This year’s ADA covered a wide range of topics relating to the complications of diabetes, with significant attention paid to diabetic retinopathy as well as some focus on chronic kidney disease, hypoglycemia, and psychosocial issues. With regards to diabetic retinopathy, we saw results from a comparative effectiveness trial evaluating Bayer/Regeneron’s Eylea (aflibercept) vs. Novartis’ Lucentis (ranibizumab) vs. Genentech’s Avastin (bevacizumab) – Bayer/Regeneron’s aflibercept performed better in many cases, but consideration of cost and baseline visual acuity added nuance to the comparison and reduced aflibercept’s advantage. Given how huge the impact of visual impairment is on quality of life, we have been incredibly happy to see these ophthalmologic drugs receive specific approvals and indications for diabetic retinopathy or diabetic macular edema recently – we think having better treatments will increase awareness. In addition to oral presentations, we attended a symposium entirely devoted to prevention and treatment efforts of diabetic retinopathy as well as discussions on the complication’s emerging therapies and need for predictive biomarkers.
An intriguing oral presentation explored the potential beneficial impact of GLP-1 agonists on chronic kidney disease, although renowned presenter Dr. Jens Christiansen (Aarhus University Hospital, Aarhus, Denmark) ended his presentation by acknowledging the lack of sufficient outcomes data on the topic – that will not be available for some time but it is an exciting area to think about – we hope the trials are designed in order to show protection if it exists. As if on cue, results from the ELIXA CVOT for Sanofi’s Lyxumia (lixisenatide) showed an intriguing potential benefit on albuminuria, although it’s hard to know how definitive the signal was. Still, it was plenty intriguing, hopefully in a way that stokes interest in further research on the impact of GLP-1 agonists on the kidney. The class effect of SGLT-2s on kidney disease is also of big interest and we’ll be excited to watch both areas.
Beyond the eyes and kidneys, there was plenty more of discussion on diabetes complications. We were very glad that Dr. David Marrero, the ADA’s President of Health Care & Education, was given the chance to deliver a special lecture on the importance of psychosocial research and care for diabetes patients, an area that continues to be complex and frustrating for time-strapped providers to address but one that is hugely impactful from a patient perspective. We continue to be surprised at the lack of funding here and hope that as a field, we can advocate for considerably more attention here. Dr. Marrero’s talk is excellent teaching to everyone in the field and represented one of the highest points of ADA for us. Psychosocial and behavioral research also earned a place at the incredibly well-attended ADA/Diabetes Care Symposium. The costs (both economic and medical) of hypoglycemia were the focus of a Merck-supported symposium on the scientific program, and a big-picture oral shared new data on the connection between genetic risk and all-cause mortality in diabetes patients in the US. We were very pleased overall with the breadth of this year’s offerings on diabetes complications and we hope to devote even more resources to this critical area in the future – when we think about cost-benefit and what prevention could do in terms of public health dollars, we are very enthusiastic about getting more focus in this area in every respect and getting the word out more effectively about what the prevention of complications could mean.
Talk titles highlighted in yellow were among our favorites from ADA 2015; those highlighted in blue are new or expanded full report additions from our daily coverage.
- Executive Highlights
- Detailed Discussion and Commentary
- Oral Presentations: Diabetes – A Mixed Bag
- Oral Presentations: Diabetic Nephropathy – Novel Pathways and Interventions
- Oral Presentation: Strengthening Our Defense Against Diabetic Retinopathy
- Special Lecture: President, Health Care, & Education Address
- Meet-the-Expert: Strategies to Address the Problematic Patient with Hypoglycemia
- Symposium: ADA Diabetes Care Symposium – Novel Clinical Interventions in Therapy That Impact the Management of Diabetes
- Symposium: The Impacts of Hypoglycemia in Diabetes (Supported by an Unrestricted Educational Grant from Merck)
- Hypoglycemic Morbidity and Costs in Diabetes
- Arrhythmias and Mortality Associated with Insulin-Induced Hypoglycemia
- Hypoglycemia Mortality in Diabetes
- Symposium: Emerging Topics in Diabetic Kidney Disease
- Symposium: The Eyes Are Windows to the Soul – Improving Care and Quality of Life for Patients with Vision Loss
- Symposium: Cardiovascular Disease Risk Factor Management in Type 2 Diabetes Mellitus (Supported by BI & Lilly)
- Symposium: Diabetic Dyslipidemia – Where's the Action in 2015?
- Symposium: Are We Putting Ourselves Out of a Job? The Changing Epidemiology of Type 2 Diabetes and Its Complications
- Symposium: The Skinny on Fat in the Islets
- Symposium: JOINT ADA/EASD Symposium – What Drives the Relationship Between Diabetes and Cancer?
- Corporate Symposium: Avoiding “Loss of Chance” (Sponsored by Genentech)
- Improving the Screening, Treatment and Referral of Patients with Diabetic Retinopathy
Detailed Discussion and Commentary
Oral Presentations: Diabetes – A Mixed Bag
Type 2 Diabetes Genetic Risk and All-Cause Mortality in the United States (152-OR)
Aaron Leong, MD (Massachusetts General Hospital, Boston, MA)
Dr. Aaron Leong presented on the potential relationship between genetic determinants of type 2 diabetes and all-cause mortality, and whether such a relationship was independent of BMI. The research group used data from the National Health and Nutrition Examination Survey (NHANES) to model mortality as a weighted function of 38 risk alleles across three BMI categories (<25, 25-30, ≥30 kg/m2). Although higher type 2 diabetes genetic risk was associated with mortality risk independently of BMI (n=6,501, OR 1.04 per type 2 diabetes risk allele, p=0.05), associations within ethnic groups differed greatly. For example, there was a negative trend between type 2 diabetes genetic risk and mortality risk in Mexican-Americans, mainly driven by patients with BMI<25 kg/m2 (OR 0.91 per type 2 diabetes risk allele, p=0.06). The ambiguity of associations between ethnic groups thus prompts the need for studies that target certain population groups, and indicate that the genetic basis for mortality due to type 2 diabetes likely involves complex interactions with non-genetic factors related to body weight and ethnicity.
Oral Presentations: Diabetic Nephropathy – Novel Pathways and Interventions
Pathways Between the Gut and Kidney – Intersection of GLP-1 Effect and Renal Function
Jens Christiansen, MD, DMSc (Aarhus University Hospital, Aarhus, Denmark)
Dr. Jens Christiansen connected the pathways between GLP-1 effect, renal function, and effects on blood pressure. He reminded the audience that renal function and urine analysis are important for measuring chronic kidney disease (CKD) and for predicting stroke and coronary heart disease (CHD), noting that there is a frequent concurrence between diabetes and hypertension. Dr. Christiansen explained that long-term GLP-1 use reduces blood pressure and is associated with significant excretions of sodium. However, in short-term tests in humans, there were no significant changes in excretion while blood pressure and cardiac output both increased; these effects were also reversed over the duration of the drug’s usage. In addition, GLP-1 agonists were found to inhibit ANG II post-receptor signaling, resulting in a 20% decrease in ANG II excretion. However, Dr. Christiansen tempered his talk with caution as he reminded the audience of the hype associated with TZDs as a reducer of blood pressure that ultimately did not translate into clinical benefit in the long run. On the other hand, he noted that GLP-1 agonists’ have looked promising in animal models and that usage has brought a whole host of effects, including the reduction of albuminuria, fibrogenesis, and inflammation. In conclusion, Dr. Christiansen stated that challenges remain and limit a fuller understanding of GLP-1 agonists in renal function in people with diabetes as he encouraged for more long-term studies to focus on nephropathy.
- A bit of a plot twist arrived with the results from the ELIXA outcomes trial for Sanofi’s Lyxumia (lixisenatide) – although the primary cardiovascular results were neutral, lixisenatide did seem to attenuate the gradual rise in albuminuria, although it is hard to know at the moment how definitive the signal was. We’ll be watching this closely.
Questions and Answers
Q: Is the action on the inflammation on fibrogenesis a direct action from metabolism of GLP-1?
A: I don’t think we know that. We’ve only seen that in animal models – we just don’t have the data.
