June 13-17, 2014; San Francisco, CA – Cardiovascular Disease and Other Diabetes Complications – Draft

Executive Highlights

ADA 2014 featured several sessions on cardiovascular disease and the various other complications associated with diabetes. As in other years, the needle has unfortunately not seemed to move much on the complications front.

Cardiovascular disease (CVD) and the CV effects of diabetes drugs continue to receive significant attention. This was the first ADA following the release of data from SAVOR and EXAMINE, the FDA-mandated cardiovascular outcomes trials (CVOTs) for the DPP-4 inhibitors Onglyza (AZ) and Nesina (Takeda), respectively – you can find our coverage of presentations related to these trials in the ADA 2014 Incretins report. Also notably on CVD, a presentation during the ADA President’s Oral Session provided evidence that LDL cholesterol may not be a good marker of CV risk in people with type 1 diabetes, underscoring the differences in pathogenesis of CV complications for people with type 1 vs. type 2 diabetes – this was fascinating. ADA 2014 reprised discussions on several important CV topics including the legacy effect and metabolic memory effect from UKPDS and DCCT/EDIC, a debate between Dr. Jay Skyler (University of Miami Miller School of Medicine, Miami, FL) and Dr. Michael Farkouh (University of Toronto, Toronto, Canada) over whether A1c control improves CV outcomes, and a Professional Interest Group session with Dr. Irl Hirsch (University of Washington, Seattle, WA) and Dr. Richard Bergenstal (International Diabetes Center, Minneapolis, MN) on the relationship between glycemic variability and complications. Truly we are incredibly moved by how many important researchers are thinking about complications – we are increasingly moved by how much could change if the needle moved just a little (lower costs, higher quality of life, happier HCPs feeling more successful).

Several sessions were devoted to hypoglycemia, namely its impact on cardiovascular, cognitive, and, importantly, economic outcomes. Notably, Dr. Geremia Bolli (University of Perugia, Perugia, Italy) presented evidence on how hypoglycemic episodes may lead to acute cognitive impairment and dementia over time (worryingly, diabetes itself is associated with a 39% relative risk increase for Alzheimer’s disease). There was also an entire session dedicated to lessons learned from hypoglycemia in landmark trials (e.g., ACCORD and VADT) – while no new data were presented during this discussion, it emphasized the close relationship between hypoglycemia and adverse cardiovascular outcomes.

On the kidney front, Dr. Rajiv Agarwal (University of Indiana, Indianapolis, IN) provided some hope that new treatment options might soon come, reviewing three large phase 3/4 trials ongoing for AbbVie’s atrasentan, J&J’s Invokana, and BI/Lilly’s Tradjenta. We look forward to one or two ADA’s from now where we should see much more on this front. Renal expert, Dr. Katherine Tuttle (University of Washington, Spokane, WA) reviewed risk factors and treatment options for chronic kidney disease (CKD) – in doing so she cautioned against exercising too tight of glycemic or blood pressure control in someone with end-stage renal disease (ESRD) due to risks associated with hypoglycemia and hypotension. During ADA 2014 we also heard several speakers (including Dr. Andrezej Krolewski of the Joslin Diabetes Center during his notable Kelly West Award Lecture) emphasize that it is time to let go of microalbuminuria as a trustworthy marker of kidney function and find a more accurate biomarker for early progressive renal decline. Wow! We think in the meantime, however, it would be positive to increase education so that the average patient was aware of their microalbuminuria levels – most aren’t, currently, we are guessing.

On retinopathy, we saw one-year data from the phase 3 VISTA-DME and VIVID-DME trials for Bayer’s anti-VEGF agent, Eylea, as a treatment for diabetic macular edema compared to the standard of care, laser photocoagulation (355-OR). Eylea demonstrated an improvement of 12.3 letters in best-corrected visual acuity compared to just 1.1 letters with laser treatment after 52 weeks. That’s pretty striking. As Dr. Lloyd Aiello (Joslin Diabetes Center, Boston, MA) suggested in his update on the management of microvascular complications, anti-VEGF agents may soon become the primary line of treatment for diabetic macular edema.

There has been minimal movement in the development of painful diabetic neuropathy treatments. Dr. Roy Freeman’s (Beth Israel Deaconess Medical Center, Boston, MA) review of new and developing drugs for the treatment of neuropathic pain delineated the limited options available (most with limited efficacy), such as anti-convulsants, anti-depressants, topical gels, opioids, and transcutaneous electrical stimulation devices. He highlighted other classes under investigation, but most new options seem far off.

Below you’ll find detailed reports on all of these topics and more. Presentation titles highlighted in blue were not previously published in our daily highlight reports during ADA. We’ve highlighted in yellow presentations we found particularly notable.

Cardiovascular Disease and Other Diabetes Complications

Oral Presentations: ADA President’s Oral Session

LDL-cholesterol Is Not a Good Marker of Cardiovascular Risk in Type 1 Diabetes: Observational Study in 30,778 Patients—A Report from the National Diabetes Register in Sweden (381-OR)

Christel Hero, MD (Institute of Medicine, Gothenburg, Sweden)

Dr. Christel Hero presented results of a large registry study (n=30,778) looking at the predictive value of LDL-cholesterol in cardiovascular risk for people with type 1 diabetes. The studies show that LDL levels are, at best, a very weak predictor of cardiovascular disease in patients with type 1 diabetes, challenging the use of LDL as a marker for cardiovascular disease and stating there is “no support” for the treatment target of 100 mg/dl. In its place, Dr. Hero’s team proposes substituting the ratio of total cholesterol to HDL-cholesterol in considering primary prevention. In Q&A, Dr. Robert Eckel challenged the notion that the ratio of total cholesterol to HDL cholesterol would serve as a useful predictor of cardiovascular disease, but he congratulated the author on a study that furthers our understanding of atherosclerosis in type 1 diabetes.

• The study included 30,778 patients with type 1 diabetes. Records were drawn from the Swedish national diabetes registry, the hospital discharge register, and the cause of death register using each patient’s national ID number. Mean follow-up was seven years and outcomes included both fatal and non-fatal cardiovascular events.

Questions and Answers

Dr. Robert Eckel (University of Colorado, Aurora, CO): Just a comment, atherosclerosis in type 1 may be a whole different process. The fact that you found that LDL is not a great predictor is really not surprising. The other thing about using the ratio of total cholesterol to HDL cholesterol is that levels of HDL cholesterol have already been reported to be higher in type 1 diabetes. You may be including HDL that may not be as functional, it might be glycosylated or have other modifications. I still think this is an outstanding study just to support the concept that atherosclerosis in type 1 is not the same animal – it may be more fibrotic and it may be more calcified.

Q: When you talk about using lipid-lowering medications, were only statins used?

A: Because of the way medications are entered into the registry we cannot tell.

Q: For the subpopulation on lipid lowering treatment – do we know their LDL values before they were prescribed medication?

A: No, we do not.

Oral Presentations: Diabetes Complications – From Head to Toe

Cognition in the Diabetes Prevention Program Outcomes Study (DPPOS) (334-OR)

Jose Luchsinger, MD, MPH (Columbia University, New York, NY)

Dr. Jose Luchsinger presented 12- and 14-year follow-up data from the Diabetes Prevention Program Outcomes Study (DPPOS) and cognitive outcomes. He found that A1C was well correlated to a decline in cognitive performance – this reinforces other studies in this realm (see below). He declared metformin “safe” from a cognitive impact standpoint, highlighting that scores on a battery of cognitive assessments were nearly equal across treatment arms (as a reminder, the treatment arms were placebo, metformin, and lifestyle intervention). On the topic of diabetes care, cognitive function, and neurodegenerative disease, Diabetes just published a suite of new articles linking diabetes and Alzheimer’s disease. While it’s not the first time articles have linked diabetes and Alzheimer’s disease, these three papers did a particularly thoughtful job of assessing the literature: De Felice and Ferreira, 2014; Kleinridders, et al. 2014; Yarchoan and Arnold, 2014. It is an exciting prospect that existing diabetes drugs could possibly be positioned to affect a huge emerging problem in the world – one that could dwarf diabetes itself.

Oral Presentations: Diabetic Retinopathy – Targets and Treatments

Vision and Diabetic Retinopathy Severity Score (DRSS) Following Intravitreal Aflibercept Injection (IAI) in Diabetic Macular Edema (DME) Patients with Hemoglobin A1c (HbA1c) Levels ≤8% and >8% at Baseline (355-OR)

David Brown, MD (Retina Consultants of Houston, Houston, TX)

Dr. David Brown summarized the results of two phase 3 trials, VISTA-DME and VIVID-DME that evaluated the safety and efficacy of intravitreal aflibercept injection (Bayer’s anti-VEGF agent Eylea) to treat patients with diabetic macular edema at two different dose frequencies (2 mg every four weeks or every eight weeks following five initial monthly doses). Further analysis examined differential efficacy in patients stratified by A1c (≤8% and >8%). As expected, Eylea was far more effective than laser photocoagulation, yielding an improvement of +12.3 letters versus 1.1 letters in best-corrected visual acuity (BCVA) after 52 weeks. Less frequent treatments of Eylea yielded similarly drastic improvements of +10.9 letters, reinforcing the superiority of the therapy over laser. However, a greater degree of glycemic control yielded greater efficacy in the laser treatment, a property that IAI did not have. Eylea has been approved outside of the US for the treatment of wet age-related macular degeneration (wAMD) and DME; within the US it is only approved for wAMD and is under review for DME.

• Two similarly designed phase 3 trials, VISTA-DME and VIDID-DME, evaluated the efficacy and safety of Eylea for treatment of DME. These trials randomized 872 patients with DME to receive either Eylea 2 mg every four weeks (2q4), IAI 2 mg every eight weeks (2q8, following five initial monthly doses), or laser treatment. The primary efficacy endpoint was the mean change in best-corrected visual acuity (BCVA) from baseline at week 52. An exploratory analysis examined BCVA and DRSS in subgroups of DME patients with baseline A1c ≤8% and >8%.
• The mean change in BCVA from baseline to week 52 in the 2q4 and 2q8 groups versus the laser group was +12.3 and +10.9 versus. 1.1 letters, respectively (p<=0.0001). Eylea yielded similar improvements in visual acuity regardless of glycemic control, but good glycemic control yielded greater improvements in visual acuity for laser photocoagulation. Dr. Brown predicted that this difference may motivate patients with diabetes to achieve greater glycemic control, in an effort to avoid the discomfort associated with vitreal injections. Eylea also yielded similar improvements in BCVA across all baseline A1cs, and at lower dosages such as every eight weeks versus every four weeks.

Oral Presentations: Contemporary Issues in the Epidemiology of Diabetes

Hemoglobin Glycation Index Identifies Subpopulations with Harms or Benefits in the ACCORD Trial (166-OR)

James Hempe, PhD (Louisiana State University, New Orleans, LA)

To preface this post-hoc analysis of the ACCORD trial, Dr. James Hempe reminded us that different people have different relationships between A1c and mean blood glucose. When patients have a higher A1c than would be predicted based on mean blood glucose, they are said to have high hemoglobin glycation index (HGI); patients with lower-than-predicted A1c have low HGI. To investigate the importance of HGI in ACCORD, Dr. Hempe compared patients’ A1c to their fasting plasma glucose (a proxy for overall mean glucose). At baseline, the high-HGI group included more patients who had baseline retinopathy or nephropathy, who were African-American or Hispanic, and who were using insulin. Patients with high HGI seem to have driven the increased mortality in ACCORD’s intensive treatment arm. By contrast, in the low- and moderate-HGI groups, intensive therapy conferred statistically significant risk reduction in major adverse cardiovascular events, ACCORD’s primary outcome. All three HGI groups had increased risk of hypoglycemia requiring assistance when they received intensive treatment. Similar data on HGI have been seen in other trials, but during Q&A Dr. Hempe said he does not think that the metric is ready for clinical use. Indeed, some questioners suggested that this study’s results could have confounded by postprandial glucose, ethnic factors, and/or treatment-induced hypoglycemia. We believe had CGM been available during ACCORD, there may be much more known about the relationship between hypoglycemia and cardiovascular disease.  

Questions and Answers

Dr. Amanda Adler (Cambridge University, Cambridge, United Kingdom): To calculate mean blood glucose, you looked only at fasting glucose, not 24-hour values or seven-point profiles. Might the discrepancy between A1c and FPG simply be due to postprandial hyperglycemia?

A: I don’t think so, but possibly.

Comment: A national agency reviewed this topic in May 2011. There is concern by many that some performance metrics, by focusing on A1c, could result in more intensification of therapy in patients with high glycation. This might be time for a major policy reappraisal. 

Q: There may be a younger subgroup of patients responsible for the increase in mortality. This has been seen by a couple groups. Did you find any evidence of this younger, more vulnerable population in your analysis?

A: Age was lower in high-HGI group, but not by a lot.

Dr. John Yudkin (University College London, London, United Kingdom): We previously did some work on patients who had a high level of A1c as measured by four different assays, compared to ambient blood glucose over 24 hours. I share concern that your assay is based entirely on fasting. The HGI differences among different ethnicities suggest that other confounders might also be at work. Also – perhaps the harms in the HGI group is based on overtreatment and hypoglycemia. If you are intensifying treatment based on A1c, risk of hypoglycemia would be higher in the high glycators than the low glycators.

Q: Could you tell us whether there was a difference in glycemic variability among the three groups? 

A: We didn’t look at that.

Dr. Adler: Should I be calculating HGIs on my patients in clinic?

A: I don’t think so; I think it needs more work.

