic and longer lifespans.

Symposium: Precision Medicine in Diabetes: How Close are We?

Precision Medicine in Common Diabetes

Angus Jones, PhD (University of Exeter School of Medicine, UK)

Dr. Angus Jones considers the differentiation between type 1 and type 2 to be a major error of practice in diabetes management. With this bold statement, he set the stage for this precision medicine symposium. Dr. Jones argued that the type 1 vs. type 2 divide creates a one-size-fits-all situation with high stakes, as all future management decisions are based on that initial checkbox. In reality, hyperglycemia has more nuance to it, Dr. Jones explained, aptly noting that “patients behave like their endogenous secretions, not like their BMI or diagnosis.” To provide a more precise diagnosis, Dr. Jones and his team have created a model which integrates an individual’s clinical features, antibody results, and insulin-related biomarkers to generate a predicted diagnosis. This group, the UK MASTERMIND consortium, takes precision medicine one step further – the aim of more specific diagnoses is to better predict which patients will be successful on which diabetes therapies. Dr. Jones is leveraging electronic health record data to identify clinical predictors for therapy response. Excitingly, he has found that females with obesity are more likely to respond positively to TZDs and negatively to sulfonylureas vs. females without obesity. No such differences exist for males by BMI. Dr. Jones performed a similar analysis comparing DPP-4 inhibitors vs. SGLT-2 inhibitors: Lower BMI and triglyceride levels are independently associated with a better response to DPP-4 inhibitors, while higher BMI and good renal function seem to predict a positive response to SGLT-2 inhibitors. Dr. Jones cautioned that it’s unlikely a prediction model will ever be able to recommend a single therapy. Instead, he hopes for more tailored treatment options, with models outputting a few select choices more likely to be successful, which HCPs can then review with their patients. Dr. Jones also emphasized the need to replicate these preliminary findings in real-world and clinical trials to minimize false positives.

• Dr. Jones has released a free diagnostic app on iTunes and Google Play, called Diabetes Diagnostics. As of now, the app takes clinical features as inputs to distinguish between type 1 and type 2 diabetes for individuals. Dr. Jones shared plans to incorporate insulin biomarkers into the model within the next year. His team is also working on creating diagnosis prediction calculators integrated directly into EHR, and is beginning to create provider-facing tools for predicting therapy response.

Symposium: Achieving Improved Compliance to Diabetes Care: The Common Task for Care Providers, Health Systems, and People with Diabetes

The Diabetes Team: How to Improve Cohesion

Dario Rahelic, MD (Dubrava University Hospital, Zagreb, Croatia); Sophie Hindkjaer (IDF, Denmark); Iryna Vlasenko, PhD (IDF, Ukraine)

Three speakers representing the interdisciplinary diabetes management team provided their perspective on how best to optimize diabetes treatment, emphasizing metrics beyond cost, mutual respect between patients and providers, and pharmacists as integral community healthcare members. For Dr. Dario Rahelic, an IDF board member and President of the Croatian Society for Diabetes and Metabolic Disorders, diabetes therapy is not just about direct cost. When evaluating a new therapy, he considers the broader impact, making sure to assess indirect effects like loss of productivity, quality of life, life years gained, and hospital visits. From the patient perspective, Ms. Sophie Hindkjaer, an IDF Young Leader living with type 1 diabetes, found that her doctor visits markedly improved once she viewed herself as an expert in her own diabetes. While her initial clinic visits felt like exams and were comprised solely of reviewing blood glucose numbers, after participating in the IDF youth leadership camp, she realized that her physician should not be scolding her, but rather working with her to improve her life. She began having productive conversations with her healthcare team by supplying and asking for context surrounding her glucose numbers. In her own words, “if you only focus on the numbers, you might miss the whole picture.” We love the idea of the empowered patient, but not everyone will have the opportunity to learn in the IDF context, so we hope to see more efforts go toward teaching providers how to be more effective.  Just as the patient should be considered an essential member of the healthcare team, so, as argued by IDF board member Dr. Iryna Vlasenko, should pharmacists. Pharmacists are often overlooked by physicians, yet they can educate patients about proper therapy use, recommend ancillary products and services, help maintain glycemic control, and prevent complications, all within a community setting. Dr. Vlasenko finds that pharmacists are underutilized, largely due to poor social and professional acceptance. Stigma doesn’t only apply to the people living with diabetes…