Q: What about DPP-4 inhibitors? Can we achieve same results as GLP-1 through DPP-4 production of GLP-1?
A: The short answer is no. There is only a short increase in GLP-1 at the start of DPP-4 therapy. The benefits have never been shown in any trials.
Q: It’s very difficult to measure ANG II. I’m sure you measured it very well, but could metabolism of ANG II be enhanced by GLP-1 leading to the result. Did you study this or speculate?
A: I agree with you, measuring ANG II is not an easy thing. The people we worked with did a good job and you need to keep in mind that this might be a cul-de-sac as we have no idea of the levels in tissue. In animal models, however, we have had the same results as in humans. But we still don’t know exactly what is going on.
Q: Did you measure AGT in any tests?
A: It did not go down significantly.
Oral Presentation: Strengthening Our Defense Against Diabetic Retinopathy
Comparative Effectiveness Trial of Aflibercept, Bevacizumab, or Ranibizumab for Diabetic Macular Edema (290-OR)
Jennifer Sun, MD, MPH (Joslin Diabetes Center, Harvard Department of Ophthalmology, Boston, MA)
Dr. Jennifer Sun presented on the results of a randomized clinical trial comparing efficacy and safety data for three anti-VEGF treatments (aflibercept, bevacizumab, and ranibizumab) at 89 clinic sites. Findings showed that aflibercept resulted in greater improvement in visual acuity on average. However, aflibercept’s benefits varied by initial visual acuity; as compared with bevacizumab and ranibizumab, aflibercept showed little difference in visual acuity for patients with mild initial vision loss, but significant improvement for those with worse levels of initial visual acuity. This is exactly the information needed to individualize patient therapy, in our view. During Q&A, Dr. Sun noted that although the study did not directly address cost effectiveness, cost vs. benefit issues may affect how clinicians and patients choose which anti-VEGF agent to use. She stated that while aflibercept has better outcomes for patients with worse/severe vision loss, it is also the most expensive of the three anti-VEGF treatments. She explained, “If one of my patients comes in with significant vision loss and all three medications are available, I would probably reach for aflibercept because I know it is most likely to provide the most benefit.” Specifically, after one year of intravitreous 1.25 mg bevacizumab, participants (n=218) had an average 10 letter improvement in visual acuity (via ETDRS Chart), compared to an average 13 letter improvement seen after one year of 2.0 mg aflibercept (n=224) and an average 11 letter improvement seen after one year of 0.3 mg ranibizumab (n=218). However she added that in communities where aflibercept is not readily available, the much cheaper bevacizumab is already commonly prescribed by many physicians ($67 vs. aflibercept’s $1,9761 price tag) and provides full visual improvement in many eyes – even up to 20/20 visual acuity. That said, bevacizumab, unlike aflibercept and ranibizumab is not FDA approved for the treatment of diabetic macular edema. Dr. Sun emphasized that a >10 letter improvement in visual acuity, which was shown for a majority of eyes with each of the anti-VEGF treatments, is a substantial vision gain for patients’ quality of life.
- As background, at the 89 sites, one eye each of 660 adults with decreased visual acuity from diabetic macular edema (DME) was randomly assigned to a standardized treatment protocol of intravitreous 2.0-mg aflibercept (n=224), 1.25-mg bevacizumab (n=218), or 0.3-mg ranibizumab (n=218). Study eyes were followed every four weeks with visual acuity and retinal central subfield thickness measured on optical coherence tomography (OCT). The primary outcome was change in visual acuity at 1 year, with secondary outcomes including changes in retinal thickness. Adverse events were recorded and hospital discharge summaries evaluated at the Network Coordinating Center.
- Upon stratifying patients into “good” or “worse” baseline visual acuity, Dr. Sun noted the increased improvement with aflibercept in comparison to the other anti-VEGF treatments became more apparent in patients with “worse” baseline visual acuity (20/50 or worse). After one year of intravitreous treatments, these patients with poorer baseline visual acuity on aflibercept exhibited an average gain of 19 letters (nearly four lines of vision on the Snellen chart), as compared to an average improvement of 14 letters (nearly three lines of vision) with ranibizumab, and an average gain of 12 letters (between two and three lines of vision) with bevacizumab. In contrast, in patients with “good” baseline visual acuity (20/32 to 20/40), all three anti-VEGF treatments resulted in “very similar” acuity improvements, each averaging eight letter gains in visual acuity.
- Additionally, aflibercept resulted in the greatest change in optical coherence tomography retinal central subfield thickness (OCT CST) over one year. Specifically, the drug resulted in a 169 um reduction in thickness, which correlates with decreased diabetic macular edema. In comparison, ranibizumab resulted in a 147 um reduction in OCT CST, and bevacizumab resulted in a 101 um reduction. Upon stratification, in those with “good” baseline visual acuity, bevacizumab still performed the most poorly (67 um reduction) compared to 119 um reduction for ranibizumab and 129 um reduction for aflibercept. Similar results were seen in patients with “worse” baseline visual acuity.
- Encouragingly, Dr. Sun noted that adverse events and visual acuity loss were rarely found in any of the three anti-VEGF treatments groups. Serious adverse events, death, and hospitalization rates were similar among treatment groups. Significant differences in frequencies of major cardiovascular events were not identified: 9% of patients experienced any cardiovascular event, excluding hypertension, in the aflibercept group vs. 9% with bevacizumab and 17% with ranibizumab.
Questions and Answers
Q: You showed the OTC results stratified by good initial vision vs. poor baseline vision; did you look at the OTC response based on initial thickness as well?
A: Yes, we did look at baseline thickness and we found that there was an interaction: when we divided eyes into those with thicker vs. thinner retinas at baseline, aflibercept had an advantage in thicker retinas.
Q: In terms of cost, aflibercept seems to work better if you have a lower baseline, but what are your suggestions for balancing the cost of this more expensive drug?
A: Cost is one of many considerations we take into account when we treat patients. Physicians will have to decide on an individual basis how to balance the greater efficacy of aflibercept, particularly for eyes that start with worse visual acuity, with the much lower cost of a drug like bevacizumab. The good news is that many eyes can improve to 20/20 visual acuity or better with resolution of diabetic macular edema with bevacizumab as well. Thus, using bevacizumab as a first-line agent may be a viable alternative for communities in which the other medications are not readily available.
Incidence of Hypoglycemia Overtreatment in the SHARE Real Life Use Population (5-LB)
K Nakamura, T Walker, J Leach, L Bohnett, J Valdes, A Balo
This late breaking poster presented the results of a study on the frequency of “rebound hyperglycemia” ( ≥180 mg/dl), which results from over treating hypoglycemia with rapid acting carbohydrates – this is very familiar to many patients and often then results in what Kerri Sparling Morrone of renowned SixUntilMe blog christened “rage bolusing” many years ago (here’s a blog about it from 2005). The Dexcom-sponsored study identified hypoglycemic events and associated glycemic rises from CGM glucose data stored on the commercial Dexcom SHARETM system – as an aside, this data is going to prove incredibly valuable over time, for analyses like this alone! Out of 1,177 users, over 50,000 hypoglycemic events were identified, with events more common during the day (8am-8pm) (59%) than at night (8pm-8am) (41%). Of these hypoglycemic events, rebound hyperglycemia followed within 60 minutes in 18% of participants and followed within 90 minutes in 26% of participants – this shows that even patients on valuable medical devices such as CGM still overtreat more often than may have been realized. The study also found that rebound hyperglycemia within 60 minutes was more common during the day (21%) than at night (13%), which could be associated with daytime meals compared to nighttime overtreatment.
Special Lecture: President, Health Care, & Education Address
Diabetes Care and Research: What is the Next Frontier?