Oral Presentations: Emerging Issues in Diabetic Nephropathy – Risks, Mechanisms, and Outcomes

Clinical Outcomes of Diabetic Nephropathy in Patients with Type 1 Diabetes Attending the Steno and the Joslin (52-OR)

Peter Rossing, MD (Steno Diabetes Center, Gentofte, Denmark)

Dr. Peter Rossing described the importance of considering kidney problems in people with diabetes, as he suggested that an excess in mortality in people with type 1 diabetes is seen mainly in patients with advanced diabetic nephropathy. His presentation focused on a retrospective analysis of the relative success of treating diabetic nephropathy at two of the premier diabetes centers in the world, the Steno Diabetes Center in Denmark, and the Joslin Diabetes Center in Boston, MA. Notably, Dr. Rossing outlined the results of an analysis of kidney outcomes in groups of about 500 people with type 1 diabetes at each center exhibiting persistent proteinuria (a sign of renal impairment). The study showed a greater rate of development of end stage renal disease (ESRD) in the patient group receiving treatment at the Joslin Diabetes Center, while a greater rate of total mortality was observed in the group at Steno. The reasons for the differences in the development of ESRD and mortality across the two centers remain unknown. Dr. Rossing noted that it will be important to conduct more focused comparative studies to determine whether there is any significant difference in standard of care between the centers that might account for the increased rate of development of ESRD at Joslin or the increased total mortality rate at Steno. He also announced at the end of the presentation that the Joslin Diabetes Center and the Steno Diabetes Center planned to enter into broader, long term collaboration with the aim of sharing strategies to optimize care for people with diabetes at both centers, and with the hope of sharing any findings with other treatment centers around the world.

• The study was conducted retrospectively based on records from the Steno Diabetes Center from 1993 to 2008 and records from the Joslin Diabetes Center between 1991 and 2004. At baseline, the two study populations were very similar. The mean baseline A1c of patients in the study group from Joslin was 9.0%, while the mean baseline A1c of patients from the Steno Diabetes Center was 9.3%. The average duration of type 1 diabetes among the patient population at Joslin was 25 years, while that of the group at Steno was 27 years. Dr. Rossing was careful to note that there were more smokers included in the group treated at Steno than were reported in the group treated at Joslin – smokers have a higher cardiovascular risk than non-smokers. The average blood pressure in the group at Steno was slightly higher than that in the group at Joslin, while patients at Joslin tended to have slightly higher levels of albuminuria than those at Steno.
• The study considered a subset of people with type 1 diabetes treated at the Steno Diabetes Center and the Joslin Diabetes Center within the date ranges listed above. Only those younger than 40 years of age who had been treated with insulin for at least a year and who exhibited persistent proteinuria were included in the study. For the purposes of the study, individuals with at least two out of four consecutive urine samples showing at least 300 mg albumin over a 24-hour period were said to have persistent proteinuria.

Questions and Answers

Q: Since the smoking rate was observed to be much higher at Steno, is it possible that the high rate of smoking could be a major contributor to the increased mortality rate? Also, what were the criteria at each center for renal replacement therapy? Was the threshold in terms of glomerular filtration rate at the start of therapy higher at Joslin, and could this have contributed to the higher reported rate of ESRD? How were these clinical indications matched across the centers?

A: Two good points. We know that smoking is a risk factor for mortality, so that could certainly contribute to the increased mortality rate observed at Steno as compared with Joslin. In terms of the threshold for renal replacement therapy, this was based on the evaluation of nephrologists at each center, so there could be differences.

Q: Yesterday we heard from Joslin that improving glycemic control after a diagnosis of diabetic nephropathy might actually lower the probability of developing ESRD. Did you look at changes in A1c to see if this could explain any difference in the rate of decline in terms of diabetic nephropathy across the two centers?

A:  I think it is important for us to look at factors like A1c during follow-up and throughout the course of the study, not just at the baseline, but that can sometimes be difficult depending on the availability of this data for patients.

Q: In this study, you are essentially comparing prevalence of ESRD and mortality at Joslin and Steno. In order to accurately estimate prevalence you need huge numbers of people. How can you justify whether the results of the study have any real significance, and that they aren’t simply a statistical fluke?

A: I think this is a very relevant point. We need to do more a more sophisticated analysis including different risk factors and looking at factors that might explain the differences across the centers. To determine just how valuable these results might be we certainly need to do a more sophisticated analysis.

Q: Do you have data regarding differences in cardiovascular mortality in the general population in Denmark and the US? Do you think it might be possible that a general difference in the rate of cardiovascular mortality in these populations might explain the difference in mortality observed in this study as well?

A: We have not looked at that yet, but I do think it is a relevant point.

Symposium: Legacy Effect, Metabolic Memory, and Implications of Clinical Care

Evidence of Metabolic Memory from the DCCT and EDIC

John M. Lachin, ScD (The George Washington University, Rockville, MD)

The landmark DCCT, and its follow up trial, EDIC, have yielded some truly significant results – notably that intensive glucose lowering reduces the risk of microvascular complications. Differences in A1c between the treatment groups almost completely explained a major reduction in complications in the DCCT, which endured for decades of follow up – even though both groups had resolved to similar A1c levels just after the beginning of EDIC. This long term risk reduction gave rise to the ‘metabolic memory’ hypothesis, which posits that long term hyperglycemia leads to physiological changes that ultimately determine the risk of complications (note that this may not be glucose toxicity per se, and work is ongoing to figure out the mechanisms). Another interesting aspect of this work is that at the beginning of EDIC, the day-to-day incidence of complications was higher in the conventional group, but fell to the same level as the (former) intensive group after about eight years. After that, the two cumulative incidence curves were parallel, but of course the intensive group never caught up. So what is the moral of this presentation? In the highly respected Dr. Lachin’s words: “The sooner you start, the lower you keep the A1c, and the longer you do it, the lower the risk of long term complications”.

• The landmark DCCT trial took place from 1983-1993, after which 96% of surviving subjects were enrolled into the follow up EDIC trial (starting 1994), which is an ongoing long-term epidemiology study. DCCT enlisted ~1,400 type 1 patients with a mean age of 27 years that were randomly assigned to one of two treatment groups – conventional and intensive therapy. The intensive group was designed to achieve near normal glucose control and sustained an A1c difference of 1.5-2.0% over the nine years of the study. The participants were also stratified into two intervention groups depending on the progression of their diabetes – primary prevention (with no microvascular complications) and secondary intervention.
• After the first four years of the DCCT, there was no significant microvascular risk reduction with intensive therapy, but then the curves started to quickly diverge, leading to a dramatic risk reduction for complications. For example, there was a 54% reduction in retinopathy in the secondary intervention group. Likewise there was a significant risk reduction for micro- and macro-albuminuria as well as retinopathy.
• Additional work showed that the highest risk for complications was among those with the longest pre-existing duration of diabetes and the highest A1c, and that the differences in A1c explained virtually all of the treatment group effects. Other factors (such as insulin dose, BMI, smoking, lipids, diet etc.) don’t explain any of the effects, leaving A1c as the dominant factor. There was a 44% reduction in risk for each 10% reduction in A1c (e.g. going from 10% to 9%). An acute reduction in A1c didn’t have an immediate effect on risk, and interestingly, the effects of prior hyperglycemia were not immediately erased by the implementation of intensive therapy.
• After the first four years of the EDIC study, there was a 70% reduction in risk of further progression to retinopathy in those who had formerly been in the intensive therapy group. Any A1c differences between the two groups quickly disappeared at the beginning of EDIC. Even so, the ten-year EDIC follow up had a 53% lower risk in retinopathy for the intensive group. Other microvascular complications followed the same pattern. Again, over 90% of the treatment group differences can be attributed to A1c differences during the DCCT. Turning to cardiovascular risk, in 2005 it was revealed that there was a 42% reduction in the risk of any cardiovascular event and a 57% reduction in (more severe) MACE outcomes between the former intervention groups. Again, this was almost fully explained by the A1c difference during the DCCT, decades before.
• The differences in risk of complications seen in the DCCT and EDIC follow up are all a reflection of ‘metabolic memory’. The ‘metabolic memory hypothesis’ is that hyperglycemia leads to physiological changes that ultimately determine the risk of complications. Evidence for this hypothesis comes from the four-year time lag and the results of EDIC.
• Metabolic memory has two components – the continued public health benefit from earlier intensive therapy, and a diminishing difference between the two groups in the day-to-day incidence of progression. Dr. Lachin showed that there is a lasting reduction in cumulative incidence of progression (the public health benefit), but also that (day-to-day) incidence of progression was much higher in the conventional group in EDIC, but over an eight year period it fell to the level of the intensive group (which was stable throughout).
• The differences in risk are all reflections of metabolic memory. This is not necessarily a direct product of glucose toxicity per se, and work is going on explain the mechanisms that drive risks through long term exposure to glucose.

Questions and Answers

Q: What benefit is gained by initiating intensive therapy later?

A: Think of it like interest in the bank. If you take a person earning 7% interest on an annual sum and another earning 9% for nine years, and then you switch them over, is the person who earned the 7% first ever going to catch up with the person who earned 9%? The answer is no. The moral is: the sooner you start, the lower you keep the A1c, and the longer you do it, the lower the risk of long term complications.

Evidence of the Legacy Effect from the UKPDS

Mark Cooper, MBBS, PhD (Baker IDI Heart & Diabetes Institute, Melbourne, Australia)

Dr. Mark Cooper presented an engaging review of “the long and winding road” of the United Kingdom Prospective Diabetes Study (UKPDS), creatively structuring his talk based on the popular Beatles’ song with the same title. While the multi-center UKPDS RCT ended in September 1997, Dr. Cooper noted that the study and its results – namely the legacy effect of glycemic control on reducing microvascular and mortality risk 10 years after randomization – are still relevant. Acknowledging that the legacy effect slide has become a common conference sight, Dr. Cooper joked, “Some people find my talks boring, but this is the data and I can’t change it.” Thus he also provided interesting perspective on “metabolic karma,” explaining that the concept of “lead time” could explain the increase in the mortality endpoint during UKPDS. Essentially, poor initial glycemic control contributes to advanced stages in the natural history of disease progression – and thus an increase in mortality risk – despite later intervention. In this sense, the legacy effect is a double-edged sword, where not only does earlier glycemic control have long-term benefits, but the earlier poor control can have risks for years to come.

• The UKPDS legacy effect refers to the benefits on myocardial infarction and all-cause mortality that became statistically significant only after the 10-year follow-up period. Specifically, the intensively managed group (sulfonylurea + insulin) experienced a 15% reduction in MI risk and 13% reduction in all-cause mortality risk, despite the fact that treatment regimens and A1c values were equivalent between the intensive and control group during the post-trial follow-up period. Additionally, earlier glucose control provided relative risk reduction for microvascular disease (24%) and any diabetes related endpoint (9%). For more detailed background on the UKPDS study and legacy effect, see our coverage of lead researcher Dr. Rury Holman’s (Oxford University, Oxford, UK) presentation at the 2012 Global Diabetes Summit.
• Explaining “metabolic karma,” Dr. Cooper emphasized that poor glycemic control today will have long-term impacts, and this is “why short-term trials cannot erase decades of hyperglycemia.” In his opinion, this legacy effect or metabolic karma provides convincing rationale for early combination therapy. He also highlighted that transient glucose excursions including hyperglycemic variability, post-prandial hyperglycemia, and diabetic complications prior to diabetes could play a role in metabolic karma.
• Specific mechanisms of advanced glycation, oxidative stress, and epigenetic determinants could help explain the legacy effect. In animal models, advanced glycation has been linked to increased atherosclerosis, and Dr. Cooper noted that sustained atherosclerosis might alter the blood vessel environment, thus contributing to long-term negative consequences. Optimistically, recent data from reactive oxidation species has been shown to reduce albuminuria. Additionally, animal models have shown that persistent activation of pro-inflammatory genes is associated with increased microvascular risk. Notably, when activating NFkB and p65 in aortic endothelial cells in animal models, vessels undergo histone modification and gain histone 3 with a lys4 methylation. Unfortunately, Dr. Cooper added that most “epigenetic data has been disappointing,” though he hedged that since such studies are following later in the disease natural history, the window of opportunity to glean epigenetic significance might already be lost.
• In Dr. Cooper’s opinion, the UKPDS was also notable in that it was a “2x2 outcome study” measuring both A1c and blood pressure. The effect of blood pressure lowering alone or glucose lowering alone conferred a roughly 20% reduction in new or worsening nephropathy. The effects of blood pressure and glucose control were nearly additive such that the combination of both conferred a 33% reduction in new or worsening nephropathy compared to conventional glucose and conventional blood pressure treatment. Dr. Cooper inferred that this additive effect supports multifactorial intervention, i.e., combination therapy.

Questions and Answers

Q: In terms of the epigenetic mechanisms mentioned at the end, is there an attempt to use the UKPDS cohort to tease out such mechanisms?

A: I don’t know if they’ve done anything with the UKPDS cohort, but in the DCCT cohort, the role of advanced glycation and epigenetics have been explored. The epigenetic data has been disappointing. We’re following very far into the natural history of the disease so maybe we missed the window to look at epigenetics. There is also work from the Joslin Diabetes Center looking at the Medallion cohort looking at important epigenetic changes.

Q: Perhaps part of an alternative hypothesis might be that exposure to a risk factor is critically important to the mechanism for which target tissue expressed damage. So in atherosclerosis maybe there is a particular target window where glucose control is important and in other timeframes it is not. Similarly, there could be specific tissues for blood pressure or other risk factors. This so-called legacy or memory may simply be due to exposure to risks that happen at a particularly vulnerable time, not necessarily because of poor glycemic control overall.

A: I agree. The VADT study that suggests less reversibility would fit with what we think about the natural history of atherosclerosis. Once calcified, it’s much harder to have reversibility. It’s partly theoretical. Maybe certain cells or organs need different time spans to see reversibility or regression.

Q: If you shifted from the treat-to-fail strategy of UKPDS to a more modern direction of treat-to-target like in the ORIGIN trial, would that have an effect on legacy?

A: That’s a reasonable viewpoint, but ORIGIN isn’t impressive in terms of organ damage, so we can’t say that. However maybe newer studies with newer drugs might see differences. Looking at SAVOR and EXAMINE though, there is no major difference in glycemic control in those studies.

Symposium: ADA Diabetes Care Symposium – New Drug Therapies, Innovative Management Strategies, and Novel Drug Targets

Best of Diabetes Care 2013-2014 – Clinical Highlights – Microvascular Complications

Andrew Boulton, MD (University of Manchester, Manchester, United Kingdom)

Dr. Andrew Boulton presented three studies on the latest research highlights in microvascular complications of diabetes: one on nephropathy and two on neuropathy. Beginning strikingly with a picture of a blind diabetes patient on dialysis and with both legs amputated, he reminded us of the devastating impact of microvascular complications. He then described the first study, which concluded that the overall prognosis of established nephropathy has improved considerably (mortality was 42% lower in a recent cohort followed from 2000-2010 compared to a historic cohort followed from 1983-2002). The second study used magnetic resonance neuroimaging to investigate the differences between diabetes patients with and without neuropathy, demonstrating that peripheral gray matter loss in neuropathic patients occurs in regions involved with somatosensory perception. Finally, the third study concluded that antibiotics and conservative surgery as treatments for diabetic foot osteomyelitis (bone infection) produce similar outcomes in terms of healing rates, time to healing, and short term complications.