• Dr. Rahelic urged the audience to avoid thinking exclusively in terms of direct cost. For a patient population whose numbers exceed those of HIV/AIDS, tuberculosis, and malaria combined, solutions can only be reached by thinking creatively. Dr. Rahelic provided the example of when he negotiated with the Croatian Ministry of Health and national insurance to make modern insulin available to type 2 patients in his country. While both entities were quick to dismiss the proposal at first due to expenses, Dr. Rahelic pointed out that the costs of hypoglycemia and weight gain associated with premixed insulin outweigh savings. Ultimately, he was able to reach a compromise, in which type 2 patients could receive modern basal insulin analogues for a more reasonable co-payment of 10-20 EUR. Up-front investment in tools that enable better glycemic control is a no-brainer, since the alternative is costly hypoglycemia and/or complications down the road.
• We were pleased to hear Dr. Rahelic mention that diabetes management encompasses more than just medication. He stressed the effects of stigma, empathy, and the amount of time patients spend with physicians, which he finds to be insufficient. In his home country of Croatia, there are only 140 diabetologists and 2,500 general practitioners, each of whom are tasked with seeing 40-60 patients per day (aka 8-12 minutes/patient). To this end, Dr. Rahelic noted the importance of nurse educators, and we add that remote and AI coaching will likely fill huge gaps in care. 
• Dr. Vlasenko detailed several studies showing the benefits of pharmaceutical intervention by pharmacists. A study published in the International Journal of Clinical Pharmacy suggested that pharmacists can reduce medical expenses and contribute to safety and efficacy, estimating the total cost savings associated with 500 interventions to be over $200,000 – more than half of the interventions helped prevent adverse drug reactions. A randomized control trial of elderly patients with diabetes and hypertension found that pharmaceutical care significantly improved health outcomes and did not increase total direct healthcare costs significantly, designating pharmaceutical intervention as a cost-effective option.
• Ms. Hindkjaer emphasized the need for patient trust. Patients are expected to talk to their healthcare team about topics they might not even be ready to discuss with their families. As an example, women with diabetes are asked to make decisions regarding pregnancy very early on. This kind of trust can only be achieved through confidentiality and shared respect. Ms. Hindkjaer also noted that providers should be open to including the patient’s support network during visits, although acknowledged that not every patient will be ready for this step immediately, if at all. IDF Europe President-elect Dr. Niti Pall later added that the patient-provider relationship comes down to four factors: trust, empathy, expertise, and information. “If you don’t get trust and empathy right, they’ll never take your expertise and information.”
• Dr. Rahelic proposed several solutions to ease the global burden of diabetes, including increasing awareness, involving politicians, facilitating cooperation between healthcare providers and national diabetes programs, and thinking globally yet acting locally. The last concept is particularly relevant given disparities across healthcare systems regarding access, technology, and reimbursement. Even in Europe, which is generally associated with high-quality care, people in Albania pay for all diabetes therapies out of pocket. There is no one-size-fits-all solution, though Dr. Pall strives for the “holy grail” that is elimination of all user fees and co-payments in medicine across the globe.

How Can Mobile Applications Contribute to Improving Compliance?