David Marrero, PhD (Indiana University, Indianapolis, IN)
Dr. David Marrero highlighted the need for increased research into behavioral and mental health aspects of diabetes to a packed audience. After describing how technologies and treatments have changed in the 39 years since he was diagnosed with diabetes and how he became interested in the intersection of behavioral health and diabetes, he made a strong case for why this intersection is the next research frontier. He first noted that diabetes and depression may be linked – people with diabetes are more than twice as likely to face depression than those without, and people with both diabetes and depression have more severe diabetes than those with diabetes alone. Moreover, mental illness is the leading cause of disability adjusted life years lost worldwide and is expected to account for more than half of the projected total economic burden from noncommunicable chronic diseases over the next two decades. Thus the next research frontier in diabetes needs to focus on behavioral and mental health, he argued. However, he noted that only 0.9% of National Institute of Mental Health Grants and 3% of ADA grants explore behavioral/social issues related to diabetes. Dr. Marrero argued that we need significant increases in funding in this realm, need to increase the number of highly trained people who address mental health issues related to diabetes, and need more research into how providers can support patients’ emotional needs. To conclude, he announced that the ADA is collaborating with the American Psychological Association to develop training programs for psychologists that focus on the unique needs of people with diabetes – this announcement was met with applause. We are very glad to hear this and also hope that the American Psychological Association fights for more integrated approaches, along with the ADA and other advocacy organizations.
- According to Dr. Marrero, the global cost of mental illness was $2.5 trillion in 2010 and is projected to increase to over $6 trillion by 2030. He stressed that the economic burden of mental illness is larger than the costs of cardiovascular disease, chronic respiratory diseases, cancer, and diabetes and that mental illness accounts for a 35% of lost global output.
- Dr. Marrero also brought up the FDA’s role in addressing these issues by pointing to the Agency’s initiatives for patient input and for improving assessments of patient-reported outcomes. He discussed how the FDA has initiated a patient-focused drug development initiative that incorporates patient preferences and outcomes in their review process for drugs and devices – see our coverage of the Agency’s blog post on this. In addition, Dr. Marrero mentioned that the FDA has asked the ADA to provide recommendations on assessment techniques for measuring patient-reported outcomes to better understand how new treatments impact quality of life. In our eyes, the challenging nature of measuring these outcomes has likely partly contributed to our lack of understanding of such issues and we are glad to see high-level organizations like the FDA being proactive on this front.
Meet-the-Expert: Strategies to Address the Problematic Patient with Hypoglycemia
Strategies to Address the Problematic Patient with Hypoglycemia
Simon Heller, MD (University of Sheffield, Sheffield, UK)
Dr. Simon Heller provided an overview of severe hypoglycemia, including why it happens, the risks in patients with type 1 and type 2 diabetes, potential technological and educational treatments, and hypoglycemia unawareness. During Q&A, Dr. Heller provided his hypothesis for why long-duration diabetes causes hypoglycemia unawareness – years of minor episodes of hypoglycemia lead to damaged cells in the brain. Turning to actionable steps, Dr. Heller presented results from several studies demonstrating that technology, such as CGM and pump therapy, can reduce severe hypoglycemic events, as can a switch to insulin analogs (citing the HypoAna trial showing a reduction with insulin analogs vs. human insulin), education, and psychological interventions. Dr. Heller remarked that he believes training people with diabetes to use insulin more safely is key and cheaper than technology. He cited the HypoCOMPaSS trial results, which demonstrated a similar reduction in severe hypoglycemia for those using technology vs. those not; what was common to all was that patients in all groups received basic education and then ongoing support from professionals. Turning to more intensive therapies, Dr. Heller also briefly presented data demonstrating that even failed islet cell transplantation can improve awareness of hypoglycemia, and partial and full islet cell transplantation can virtually restore awareness of hypoglycemia – though he also noted that this option is not widely feasible. Dr. Heller closed his session with his pathway for hypoglycemic problems: (i) identify potential hypoglycemia unawareness; (ii) work closely with diabetes nurses/dieticians; (iii) provide structured training in insulin self-management; (iv) put the patient on CGM/pump therapy; (v) address major psychological barriers; and (vi) consider islet cell transplantation.
Questions and Answers
Q: I’ve noticed more hypoglycemia recently, with several nurses training patients to correct blood glucose levels with additional insulin doses. How do you deal with a more aggressive insulin plan?
A: You can get into a pattern of overcorrection, and it turns into chasing your tail. One problem is that we have a standard correction dose, and we tend to oversimplify; we use a unit of rapid-acting insulin to reduce glucose by 3 mmol/liter, but we need to teach patients to use other information. For example, if glucose levels are going up, one correction dose is not enough. If it is going down, they should take less than one unit. Patients have to be warned of consequences and try and use corrective doses with this in mind.
Q: You talked about preventing hypoglycemia, but emphasized not letting your patients run high. That is virtually impossible. How do you tell your patients to do that?
A: It’s a compromise. In special cases you have to be cautious – some patients are told to just run their glucose targets extremely high for a few months. The issue is actually that they could be having hypoglycemia during the night, even if they are running high during the day. In trying to reverse hypoglycemia, that gives the wrong message. It is possible to reverse unawareness in part, although it is challenging for both patient and professional.
Q: Will long-standing patients not on intensive control still experience this unawareness phenomenon?
A: A long duration of diabetes will cause hypoglycemia – it’s not just tight control. My idea is repeated episodes of hypoglycemia over years probably damage glucose-sensing cells, arguably in the hypothalamus. If these cells are damaged over the years and unable to initiate normal physiological protection, there’s the effect of long duration due to episodes of hypoglycemia. Add to that the need for intensive control, and you have more hypoglycemia. Even with long duration diabetes, you can reverse some unawareness, and islet cells can help bring back some normal physiology.
Q: Does neuropathy contribute to hypoglycemia unawareness?
A: There is some evidence of a specific effect, however, typically those with neuropathy have a long duration of diabetes, so it is difficult to separate the two.
Q: As long as low-risk patients are in good glycemic control, what is the frequency of minor hypoglycemia events that I should avoid?
A: A group of us met to try to answer that question – it’s important. In our training program, we have said two to three episodes a week are fine. I don’t know if there’s evidence for that. Possibility, those can accumulate and cause damage. Then, there is the hypoglycemia that all sustain during night that we don’t measure, and is asymptomatic. All values for the number of acceptable minor hypoglycemia events are totally arbitrary, and there is no evidence to back it up.
Q: What are your thoughts on hypoglycemia and patients retaining a driver’s license?
A: In the EU, one needs to have total unawareness to lose a driving license. In my view, the question is asked the wrong way around. A van driver who had full awareness and didn’t test his glucose levels ended up crashing and killing somebody – he went to jail. Patients need to test their glucose before they drive. Most patients don’t test, which is of considerable concern. For a patient with some awareness, if they can be persuaded of how important it is to check their blood glucose before driving, I will support the retention of their license, but it varies a lot in different countries.
Q: What happens when a patient has hypoglycemia unawareness, but completely denies it?
A: We need to work with them. When we put our patients in a group, they understand each other. You’re right, these are huge issues. There’s a study on partners of patients, and it’s depressing because there are partners reviving their partner with diabetes, who sometimes deny there’s a problem. There is one quote from a partner saying, I didn’t bargain for this when I got married.
Q: What’s your view on where the economic discussion should be for patients with type 2 diabetes?
A: Severe hypoglycemia is expensive, and less severe hypoglycemic events are less expensive. But the economic argument is winning – indications for better treatment and also resetting glycemic goals. This may help us to make it easier to use more expensive therapies to reduce severe hypoglycemia.
Q: Do you have experience with structured programs for the pediatric benefit, and at what age?
A: There is one trial with young adolescents in the UK. Interestingly, it didn’t improve A1c and didn’t have an effect on severe hypoglycemia. There is an urgent need for courses for parents with children who have diabetes, and I’m unaware of a publication where that has been done. In terms of adolescents, structured programs on their own are inadequate. We have to combine training with other techniques, such as psychology and education. One problem with kids, at least in the UK, is that they hate having diabetes, and will do anything not have it. We need to get to kids early and train them and their parents. We just need the parents to buy in. This is still in the early days.
Q: How often should people test during the night, and at what time?
A: I have a 3 AM rule, but you won’t be surprised that 80% of my patients don’t follow it. Where you have CGM and are taking advantage of that, then you can identify your unawareness throughout the night and take steps to prevent that. It’s horrifying the hours of hypoglycemia that patients sleep through. Where it can be afforded, CGM is really important if you don’t want a 3AM test.