• The study on diabetic nephropathy compared a historical cohort of patients with type 2 diabetes and nephropathy to a more recent cohort. The more recent cohort (n=543) was followed from 2000-2010 for a median of 7.4 years and underwent RAS inhibition and cardiovascular risk factor intervention (Andresdottir et al., Diabetes Care 2014). The study found that the age-adjusted crude mortality rate decreased by 42% from the historic cohort, which was followed from 1983-2002 (Rossing et al., Kidney Int 2004). This is encouraging and perhaps not terribly surprising given that overall glycemic control has also greatly improved over the past three decades.
• The imaging study found that patients with both painful and painless peripheral nephropathy had less peripheral gray matter volume than the controls with and without diabetes. The study involved 36 healthy patients and 36 type 1 diabetes patients, including nine patients with painful diabetic peripheral neuropathy, nine with painless diabetic peripheral neuropathy, and 18 with diabetes but without peripheral neuropathy (Selvarajah et al., Diabetes Care 2014).
• In the diabetic foot osteomyelitis trial, primary healing was achieved in 75% of patients on antibiotics and 86% of patients who underwent surgery (p=0.336). The prospective, randomized, controlled trial took place at a single center and involved 37 patients with neuropathy and diabetic foot osteomyelitis. The antibiotic group took antibiotics for sixty days, while the surgery group underwent conservative surgery and postoperative antibiotics for ten days. Median time to healing was seven weeks for the antibiotics group and six weeks for the surgery group (Lazaro-Martinez et al., Diabetes Care 2014).

Best of Diabetes Care 2013-2014 – Diabetes and Cancer

Derek LeRoith, MD, PhD (Mount Sinai Medical Center, New York, NY)

Dr. Derek LeRoith shared results from a multitude of studies exploring the potential link between type 2 diabetes and various cancers, as well as those between common diabetes therapies and cancer. As has been well established by a large number of epidemiological studies, there is a positive association between diabetes and risk of various types of cancers, with the exception of prostate cancer in men with type 2 diabetes. Dr. LeRoith then shifted the focus to three recent studies from Diabetes Care. The first study by Li et al. found an increase in disease burden of cancer in patients with diabetes using insulin, with the burden increasing with number of years diagnosed. The second and third studies explored whether the most common treatments – metformin and insulin – were associated with these increases in the long term. The two studies, by Bordeleau et al. and Lega et al. found a neutral association between cancer and prolonged insulin and metformin use. However, Dr. LeRoith found these studies to be incomplete and expressed the need for further prospective studies of these therapies at higher dosages.

• Drawing from the hundreds of papers regarding cancer mortality in individuals with type 2 diabetes, there is a consensus that diabetes is positively associated with an increased risk of cancer at specific sites. Among these sites is the liver, where type 2 diabetes is associated with a 2.51 risk ratio in both men and women. Interestingly, there appears to be a decrease in risk ratio for prostate cancer in men (0.88 risk ratio). Dr. LeRoith hypothesized that hyperglycemia and other diabetic factors are involved in the androgen system. Despite the lower risk of prostate cancer onset, obese individuals with type 2 diabetes actually have an increased risk of mortality from prostate cancer.
• Dr. LeRoith shared the results from three recent studies published in Diabetes Care that examined associations with insulin, metformin, and cancer epidemiology.
  
  • The first study conducted by Li et al. mapped adjusted prevalence rates of cancer in men and women by duration of diagnosed diabetes in people using insulin. For both men and women, there was a linear trend between duration of diabetes diagnosis and prevalence of cancer (p<0.0001). The rates of cancer ranged, in men, from 2.4% for 5-9 years after diagnosis to 3.1% for ≥15 years, and, in women, 1.8% to 2.8% for the same respective age categories. The results suggest an increased burden of diagnosed cancer with increased duration of diabetes patients with type 2 diabetes using insulin. This result led to the question of whether there is an increased risk of cancer with more anti-diabetic medication, or whether the increased burden is what naturally occurs after the onset of diabetes.
  • The second and third key studies found a neutral association of insulin therapies, omega-3 fatty acids, and metformin with various metrics of cancer risk. Bordeleau et al. used data from the ORIGIN trial to explore cancer outcomes in patients on a combination of glargine insulin and omega-3 supplementation versus placebo. After a 6-year follow-up the researchers determined that glargine and omega-3 fatty acids have a neutral association with overall cancer outcomes, but did not delve further into higher dosages for either comparator (n=12,537). In addition, a third key study by Lega et al. found a neutral association between prolonged metformin use and overall morbidity in elderly patients with and without breast cancer.

Symposium: Hypoglycemia and Cardiovascular Disease- Lessons from Outcome Studies (Supported by an unrestricted educational grant from Merck)

Evidence from ACCORD

Mark Feinglos, MD (Duke University, Durham, NC)

 Dr. Mark Feinglos discussed the implications of controversial evidence from the ACCORD trial regarding the risks and benefits of intensive glycemic control in people with diabetes. The ACCORD trial had been designed to test the impact of glycemic control, blood pressure, and levels of blood lipids and lipoproteins on the risk of cardiovascular disease in people with type 2 diabetes at high CV risk. The glycemic control arm of ACCORD compared CV outcomes across two groups - those on an intensive glycemic control program with a target A1c of 6%, and those on a more standard program with a target A1c between 7.0-7.5%. In both arms, the median baseline A1c was 8.1%. The intensive glycemic control group in the ACCORD trial was terminated early, after 3.7 years, as a result of a statistically significant (p <0.05) increase in all-cause mortality as compared to the standard group. Despite the increase in all-cause mortality, there was no appreciable difference in the composite CV outcomes across the two groups, a figure that takes into account the first instance of nonfatal myocardial infarction (MI,) nonfatal stroke, or cardiovascular death in individuals involved in the trial. Dr. Feinglos argued that the increase in all-cause mortality may not have resulted directly from hypoglycemia, or from intensive glycemic control over the long term in individuals with type 2 diabetes. If no solid causal relationship between tight glycemic control and an increase in all-cause mortality can be drawn based on the results of the ACCORD trial, it becomes easier to argue in favor of intensive glycemic control in individuals with type 2 diabetes as a net positive based on improved microvascular outcomes, including a decreased risk for blindness, renal failure, and amputation in people with type 2 diabetes. For a more detailed discussion of the pros and cons of intensive A1c control in people with type 2 diabetes, see our coverage of the debate between Dr. Jay Skyler (University of Miami, Florida,) and Dr. Michael Farkouh (University of Toronto, Ontario) that took place on day two of ADA 2014.

• Dr. Feinglos raised several points that suggested a lack of causality between tight glycemic control and the increase in all-cause mortality. He acknowledged that those in the intensive control group experienced hypoglycemic events with greater frequency and severity than those in the standard control group. Dr. Feinglos also noted that severe hypoglycemia has been linked with an increased rate of mortality in those who are elderly and have other risk factors. However, he suggested that there was no evidence to implicate hypoglycemia as a proximate cause of death in the ACCORD trial, saying: “there is no evidence that people died specifically because of hypoglycemia”. Of the 431 deaths in the ACCORD trial with sufficient information available to adjudicate for hypoglycemia, it was determined that hypoglycemia did not contribute to death in 389 cases, that hypoglycemia was a possible contributor to death in 38 cases, a probable cause in three deaths, and the definite cause of death in only one instance. Dr. Feinglos also highlighted data that showed that while the mortality rate in the intensive control group was higher than that in the standard control group among those who had never experienced a severe hypoglycemic event, the reverse was true among those who had experienced at least one severe hypoglycemic event requiring medical assistance. He concluded that, while deliberately induced hypoglycemia is never recommended, repetitive hypoglycemia may provide some protection from cardiovascular death in those with type 2 diabetes.

Evidence from VADT

Dr. Stephen Davis, MD, (University of Maryland, College Park, MD) and Dr. Peter Reaven, MD (University of Arizona, Scottsdale, AZ)

Presenting in tandem, Dr. Stephen Davis and Dr. Peter Reaven discussed data from the Veterans Affairs Diabetes Trial (VADT) focusing on the incidence of severe hypoglycemia among the study’s participants. As a reminder, the VADT concluded in 2008 and looked at the effect of intensive glycemic control on cardiovascular death (CVD) and mortality in patients with type 2 diabetes (please read our coverage from ADA 2009 here). Dr. Davis began the presentation with a review of outcomes associated with hypoglycemia in VADT. In the trial, the intensive treatment arm achieved a 6.9% A1c compared to 8.4% in the standard treatment arm and experienced significantly more hypoglycemia. Patients were quite old (mean age of 62 years at baseline) with advanced diabetes (9.4% baseline A1c; 40% had a history of macrovascular complications and 72% had a history of hypertension). In the trial, severe hypoglycemia was significantly associated with increased rates of cardiovascular disease, cardiovascular death, and all-cause mortality, underscoring the need for better hypoglycemia prevention. Dr. Reaven then took the stage to present a post hoc analysis of the VADT looking at the relationship between race and hypoglycemic events. Interestingly, patients identified as Hispanic had the lowest cardiovascular risk between 0.6-0.75 compared to black and white non-Hispanics.

• Dr. Davis began his talk by analyzing the relationship between severe hypoglycemia, defined as a loss of consciousness requiring assistance from another person, and adverse events. Of the 1,791 veterans followed by this study, the majority of participants in both arms experienced hypoglycemia to some degree (with 90% in the intensive arm and 80% in the standard arm). Ultimately, cases of severe hypoglycemia among patients receiving intensive treatment occurred at a rate 3.5 times greater than those on standard therapy, and the incidence of severe hypoglycemia increased before a primary event, cardiovascular death, or mortality.
• Dr. Davis outlined several patient characteristics associated with greater risk of hypoglycemia in VADT: the strongest predictors for incidence of hypoglycemia were age, duration of disease, low C-peptide and insulin at baseline, being in the intensive treatment arm, history of hypoglycemia, A1c, creatinine, and prior cardiovascular events. Low BMI also predicted higher risk of hypoglycemia. Age was a much stronger factor in the intensive therapy group, and history of hypoglycemia was not as important. Rates were highest in people with a diabetes duration of 13-15 years. Higher rates of hypoglycemia were more common in people with low A1cs in the intensive treatment arm, but not in the conventional treatment arm.
• Patients with severe hypoglycemia had about a two-fold increased risk of having a primary cardiovascular event in both treatment groups. The relative risk for death after a cardiovascular event in those who had had severe hypoglycemia was greater in the standard group, but not in the intensive group. The risk of death from any cause was higher in those who had had severe hypoglycemia in both groups.
• Following Dr. Davis’s review of the study’s results, Dr. Reaven presented a post hoc analysis of the VADT looking at the relationship between race and hypoglycemic events. Patients were divided into three groups based upon broad racial categories—white non-Hispanic, black non-Hispanic, and Hispanic—and then compared in relation to the incidence of hypoglycemia. While all three groups displayed similar patterns of hypoglycemia with intensive treatment, there were slight differences in the outcomes assessed. Most notably, participants among the black non-Hispanic and Hispanic cohorts had a lower incidence of hypoglycemia than white non-Hispanic patients even when adjusting for baseline. Patients identified as Hispanic also had the lowest cardiovascular risk between 0.6-0.75 compared to black and white non-Hispanics; Dr. Reaven posited that this might result from the decreased prevalence of atherosclerosis among Hispanic patients, which produces higher vascular calcium and better glycemic response to treatment. Still, these findings need to be confirmed and did not include female participants.

Symposium: Consequences/Impact of Hypoglycemia (Supported by an unrestricted educational grant from Merck)

How Hypoglycemia Kills

Christian Meyer, MD (Translational Research Institute for Metabolism and Diabetes, Orlando, FL)

Dr. Christian Meyer called on results from recent high profile trials in diabetes, including ORIGIN, VADT, ACCORD, and ADVANCE, in order to highlight a correlation between hypoglycemic events and an increased risk of mortality. Over the course of his presentation, Dr. Meyer outlined three possible physiological mechanisms that could support the idea of a causal relationship between higher rates of severe hypoglycemia and an increase in all-cause mortality. He began by noting that symptoms of hypoglycemia can contribute to an increased rate of motor vehicle accidents, and that extremely low blood sugar can lead to convulsions, coma, and death. Dr. Meyer also highlighted several effects of hypoglycemia on the circulatory system that could account for an increase in cardiovascular events and all-cause mortality. He stated that both hypoglycemia and resultant hyperinsulinemia could account for a decrease in baroreflex (blood pressure regulating) sensitivity and an increase in cardiac arrhythmia, both of which might contribute to increased mortality. Finally, Dr. Meyer presented data that suggested that hypoglycemia might lead to capillary closure thrombosis and atherogenesis (formation of atherosclerosis in the arteries), both of which would place more stress on the heart by increasing resistance to blood flow through the vasculature, resulting in an increase in cardiovascular events and overall mortality.

• Dr. Meyer highlighted a correlation between hypoglycemic events and a decreased rate of repolarization in the myocardium, as well as decreased sensitivity of the baroreflex. He suggested that in rats, the rate of repolarization of the myocardium is prolonged during episodes of severe hypoglycemia. This prolonged repolarization period is associated with an increased rate of arrhythmias, including premature atrial and ventral complexes. The sensitivity of the baroreflex determines how well the heart is able to sense changes in blood pressure, and Dr. Meyer noted that decreased sensitivity of the baroreflex is a well-established predictor of mortality.

Questions and Answers

Q: On the last slide, you mentioned instances of coma leading to death. In this study, we looked at rats undergoing severe hypoglycemia, and all of them went into a coma. Most of the rats survived, and in those that died we have evidence that they ended up having arrhythmia, which was the real cause of death. I don’t think that the coma itself led to death in these rats. I would propose instead that it was actually arrhythmia that led to death in those cases.

A: Thank you.

Q: How many episodes of hypoglycemia does one need to have before we can expect significant complications, like atherosclerosis and mortality? Can we say assuredly that a couple of episodes can make a person more likely to experience either of these complications?