David Klonoff, MD (Mills-Peninsula Health Services, San Mateo, CA)

Mills-Pensinsula Medical Center's Dr. David Klonoff discussed the factors that will augment digital health adoption and suggested how to lower patient and HCP barriers. He broke down the primary factors that each stakeholder looks for in digital health products: Usability (for patients), clinical benefit (for healthcare providers), economic benefit (for payers), security (to satisfy product regulators), and data privacy (to satisfy legal regulators) – of course, there is plenty of overlap in this list. He went into more detail on how to make these products more appetizing for patients and providers: Providers look for interoperability with digital systems (something he believes the market will enforce in the long run), EMR compatibility, compatibility with professional standards, and safety in a mobile platform environment (Does the phone/software prioritize the medical app while you’re playing Angry Birds?.. Something FDA is certainly aware of and taking into consideration as companies seek to use phones as primary displays and control device functions from apps). Dr. Klonoff believes patients look for easy log-in (though noted simplicity must be balanced with security), simplified data and alert displays, no increase in (or less) work, time, and cost, coupled with improved outcomes and “no friction.” We think all of these can be boiled down to a slightly modified version of his third bullet: Patients will widely adopt digital health for diabetes if the quality of life and/or health benefits outweigh the burden of using them. As that balance improves, more will adopt and use the products. He went on to speak briefly about the quality of digital health clinical data, a lack of research into the benefits of social media (prominent patient advocate Mr. Bastian Hauck pushed back), and pharma’s growing involvement in digital therapeutics.

• Dr. Klonoff listed a number of common flaws he sees in mHealth data generation and analysis: “mHealth clinical trials have produced good outcomes, but aren’t necessarily producing the best data of all time.” He advised audience members to first ask whether or not the data was generated via a randomized controlled trial. “Some digital health companies advocate for getting rid of RCTs – they say that once the trial is done, analyzed, and published, the technology is out of date and a next-gen product is on market. Make sure you’re looking at good data.” He didn’t offer many alternatives, except for doing n=1 trials at scale, wherein one patient and all his/her possible confounds are examined at a time, and then all conclusions from all patients are analyzed – sort of like a meta-analysis of individual level data. RCTs are certainly still needed, but we do see value in complementing them with real-world data (as does FDA), since the technology innovation cycle is rapid and apps are often multi-modular and therefore difficult to study in a simple RCT.
  
  • We agreed wholeheartedly with Dr. Klonoff’s caveat to look out for a small n, big p, and small t. Indeed, it is fallacious to draw definitive conclusions from studies with small sample sizes, statistically insignificant differences, and/or performed over a short time period. Dr. Klonoff suggested that trials in digital health have to be at least a year, but then suggested products must constantly be refreshed to maintain engagement.” We assume the only way for companies to navigate this balance is to choose one side, or do one-year studies with built-in product updates throughout.  
• Patient advocate and active #dedoc member, Mr. Bastian Hauck – thinking that Dr. Klonoff had denigrated social media during his talk – pushed back during Q&A. Dr. Klonoff later clarified via email that he believes research into the benefits of social media on treatment adherence is lacking – he didn’t comment on overall benefit. To be clear, Dr. Klonoff doesn’t discourage social media use – he just doesn’t outright encourage it either based on the evidence he has seen. Mr. Hauck’s passionate comments were worth sharing anyhow: “The counterpoint is, we always talk about social media without defining it. We’re not doing anything new. We don’t need RCTs here, in my opinion. We have a lot of evidence showing peer-to-peer support, getting patients together to talk things through, is helpful. Social media is just a new means of communication. Same community work, just at a much faster pace. We’re always trying to scale things up and make things digital, and we’re not there yet in many cases, like AI, but with social media, we are already there. Making it faster and scaling. Yet we’re still getting so many counterpunches. We don’t need evidence to prove that communication is going to work.” The only reason we can think of for performing an “RCT” of social media use is to demonstrate benefit so that hesitant healthcare providers would more actively direct their patients to try it. On the other hand, social media is free, so there’s little barrier to access, and therefore little need to convince payers that it’s effective (though perhaps they could financially incentivize people to use social media).
• When Dr. Klonoff first became a doctor, he noted that every innovation at big meetings was a drug. “Now, what really gets the buzz is new software and digital therapeutics,” he said. He pointed to Lilly’s FDA-cleared Go Dose, Novo Nordisk and Glooko’s recently-launched Cornerstones4Care, and Sanofi’s partnership with Evidation Health to mine behavioral trends and outcomes for insights into new product design and how to deploy current products. The list goes on – and this digital explosion is only starting to take off. Where will it be in five years?