Symposium: ADA Diabetes Care Symposium – Novel Clinical Interventions in Therapy That Impact the Management of Diabetes
Best of Diabetes Care 2014 – Psychosocial and Behavioral Research – Depression, Distress, and Glycemia
Mary de Groot, PhD (Purdue University, Indianapolis, IN)
Dr. Mary de Groot opened her presentation stating that, “it’s an exciting time for depression research in diabetes” and discussed three of this year’s pivotal papers on the psychosocial aspects of diabetes. The first paper examined the relationship between type 1 diabetes and depression in children by comparing outcomes of youth with diabetes to their siblings without diabetes. Dr. de Groot noted that the few previous studies on the relationship had mixed results on the rates, but no previous study had assessed these rates in siblings. With observational data from the Swedish Child Diabetes Registry from 1973 to 2009, the study found rates of psychiatric disorders at six months post-diagnosis to be three times greater in children with type 1 diabetes than in the general population (from the data of non-diabetic siblings). Dr. de Groot’s second highlighted paper discussed the association of systematic inflammation with depression in people with type 2 diabetes. In this study, a cohort of newly diagnosed patients with type 2 diabetes were tested both for depression and for twelve inflammatory markers; notably, findings demonstrated an association between the multiple markers and depression at time of diagnosis. The last paper was a first ever head-to-head examination in both type 1 and type 2 diabetes populations of a diabetes-specific cognitive behavioral therapy (CBT) vs. an anti-depression medication, sertraline. Outcomes were similar at both 12 weeks and one year with sertraline being associated with slightly better outcomes at one year; however, both treatment options only reached a low level of achieved response (46%). As noted by Dr. de Groot, all three trials represented significant advancement in the field of psychosocial research in diabetes.
Symposium: The Impacts of Hypoglycemia in Diabetes (Supported by an Unrestricted Educational Grant from Merck)
Hypoglycemic Morbidity and Costs in Diabetes
Brian Frier, MD (University of Edinburgh, Edinburgh, UK)
Dr. Brian Frier set the stage for the symposium by providing an overview of the morbidity and costs of hypoglycemia in diabetes. He emphasized that hypoglycemia has serious acute costs, but equally as costly are the long-term consequences including chronic syndromes, worsened complications, impaired awareness of hypoglycemia, and reduced quality of life. Additionally, on a particularly insightful note, he stated that while the psychosocial effects and fear of hypoglycemia are undoubtedly high, these are “unquantifiable” outcomes. Furthermore, Dr. Frier described the estimated economic costs as “only the tip of the iceberg” since most of this cost data comes from hospital emergency room (ER) visits; in actuality, up to 90% of hypoglycemic events are treated in the community (Donnelly et al. Diabet Med, 2005), thus reframing economic costs as “a serious underestimate.” (We note this is old data and would assume it may well be an even higher percent treated in the community – but the cost is much larger since the exposure of diabetes is much greater.) He noted that more worrisome is that very little is known about the long-term costs of hypoglycemia-related morbidity, describing it as “a gaping black hole” in our knowledge.
- Dr. Frier described several “imponderables” that prevent accurate estimates of the economic costs of severe hypoglycemia. Firstly, measuring the frequency of hypoglycemia is difficult, particularly for non-severe events as well as events in elderly patients and non-insulin-treated type 2 diabetes. Secondly, the incidence and cost of hypoglycemic morbidity and its direct consequences are still unknown. These morbidities include accidents causing injury, vascular events (cardiac, neurological), and driving and workplace mishaps, as well as the cost of long-term psychological morbidity (fear of hypoglycemia) with impact on glycemic control and risk of diabetic complications.
- In a National Ambulatory Medical Care Survey in the US from 1993-2005, five million emergency department visits for hypoglycemia were recorded and 25% resulted in hospital admission (Ginde et al., Diabetes Care 2008). Dr. Frier expounded on the economic burden of these hypoglycemia-related ED visits, noting that severe hypoglycemia (SH) costs are higher when patients are hospitalized; in the UK, a single episode of hypoglycemia in type 1 and type 2 diabetes were 887 pounds and 892 pounds, respectively, compared to 256 pounds and 238 pounds in an outpatient community setting (Hammer et al., J. Med 2009). Dr. Frier argued for a shift to treating patients outside of hospitals, where he noted hypoglycemia expenses to be “incredibly escalated.”
Questions and Answers
Q: The last few large randomized controlled trials in type 2 diabetes have shown an association between severe hypoglycemia and severe cardiac events. However, it’s usually several months after hypoglycemia where we are seeing these severe cardiac events; could you elaborate on what you think is going on?
A: I don’t know if we’re looking at months because some of these cardiac events are just a few days after the event. I believe Dr. Simon Fisher may address this later, but basically hypoglycemia is setting an individual up to be more susceptible to severe cardiac events. I don’t want to pre-empt Simon, but if a patient has lots of hypoglycemia, then this preconditions the heart. The concept is that various other things are happening like changes in coagulation and inflammation, which last for a considerable amount of time, thus the days to weeks delay. We have to change our thinking on hypoglycemia. It is not a short-lived event.
Arrhythmias and Mortality Associated with Insulin-Induced Hypoglycemia
Simon Fisher, MD, PhD (University of Utah, Salt Lake City, UT)
Dr. Simon Fisher presented animal model results showing the insulin-induced hypoglycemia effects on arrhythmias and mortality. He explained the mechanism behind severe hypoglycemia-induced mortality otherwise known as “dead in bed syndrome”: a huge surge in the counter-regulatory sympathoadrenal response to hypoglycemia causes cardiac arrhythmia and subsequent cardiorespiratory arrest. He noted that preventing or blunting this counter-regulatory surge could prevent cardiorespiratory arrest causing mortality. Indeed, Dr. Fisher’s group found that providing rats with an alpha/beta blockade before insulin-induced hypoglycemia completely prevented mortality (n=13) vs. 30% mortality in control with no alpha/beta blockade (n=12). Furthermore, pre-administration of a beta-blocker specifically prevented mortality (n=5) vs. 50% mortality with an alpha-blocker (n=6) and 30% mortality in the control group (no blockade, n=12). Also, paradoxically to the prevailing hypothesis that recurrent hypoglycemia is solely maladaptive (hypoglycemic unawareness, impaired counter regulation, increased risk of hypoglycemia), Dr. Fisher argued that it might have some adaptive benefits as well, including preconditioning against severe hypoglycemia, neuroprotection, preserved cognition, seizure prevention, and most importantly, mortality benefit. Rat models with recurrent hypoglycemia showed <5% mortality compared to 20% in control and 35% in the diabetes arm without recurrent hypoglycemia model.
- Dr. Fisher highlighted “the one slide of data that you need to know” which showed that adrenergic blockade prevented death due to severe hypoglycemia. Rats given alpha/beta blockers (n=13) showed 0% mortality vs. 30% mortality in the control group (n=12) (p<0.029). Mechanistically, their data showed that prolonged rapid heart rate predicted mortality in these rats. In control groups (without adrenergic blockade), rats that died from severe hypoglycemia exhibited 450 bpm heart rate vs. 340 bpm in rats that survived severe hypoglycemia and 350 bpm in rats at basal insulin levels. In comparison, all of the rats that received alpha- and beta-blockers survived, with those undergoing severe hypoglycemia exhibiting heart rates of just 200 bpm. More specifically, researchers found the alpha/beta blockade reduced cardiac arrhythmias, completely preventing first, second, and third degree heart blocks. This data was both highly specific (95%) and sensitive (89%).
- By specifically isolating administration of an alpha vs. beta-blocker, results showed that beta blockade reduced arrhythmias and completely prevented mortality (n=5) vs. 50% mortality with just an alpha-blocker (n=6) and 30% mortality with in controls, i.e. no blockade (n=12).
- Dr. Fisher concluded that adrenergic blockades, specifically administration of a beta-blocker, prevented the sympathoadrenal response (of norepinephrine and epinephrine), which is believed to cause cardiac arrhythmias and subsequent cardiac arrest in “dead in bed” syndrome. Electrocardiogram (ECG) readings of the study’s rat models found QTC prolongation and tachycardia during insulin-induced hypoglycemia, which Dr. Fisher noted was previously found in human subjects (Frier et al., Diabetes Care 2011). Dr. Fisher’s group was able to leverage the use of an animal model, simulating hypoglycemia levels too low to be studied in human participants in order to assess what happens after QTC prolongation. Researchers found the QTC prolongation was followed by premature ventricular contractions (PVCs) and subsequent first, second, and third degree heart blocks, the latter of which is associated with mortality in rats.