A: In this presentation, I aimed to point out some potential causes of mortality as a result of hypoglycemia. At this point, no one really knows how many hypoglycemic episodes might be necessary to increase risk of complications, or whether hypoglycemia truly contributes to an increase in mortality. We know that there are changes in coagulation, and whether this ultimately contributes to mortality remains to be seen.

Q: You pointed out a number of mechanisms and a major concern and question that comes up repeatedly is whether mild or moderate hypoglycemia has an adverse or a beneficial impact on the risk for mortality. Can you tell us what your view is regarding moderate hypoglycemia as potentially contributing to some sort of ischemic preconditioning? If this is the case, how can it contribute to mortality at the same time, and how might we determine which effect predominates?

A: This is a great question. In principal I think most would agree that antecedent hypoglycemia is not a good thing. Whether or not it prevents some of the complications of subsequent hypoglycemic episodes is a valid question. There are several potential reasons this might occur, including the idea that people who have experienced a serious hypoglycemic event before might behave differently, or have a better idea of what to do when they find themselves in that situation. There might also be some decrease in the counter regulatory response to hypoglycemia in those that have experienced it before, such that subsequent hypoglycemic episodes have a lower risk of mortality. At this point we don’t have an answer for this question.

Q: Did you encounter any data on the relationship between the duration of hypoglycemic events and the risk of death?

A: I don’t think we have an answer to this; we would need to take advantage of continuous glucose monitors (CGM) for that type of study. Good question.

Comment: Of course, hypoglycemia is a risk condition for cardiovascular disease and mortality for the reasons that you have presented. However, you must realize that there is some controversy regarding the interpretation of these data. One might reasonably suggest that people do not die because of hypoglycemia, but that an increased frequency of serious hypoglycemic events could be an indicator that someone is going to die. Hypoglycemia could be a result of frailty, underlying disease, or some other weakness which leads to hypoglycemia which is the associated with an increase in cardiovascular events and mortality.

A: I totally agree with that, these are just associations; we can’t pretend to have any evidence for causality. There may well be other factors contributing both to mortality and hypoglycemic events, such that hypoglycemia is not a cause of mortality, but simply associated with it. \

Hypoglycemia, Cognitive Impairment, and Dementia

Geremia Bolli, MD (University of Perugia, Perugia, Italy)

Dr. Geremia Bolli presented evidence on how hypoglycemic episodes may lead to acute cognitive impairment, and possibly chronic cognitive impairment and dementia over time as well. Diabetes itself is associated with a 47% increased relative risk for all dementia, a 39% relative risk increase for Alzheimer’s disease, and a 138% relative risk increase for vascular dementia. Young children and the elderly are more susceptible to hypoglycemia, and thus more susceptible to the chronic impairment of cognitive function as a result. The association is bidirectional, as results from the ACCORD-MIND study determined that dementia also increases the risk of hypoglycemia, especially in older patients. Dr. Bolli concluded with an appeal for established strategies to prevent hypoglycemia in children, adults, and the elderly. Prevention of hypoglycemia may help prevent long-term impairment in cognitive function, especially in children and elderly populations.

• Children and the elderly are at higher risk of chronic cognitive impairment from hypoglycemia. A study of cognitive function in patients with type 1 diabetes with early exposure to severe hypoglycemia found that over 16 years of follow-up from early childhood, patients that experienced episodes of severe hypoglycemia had significantly reduced problem solving, verbal function, and psychomotor efficiency in comparison to a cohort with no exposure to episodes of severe hypoglycemia (p<0.001). In a study of older adults with a mean age of 62 living with diabetes for an average of 9.9 years, a longer duration of diabetes and higher fasting plasma glucose levels were associated with lower grey matter volumes in the brain (n=614, p<0.01). In addition, fasting plasma glucose levels were inversely correlated with the volume of ischemic lesions in the brain (p<0.04).

Symposium: Diabetic Kidney Disease – What’s in the Current and Future Toolbox?

Future Tools – Promising New Therapies for Diabetic Kidney Disease

Rajiv Agarwal, MD (Indiana University, Indianapolis, IN)

Dr. Agarwal opened by grimly noting that during the 30 minutes of his presentation, 1,000 people in the world on dialysis would die. He painted the current state of diabetic nephropathy treatment as dark and bleak, but with a glimmer of hope on the horizon with the current treatments in development. Indeed, there are three major phase 3 or 4 trials for promising compounds: endothelin receptor antagonists (AbbVie’s atrasentan), SGLT-2 inhibitors (J&J’s Invokana [canagliflozin]), and DPP-4 inhibitors (BI/Lilly’s Tradjenta [linagliptin]). Dr. Agarwal provided his pro/con assessment of each of these compounds and studies. Dr. Agarwal closed with cautious optimism, nostalgically hoping that some abandoned therapies might be resurrected – he did not mention Reata’s much-hoped for bardoxolone methyl, and although if there is indeed any hope on that front, we would also still be holding out for it, we understand that data was uniformly troubling from a safety perspective and hope that we can get out soon.

• With regards to AbbVie’s endothelin-A receptor antagonist, atrasentan’s pros and cons: atrasentan has had promising phase 2 results (~35% reduction in albuminuria after 12 weeks in the RADAR program) but may have a limited scope of applicability because the phase 3 SONAR trial will exclude patients with heart failure. We note, though that in phase 2, the reduction in albuminuria on atrasentan did not translate into an improvement in GFR.
• Dr. Agarwal referred to the SGLT-2 inhibitor Invokana as “a diuretic with brakes” since its effect on improving albuminuria (by about 30-35% based on post-hoc analyses of phase 3 data) is also accompanied by a slight deterioration in GFR. Dr. Agarwal believes the mechanism has a strong pathophysiological basis (in reducing intraglomerular pressure) and excellent safety, but that it may not work well in the later stages of kidney disease and that the risk of genitourinary infections may be more pronounced in patients with CKD due to their immunosuppressed state (we’ll have to wait for results from J&J’s CREDENCE renal outcomes trial).
• Finally, BI/Lilly’s DPP-4 inhibitor Tradjenta is being studied in the CARMELINA cardiovascular outcomes trial with renal outcomes as a secondary endpoint. Again, post-hoc phase 3 analyses have shown nearly 30 mg/g reductions in urinary albumin to creatinine ratio (UACR), but a major con is that DPP-4 inhibitors have a negative interaction with ACE inhibitors, a class of blood pressure lowering drugs that is commonly used by many people with diabetes.
• Several other pathways are being studied in earlier-phase trials, including CCR2 receptor antagonism (BMS and Pfizer have compounds in this area), Jak1/Jak2 inhibition (Lilly), TGF-beta antagonism (Lilly), NADPH oxidase inhibition, mineralocorticoid receptor antagonism (Bayer Pharma), and NHE3 inhibition.

Current and Future Tools – Putting It All Together for Diabetic Kidney Disease Risk Stratification

Katherine Tuttle, MD (University of Washington, Spokane, WA)

Dr. Katherine Tuttle reviewed risk factors for chronic kidney disease (CKD) and approaches to treating CKD. Dr. Tuttle demonstrated that hyperglycemia and hypertension contribute to CKD risk but also explained that intensive glycemic and blood pressure control have minimal and sometimes negative effects on CKD risk. Moving onto more environmental risk factors, Dr. Tuttle highlighted that obesity increases risk of CKD, stressing the importance of weight management. She also showed data on how popular “high protein-low carb” fad diets actually have negative impacts on the kidney, increasing risk of CKD. Additionally, she pointed out that smoking, adverse prenatal exposures, and periodontal disease also increased risk for CKD.

• For people with end stage renal disease (ESRD, the severest form of renal failure), Dr. Tuttle stated that intensive glycemic control compared to conventional glycemic control has minimal effects and, in fact, may actually be harmful due to increased hypoglycemia risk. Examining the relationship between death risk and glycemia for people with diabetes and CKD, Dr. Tuttle found that the “sweet spot” lies between A1c levels 7-8%, at which mortality rates are the lowest. She explained that many years are required before reduced risks are evident with intensive glycemic control.
• Dr. Tuttle dispelled the myth of treating hypertension in CKD with ACE inhibitors, ARBs, and dual RAS blockade. Showing results from the RASS and DIRECT studies, she showed that there were no benefits in terms of renal structural endpoints, GFR, or albuminuria with these agents, which are considered the standard of care for CKD. Similarly, intensive blood pressure control of systolic blood pressure levels between 120 and 140 mmHg led to higher risks of hypotension, syncope, and decreased GFR. On the other hand, this intensive blood pressure control did lead to lower risk of stroke and macroalbuminuria. Dr. Tuttle mentioned how guidelines on blood pressure have become more conservative and thus slightly higher.
• Obesity is a major contributor to the development of CKD, with the 34% of CKD in women and 24% in men attributable to obesity. The risk of elevated cystatin C also increases progressively with BMI. Dr. Tuttle stated how histological abnormalities are common in obese patients and that weight loss improved CKD risk factors such as hyperglycemia and hypertension as well as reduced albuminuria. However, these benefits were less clear in people who are overweight rather than obese.
• Showing results of various mechanistic studies, Dr. Tuttle explained how “high protein” diets increase CKD risk. These diets have been shown to lead to glomerular hyperfiltration and hypertension, RAS activation, as well as formation and activation of AGE/RAGE. Conversely, meta-analyses of “low protein” diets demonstrated that such diets helped prevent ESRD and death in people with type 1 diabetes and CKD. Likewise, another study found that those who follow vegetarian diets have a greatly reduced renal risk compared to non-vegetarian diets. From this data, Dr. Tuttle suggested that the source of dietary protein may be a solution to the CKD dilemma.
• Additionally, Dr. Tuttle showed that smoking significantly increases risk of CKD, particularly in people with diabetes. In terms of prenatal exposures, having a mother with type 2 diabetes increases risk of CKD and ESRD. Higher frequency of albuminuria is also associated with especially low and high birth weights. Another significant environmental risk factor is periodontal disease, of which moderate to severe levels increases risk of albuminuria by 2 to 3 fold.

Questions and Answers

Q: I agree that we’re not making much progress on this. But what do you expect when we treat the disease late with imperfect markers and such heterogeneity of risk within the group? There is a familial component to diabetic nephropathy. So somehow we need to identify patients early and use aggressive treatment when warranted. Now we’re treating everyone with retrospective and imperfect markers.

A: If we are able to risk profile people earlier, then we can leave the people who can do well alone and focus our efforts on those who need more intensive management.

Symposium: Gastrointestinal Regulation of Metabolism and Cardiovascular Disease Risk

Gastrointestinal Flora-dependent Nutrient Metabolism and Cardiovascular Disease

W.H. Wilson Tang, MD (Cleveland Clinic, Cleveland, OH)

Dr. W.H. Wilson Tang presented on a novel topic of study for the pathogenesis of cardiovascular disease – the composition of gastrointestinal flora and its metabolites. In both mouse and human studies, increased plasma trimethylamine N-oxide (TMAO) levels have been associated with an increase in risk of cardiovascular disease (p<0.001). Dr. Tang concluded that intestinal microbiota are responsible for TMAO production, and that increased plasma TMAO was associated with an increase in risk of cardiovascular events. Currently, there are no known genetic determinants of TMAO levels in humans, so he indicated there was much room for further investigation on whether genetics play a role in susceptibility to TMAO-linked cardiovascular events.

• Mouse studies have shown a relationship between three metabolites of the common dietary lipid phosphatidylcholine (specifically choline, trimethylamine N-oxide [TMAO], and betaine) with risk of cardiovascular disease (Wang et al.). These three metabolites of phosphatidylcholine were found to be produced by gut microbes, as germ-free mice with no gut microbiota did not produce the three metabolites prior to exposure to the wild. This conclusion was supported by the cessation of metabolite production when wild-type mice were induced with antibiotics to suppress gut microbiota. Experimentally increasing plasma levels of choline, TMAO, and betaine were all associated with an increase in odds ratio for cardiovascular disease (p<0.001 for all).
• A related study conducted by Tang et al. translated these results in human trials, and similarly found increased plasma levels of TMAO were associated with an increased risk of major cardiovascular events (p<0.001). The study evaluated 4007 patients undergoing elective coronary angiography over 3 years of follow-up, and quantified plasma and urinary TMAO, plasma choline, and plasma betaine in these patients. During the study period, a subgroup of patients were subjected to intestinal microbiota suppression by administration of broad-spectrum antibiotics, and similarly to the mouse trials, were found to have significantly reduced plasma TMAO during the administration period. Dr. Tang hypothesized that supplementation of certain foods leads to increases in TMAO production by gut microbiota, which would subsequently lead to the downstream increase in plasma TMAO.

Questions and Answers

Q: Do changes in microbiota in obesity lead to increased TMAO production?

A: The real question should be what the microbial compositions associated with different microbiota disease states may be. I think some of them do [lead to increased TMAO production] – the problem that we face is that there is actually quite a wide range of microbiota. What most people have tried to look at is the enzymes produced by different species. There are many types and this is something that needs to be explored.

Q: Were the cardiovascular risk outcomes adjusted for typical covariants – glucose, LDL, HDL, BMI and so forth?

A: Yes. they were adjusted for all covariant factors.

Symposium: Diabetic Dyslipidemia — New Insights and Emerging Therapies

Recent Safety Concerns of Statin Therapy – Fact or Fiction?

Rob Hegele, MD (University of Western Ontario, London, Canada)

Due to a last minute family emergency, a colleague of Dr. Rob Hegele’s presented his slide deck in the last presentation of the diabetic dyslipidemia symposium. While we were unable to catch his name, he represented Dr. Hegele well, adding his own clinical experience to lend a more personal nature to the presentation. As promised by the title of the talk, the potential side effects of statins were divided into three categories: proven not to be side effects (fiction), side effects that require further study, and side effects that consistently appear in patients on statins (fact). In the category of fact, he focused largely on myopathy but towards the end, and in Q&A, delved into statin’s ever so slight blood glucose elevating effect. He argued that while we cannot ignore the increase in blood glucose, it is very small and heavily outweighed by the cardiovascular and mortality benefits that accompany statins. For example, treatment of 255 patients with statins will only add 1 case of diabetes while preventing 5.4 vascular events. It was terrific to hear the specific data on this.