Symposium: The Beta Cell in Type 2 Diabetes – What Are the Changes and Are They Reversible?

Human Islet Cell Heterogeneity and Changes in Type 2 Diabetes

Jesper Gromada, PhD (Regeneron, Tarrytown, NY)

Dr. Jesper Gromada presented data on islet cell subpopulations obtained using a technique that allows for isolation and mRNA sequencing of individual cells. This exquisite level of granularity yielded some fascinating findings. In samples from people without diabetes, Dr. Gromada’s team was able to identify a subpopulation expressing high levels of cellular stress genes. Many of these cells produced only low levels of insulin and/or had upregulation of unfolded protein response (UPR) genes. These findings support a model whereby beta cells under stress first begin showing stress markers, then turn off their insulin secretion and upregulate the UPR response to try and cope, then slowly recover. Although some stressed cells may die if overly stressed, Dr. Gromada’s study did not find upregulation of genes that cause apoptosis, otherwise known as programmed cell death.

• Dr. Gromada’s team is now examining cells from individuals with type 2 diabetes. While there have not been enough samples collected yet to allow for full analysis of islet cell subtypes, the team has already identified 245 genes that exhibit different regulation vs. individuals without diabetes – most associated with islet growth and function. One major benefit of the technique Dr. Gromada’s team is using is that it can target changes in gene regulation to specific cell populations (alpha vs. beta vs. delta vs. other), eliminating some mechanistic guesswork.

Questions and Answers

Q: I have a question about kinetics. How fast do you think the cycle from unstressed to stress, to downregulated insulin production, to recovery happens? Every day, every meal, or only occasionally?

A: I have no idea but it cannot be that common. Our working hypothesis is that there is an increase in the proportion of stressed insulin-producing cells in type 2 diabetes – that diabetes pushes cells faster into the high-insulin stressed group, and they recover only slowly. Since we have low replication and more cells pushed out, that’s how we theorize beta cell mass slowly goes down, though we don’t have the data to support that yet.

Q: Did you check to see if the same islet cell subpopulations existed in type 2 diabetes islets?

A: In the type 2 diabetes data we have, we don’t have enough cells to thoroughly analyze subpopulations, but from the limited donors we have, we do seem to be seeing the same subpopulations of cells.

Durable Reversal of Beta Cell Failure by Calorie Restriction

Roy Taylor, MD (Newcastle University, UK)

Dr. Roy Taylor, a proponent of the controversial fat-centric “twin cycle” hypothesis of type 2 diabetes mediated by excess liver and pancreatic fat, reviewed his previous work and provided an update on his current project: the DiRECT trial of extreme low-calorie diet for diabetes remission. He disclosed that 12-month data from the study will be presented at IDF this December. We of course will be interested to see whether a weight loss intervention delivered in primary care can yield diabetes remission in the >300 type 2 diabetes patients enrolled. It is definitely ambitious, although Dr. Taylor’s previous COUNTERPOINT study did demonstrate a sustained rebound in beta cell health in patients who underwent a short-duration extreme low calorie diet – at least in patients with more recently diagnosed diabetes. We admire Dr. Taylor’s dedication to evaluating the “twin cycle” and diabetes-remission-by-extreme-weight-loss hypotheses, and we look forward to seeing whether they will be borne out by the DiRECT trial. Even if the theory is right, there is fair skepticism about how scalable his extreme caloric restriction interventions may be.