- Dr. Fisher also proposed that recurrent moderate hypoglycemia could have the benefit of inducing a blunted sympathoadrenal response, thus resulting in fewer cardiac arrhythmias and decreased mortality. Diabetic rats in which recurrent moderate hypoglycemia was induced (n=27) were consistently protected (<5% mortality after severe hypoglycemia) vs. 35% mortality in the diabetic rats without recurrent hypoglycemia and 20% mortality in the control group with no background diabetes (n=123). Rats with recurrent moderate hypoglycemia had limited damage to memory and learning areas of the brain after 90 minutes of severe hypoglycemia compared to euglycemic controls (Puente et al., Diabetes, 2010).
Questions and Answers
Q: Was there any way you could measure if pre-treatment with alpha/beta blockade improved hypoglycemia awareness?
A: As you can imagine, it was very difficult to assess hypoglycemia awareness in our rat model. We gave the rats questionnaires but they refused to fill them out [audience laughter].
Hypoglycemia Mortality in Diabetes
Philip Cryer, MD (Washington University in St. Louis, St. Louis, MO)
Addressing a packed audience, the great Dr. Philip Cryer reviewed hypoglycemia mortality in type 1 and type 2 diabetes. He emphasized that, while there is an association between the occurrence of hypoglycemia and death, this does not establish that hypoglycemia was the cause of all, or even any, of the deaths. Dr. Cryer reviewed evidence from randomized controlled trials (including the NICE-SUGAR and ACCORD trials), highlighting that increased mortality has been reported during intensive therapy compared with less intensive, glucose-lowering therapy in ICU patients and in patients with type 2 diabetes. Recent estimates suggest that anywhere from 4% to 10% of deaths of people with type 1 diabetes were due to hypoglycemia. Dr. Cryer emphasized that there is an iatrogenic hypoglycemia mortality rate in both type 1 and type 2 diabetes. In addition, he outlined the implications of hypoglycemic mortality, emphasizing the goal to aim for the lowest A1c value that does not cause severe hypoglycemia and that preserves awareness of hypoglycemia with little or no symptoms. He argued that this should be done by accounting for the patient’s degree of endogenous insulin deficiency and drug treatment, keeping in mind that the greatest risk of hypoglycemia is in those with type 1 diabetes and on insulin/sulfonylurea/glinide treatment. Dr. Cryer then turned to a discussion of hypoglycemia-associated autonomic failure (HAAF), which occurs when iatrogenic hypoglycemia reduces sympathoadrenal and symptomatic responses to the same level of hypoglycemia that follows. He concluded by arguing that HAAF is both maladaptive and adaptive, in that it is associated with an increased risk of severe hypoglycemia during intensive glycemic treatment but also has evidence from rat models showing reduced frequency of death during hypoglycemia following previous exposure to recurrent moderate hypoglycemia, a model of HAAF.
Symposium: Emerging Topics in Diabetic Kidney Disease
Global Burden – Aging Populations and Rising Frequencies of Kidney Disease
Tazeen Jafar, MD, MPH (Duke-NUS Graduate Medical School Singapore, Singapore)
In a timely talk on the global burden of kidney disease, Dr. Tazeen Jafar stressed that kidney disease is a widespread, cost-intensive morbidity. Globally, chronic kidney disease (CKD) (Stage 3-5) prevalence is 7% and the expected number of patients with CKD is 300 million. CKD prevalence rates are high across all regions, and especially high in Southeast Asia and Europe. Although the disease burden is very high, many individuals living in middle- and low-income countries are unable to afford the high costs of dialysis. Dr. Jafar argued that kidney transplantation is a more cost-effective solution compared to dialysis; however, the limited numbers of kidney donors available make this option unviable for many. Dr. Jafar concluded her presentation with a call to action, for inclusion of CKD in the public health agenda with population-wide programs for prevention of CKD. These efforts will include screening for CKD among high-risk individuals such as those with diabetes and hypertension and prompt institution of multifactorial therapy for preventing cardiovascular disease and progressive CKD. She also encouraged the audience for more research on novel therapeutic targets as well as on nontraditional pathways on the link between CKD and cardiovascular disease (i.e. fluid overdose, anemia).
Q: Are there any global difference in dialysis outcomes that we can learn about?
A: Access to dialysis has been poor. Survival on dialysis is also suboptimal. The median survival for people on dialysis really depends on age and comorbidities. For individuals aged 44-64, it is about 4.4 years. In Japan, it is much better. We know life expectancy is better. Many theories have been advanced as to why this is the case. One hypothesis is that people in Japan have a reduced sub-clinic arthrosclerosis burden. Also, access to dialysis is better in Japan and they have the greatest number of nephrologists per capita there also. The Japanese also have the best fistula access placement rates. Timely placement is really important for patients.
Symposium: The Eyes Are Windows to the Soul – Improving Care and Quality of Life for Patients with Vision Loss
Out With the Old and In With the New – Emerging Therapies for Diabetic Macular Edema
Lloyd Paul Aiello, MD, PhD (Joslin Diabetes Center, Boston, MA)
Dr. Lloyd Paul Aiello reviewed the history of therapies for diabetic macular edema (DME), highlighting how far treatments have advanced since the mid-twentieth century. Specifically, Dr. Aiello pointed to vascular endothelial growth factor’s (VEGF) discovery in the 1990s as a key turning point in shifting the clinical paradigm, as VEGF is an important factor to look at for mediating diabetic retinopathy and DME. Dr. Aiello cited RIDE/RISE pooled data and other studies funded by the Diabetic Retinopathy Clinical Research Network, which led to the approval of two anti-VEGF agents (Roche/Genentech’s Lucentis [ranibizumab] and Regeneron’s Eylea [aflibercept]) and use of a third (Genentech’s Avastin [bevacizumab]) for the treatment of DME causing vision impairment – we note the third is not approved for DME but is used off-label as it is much cheaper. Challenges associated with these drugs include the fact that Avastin is not FDA-approved for intraocular use, the high costs of these drugs, and the need for multiple visits and injections. However, Dr. Aiello also pointed to these treatment options’ many benefits including low complication rates, minimal side effects, and the reduced need for laser treatment. Looking forward, Dr. Aiello emphasized the need for predictive biomarkers to help individualize future treatment, specifically pointing to the potential impact of the adaptive optics scanning laser ophthalmoscopy (which can remove over 90% of optical aberrations) as it is currently being used to look at the association between microaneurysms and predictive biomarkers.
Questions and Answers
Q: Do you know of other factors that determine who is going to get diabetic macular edema vs. diabetic retinopathy?
A: Many people have been looking at this for a long time. There are clearly genetic components, but it is not simple. Clearly genes, predisposition, and environmental factors all play a role. There is a lot of good work going on to determine who gets the disease and who doesn’t.
Symposium: Cardiovascular Disease Risk Factor Management in Type 2 Diabetes Mellitus (Supported by BI & Lilly)
Cardiovascular Risk Factor Management in Diabetes – Where Are We in 2015?
Sherita Golden, MD (Johns Hopkins University School of Medicine, Baltimore, MD)
Dr. Sherita Golden began her presentation with a widely known observation that people with diabetes are at a higher risk of cardiovascular disease from a large meta-analysis of over 100 prospective cardiovascular disease studies in people with diabetes. She introduced the ABCs of diabetes care towards CVD prevention, which encompass A1c and aspirin, blood pressure, and cholesterol. However, she demonstrated that meta-analyses of large-scale trials demonstrated that A1c reduction below the target of 7% did not produce significant CVD risk reduction. While aspirin use is effective in secondary CVD prevention among individuals with diabetes, it is not effective for primary CVD prevention. In addition, aggressive blood pressure lowering below current targets did not significantly reduce CVD risk. Lastly, she addressed the matter of obesity (or what she called the “culprit” of diabetes) by comparing several meta-analyses of varying surgical methods for obesity control. Of all the methods, more invasive surgeries have the most dramatic effects on glycemic control as well as weight reduction. In considering pharmacological options for treating diabetes, patients place a premium on the effect of the therapy on weight, but Dr. Golden noted that this consideration must also be balanced with medication cost and the patient’s insurance coverage.