• Some potential safety concerns have been proven to be fiction. Dr. Hegele’s colleague stated that the risk of cancer as a result of statin use has been very well studied, and statins have been shown to have no effect on cancer. Statin use is also associated with a small increase in transaminase levels, but not high enough to be clinically significant – supported by the fact that screening for liver function has become less popular.
• On some safety concerns, the jury is still out. The presenter said that discerning any neuropsychiatric effects of statins is “a tough one”. There has been no firm proof, but animal studies suggest that there are some effects. Another concern is memory loss – according to the FDA, some individuals suffer from noticeable but ill-defined memory loss that can be reversed on discontinuation.
• Myopathy is the biggest barrier to statin use. The speaker emphasized that myopathy (including night cramps and muscle weakness) is far and away the most common side effect he sees as a result of statin treatment.
• Statins cause a small elevation in blood glucose and may modestly hasten the onset of diabetes in populations already predisposed.  Several trials have consistently shown that statin use is correlated with a modest increase in blood glucose.  Still, cardiovascular and mortality benefits are considered to far exceed the risk of triggering type 2 diabetes. According to the speaker, the treatment of 255 patients with statins will only add 1 case of diabetes while preventing 5.4 vascular events.

Questions and Answers

Q: Have you treated patients who experienced neuropathy and nerve pain while on a statin?

A: There have been some papers on that. I would put this in the category of side effects on which the jury is still out.  We don’t quite know what to make of this and it has not been reproduced.  In the clinic, I have not personally seen it. There may have been one or two cases, but taking them off the statin did not help.

Q: What type of risk is posed for patients with prediabetes with anA1c of 5.7% to 6.45%?

A: There are many drugs we used where you actually see a marked increase in blood glucose. We never see changes in glucose with statins – that is why the JUPITER trial took us by surprise. I have many patients with impaired glucose tolerance, prediabetes, but I never see an adverse effect from statins. It would be hard to tell what role, if any, they are playing as a patient progresses over the years.

Symposium: Update on the Assessment and Management of Microvascular Complications for the Practicing Clinician

Update on the Assessment and Management of Microvascular Complications for the Practicing Physician

Lloyd Aiello, MD, PhD (Joslin Diabetes Center, Boston, MA)

Dr. Lloyd Aiello presented a multistep process to assess and manage retinopathy in patients with diabetes. He opened with a startling statistic – retinopathy is prevalent in 49% of all patients with diabetes, and within 15 years after diagnosis, over 95% of patients develop some degree of retinopathy. Dr. Aiello’s paradigm begins with identification of patients with potential for retinopathy. He strongly believes that all patients with type 1 diabetes should have an ophthalmological examination within the first 5 years of diagnosis, and patients with type 2 diabetes should have this examination at the time of diagnosis, instead of waiting for symptoms. Next, he recommended life-long evaluation and education, along with optimizing systemic factors such as glycemic levels and blood lipids. Identification of complications and timely intervention concluded the paradigm, with VEGF inhibitors as the primary line of treatment for diabetic macular edema.

Questions and Answers

Q: Given the fact that this is a huge epidemic is there a move to try and get optometrists licensed?

A: We can’t possibly address the issue of diabetic retinopathy with ophthalmologists alone. There is also a push for telemedicine programs to address the growing issue. As far as licensing, this is a state by state issue is thus limited to each locality.

New and Developing Drugs for the treatment of Neuropathic Pain in Diabetes

Roy Freeman, MD (Beth Israel Deaconess Medical Center, Boston, MA)

Dr. Roy Freeman lamented that there are currently very few treatment options for diabetic neuropathy, and the ones that exist have limited efficacy. Existing drugs such as pregabalin (Pfizer’s anticonvulsant Lyrica) and duloxetine (Lilly’s anti-depressant Cymbalta) have unfavorable response rates and require high dosages to achieve optimal therapeutic effect. The latest drug approved for treating diabetic painful neuropathy, tapentadol (J&J’s opioid Nucynta), shows potential as a tertiary line of therapy but raises concerns of abuse and misuse due to its opioid classification. Dr. Freeman noted that a turning point is taking place in the field of diabetic neuropathy pain therapies, as many emerging treatments such as TRPV1 agonists/antagonists and transcutaneous nerve stimulation are likely to undergo clinical and preclinical trials.

• Dr. Freeman reviewed the efficacy of tapentadol, a centrally-acting analgesic and the latest FDA-approved drug to treat painful diabetic neuropathy. As an opioid, it remains as a secondary or tertiary line of therapy but has a much safer profile and less potential for abuse in comparison to other opioid medications. In an enriched enrollment randomized withdrawal trial, patients on tapentadol experienced a mean reduction in pain by 1.3 points over placebo on the 10-point pain scale (n=588). In terms of response rate, 38% of patients reported 50% improvement on tapentadol versus 25% of patients reporting 50% improvement on placebo.
• Noting a trend towards more individualized therapy for pain management, Dr. Freeman briefly introduced several other classes of therapies with potential clinical applicability. Among the classes mentioned were transcutaneous nerve stimulation devices (an example is NeuroMetrix’s Sensus), TRPV1 agonists/antagonists, total capsaicin therapy, Na(v) 1.7 antagonists, and anti-NGF molecules. Some are already undergoing trials to treat other conditions, such as Na(v) 1.7 antagonists for inherited erythromelalgia. Other therapies, such as transcutaneous electric nerve stimulation have Level B proof from the American Academy of Neurology towards treating pain from diabetic neuropathy. All of these emerging classes require further investigation through clinical trials in order to establish clinical efficacy, especially regarding the 50% response rate.

Symposium: Complications – The Human Side

Patient Beliefs and Perceptions About Complications

Marilyn Ritholz, PhD (Joslin Diabetes Center, Boston, MA)

Dr. Ritholz gave a vivid presentation centered around patient quotes and selected results from interview-based studies. She used quotes and two case studies to demonstrate the point that while self-efficacy could empower patients, it could also give them a sense of shame or guilt if they develop complications. Moreover, some patients are motivated by the risk of complications to change behavior while others simply feel helpless as a result. She cited a study of 129 type 1 diabetes patients where patients overestimated their risk of complications but also over-estimated the benefit of intensive therapy in reducing their risk. In another study of 32 adults with type 2 diabetes, most participants acknowledged that knowing the complications had a positive effect on self-management. Dr. Ritholz went on to provide some preliminary results from her group’s ongoing interview-based study. Out of 41 participants with type 1 diabetes, 38 thought that they could prevent complications to some extent. Patients in this study were most frequently worried about loss of independence and shorter lifespan. Dr. Ritholz recommended that clinicians have discussions with their patients about their beliefs, expectations, and self-efficacy and help them to develop active management behaviors without feeling guilty if complications do develop.

• Dr. Ritholz used quotes and case studies to give examples of how her own patients viewed the complications of diabetes. One patient viewed his diabetes “as the bully whom [he] had to hide from,” an example of how patients might try to ignore the risk of complications. One woman expressed that having control “is wonderful, but it can also be awful because… one cannot help but feel a sense of culpability if things start to go badly.” Dr. Ritholz used two case studies to demonstrate how different patients could have completely different reactions to the threat of complications. After being diagnosed with macular edema, the first patient completely changed her behavior and managed to bring her A1c from 8.8 to 7.1% in one year, while the second patient stated that “the big victory of reducing your chances for developing complications ten to twenty years after diagnosis becomes a phantom after a while”, and remained at an A1c of 9%.
• Interview-based studies have shown that patients are in general motivated by knowledge of complications. In one study of 129 type 1 diabetes patients with mean age of 30 years and mean duration of diabetes of 15 years, patients greatly overestimated risk of various complications, and overestimated the benefit of intensive therapy on risk reduction as well. In a study of 32 adults aged 60 or older with type 2 diabetes, most participants acknowledged that knowing the complications had a positive effect on self-management. Finally, Dr. Ritholz presented preliminary results from an ongoing interview-based study by her group. Out of 41 participants with type 1 diabetes, 67% of respondents said "Yes", they thought complications could be prevented, and 27% said "Yes and no". Only 7% thought that “No,” complications could not be prevented. The mean age of participants was 55, with mean time since diagnosis of 33 years, and 66% self-reported microvascular complications.

Questions and Answers

Q: Do you recommend for folks to tell patients about complications to help motivate them?

A: I think it’s very individually based. If you know your patients well enough, you should know if complications will motivate them. I think it’s most important to ask them what they believe, what they expect, and what their self-efficacy is like.

Q: For patients newly diagnosed with type 1 diabetes, I tend to avoid discussion about complications because I don’t want to scare people.

A: This is similar to the last question. It shouldn’t be the first thing we bring up. The important thing is, you have to know your patient – what they think, what they believe – and then you can have a good discussion. Complications should be part of the discussion, but they shouldn’t be presented as an ugly thing you should be ashamed of.

Q: I’m wondering if you looked at age differences and duration differences, for example, people are having complications in their twenties versus in their fifties, or started having complications different numbers of years after diagnosis.

A: Those are excellent questions, and we will definitely look at that. This is only preliminary data and we haven’t had a chance to analyze it in depth.

Q: Did you ask patients how they learned about complications? If we leave them without explanations, they will often go to the Internet, where they are alone and without hope.

A: We did ask who they relied on most for information about complications, but we haven’t analyzed the responses yet.

How to Talk about Complications Risk to People with Diabetes

Richard Jackson, MD (Harvard Medical School, Boston, Massachusetts)

Dr. Jackson advised physicians and healthcare providers to be less pessimistic when talking to patients with diabetes about risks associated with complications. In addition to scaring them, being pessimistic to patients with diabetes is ineffective in compelling them to work toward reducing risk of diabetes complications. Dr. Jackson suggested that being pessimistic to patients with diabetes often causes them to deny the actual complications risk. Furthermore, the amount of pessimism expressed to patients may be unwarranted given the improvement in complication rates in recent years. According to Dr. Jackson, physicians and healthcare providers should therefore give a sense of hope to patients with diabetes by providing optimism while helping them reduce complications risk.

• Things that worry physicians and healthcare providers are not necessarily what worry people with diabetes. Physicians and healthcare providers are worried patients will develop sustained three-step retinopathy – reflected in data from the Diabetes Control and Complications Trial (DCCT). On the other hand – reflected in data from the Epidemiology of Diabetes Interventions and Complications (EDIC) study – patients are worried they will develop proliferative retinopathy since they are scared of losing their vision.
• Patients in denial of complications risk actually feel that they are doomed with diabetes despite data showing that people with diabetes are living longer. Dr. Jackson conducted a study on people with diabetes in the community, not only finding that almost all of them believed that diabetes is a serious disease, but also finding that most of these people believed that they were doomed from diabetes. Yet EDIC data from 2008 shows that diabetes complications are decreasing rapidly relative to Steno data in 1978. Despite reduction in diabetes complications over the past 30 years, people with diabetes are still suffering due to: late start in diabetes intervention, poor health care advice, confusion, too many choices, and sense of hopelessness. Dr. Jackson stressed that the most important thing is to make sure that people who are in denial continue to work toward reducing complications risk.
• It is the goal for every physician that when patients leave, they feel more confident and comforted than when they arrived. Even when patients come in with a difficult problem, physicians need to listen and empathize with patients while delivering information that is appropriate and beneficial. Overall, the primary job of physicians and healthcare providers is to give patients hope, either through instilling patient self-efficacy or through improving technical outcomes.

Question and Answer

Q: How do you talk to people who are facing even higher risk with severely high A1c levels?

A: I think that you look for pieces where they can be successful. If their blood pressures are nice, or if their cholesterol levels are good, then informing them of these things would be helpful. I think that if they understand that they have some hope, since these populations often face higher risk situations because they are hopeless – so if you can show them some areas where they have gained ground with diabetes would help. But I do know that these people are one of the most rewarding populations to work with if you are able to help them.

Symposium: Joint ADA/ASN Symposium – Diabetes and Advanced Chronic Kidney Disease – Diabetologists and Nephrologists on the Front Line

Collaborative Care for People with Diabetes and Advanced Chronic Kidney Disease--The Diabetologist and the Nephrologist

Mark Molitch, MD (Northwestern Feinberg School of Medicine, Chicago, IL)

Addressing diabetologists and nephrologists alike, Dr. Molitch began his presentation by emphasizing the importance of glycemic control in delaying the onset of end-stage renal disease in patients with diabetes and chronic kidney disease. Maintaining systolic blood pressure in the 130-140 mmHg range also led to beneficial effects in slowing the progression of ESRD, but values below this range lead to an elevated risk for cardiovascular complications from hypotension. He then narrowed his focus on patients with eGFR values below 60 ml/min/1.73 m² in order to review safety profiles of a variety of glycemic control therapies. For metformin, Dr. Molitch noted that current American renal threshold for metformin use was much stricter than that of other agencies, and proposed an alternate treatment paradigm that was more liberal in allowing metformin use. At GFR <30 ml/min/1.73 m², he recommended stopping metformin, and at GFRs of 30-60 ml/min/1.73 m² he advised limited dosing and/or more frequent monitoring. For other drug classes, he similarly recommended halting GLP-1 at GFR <30 ml/min/1.73 m², and stopping SGLT-2 therapy at GFR <45-60 ml/min/1.73 m² depending on the brand (the threshold for Forxiga is 60 ml/min/1.73 m² and for Invokana is 45 ml/min/1.73 m²). Dr. Molitch concluded by recommending patient referral to a nephrologist with the progression of CKD, and emphasized the need for both nephrologists and diabetologists to coordinate therapeutic goals in their patients.

Symposium: Toe-to-Heel—Searching for Answers to the Diabetic Foot Dilemma

Roger Pecoraro Award Lecture—Why Does Acute Disease of the Foot Become So Chronic in Diabetes?