• For background, the twin cycle hypothesis implicates excess liver and pancreatic fat in the pathophysiology of type 2 diabetes. The two cycles are (i) positive calorie balance causing liver fat to increase, causing insulin resistance and increased insulin output. This creates a vicious cycle of fatty liver disease. (ii) The spillover fat (as triglycerides) is taken up by pancreatic islets causing insulin resistance and another vicious cycle, which culminates in an acute insulin crisis, beta cell de-differentiation, and the diagnosis of type 2 diabetes.

Questions and Answers

Q: What differentiated the responders from non-responders in COUNTERPOINT?

A: As a group, they were indistinguishable clinically apart from the duration of their diabetes. The responders were almost all short duration – less than 10 years. Over 11 years duration, we generally observed no response.

Q: I am reminded of a study published by Dr. Ralph DeFronzo’s group in 2003 that found that lipid infusion reduced glucose-stimulated insulin secretion in people with a family history of type 2 diabetes.

A: Yes, that was an important study – one I mentioned in my grant application for my current study. It demonstrates the importance of lipids in initiating this process.

Q: You ascribe what you see to pancreatic fat via imaging. Have you looked at circulating markers like glucose, fatty acids, and amino acids?

A: Plasma fatty acids increased during starvation, which is no surprise. At one week after the resumption of feeding, there was normalization of hepatic insulin sensitivity despite the increase in plasma fatty acids. Fatty acids in plasma don’t impinge much on beta cell metabolism. The payload from VLDL and LPL is the big bomb on the pancreas. The glucose normalizes of course and will have an affect on beta cell function, but it’s relatively modest. Removing fat from the beta cell environment decreases VLDL secretion.

Comment: Well I think glucose lowering is important, too. Work in China has shown that acute short-term reductions in glucose can cause diabetes remission.

Q: I’m questioning whether we should have so much emphasis on fat. It could be that you are only reducing the glucose load and in that way relieving stress on beta cells.

A: We’ve considered that, though the time course seems to favor the importance of fat. Type 2 diabetes has to start with a trigger … there has to be an etiological buildup. As soon as glucose rises, the glucose will play an important role, but if measurement of pancreatic fat is done precisely, we can rely on that, and the time course seems in favor of fat playing an important role.

Q: To preserve the weight loss after the caloric restriction period is over, was there a specific diet, or did you just tell people to avoid weight gain?

A: It’s very important to avoid diets. People were advised to eat whatever they found most agreeable and pleasant to keep their weight down. For most, it was a low-ish carb pattern. The key was portion size, and we did tell people to avoid takeaway meals. But the final arbiter is the weight scale.

Q: Where is the fat located in the pancreas?

A: We can’t be definitive, but most likely it is intracytoplasmic within islets. 

Bariatric Surgery and the Beta Cell: Where Does the Miracle Occur?

David D’Alessio, MD (Duke University, Durham, NC)

Bariatric surgery expert Dr. David D’Alessio drew upon recent and ongoing research to suggest a model explaining bariatric surgery’s impact on the beta cell and glucose regulation. He focused on forms of bariatric surgery that expedite nutrient delivery to the gut: Roux-en-Y gastric bypass and vertical sleeve gastrectomy. At baseline, candidates for bariatric surgery with obesity and type 2 diabetes are hyperinsulinemic, with a normal or decreased incretin effect. Immediately post-op, beta cell function increases markedly, likely driven by an augmented incretin effect. Over time, however, with weight loss and increased insulin sensitivity, the insulin secretion rate and beta cell sensitivity to glucose and incretins gets dialed back.

• Dr. D’Alessio argued that instead of looking to the progressive pathophysiology of type 2 diabetes to inform drug development, it would be better to examine bariatric surgery, which in many ways is the disease progression in reverse. Also on the topic of therapeutic relevance, he suggested that beta cell responses to bariatric surgery – and the variation in response between different patients – might help explain why some patients’ diabetes responds well to bariatric surgery (i.e. remission) while other patients’ diabetes responds poorly (i.e. recurrent hyperinsulinemic hypoglycemia). 