- Dr. Golden asked a provocative question after reviewing the conclusions of ACCORD and VADT: did the studies focus on the right subgroups? She noted that there is a trend of increasing diabetes incidence among older adults, women, and ethnic minorities, especially Latino and African-American groups. A meta-analysis of over 100 prospective studies evaluating cardiovascular disease determined that patients with diabetes have an increased risk of vascular disease. In addition, the ACCORD and VADT studies found that groups with A1c, blood pressure, or cholesterol reduction found no corresponding reduction in the incidence of any CVD endpoint. In referring back to the increasing incidence of diabetes in specific groups, she then inquired whether these studies focused on the correct subgroups of patients.
- Dr. Golden outlined the ABCs of diabetes care as potential components of preventing cardiovascular disease. She discussed the “A”, or A1c, by stating that tight glycemic control at A1c levels <7% resulted in no significant reduction of cardiovascular (ACCORD, VADT trials) and could even be associated with an increase in cardiovascular mortality (Look AHEAD trial). For the “B”, blood pressure, she noted that the ADA recommends a target of <140/90 mmHg as a target endpoint, though recently lowered the target to <130/80 mmHg for younger patients. She reminded attendees that the ACCORD study found an increase in overall complications associated with more intensive blood pressure management. Regarding the “C”, cholesterol, she summarized recent ADA and ACC/AHA recommendations that shifted the focus from numeric target-based statin therapy to overall risk stratification.
- In the final component of the talk, she addressed the role of obesity as the “culprit” of diabetes and the efficacy of interventions targeting obesity. She raised the findings of the Look AHEAD study, pointing out that increased physical activity (~180 minutes per week) led to the primary endpoint of significant weight reduction, but no significant difference in the incidence of cardiovascular disease after 9.5 years (n=5,145). However, she also pointed to a meta-analysis of 22,000 bariatric procedures, in which the most invasive procedures resulted in the most dramatic weight loss and remission of diabetes. In particular, one study demonstrated that adjustable gastric binding resulted in 73% diabetes remission in the intervention group vs. 13% in medical treatment arm (n=60, baseline BMI = 30-40 kg/m2, p<0.05). Furthermore, the treatment group experienced significant differences in weight reduction, fasting plasma glucose, and A1c.
Glycemic Control in Type 2 Diabetes
Deborah Wexler, MD (Massachusetts General Hospital, Boston, MA)
Dr. Deborah Wexler began her talk by emphasizing the urgency of macrovascular complications as the greatest cause of mortality in people with type 2 diabetes. She reviewed DCCT and UKPDS results that indicated a curvilinear relationship between cardiovascular disease (CVD) event rates and A1c levels, with a dramatic increase after an A1c of 7%. Despite the indication that A1c management improves CVD outcomes, the ACCORD study (n=10,251) comparing A1c targets of 6% to 7.5% led to an overall increase in all-cause mortality, with the cause unclear, as well as a threefold increase in hypoglycemic events, and a twofold increase in weight gain. According to Dr. Wexler, other contemporaneous studies of intensive glycemic control such as the ACCORD study (which achieved a 6.5% A1c in the intensive group and a 7.5% A1c in the control group) and the VADT study (which achieved a 6.9% A1c in the intensive group and a 8.4% A1c in the control group) showed no benefit or harm within the duration of the randomized portions of the studies. The balance of evidence indicates that intensive glycemic control to lower A1c below 7% had no harmful effects, but did not provide any reduction in risk for cardiovascular disease over the duration of the trials (all less than five years).
- Over a 17-year follow-up period from the DCCT/EDIC studies of individuals with type 1 diabetes, intensive control achieving an A1c of 7% compared to 9% in controls reduced the risk of major cardiovascular adverse events by 50% (p=0.018). In addition, the UKPDS study of people with type 2 diabetes supported the notion that intensive therapy provides relatively higher benefits in CVD prevention though in a nod to cardiovascular outcome trials ongoing now – it took quite awhile to get to this point of proof and this makes the three to five year timelines seem far too short (even given that UKPDS was patients more recently diagnosed). In UKPDS, over 20 years of follow-up, the intensive therapy group of sulfonylurea and insulin use had a 15% cumulative risk ratio for myocardial infarction, less than half of the 33% risk ratio for the standard care group on metformin (p=0.005). These findings thus support the hypothesis that intensive therapy may provide a beneficial effect towards reducing CVD risk – we assume the metformin group had a higher A1c and poorer control overall.
- In the ADVANCE-ON study data released in October 2014, intensive care did not show any improvement in CVD outcomes in comparison to standard care (n=1140, p>0.05). The initial baseline A1c of 7.5% improved but then regressed back to 7.5% during the follow-up period. Despite the neutral effect on CVD outcomes (at least for that time period), the intensive care group did show a significant benefit in end-stage renal disease (ESRD) outcomes vs. standard care (p=0.007). However, the incidence of ESRD itself was very rare, with 29 cases in the intensive group vs. 53 in the standard care group.
- Dr. Wexler called the late-breaking news the report of the longer term-follow up of the VADT trial, which showed reductions in cardiovascular outcomes over almost 10 years of total follow up. Since the benefit of intensive glycemic control on CVD accrues over years, Dr. Wexler noted that further analyses of these cohorts, particularly from the ACCORDION observational follow up of the ACCORD cohort, may reveal additional information. The means of achieving glycemic targets, for example, may have a significant effect due to their effects on weight gain and hyperglycemia as well as off-target drug effects – it would be useful to know more about this.
Symposium: Diabetic Dyslipidemia – Where's the Action in 2015?
The Typical Diabetic Dyslipidemia Presents a Plethora of Drug Targets for Reducing Atherosclerosis
Marshall Elam, MD, PhD (University of Tennessee Heath Science Center, Memphis, TN)
Dr. Marshall Elam presented several exciting drug targets for reducing atherosclerosis in patients with diabetic dyslipidemia, focusing on LDL concentration, hyperglycemia, and triglyceride rich lipoproteins as potential treatment targets. Consistent with current treatment guidelines, Dr. Elam recommended the use of moderate to high intensity statins to lower LDL concentrations for type 2 diabetes patients over the age of forty. Using the IMPROVE-IT trial as evidence, he also indicated that the use of ezetimibe (a cholesterol absorption inhibitor) in combination with background statin therapy may reduce the risk of cardiovascular events in patients with pre-existing cardiovascular disease. As for hyperglycemia, although Dr. Elam did not discuss ways to reduce hyperglycemia, he did suggest that glycemic control reduces triglyceride levels by decreasing new lipid synthesis and VLDL. Even so, Dr. Elam took note that although individual trials of intensive glycemic control have failed to show reduced cardiovascular disease (CVD) events, a long-term post trial follow-up of The Veterans Affairs Diabetes Trial reported a 17% lower rate of primary CVD events. Dr. Elam concluded his presentation with evidence that fenofibric acid in combination with rosuvastatin increases HDL concentrations and lowers both triglyceride and LDL concentrations; however, the data are mixed as to whether fibrate therapy reduces CVD risk.
- Dr. Elam reviewed the characteristics of diabetic dyslipidemia, which include increased triglyceride-rich lipoproteins, decreased HDL concentration, and altered compositions of triglyceride-rich LDL. According to him, experimental evidence demonstrates a mechanistic link between diabetic dyslipidemia and cardiovascular disease. Most notably, the altered LDL composition in patients with diabetic dyslipidemia results in an increase of small, dense LDL particles that are more likely to be absorbed by the arterial wall and become oxidized. Furthermore, these particles are thought to be somewhat more atherogenic than normal LDL particles.