William Jeffcoate, MRCP (City Hospital, Nottingham, United Kingdom)

Dr. William Jeffcoate reviewed the pathogenesis and treatment of diabetic foot ulcers. In the course of diabetic foot ulcers, chronic inflammation results from a number of factors, including infection and dysfunctional macrophages and thus they take, on average, 75-80 days to heal (with the exception of heel ulcers that require a whopping 200-237 days). Currently, a variety of treatments are available to treat diabetic foot ulcers ranging from debridement to topical applications  to grafts or skin substitutes, but there is a lack of very robust evidence to support their use. On a positive note, Dr. Jeffcoate reported that, compared to data from the 1990s, the number of amputations related to foot ulcers has halved in industrialized nations from an average of 3-4 procedures for every 1,000 diabetes patients to 1-2 per 1,000. A major problem that still exists, though, is variations in regional standards of care. One study found that the number of amputations for diabetic foot ulcers differed by a factor of nearly 10-fold within the United States which he speculated might result from disparities in education or practice. Dr. Jeffcoate recommended that a national audit of patients with diabetic foot ulcers be taken to identify best practices and allow for comparisons among physicians and specific populations. Throughout Dr. Jeffcoate’s presentation, a running theme was the deficiency in research concerning diabetic foot ulceration that could help to improve care

Current Issues: Can Better Control of HbA1c Reduce Cardiovascular Risk?

Pro – There is Value in Controlling HbA1c

Jay S. Skyler, MD, MACP (University of Miami Miller School of Medicine, Miami, FL)

The grand Moscone North ballroom was packed for this highly anticipated debate in which the legendary Dr. Skyler argued a resounding “yes” for whether there is value in controlling A1c in reducing cardiovascular disease risk. In savvy debate strategy, Dr. Skyler cut straight to the rebuttal by addressing the infamous trilogy of studies – ACCORD, ADVANCE, and VADT – that failed in primary analysis to show statistically significant CVD risk reduction due to glycemic control. Yet Dr. Skyler argued that inadequate study length, competing medications like ACE inhibitors and statins, and prior history of CVD did not provide room to see benefits of glycemic control on CV risk reduction. Notably, subgroup analyses in each of these trials of patients without CV event history proved that earlier intensive treatment could in fact reduce CV risk. In support of his argument, Dr. Skyler also reviewed the STENO-2 study, EDIC/DCCT, and UKPDS which all showed significant CV risk reduction only after long-term follow-up. Early intensive treatment provides long-term benefits, i.e. a “legacy effect,” and such follow-up evidence may shape future treatment guidelines. Dr. Skyler also cautioned that data on macrovascular effects of intensive treatment have been less conclusive in these studies and require further evaluation – a sticking point that his opponent in the debate Dr. Michael Farkouh (Mount Sinai Hospital Toronto, Ontario) later emphasized.

• Starting with ACCORD, Dr. Skyler argued that the early termination provided an inadequate amount of time (3.5 years) to show risk reduction in standard MACE (major adverse cardiovascular events – non-fatal MI, non-fatal stroke, and CVD death) with glycemic control. Importantly, when assessing the primary outcome by subgroup, two thirds of patients who had no history of CV disease showed statistically significant risk reduction in MACE.
  
  • Similarly, in ADVANCE, those patients with no history of macrovascular disease and microvascular disease showed 14% and 11% risk reduction in MACE, respectively. Additionally, concurrent medication of ACE inhibitors and statins may have masked the risk reduction benefit of glycemic control in ADVANCE.
  • VADT data showed similar results, where patients with baseline coronary artery calcium (CAC) scores of 0-10 showed benefit with intensive therapy. CAC scores infer the presence of coronary atherosclerosis by measuring the amount of calcium in the coronary arteries. Unsurprisingly, with larger baseline CAC scores (increasing up to 400), benefit of glycemic control decreased. Dr. Skyler emphasized, “If you start glycemic control early enough such that you don’t have background disease, you have much greater chance of success in reducing CV risk.”
• To further support his argument, Dr. Skyler reviewed the STENO-2 study, EDIC/DCCT, and UKPDS, which all showed significant risk reduction in composite CV score was only apparent after long-term follow-up. With a friendly shout out to Dr. Rury Holman (lead co-investigator of UKPDS) in the front row, Dr. Skyler highlighted that UKPDS’ “legacy effect” underscores this importance of long-term follow-up in showing statistically significant risk reduction.
• Regarding the 22% increased risk of all-cause mortality in ACCORD, which resulted in the trial being terminated early, Dr. Skyler clarified that the patients who died during the trial “were patients whose A1c did not go down even with intensive treatment.” The ACCORD trial design required that providers had to increase treatment even if A1c <6.0% if more than 50% of SMBG tests over four days were >100 mg/dl for fasting glucose or >140 mg/dl for two-hour post-prandial glucose. Treatment was lessened only in the presence of hypoglycemia. In an illuminating example, Dr. Skyler asked the audience if anyone would use this standard treatment with their patients. Not a single hand in the 400-person crowd raised their hand. He emphasized that such an extreme treatment strategy for glycemic control allows room for adverse events.

Con – There Is No Proven Value in Controlling HbA1c

Michael Farkouh, MD (University of Toronto, Toronto, Ontario)

Dr. Michael Farkouh acknowledged Dr. Skyler’s assertion that strict control of A1c values in people with diabetes can prevent damage to the microvasculature, and that “aggressive” treatment of type 1 diabetes in young individuals can result in fewer overall cardiovascular events in those individuals. However, he maintained that no solid evidence demonstrates that tight control of A1c can reduce macrovascular complications in type 2 diabetes. He suggested that a focus on glycemic control is not sufficient when considering people with type 2 diabetes, especially given the very real threat of serious macrovascular complications.  He suggested instead that some of the resources spent lowering A1c levels in type 2 diabetes should be spent reducing LDL levels and providing statins to more diabetes patients. Dr. Farkouh also raised some concerns that adverse macrovascular outcomes, including heart failure, might be associated with intensive glycemic control and aggressive treatment of type 2 diabetes. He concluded his presentation by calling on the audience to consider whether these safety concerns might make the risks associated with tight glycemic control too great for any potential benefit.

• Dr. Farkouh outlined some reservations regarding data on glycemic control presented in the ACCORD trial. He suggested that a more careful analysis of the cardiovascular death rate might be necessary, since much of the difference in mortality rate resulted from unexpected, sudden death. Given the sudden nature of much of the mortality in individuals with higher A1c levels, Dr. Farkouh noted that these deaths might reasonably be attributed to metabolic aberrations or neurologic influences on the heart, rather than the degree of glycemic control in affected individuals.
• Dr. Farkouh highlighted the dangers of focusing on tight glycemic control in type 2 diabetes while neglecting other measures of health. He described diabetes as a “cardiovascular disease with an endocrine basis,” and suggested that LDL levels and blood pressure might actually be more important measures of overall health in people with type 2 diabetes than are A1c levels. Dr. Farkouh noted that great improvements in the quality and length of life could be made by investing additional resources in reducing LDL levels and providing more type 2 diabetes patients with statins to help prevent adverse cardiovascular outcomes. He stated that an ideal LDL level to aim for might be as low as 40 mg/dl, or 1 mmol/l, and he implied that many people with type 2 diabetes are fairly far off this number due to a relative lack of focus on LDL control in diabetes therapy. Although Dr. Skyler said that a higher A1c level predicts higher cardiovascular risk in people with diabetes, Dr. Farkouh maintained that there is no hard evidence at this time to support any such trend – we assumed the long-term UKPDS data was one starting point. .

Questions and Answers

Q: If you are using SAVOR as a negative study, Dr. Farkouh, you’re tagging at the end of long studies for CV risk reduction. We would need a long-term study evaluating excellent control starting from the beginning of type 2 diabetes for a long period of time. In all these studies, combination with insulin and sulfonylureas all induced hypoglycemia. This is a challenge for all these studies

Dr. Michael Farkouh (Mount Sinai Hospital, Toronto, Ontario): I was pointing to SAVOR because we thought it would be our savior. In a meta-analysis, it showed 30-40% risk reduction. I only mentioned it because of side effects. I agree with you completely. We have a lot of hypotheses, and we have “fuel” to do another UKPDS-like trial. We have to start our therapies earlier and follow more mechanisms earlier. I don’t think we understand much yet on the CV side.

Dr. Jay Skyler (University of Miami Miller School of Medicine, Miami, FL): We need to appreciate that SAVOR is a two-year study. If you want to see differences in outcomes, you need to do the study for long enough. My bias is that SAVOR was designed to show no increased risk. That’s what FDA guidelines require. If you wanted to show benefit, you have to design a longer-term study to achieve beneficial effect with any intervention. I would want to look at people in the earlier course of the disease and follow them for a longer time. I think also that in long-term studies, we need better adherence, as Dr. Farkouh pointed out. We need to see that patients can get the benefit that we are trying to provide. In the real-world, non-adherence is even worse. There is a 22% chance that people starting on a statin will continue on that statin long-term. We need to pay more attention to getting patient adherence.

Dr. Bernie Zinman (Mount Sinai Hospital, Toronto, Ontario): Dr. Skyler, when you talked about VADT, you showed that attractive curve to suggest short duration and mentioned that you haven’t seen that published. Well that was probably because that analysis was flawed. In actuality, the analysis wasn’t done carefully.

Q: I have a question for Dr. Farkouh: You seemed to emphasize that it is important not to rely too much on subgroup analyses and extrapolation. If I recall, you suggested that we should try to lower LDL cholesterol to 40 mg/dl or 1 mmol, is that correct? Is that number an extrapolation, or is there any clinical evidence that 1 mmol might be a good target?

Dr. Farkouh: That was an opinion of my own, it was not evidence based. There is some evidence, since it has been suggested that human LDL levels were in that range when we were still hunter-gatherers. In the JUPITER trial, LDL cholesterol levels were brought down to about 50 mg/dl, but in most studies involving people with diabetes we are nowhere near achieving this goal. That may be due in part to some biological difference in those with diabetes versus those without. However, I believe that with some of the new drugs in development we can lower LDL levels to an acceptable range in people with diabetes, and that this should be something to look for.

Comment: I wanted to emphasize the importance of duration of studies and the consequence of that on effect of reduced glucose on CV outcomes. I would point to a longer-term follow up of VADT that could address that. We have a poster that shows the effects of 5-6 yrs of intensive control, showing CV outcomes were reduced at longer term follow up.

Q: What would you recommend in the case of a patient treated with insulin who has an A1c around 6% and who is otherwise doing well, but has a remote history of cardiovascular disease and is on a statin? Would you relax the therapy or keep it the same?

Dr. Skyler: I think that if there were instances of significant hypoglycemia I would relax the therapy, but if not and the patient is achieving a low A1c, I see no compelling reason to change the treatment.

Dr. Farkouh: I agree completely. I have a number of patients in that range and I don’t see any issue with that as long as they aren’t having any adverse effects as a result of the treatment.

Q: Dr. Farkouh, do you believe it’s feasible to do a mega trial showing that reduction in A1c is effective in reducing CV risk? If yes, what would be your idea for this kind of trial?

Dr. Farkouh: Yes, I do believe it’s possible. It comes down to newer agents, particularly with GLP-1 agonists and DPP-4 inhibitors. As you know, there are a number of ongoing studies that we need to report on, and we need to be measuring not just MI and stroke, but also heart failure. I don’t want to say we need new trials; there are some very exciting ongoing trials that could provide useful information and show CV benefit. Let’s see what happens here. The cardiovascular community is very excited about GLP-1 agonists.

Q: I think Dr. Farkouh made an excellent point in suggesting that there isn’t any great evidence for a reduction in macrovascular events associated with decreased A1c levels in people with type 2 diabetes. Is there any scientific evidence that demonstrates an improvement in cardiovascular outcomes associated with tighter glycemic control? I understand that the scientific evidence for this in people with type 1 diabetes is excellent. Also, Jay, how would you prioritize different interventions for type 2 diabetes, including glycemic control, lipid levels, and blood pressure interventions?

Dr. Skyler: I don’t think that any clear-cut evidence for a link between macrovascular outcomes and glycemic control exists at this point. Meta analyses suggest that tighter glycemic control may benefit some people with diabetes. In terms of decreasing the overall number of cardiovascular events, lowering blood pressure and lowering LDL levels are both more important than improving A1c levels. I believe I made that point during my presentation. We need to treat the whole patient, so it is important to address all of those parameters in some capacity. I still believe that it is worthwhile to try to improve glycemic control, whether or not there is any improvement in the number of macrovascular events, since tighter glycemic control is bound to benefit microvascular outcomes.

Comment: I agree, I am also not particularly anxious to have patients lower their A1c levels for the purpose of avoiding cardiovascular events, since I know they’re going to see a major microvascular benefit.

Comment: We are talking about glycemic control being equivalent to A1c control. But in my point of view, I’m looking at A1c in diabetes patients as a cardiologist might look at one node in an EKG. A1c doesn’t reflect the entire picture. Do you have any comments on this?

Moderator: Yes, A1c isn’t the best measure of CV risk, but it’s the best measure we have of glycemic control. In DCCT the difference between outcomes from conventional to intensive was almost entirely explained by A1c.

Q: I recently read a paper that I think is very important with respect to this debate, it was published by Hanson in Diabetologia 2013. The study looked at the causes of death in all people with diabetes in Denmark. In this study, there were 47 deaths observed to be caused by cardiovascular events in people with diabetes for every one death caused by a microvascular event. I don’t mean to undercut the importance of avoiding blindness, dialysis, amputation, and other consequences of microvascular problems, but I think we need to seriously consider prioritizing therapies that address macrovascular outcomes as well given these results.

Dr. Farkouh: I am familiar with that data and I think it’s compelling. I believe we are not treating patients effectively. It is important to consider that some people might benefit from improving their glycemic control, but I think we’re undertreating patients on other fronts as I pointed out earlier.

Dr. Skyler: Michael said it.

Comment: I presented one of my studies based on primary data from UKPDS here at ADA. I looked at the trajectory of A1c over two years and immediately before MACE measures. In these patients (n=20,000), when looking at A1c along with lipids, blood pressure, and BMI, patients who have A1c >7.5% for over 2 yrs, have an 8-25% increased risk of MACE. But at the individual level of A1c and effect on MACE there is no significant effect. When risk factors are looked at together – and my study was a seven-year follow up – A1c in conjunction with other risk factors showed a visible CV risk outcome.

Dr. Skyler: Yes, that’s interesting. There are a number of studies that do this in a multitude of ways.

Moderator: I’d add that your study doesn’t address the issue of intervention. If you intervene, what’s the outcome?

Q: I think it is interesting that we are forced to look at macrovascular outcomes, but that we consider microvascular disease. Our priorities might also be different if we were to look at microvascular outcomes like blindness, or renal failure, but to see death from renal failure we would have to be looking ten to twenty years out. I am intrigued by coronary scans, and other considerations of the course of macrovascular disease, besides the marker of death as an endpoint.