Questions and Answers

Q: Is the improvement in beta cell function after bariatric surgery dependent more on the specific surgical approach, or on the level of weight loss achieved?

A: Vertical sleeve gastrectomy and Roux-en-Y gastric bypass do different things than procedures like gastric banding that behave more like dieting and don’t cause an increase in insulin secretion early on. Procedures that increase gut nutrient flux behave differently than ones that are restrictive.

Symposium: Cognitive Impairment and Alzheimer’s Disease in the Type 2 Diabetes Patient

Diabetes as an Accelerator of Alzheimer’s Disease: Underlying Mechanisms and Potential Treatments

Fernanda De Felice, PhD (Queen’s University, Kingston, Canada)

Dr. Fernanda De Felice summarized the latest research on the link between Alzheimer’s Disease and diabetes, a topic that’s quickly gaining attention as Alzheimer’s Disease becomes a public health issue in its own right, and as thought leaders increasingly refer to it as “type 3 diabetes.” Insulin expression in the brain is lower in people with Alzheimer’s Disease compared to a background population. Insulin receptors are downregulated due to the action of toxins associated with Alzheimer’s. Accordingly, this condition increases the risk of type 2 diabetes and vice versa, leading Dr. De Felice to strongly urge providers to track blood glucose levels in people at risk for cognitive disorders. Given the growing number of young people with type 2 diabetes, Dr. De Felice also emphasized the need to find earlier indicators of Alzheimer’s. By the time this cognitive condition manifests clinically, it’s most often too late to treat. Dr. De Felice described an interaction between endoplasmic reticulum (ER) stress, obesity, insulin action, and type 2 diabetes, and then pointed out how the same markers for ER stress are observed in the brains of Alzheimer’s mice. The similarities between these two diseases don’t end there – both begin with inflammation, which activates the cell stress pathway, eventually resulting in insulin resistance. In the brain, this stress is also related to synaptic malfunctioning and cognitive decline.

• Researchers are hard at work leveraging the parallel pathways of type 2 diabetes and Alzheimer’s Disease to design new therapies. Wake Forest’s Dr. Suzanne Craft is currently leading a large clinical trial SNIFF (the Study of Nasal Insulin in the Fight against Forgetfulness), investigating the potential protective effect of insulin on synapses. The study has identified that GLP-1 agonist liraglutide (Novo Nordisk) can attenuate loss of neuronal insulin receptors in monkeys, preserving appropriate synapse morphology. Dr. De Felice also detailed the role of irisin, a newly-discovered hormone released by the muscle upon exercise. Irisin is also expressed in the brain, associated with metabolic effects, and found to be reduced in both human and mice Alzheimer’s brains. When Alzheimer’s mice are treated with irisin, memory is improved, suggesting a potentially powerful therapeutic target.  

Lifestyle in Cognitive Impairment and Type 2 Diabetes: Is There Ground for Joint Prevention?

Jaakko Tuomilehto, MD (University of Helsinki, Finland)

As the prevalence of Alzheimer’s Disease steadily rises (by 2047, experts predict Alzheimer’s prevalence will be 8x what it is today), prevention efforts are becoming paramount. Prevention expert Dr. Jaakko Tuomilehto took the stage to discuss the role of lifestyle, describing similar interventions as those prescribed for prediabetes. He highlighted findings from the Finish Diabetes Prevention Study (DPS), in which dementia risk correlated with a lower intake of total fat and saturated fat, as well as with increased physical activity. Likewise, preliminary data from the FINGER study published in the Lancet demonstrated that a multi-domain lifestyle intervention (diet, exercise, cognitive training, and vascular risk monitoring) in an at-risk elderly population is associated with significant improvements in executive functioning and processing speed. Good glycemic control was not sufficient to preserve cognitive function, but these lifestyle changes were promising. It’s estimated that a 10%-25% reduction in all seven risk factors for Alzheimer’s Disease (diabetes, hypertension, obesity, depression, inactivity, smoking, and cognitive activity) could prevent 1.1-3.0 million cases worldwide. Moreover, a five-year delay in the onset of Alzheimer’s would decrease prevalence by 50%. Dr. Tuomilehto’s talk outlined a compelling case for lifestyle prevention strategies, as they could impact individual health outcomes/quality of life as well as the state of Alzheimer’s from a public health perspective.