Symposium: Are We Putting Ourselves Out of a Job? The Changing Epidemiology of Type 2 Diabetes and Its Complications
Trends in Macrovascular Disease
Edward Gregg, PhD (Centers for Disease Control and Prevention, Atlanta, GA)
The renowned Dr. Edward Gregg discussed the trends in diabetes-related complications and interventional needs. He focused on five outcomes to get a spectrum of complications for which there is reasonable data over time, including acute myocardial infarction (AMI), stroke, lower-extremity amputation, hyperglycemic death, and end stage renal disease (ESRD). While rates of myocardial infarction (MI) and stroke have decreased in people with diabetes, ESRD rates have not. We would note that due to the sheer absolute increase in people with diabetes, we hope that the research and advocacy communities continue to work hard on much greater reduction in complications. We are so glad for the slew of CVOTs ongoing in terms of safety data being amassed – on the other hand, now that a number of researchers have generated enough safety data, we have many more questions about efficacy – do any of the new compounds help prevent CVD or renal disease? This information seems vital to have from a public health perspective, particularly when the agents go generic, although most trials end relatively early and do not have even passive follow up data collection to learn what happens to patients. Notably, individuals aged 20-44 years have experienced the greatest relative increase in diabetes, but have the smallest improvements in care and risk factors. The future implications of this are unknown but are concerning as these individuals will have many years lived with diabetes and its related complications.
- The absolute difference in rates of MI and stroke has decreased between people with and without diabetes between 1990 and 2010. Further, the relative risk (RR) of MI has decreased from 3.8 in 1990 to 1.8 in 2010, and the RR of stroke has decreased from 3.1 to 1.5. In this time, there has also been a decrease in the rates of amputation and hyperglycemic death, but rates of ESRD have only mildly decreased. We are very glad to hear most of this as improvement. But relatively speaking, the sheer number of people with these complications has increased so extensively due to the magnitude of exposure – this is depressing, indeed, and should require greater intensity of focus.
- Dr. Gregg demonstrated that the millennial generation has had the largest increase in diabetes but the smallest improvement in diabetes-related complications. Individuals born between 1980 and 2000 have the highest levels of obesity and type 2 diabetes ever, but they are experiencing the smallest improvements in cardiovascular events (AMI, stoke, in-hospital death). This was surprising and disconcerting to learn. Rates of these complications has increased in individuals aged 45-64 years between 1990 and 2010, but have decreased in those aged 65-74 years.
- While it appears that there have been improvements in MI and stroke, there are still many concerns for the epidemiology and prevention of diabetes. Specifically, it is important to define success in rate reductions appropriately – while MI and stroke have decreased in older adults, younger adults are still at risk. In addition, the increase in the number of life years exposed to complications is concerning because we have more people spending more time with diabetes. Diversification of complications is also leading to fewer healthy years for those with diabetes than those without. Notably, the new generation of individuals with diabetes is yet to be defined and the millennial generation is experiencing increased rates of obesity and diabetes, more so than has been seen in past. This population will be living with diabetes and potentially its complications longer than previous generations and we do not currently know what their complications will look like over the long term. Lastly, averages are obscuring important variations, especially with regard to geographic variations in cardiovascular health in the US.
Questions and Answers
Q: It is misleading to present something as a fact and then footnote that it may be biased.
A: We have to acknowledge that the biases are there. We have tried to do a sensitivity analysis but we do have to make some big assumptions. I would suggest that they don’t change our conclusions.
Trends in Microvascular Disease
Katherine Tuttle, MD (University of Washington, Spokane, WA)
Dr. Katherine Tuttle focused this talk on the increasing rates of chronic kidney disease (CKD), which are largely driven by the increasing rate of diabetes. Importantly, and depressingly, end stage renal disease (ESRD) prevalence rates attributed to diabetic kidney disease (DKD) are also increasing despite stabilizing or improving incidence rates. While there have been reductions in myocardial infarction, stroke, and amputations, these trends have not been seen with CKD and ESRD. Importantly, diabetes and CKD also increase the risk of diabetes-related complications, such as retinopathy (10-fold increase), glaucoma (1.5 fold increase), lower extremity ulceration (5-fold increase), and amputation (2-fold increase). Thus, Dr. Tuttle stressed the urgent need for novel therapies to treat CKD. We have high hopes on this front for Invokana and salute J&J for undertaking massive trials to investigate whether the drug is renal protective.
Questions and Answers
Q: One of the most sobering things about diabetic nephropathy is that only 50% of patients with DKD know that they have DKD. If you look at stage 3, only 10% know they have it. This is distressing as we are asking patients to take medications for something that they are not aware of. We need to do more to educate our patients about kidney disease. I recognize that a lot of people may not tell their patients about DKD but we should.
A: I agree. Awareness and detection lead to intervention.
Symposium: The Skinny on Fat in the Islets
Lipotoxicity and Beta Cell Dysfunction in Type 2 Diabetes – Interventional Strategies
Kieren Mather, MD (Indiana University, Indianapolis, IN)
Dr. Kieren Mather reviewed literature on the effect of fatty acids on beta cell function, which suggests that elevated fatty acid uptake is associated with reduced beta cell function. While fatty acids are a normal component of diet, under conditions of excess, they can be toxic to beta cells and lead to dysfunction and apoptosis. Regarding potential interventions, Dr. Mather pointed to approaches that improve beta cell function including pioglitazone and weight loss interventions. However, much remains to be defined in regards to the contributions of lipotoxicity to beta-cell dysfunction and treatment options that can lead to successful restoration of beta cell function. We are excited to see the results of the RISE consortium, and which interventions may lead to improvements of beta cell function.
- Dr. Mather explained how pioglitazone may lead to improvements in beta-cell function, pointing to findings of the ACT NOW study. In this study, patients were randomized to pioglitazone 45 mg/day or placebo, and were observed for 2.4 years; over this time, 45 patients in the placebo group and 15 in the pioglitazone group developed type 2 diabetes (p<0.0001). In the pioglitazone group, 48% achieved normal glucose tolerance vs. 28% in the placebo group (p<0.005), with individuals achieving normal glucose tolerance experiencing the greatest improvements in beta cell function, and thereby insulin sensitivity. In addition, Dr. Mather cited a 2013 article by Dr. Ralph DeFronzo (University of Texas Health Science Center, San Antonio, TX), which demonstrated that pioglitazone had the ability to improve beta cell function in individuals with impaired glucose tolerance who progressed to normal glucose tolerance.
- In addition, Dr. Mather mentioned the Restoring Insulin Secretion (RISE) Consortium’s Beta Cell Restoration Through Fat Mitigation (BetaFat) study as one to look forward to in evaluating the effect of weight loss on beta cell function. The study, which is currently enrolling, will evaluate if weight loss achieved through gastric banding will be superior to treatment with metformin in preserving or restoring pancreatic beta cell function in people with prediabetes or mild type 2 diabetes. Overall though, Dr. Mather noted that any weight loss interventions (lifestyle modification, pharmacologic, or surgical approaches) may also improve beta cell function.
Questions and Answers
Q: Do you have data on the lipotoxicity on alpha cells or glucagon release?
A: I could not find any of these data.
Q: What are the effects on lipotoxicity on GLP-1 function on beta cells?
A: I have not seen any data to that effect.
Symposium: JOINT ADA/EASD Symposium – What Drives the Relationship Between Diabetes and Cancer?
Evidence Linking Diabetes and Cancer – Metabolic Players and Effects of Diabetes Treatment
Andrew Renehan, PhD (University of Manchester, Manchester, UK)
Dr. Andrew Renehan kicked off this symposium by providing a broad overview of the link between diabetes and cancer mortality, concluding that any association between the two at this point is “spurious” and an extrapolation of data. Instead, he cautioned the audience to wait for long-term results (>10 years of data) before making any meaningful conclusions. He did provide some insight into a new European research group currently in the works to study this association; as of now 19 different partners are involved and will explore the link between diabetes and cancer. This consortium will focus on five integrated work areas: (i) excess weight, diabetes, and cancer risk/survival; (ii) dysglycemia, diabetes, and cancer risk; (iii) diabetes drug treatment and cancer risk; (iv) the impact of diabetes on cancer survivorship; and (v) the burden of the diseases.