Dr. Skyler: Here, you seem to be touching on the biomarker enigma that exists in so many different places. It is not just limited to myocardial infarctions or cardiovascular deaths. It is very tough to validate biomarkers – the whole process is a fishing experiment to some extent. We need to do prospective studies with hard outcomes in order to validate, which becomes part of the dilemma, but it is certainly worth considering.

Q: Why is the timing so different for risk reduction for CVD, lipids, and BP lowering? We don’t have a very good understanding of biologic mechanisms. What is the mechanism for glycemic control?

Moderator: The underlying pathophysiology may be different, so you need to intervene with different agents at different times.

Dr. Farkouh: There is a constant risk over the course of a patient’s lifetime. When you get to the point of having diabetes, that’s where there may be a more important role. Once you have it, the slope of a curve isn’t that steep and takes time to make an outcome difference. Patients may be so far gone. All the data lends itself to intervening early and even before diabetes.

Q: Can you comment on the whether or not you think statins might be responsible for an increased risk of diabetes in some cases, and whether this should be a consideration before prescribing statins to those with prediabetes?

Dr. Farkouh: This data comes from JUPITER and other studies linking statin use with diabetes. When we have drilled down more extensively, we find that folks that develop diabetes are already on the road to diabetes, in that they typically have two or three risk factors. In JUPITER I believe the time differential in terms of developing diabetes was only 100 days between the two groups. I also just read something suggesting that many patients on statins do not exercise to the same degree as those not on statins, so that could be a contributing factor also. I don’t know exactly what prompts the correlation between statin use and the development of diabetes, but it does not seem to greatly accelerate the process anyway. 100 days is a very small time difference.

Q: If a patient had prediabetes would you put them on a statin?

Q: Wouldn’t you agree that the potential benefit of using the statin far outweighs the risk of developing diabetes?

Dr. Farkouh: I agree, I would place the patient on a statin if I thought it was necessary. I think the benefit is far greater than the risk.

Q: Rosiglitazone basically pushed the FDA to set guidelines for requirements for CV safety studies. However, now a second look at that data isn’t as convincing, yet the CV requirement still exists. The unintended consequence is that a lot of major diabetes companies are getting out of diabetes because of these CVOTs. Our company [Takeda Pharmaceuticals] is committed to diabetes, but our senior management now continuously asks, “Why are we still in diabetes?” Is there any move from diabetologists and cardiologists to get together and say, “Okay, it was the right precaution at that time, but looking back, we have other data. We should reassess whether this I necessary.” These requirements are pushing major pharma companies to focus a lot of R&D in other fields like oncology. Major pharma is on their way out, like Roche got out altogether.

Dr. Skyler: The need to demonstrate safety was precipitated by rosiglitazone and maybe that wasn’t the right case at the time, but I don’t think that matters anymore. CVD is a major consequence that causes death in diabetes. That being the case, we don’t want to give medications that might increase CVD risk. To demonstrate that there is no increased risk may be the right thing to do, even though the initial stimulus may not apply anymore. I think it is perfectly reasonable to ask for benefit. I wouldn’t back away from FDA’s stance.

Dr. Farkouh: I think one benefit of the guidance is that it got the cardiovascular community in the diabetes game, and we needed to be. Heart failure is really important and needs adjudication and regulation. The guidance may have been reactionary, but it was right.

Dr. Zinman: I think we’re far better off today with those studies to talk about safety early in the lifecycle of drug. This could be a long debate.

Comment: It raises a point that I fully agree with; long-term safety should be done. However the question is when should it be done, premarketing or around marketing?

Dr. Zinman: Studies are initiated after launch or at the same time. As you know, it’s not a requirement to be done before. It’s a big debate that could go on for hours, so we’re going to hold off on that.

Q: Dr. Farkouh, you mentioned diastolic heart failure. If I am not mistaken, women have a higher risk of diastolic heart failure, is this correct? Why is that? It seems like most cardiologists seem to pay more attention to systolic heart failure than diastolic heart failure, do you think this is an issue that needs to be addressed?

A: I think this a very important issue. Systolic heart failure used to be regarded as a more serious condition, but in fact both systolic and diastolic heart failure have equally poor outcomes. I am not aware of any difference between sexes in the relative rates of systolic or diastolic heart failure.

Q: When studying drugs for CV endpoints, a confounding issue is that the populations are usually people who have advanced disease stages in order reach a required event rate. I understand though that the studies could be even longer and more expensive if the population used people early in disease progression. Should we start earlier on?

Dr. Skyler: You raised the big dilemma. If you want to show the benefit Dr. Farkouh talked about, you should assess people early, but you’re right, those CVOTs would be very long and expensive. But these are measuring safety, so trials are looking at people who may have increased risk in order to meet that event endpoint. It’s a clear dilemma and there is no easy solution to doing a bigger study that is long enough with both categories.

Interest Group Discussions: Professional Interest Group Discussion on Complications

Glucose Variability (Dysglycemia) and Diabetes Complications – Does it Matter? (Con)

Richard Bergenstal, MD (International Diabetes Center, Minneapolis, MN)

Dr. Richard Bergenstal asserted that he is a “supporter of the Irl Hirsch ‘Beyond A1c’ Movement,” in the sense that beyond can mean “in addition to.” However, he argued that hypoglycemia is a more important focus for this “movement” than glycemic variability. Hypoglycemia has been shown to be associated with mortality, complications, emergency-department visits, hospital admissions, cost, and worse quality of life. Therefore Dr. Bergenstal believes that clinicians should start to supplement the A1c with standardized, CGM-based metrics of hypoglycemia developed by himself and his colleagues; he said that in the long term perhaps A1c could even be replaced by CGM-based time in range. As for glycemic variability, he said that it has been definitively linked only to reactive oxygen species and inflammation. In conclusion Dr. Bergenstal challenged Dr. Hirsch to conduct outcomes-based research on whether glycemic variability matters for complications. 

• Dr. Bergenstal acknowledged that A1c is not perfect, but he argued that is widely applicable and that its use has led to better health for people with diabetes. He noted that rates of microvascular and macrovascular complications in diabetes have fallen dramatically since the mid-1990s (Gregg et al., NEJM 2014) – a decline that he attributed in part to the focus on A1c control since DCCT and UKPDS. Dr. Bergenstal also referenced the theory that A1c is not an appropriate metric for African-Americans or Hispanics, due to biological differences in glycation. However, he dismissed this theory based on evidence presented on the prior day by Dr. Elizabeth Selvin.
• Dr. Bergenstal argued that clinicians should assess their patients by supplementing the A1c with CGM-based metrics of hypoglycemia. Specifically, he favors standardizing CGM data analysis using a format developed by himself and his colleagues – the Ambulatory Glucose Profile (AGP) (Bergenstal et al., J Diabetes Sci Technol 2013). The AGP includes the percentage of time spent below 70 mg/dl, 60 mg/dl, and 50 mg/dl, based on at least two weeks of CGM. He explained that these cutoffs correspond to counterregulation of low blood sugar, adrenergic symptoms, and neuroglycopenia, respectively.

Glucose Variability (Dysglycemia) and Diabetes Complications – does it matter? (pro)

Irl B. Hirsch, MD (University of Washington, Seattle, WA)

The highly regarded Dr. Irl Hirsch provided a resolute, yet balanced, argument for glucose variability as a key factor in the development of diabetes complications. Dr. Hirsch noted that his interest in dysglycemia was originally piqued by the results of the DCCT study, which demonstrated that intensive treatment of type 1 diabetes reduced the risk of complications relative to conventional treatment. However, A1c levels seem to explain less than 6.6% of the variability in retinopathy risk (Lachin et al., Diabetes 2008). This point is subtle and sometimes ignored; indeed, Dr. Hirsch quipped that “the majority of researchers don’t understand the DCCT.”. Dr. Hirsch believes that glycemic variability is one of the factors that explains why people with the same A1c values have different complications risks. Even more controversially, Dr. Hirsch also suggested that the development of NPH and Lente insulins may have “set diabetes therapy back over 50 years,” because they led patients to use twice daily premixed insulin rather than basal-bolus therapy. In particular, Dr. Hirsch was referring to the fact that pre-mixed insulins do not provide the glycemic control that basal-bolus therapies with modern insulins now do; he cited data illustrating that the introduction of prandial insulins in the late 1990s, which reduced blood glucose spiking, have been associated with a reduced prevalence of diabetic retinopathy.

• As a reminder, the results of the DCCT trial indicated that intensive treatment of type 1 diabetes reduced the risk of sustained retinopathy relative to conventional treatment. The trial enrolled 1,441 type 1 diabetes patients, aged 13-39, for a mean of 6.5 years. Intensive treatment involved pump therapy or at minimum three insulin injections/day, while conventional therapy consisted of only one or two insulin injections/day. Based on these data, Dr. Hirsch argues that the blunting of postprandial spikes in the intensive treatment group may have been partially responsible for the reduced risk of microvascular complications.
• Dr. Hirsch proposed that the diabetes community has been fooled by the statistics surrounding the DCCT results, such that “the majority of researchers don’t understand the DCCT.” In particular, one conclusion drawn from the DCCT results was that “96% of the beneficial effect of intensive vs. conventional therapy on the progression of retinopathy is explained by the reduction in the mean A1c levels.” A1c levels do explain the majority of the difference between intensive and standard groups, but in fact the between-group difference explains only 6.6% of the overall variability in retinopathy risk (Lachin et al., Diabetes 2008). Thus the vast majority of complications risk is explained by other factors – perhaps including glucose variability. He encouraged the audience to be skeptical of oversimplified statistics, noting that “the average human has one breast and one testicle.”
• Dr. Hirsch proposed that “introduction of insulin glargine, NOT the DCCT, is the major event” that improved type 1 diabetes insulin therapy in the US in the mid-1990s. He believes that glargine was the reason so many more patients started using basal-bolus therapy, which he said provides superior postprandial control compared to premixed insulins using NPH or Lente insulin. Speaking through a character in his slideshow, Dr. Hirsch provocatively suggested that perhaps “the development of NPH and the Lente insulins … set diabetes therapy back over 50 years” because these drugs encouraged use of premixed formulations.
  
  • “This was my ‘Aha’ moment,” explained Dr. Hirsch, citing data from 1998-2003 that investigated the frequency of insulin injections per day and the prevalence of diabetic retinopathy, which demonstrated a negative correlation between these variables over this time period. Dr. Hirsch suggested that the increase in the frequency of insulin administration reflected greater glycemic control, which appeared to be correlated with fewer diabetes-related complications.
• Glycemic variability has been shown to result in significant alterations of normal homeostasis, such as increased oxidative stress and inflammation. However, Dr. Hirsch recognized that the mechanism by which glycemic variability might mediate diabetes complications remains unclear. He does believe that a randomized control trial would bear out his hypothesis that dysglycemia increases the risk of cardiovascular events – so do we!

Questions and Answers

Q: Variability in A1c over time has also been associated with complications. Could you discuss this?

Dr. Hirsch: In DCCT, variability in A1c has been associated with differences in retinopathy and nephropathy; this work was done by Dr. Kilpatrick with publicly available data. I’m curious what you think about that, Dr. Bergenstal.

Dr. Bergenstal: My point was that throwing out A1c doesn’t make sense. The relevance of A1c variability is all the more reason to measure A1c. To Dr. Hirsch’s point about Lantus being important, I think that if there wasn’t DCCT, there would be no Lantus or pre-meal bolusing. Why try to create better products to get A1c down if it didn’t make a difference? I’m not opposed to optimizing glycemic variability; we just need to do trials to show that it makes a difference in terms of complications.

Q: There is a lot of evidence that the postprandial state can be a toxic period of time. And when it’s more toxic, the higher glucose levels are. Oxidative stress and inflammation are increased in those who are hypoglycemic.  Could you comment on the basic studies showing these effects?

Dr. Bergenstal: We have a lot of data to say it seems like a bad thing. We don’t have data to say how, if we intervene to reduce it, that will improve outcomes. Sometimes we’re surprised with randomized control trials and what they end up showing. We end up agreeing. My point wasn’t that glycemic variability is a bad thing or doesn’t make sense. It just doesn’t make sense to call it a marker right now. Let’s do the trial and see what we get, then we’ll be able to add it.

Dr. Hirsch: I would be fine with glycemic variability incorporating hypoglycemia as one component of that.  We want to do everything possible to reduce hypoglycemia. No one would disagree with that. On that point alone, we would want to reduce glycemic variability to reduce hypoglycemia. That may be more true in the type 1 population. If you go and look at retinopathy, there was always more in type 1 than type 2. The reason is because we had much more variability and the retinopathy had an opportunity to express itself sooner. That’s always been something I’ve thought. No way to prove that. But we use that to make a hypothesis. In fact, Dr. Bergenstal is on a committee to study these issues, and hopefully we’ll have an opportunity to present and address these issues soon.

Q: This meeting throws some doubt on A1c as a predictor of complications, and on its use as a diagnostic marker.

Dr. Hirsch: A1c is the best biomarker we have that we know of. We will continue to use it, and we should. I’m not bashing what we’ve learned in DCCT, UKPDS, or ACCORD. My point is that I want to find a better gold standard, and I think it might be CGM.

Dr. Bergenstal: That I agree with completely.

Q: Will you please comment on the contribution of A1c, glycemic variability and hypoglycemia on microvascular complications between type 1 and type 2 patients and, in the type 2 group, between insulin users and non-users?

Dr. Hirsch: We might have to have another session to discuss that.

Dr. Bergenstal: That’s a rather large topic. The A1c seems to be important in both, and hypoglycemia is important in both, and glycemic variability has more room for improvement in type 1s. So wherever it turns out to fit, it will play a big role in type 1s.

Q: Both of you made a case for a better definition or biomarker of variability. Dr. Bergenstal, you specifically said not to use CONGA. Could you address what the problems are and suggest what might be feasible biomarkers?

Dr. Bergenstal: I was a little joking about CONGA. For glycemic variability to rise up to a translatable factor we can address, we have to standardize it. I don’t think we’re even there yet with hypoglycemia, so that was my first push. Please let’s know which interventions cause more hypoglycemia. SD is commonly used; coefficient of variation is probably better. Interquartile range is best for practice, I think, because you can visualize it, and patient can see it. I think that coefficient of variation and IQR are some of the markers I would push for.