Oral Presentations: Clinical Impact of Hypoglycemia

Weight Gain is Associated with Mild to Moderate Hypoglycemia in Patients with Type 1 Diabetes: Results from the DCCT

Anisoara Bumbu, MD (AP-HP, Paris, France)

Dr. Anisoara Bumbu presented an analysis of DCCT data showing that weight gain is correlated with increased mild to moderate hypoglycemia in patients with type 1 diabetes. The DCCT established that intensive glucose control prevents chronic complications, but the more aggressive approach also increased hypoglycemia risk and weight gain. In turn, Dr. Bumbu explained, weight gain lowers long-term therapy adherence and can increase the risk of other complications, including nephropathy and coronary artery disease. She reviewed data showing a weak association between severe hypoglycemia and weight gain in the DCCT, but described how less work has been done on more-frequent, less-severe hypoglycemia – until now. Using available data on the 1,441 patients with type 1 diabetes age 13-39 who participated in the DCCT (either conventional or intensive arm), a hypoglycemia score (number of blood glucose values <70 mg/dl divided by total number of blood glucose measurements) was calculated for each participant. Hypoglycemia scores were associated with severe hypoglycemia, but this new analysis also found a significant association between hypoglycemia score and total weight gain/average annual weight gain (R²=0.021, p<0.001). Over 7.5 years of follow-up, mean total weight gain in this sample was 16 lbs. When splitting hypoglycemia scores into tertiles, Dr. Bumbu showed a trend of increased weight gain: The third of lowest scores gained a total of 12 lbs on average vs. 18 lbs and 19 lbs for the second and first highest tertiles (p<0.008). When adjusting for age, sex, duration of diabetes, treatment arms, baseline A1c, and baseline BMI, inter-tertile differences remained highly significant (p<0.001). These results contribute to a growing body of evidence demonstrating the importance of avoiding hypoglycemia in patients with type 1 diabetes, and the meaningfulness of outcomes beyond A1c.

Corporate Symposium: Real-World Challenges in Type 2 Diabetes (Sponsored by Servier)

Why a Paradigm Shift is Needed

Luc Van Gaal, MD (Antwerp University, Belgium); Steven Edelman, MD (UCSD, San Diego, CA); Richard O’Brien, MD (University of Melbourne, Australia); William Polonsky, PhD (Behavioral Diabetes Institute, San Diego, CA); Eduard Montanya (University of Barcelona, Spain)