- Dr. Renehan also reviewed his recent paper just accepted by Carcinogenesis, assessing relationship between human insulin, super-mitogenic insulin (X10), and IGF-I on IGF-IR and IR expression in 17 human adenocarcinomas. Results found that ligand mitogenic potency, relative to human insulin, increased with increasing cell-specific IGF-IR/IR ratio. Dr. Renehan translated these results as a potential framework for the in vitro evaluation of cancer-relevant bio-assays for comparisons of insulin analogs. He noted were the effects of insulin analogs beyond 10 years on tumor subtypes was still unanswered.
- Dr. Renehan closed his presentation by posing a striking, hypothetical question to the audience: With improvements in diabetes care and concurrent decrease in cardiovascular mortality, will cancer-related mortality be the “next sticking point” for diabetes drug development?
Questions and Answers
Q: In the literature, it seems glucose is getting the short shift. Strictly controlled glucose showed no effect on cancer mortality, but this seemed to contradict basic science research that shows tumors growing better in high glucose environments. Can you explain this?
A: Yes, that point was a deliberate contraindication trying to illustrate the dichotomy happening. You’re absolutely right; there is a lot of lab data that shows that. One of the work packages in the consortium will look at this.
Q: In context of your slides showing the influence of IGF-1 receptors to insulin receptor ratio, glargine, and mitogens on cancer risk, how much do you think we should be looking at IGF in terms of bioavailability?
A: Great question, the bioavailability of IGF-1 is very hard to measure. I’ll have to talk to you about that later on.
Q: Is there any dialogue between the Diabetes and Cancer Research Consortium (DCRC) and the European Medicines Agency?
A: Yes, but there should be more.
Corporate Symposium: Avoiding “Loss of Chance” (Sponsored by Genentech)
Improving the Screening, Treatment and Referral of Patients with Diabetic Retinopathy
Vivian Fonseca, MD (Tulane University, New Orleans, LA)
Dr. Vivian Fonseca, one of the truly great all-time endocrinologists ever, introduced the symposium, which continued the theme of high-tech and interactive corporate symposia. He began by eliciting a series of questions about the audience’s demographics, fields of expertise, and initial decision-making in response to signs of retinopathy. The audience consisted mostly of MDs, making up nearly half of the attendees. Although the symposium attendance was low, Dr. Fonseca remained engaged in the event and tailored his introduction to the target audience. He conceded his limited knowledge about diabetic macular edema, stating that he would refer his patients to the ophthalmologist when his patients developed retinopathy. With this concession, he introduced the specialists that would present at this symposium. We think Genentech was very lucky to have Dr. Fonseca introduce this meeting.
Sangeeta Kashyap, MD (Cleveland Clinic, Cleveland, OH)
Dr. Sangeeta Kashyap began her presentation by emphasizing the high incidence of retinopathy in people with diabetes with relatively longer durations after initial diagnosis. About one in four people with diabetes develop retinopathy (we have actually heard much higher ranges over a lifetime), and this complication is one of the most common and indiscernible sources of visual impairment. People with type 1 diabetes have a higher incidence of retinopathy while type 2 diabetes patients have a lower incidence that increases with insulin use. Due to the subtlety of this complication and the lack of knowledge on the patient side, retinopathy remains one of the most challenging issues to address in people with diabetes for a long time. In her presentation, Dr. Kashyap reviewed the incidence and effects of retinopathy, and addressed the standard guidelines for interventions. Most notably, she discussed the results of a study at the Cleveland Clinic assessing the efficacy of a telemedicine intervention in addressing diabetic retinopathy, which demonstrated that this form of intervention may not only be cost effective but can also successfully result in referrals to specialist care. In a study of 1935 VA patients, this telemedicine approach determined that 24% of the patients had abnormal retinal photographs, with more than 40% having non-macular diabetic retinopathy. Telemedicine supervisors then directed the patients to specialists, and the percentage of agreement between retinal screening via telemedicine and ophthalmic examination for all diagnoses was an impressive 90% with a sensitivity of 74%. These findings follow the recent theme on using telemedicine as a promising new approach in detecting early diagnoses and reducing cost.
Jennifer Sun, MD (Joslin Diabetes Center, Boston, MA)
Dr. Jennifer Sun discussed the role of imaging as a key to determining the risk of retinopathy progression, in addition to its role as a diagnostic tool. She began by reviewing the methodology behind color fundus photography, fluorescein angiography, and optical coherence tomography for the room of primarily non-ophthalmologist healthcare professionals. She also reviewed the current Early Treatment Diabetic Retinopathy Study’s (ETDRS) recommended standard protocol for color fundus photography, which involves capturing seven images of the eye, for a total ~90 degree view of the retina or about 30% of the entire surface. However, new ultra wide field imaging technology now produces images showing 200 degrees of the retina, or about 82% of the retinal surface. Dr. Sun emphasized the significance of this difference and suggested that, in about 10% of eyes, imaging of peripheral lesions might have indicated more severe retinopathy than results from traditional imaging. She then provided compelling evidence that imaging peripheral lesions may give a better indicator of risk than the traditional method. In a four-year study, 35% of eyes with predominantly peripheral lesions had diabetic retinopathy that worsened by two steps or more while only 11% of those without predominantly peripheral lesions did the same.
Rishi Singh, MD (Cleveland Clinic, Cleveland, OH)
Dr. Rishi Singh reviewed the availability of treatment options for retinopathy, incorporating a historical perspective into the approaches to this debilitating complication. Most notably, Dr. Singh presented findings from studies on the comparative efficacies of three different anti-VEGF drugs towards improving visual acuity. In the overall cohort, the study found that there were significant differences in the drugs aflibercept, bevacizumab, and ranibizumab in improving mean acuity letter score (n=660, aflibercept>bevacizumab (p<0.001), aflibercept>ranibizumab (p=0.03). In groups with a baseline visual acuity of 20/50 or worse, aflibercept showed a significantly greater improvement in mean change of visual acuity letter score. Despite concerns of safety risks such as infection, Dr. Singh expressed that infection rates were remarkably low, and continuing best practices will lower these rates even more. In sum, Dr. Singh expressed that anti-VEGF agents are the most effective approaches to improving retinopathy as well as visual acuity.
Questions and Answers
Q: What is the optimal dose of fenofibrate? Why would you choose fenofibrate over TZD?
Dr. Kashyap: Most of the studies have looked at 160 mg. I would say 160 mg is sufficient. With TZDs, you see an increase in macular edema. Fibrates are favorable and protective but there are other options to lower TGs and improve glucose control.
Q: Do you use much ultra-wide fields today? Do you need that?
Dr. Sun: I do use ultrawide field imaging in my clinic. At this point in time, standard use of ultrawide field imaging is not yet the evidence-based standard of care, since only preliminary, single center studies are available. Nonetheless, at Joslin we have transitioned to using ultra-wide fields because you can evaluate the retinal periphery so much more effectively. The high costs of these instruments may be prohibitive for some clinics, but hopefully the technology will continue to become more affordable and available over time.
Q: Is there a dose for these anti-VEGF antibodies? Do you struggle over giving more than is necessary?
Dr. Singh: I’ve had situations where we’ve given higher doses for some patients. The challenge with this disease range is not the same. There’s lots of variability and so we choose the dose that we think is most effective for all patients.
Q: You alluded that retinopathy is more difficult to detect. What makes the eye so different?
Dr. Kashyap: Vascular disease is not all the same. This is the same issue with heart disease and peripheral vascular disease. Patients who don’t even know they have diabetes experience neuropathy, and the same is true of retinopathy.
Q: How do you dilate the eye remotely for telemedicine? Do you need to?
Dr. Sun: You don’t necessarily have to dilate the eye for telemedicine initiatives. The technology of fundus cameras has become so much better. Now, many cameras including the ultrawide field cameras have the ability to take a good quality retinal photo through an undilated pupil very rapidly. We use this technology in the Joslin Vision Network, the telemedicine arm of the Joslin clinic.
Q: Are there any indications to limit anticoagulation therapy in favor of treating retinopathy?
Dr. Sun: You shouldn’t limit anticoagulation therapy for patients who need it for other reasons. Pick the heart over the eye.
-- by Melissa An, Samiul Haque, Varun Iyengar, Stephanie Kahn, Lisa Rotenstein, Sarah Odeh, Mallika Tamboli, Jenny Tan, Manu Venkat, Maxwell Votey, and Kelly Close