Melbourne’s Prof. Richard O’Brien, UCSD’s Dr. William Polonsky, and Barcelona’s Prof. Eduard Montanya discussed real-world challenges in type 2 diabetes, identifying adherence as the primary driver for the gap between outcomes observed in clinical trials versus real life. Dr. O’Brien cited a recent study (from Dr. Polonsky’s group) demonstrating that 75% of the differences in A1c reductions seen in clinical trials for GLP-1 agonists vs. real-world data can be explained by non-adherence. For DPP-4 inhibitors, the paper suggests that 72% is due to non-adherence. Dr. O’Brien urged physicians to discuss adherence with their patients, citing that one third of prescriptions for diabetes medications are never filled. Dr. Polonsky took adherence a step further, diving into critical patient beliefs surrounding medication. The issue, he said, is that diabetes medications lack short-term, tangible benefits, while cons such as burden and real/imagined adverse effects are plentiful – we wonder if VR, simulation, and higher tech education might help close this gap. For example, here’s what happens to the body when glucose levels are high, here’s how you will age when glucose levels are high, etc. Dr. Polonsky provided the telling example of an exercise he performs with type 2 patients, in which he shows them the profiles of two hypothetical patients, one of whom has at-goal A1c but takes two medications and is on insulin, while the other has a high A1c, but is not on any medications. When asked which patient is doing better, the vast majority say it’s a tough question. In other words, some people with diabetes equate more medication with failure. Yikes! The onus for this misconception is largely on providers, who sometimes threaten patients with more medication if they don’t improve behavior. Dr. Polonsky emphasized working on the patient-provider relationship, citing several studies demonstrating that improved trust is associated with greater adherence. So how do we shift the paradigm? Dr. Montanya mentioned a study demonstrating that triple combination therapy immediately following diagnosis (instead of a step-wise add-on approach over four months) conferred a greater A1c improvement. His argument was in favor of early combination therapy, but this could also tie in to adherence: Presumably, a stepwise approach is perceived as consecutive failures, while the immediate intensification is simply a medication regimen that drives right to success, so patients are more likely to stick to it. Dr. Montanya also suggested telemedicine as a potential approach to improve adherence, although acknowledged that meta-analyses yield mixed results and tend to demonstrate only short-term efficacy. He, and many thought leaders we’ve heard from recently, are particularly excited about ITCA 650, the six-month implantable exenatide pump from Intarcia. He discussed the FREEDOM-1 and -2 trials demonstrating significant reductions in A1c and body weight, and sees real potential in the pump to drive adherence. Once implanted, it works! We also see very high potential in novel ways to take and track medication, such as the super brilliant Pill Pack(“Pharmacy Simplified”). Poor adherence is a complicated affair, one that costs the health system huge sums of money – addressing it will take a carefully-crafted combination of support, technology, and design.

Questions and Answers

Q: What is the best way to approach a patient about being adherent?

Dr. Polonsky: What we see is healthcare providers will say, “I don’t know this data regarding adherence, I don’t see that.” That probably has to do with how we ask the question. It’s common for providers to say: “Look you haven’t had any problems managing your meds, have you?” The patient is almost guaranteed to answer no. There’s an opportunity to normalize the situation. Instead say, “I know people struggle taking medication, what kind of trouble do you have with your medication?” It’s important to open up the door to normalize the issue. Bravo!

Posters

Low Income Predicts Cardiovascular Event Risk Independently from the Presence of Type 2 Diabetes and Pre-Existing Coronary Artery Disease

R Saely, A Vonbank, C Saely, C Lins, D Zanolin, A Leiherer, A Schuler, A Muendlein, A Mader, P Schwerzler

A diverse research team from Austria, Liechtenstein, and the US presented a poster demonstrating that low income is an independent risk factor for CV events, regardless of a patient’s diabetes status or pre-existing coronary artery disease (coronary stenosis with lumen narrowing 50%).While it’s known that low socioeconomic status is associated with increased CV risk, low-income populations also show disproportionately high rates of type 2 diabetes and related complications (including macrovascular events). It was not known whether the association between low socioeconomic status/CV risk was independent of type 2 diabetes. Out of a cohort of 389 individuals referred to coronary angiography for the evaluation of established or suspected stable coronary artery disease, those in a higher income bracket were 32% less likely to experience a CV event (HR=0.68, 95% CI: 0.51-0.92, p=0.011) over eight years, after adjusting for age, gender, smoking, LDL, HDL, hypertension, BMI, waist circumference, type 2 diabetes, and baseline coronary artery disease. The incidence of CV events for those earning <€20,000/year was 62% vs. 5% among those with an annual income >€35,000. The poster did not specify whether the patient cohort was established from multiple countries, and we wonder whether differences exist on a geographic basis related to differing healthcare systems and access. There’s clearly a lot of work to be done here to assist this under-served population, requiring multidisciplinary efforts. 

-- by Adam Brown, Ann Carracher, Abigail Dove, Brian Levine, Payal Marathe, Maeve Serino, Manu Venkat, and Kelly Close