Dr. Hirsch: CGM is available only to a small number of people on a regular basis. Even with fingersticks, I can’t get strips for patients not using insulin anyway. I think over time that things will transform by using CGM-based definitions. I am partial to coefficient of variation because it accounts for both mean and standard deviation. That said, I think it needs to be based on evidence more than what Rich and I think. In the study that he and I are conducting, we will be looking at patients using CGM and seeing which measures of glycemic variability correlate best with reactive oxygen species, inflammation, and hypoglycemia – symptomatic or not. We will be able to speak more scientifically than we can now. 

Q: Apart from the quantum availability, the rate availability seems to be important. Therefore, chunking the data in smaller quantums, like fructosamine, would be more useful than glucosamine, which chunks the data into bigger intervals. What do you think about that?

Dr. Hirsch: If we had a very reliable biomarker to use in addition to A1c, that would be good. For example, we don’t have good access to glycated albumin in the US, especially for patients with renal disease, which, to your point, that’s looking at a smaller time with respect of average glucose. We are going to develop better metrics for looking at this. None of this really matters unless we look at associations with complications and hard endpoints. Looking at cytokines in a test tube is not enough

Dr. Bergenstal: I agree. We’re all in agreement on this point. I’d rather have a short one [biomarker] and a long one – called glucose – than a bunch of middle ones.

Q: With today’s tools, we can mimic but we cannot match what the individual without diabetes has. Can you start showing what the young, non-diabetic shows when they are measured with CGM?

Dr. Bergenstal: Yes, I had a slide in my presentation, but I took it out. It’s amazing what those profiles look like.

Dr. Phillip Cryer: I would hope that pharma and that those in design of clinical trials would consider inclusion of rigorously measured CGM data – ongoing, throughout – for all clinical trials that involve drugs with potential to cause hypoglycemia – insulins, sulfonylureas, glinides. I appreciate the nice things both of you said about me. Our work started in the 1970s. It took off only with a collaboration with the master of human metabolic physiology and pathophysiology, who is here today: Jack Gerich.

Q: If you look at pediatric downloads, we see that blood glucose goes all over the place.  In fact, SD in these patients is nearly double what it is in adults. But studies have described that the years before puberty counts less than the years after puberty. I’m having trouble understanding. Could you help me solve this

Dr. Bergenstal: I don’t even understand my own kids, so I don’t know if I could help you.

Dr. Hirsch: When I read recent reviews on this, before/after puberty business, in my reading, I saw this as controversial. So this is good to know. I learned something. My guess is that the world of pediatrics is different from the world of adults. You don’t see retinopathy with children. It would be fascinating to put a CGM on a group of 8-year-olds and compare that to a group of 20-year-olds with the same amount of variability. Will you see the same amounts of oxidative stress? Right now, it’s all speculative. We need data. But that’s a study we could do.

Q: Which variability parameter should we use to measure glycemic variability?

Dr. Bergenstal: We discussed this briefly. For research purposes, coefficient of variation seems like a good one. But you also want to use this as a teaching point, so I recommend interquartile range. Those are the two I like.

Dr. Hirsch: For research, I also like coefficient of variation. In clinical practice, all the meter downloads give standard deviation (SD), whether you like it or not. I have learned to like it because I have learned how to use it. You can’t look at it by itself, because it depends on the mean. I like to see SD x 3 to be less than the mean. This is difficult to do. Failing that, I see whether SD x 2 is less than mean. But this works only if the mean between 120 mg/dl and 180 mg/dl. In the clinic when using SMBG – and that’s what we’re talking about now, because almost everyone has access to that – I like low blood glucose index (LBGI). I can explain Dr. Kovatchev’s formula to patients, and patients really understand it.

Q: Can you give some brief comments on detemir vs. others insulins in glycemic variability?

Dr. Hirsch: It may be true that variability of different insulins do differ. If so, then you have to translate what that means for glucose. And if someone is on prandial insulin, that complicates things.

Dr. Bergenstal: We’re in an era now when we need CGM to compare one insulin to another. We need a proper protocol, looking at hypoglycemia, etc.

Meet-the-Expert Session: Advances in Basic Science of Diabetic Kidney Disease and How They Benefit the Clinician

Advances in Basic Science of Diabetic Kidney Disease and How They Benefit the Clinician

Kumar Sharma, MD (University of California at San Diego/VA, La Jolla, CA)

Fielding a variety of questions from the audience, Dr. Kumar Sharma said that in the next two-to-three years we will learn more about how well kidney disease can be treated by blocking specific inflammatory pathways; he specifically mentioned that a NADPH oxidase inhibitor is in phase 2 trials. He also expressed excitement for potential early biomarkers of kidney disease and therapeutic response, such as blood levels of soluble TNF receptor and urine levels of a dozen specific metabolites. In response to a question about the “alarming” rates of nephropathy in young people with diabetes, Dr. Sharma said that he was not aware of any trials that longitudinally track complications in adolescents with prediabetes and type 2 diabetes.   

• In a brief research review before the discussion period, Dr. Sharma explained that basic theories on diabetic kidney disease remain “relatively stable”: insulin resistance and high glucose harm multiple types of cells in the glomerulus (the part of the kidney that filters the blood), eventually causing proteinuria and reduced glomerular filtration rate (GFR). The disease process seems to involve protein kinase C, TGF-beta, EGF, and reactive oxygen species (ROS). However, Dr. Sharma’s group has found evidence that higher ROS made by the mitochondria might actually lead to less inflammation and less ROS in other parts of the cell. Meanwhile new advances in epigenetics suggest that fetal exposure to high glucose could increase the risk of kidney disease – a theory that would support the importance of good care for pregnant women with diabetes (Ko et al., Genome Bio 2013). Other recent research suggests that the kidney’s proximal tubule might be a key mediator of damage to glomerular podocytes (cells that maintain the barrier between the blood and renal filtrate); this proposed pathway involves sirtuin 1 and claudin 1 (Hasegawa et al., Nat Med 2013).

Meet-the-Expert Session: Management of Diabetic Kidney Disease – The Diabetologists Perspective

Management of Diabetic Kidney Disease – The Diabetologists Perspective

Rudy Bilous, MD (Newcastle University, Middlesbrough, UK)

In this highly interactive meet-the-expert session, Dr. Bilous answered questions from the audience on best disease-monitoring practices, the necessity for better biomarkers, and unmet research needs. Dr. Bilous emphasized the necessity of individualizing treatment regimens, noting that each patient responds differently to various antihypertensive therapies, RAS blockade doses, and loop diuretics. Regarding disease monitoring, Dr. Bilous highlighted the unmet research need of better biomarkers for chronic kidney disease (CKD), as albuminuria has drawbacks as a CKD marker. Unfortunately, little is actually known about the role of albuminuria as Dr. Bilous commented, “There is scarce evidence on whether albuminuria is driving renal failure progression or is simply a designation of an underlying process that perhaps isn’t even amenable to treatment.” Looking forward to new therapies, Dr. Bilous also briefly highlighted research on agents that affect the inflammatory pathway, particularly focusing on the interstitial tubules. He added that several phase 2 trials are being conducted on NCP-1 antagonists and IL-1 and IL-6 antagonists, and the diabetic nephropathy community will likely hear much more about these anti-fibrotic mechanisms in the next couple of years.

• For monitoring diabetic kidney disease in the clinic, Dr. Bilous highlighted the importance of glycemic monitoring (diet, insulin regimen, injection sites, and individually adjusted A1c targets) as well as frequent assessment of comorbidities. He commented that fortunately the United Kingdom has a mandatory diabetic retinopathy screening program, but urged providers in the audience to also closely monitor retinopathy, neuropathy, and foot problems.
  
  • Additionally, Dr. Bilous noted that for patients with moderate albuminuria who have not yet progressed to end-stage renal disease, he focuses on monitoring renal glomerular filtration rate. His patients find the graphs of glomerular filtration rate (GFR) plotted over time much more helpful in visualizing disease progression compared to him just telling the patient that they’ve developed proteinuria.
• Dr. Bilous also pinpointed some of his own key clinical practices for managing hypertension: optimum RAS blockade doses, combining loop diuretics with RAS blockade compounds, and closely monitoring salt intake. He was careful to note that the role of salt restriction is still unclear and that dropping blood pressure too severely in elderly patients was dangerous.

Questions and Answers

Q: Is there anything that can be done other than salt restriction to improve the disease course of macroalbuminuria? Despite good control of glycemia, blood pressure, lipids, and protein in the diet, some of my patients are still getting increasing proteinuria.

A: Some data has shown that you can push the renal angiotensin process with maximum doses, but you must be careful about serum potassium. If blood pressure is already 120/180, A1c is 8.0% or less, lipids are well-controlled, and the patient is on a reasonably low protein diet, then there currently aren’t any other evidence-based treatments to slow disease progression. In non-diabetic kidney disease, NSAIDS have been shown to reduce the level of proteinuria, but that can be difficult for the GFR. Sadly, if you’ve done all the above and the patient still has progressive proteinuria, then there’s not a lot you can do. You should also make sure that diabetes is the cause, and testing for retinopathy is a foolproof way to test for this.

Q: Is diabetic kidney disease really preventable? We know that familial genetic factors can contribute to diabetic nephropathy despite good control. How significant of a contributor are genetics to diabetic nephropathy?

A: Studies on familial aggregation have been done in patients with type 1. Rare gene markers have been identified in type 2 as well. In genome wide scanning, a few areas of the genome are more frequent in people with diabetic kidney disease, but as far as I’m aware, there is no gene product that contributes causally. Even families with history of nephropathy where you know drivers are nature in response to nurture, you must still consider environmental factors like diet, lifestyle, etc. In my own practice, other than exploring family history of diabetes, we often don’t go into family trees and genetics. However, in terms of research it’s important that we continue to pursue these.

Q: In those patients not yet with end-stage renal disease but rather moderate albuminuria, what should providers track?

A: It depends on what we want to talk to our patients about. Most patients know that when we tell them they’ve developed proteinuria, it’s probably not good news. But what patients really want to know is if they are going to end up on dialysis or need renal replacement. With my patients, I focus on renal glomerular filtration rate (GFR) which you can plot on a graph and see the change over time. My patients find that visualization useful.

Q: I was in Manitoba where they have high rates of type 2 diabetes in children. They’re reporting that children with type 2 are more rapidly developing complications, including nephropathy, compared to children with type 1. How do you manage your type 2 patients vs. type 1 patients?

A: Microvascular complications are really serious in young patients. In my experience though practicing in the UK, type 2 diabetes in young people is not as big an issue as in the US. Yet more children in secondary and middle school are becoming overweight, so it’s only a matter of time before we see more children developing type 2 diabetes.

So why are children with type 2 more prone to complications? I think there are several possibilities: 1) There may be a pubertal association between increased growth hormone/GH binding proteins and nephropathy. This link has been shown in rodents. 2) Perhaps there are hormonal aspects. In young boys, increased testosterone is deleterious in association with diabetic kidney disease. But such a deleterious effect is less so prevalent with estrogens. 3) The kidney is fully developed by the time of puberty, but if there are aspects of metabolic syndrome early on, then there possible effects on the developing glomerulus, not to mention fetal programming. Most of these children developing type 2 are born to mothers with either gestational or overt diabetes or who are overweight. The uterine environment could have made the developing organs more prone to damage.

Q: Are there any newer biomarkers available to identify chronic kidney disease in adults? Second, is there a difference in chronic disease outcomes for newer glycemic agents or newer insulins?

A: In terms of biomarkers, at the moment we don’t have anything as effective as albumin even though albumin itself has tons of drawbacks.

For your second question, a lot of studies are also looking at studies in glycemic control i.e., A1c is the primary outcome, yet none of them are necessarily looking at how patients get to this A1c level. They talk about the intensification of treatment but that means adding extra insulin and therapies. Yet for example, DPP-4s are more effective at lowering glycemic levels in Asian patients. We should adopt the ADA/EASD statement on individualized treatment, as different drugs are more effective in different patients. Maybe we should also be talking about GLP-1 agonists earlier in treatment rather than later. As far as I’m aware, there are no good studies.

Q: If you have a patient with rapidly progressive proteinuria, would you aim for super-normal doses of ACE inhibitors or ARBs or would you think about combining them?

A: For the combo of ACE inhibitors and ARBs, there is a directive in the EU that it shouldn’t be used in diabetic kidney disease patients. There are also some new non-steroidal mineralocorticoids that we may look at in the future.

Q: When we send patients to nephrologists, the nephrologists sometimes take their prescriptions above and beyond normal doses. How high should you go?

A: Some prescriptions have gone over 160 mg. That’s very high and definitely not cheap. Yet they do show that you can reduce albuminuria further. The patients with the worst albuminuria are those that progress the fastest. We don’t know whether albuminuria is driving that progression or increased albumin simply designates an underlying process we aren’t aware of which may not even be amenable to treatment. We need better research that looks at those fast-track patients. We’ve all had patients that have albuminuria and are progressing quickly, even if blood pressure is well controlled, yet we don’t have any therapy for these cases. There is a need to be looking at those patients with high-rates of declining GFR.

Q: Would you try a new strategy using vitamin B1, thiamine, to prevent diabetic kidney disease? There is mounting evidence from Pakistan and India that thiamine can prevent microalbuminuria in early diabetes and nephropathy stages. There is also evidence that in patients with diabetes, thiamine transporters are down-regulated. What do you think of this as an expert? How should this research be taken forward where thiamine has absolutely no side effects and can help diabetics prevent or delay kidney disease?

A: The role of thiamine in randomized controlled trials have been mixed. Some suggest a reduction in albuminuria. Some ongoing phase 2 trials are exploring Vitamin B and its analogs in type 2 diabetes. I’m not sure where they’re at in terms of results, but the role of thiamine has been implicated in nephropathy progression and it does have some affect in albuminuria. As far as I know, there aren’t any trials that show thiamine’s effect on GFR or other kidney function.

Also, there is intriguing work on turmeric derivatives that seem to reduce albuminuria in some patients. Some small phase 2 trials have been conducted on these turmeric derivatives, other herbal medicines, and spice derivatives. We could learn from such nutritional research on dietary supplements.

Q: There is evidence from basic science that inflammatory reactions are part of the pathogenesis of diabetic nephropathy. Are you aware of any clinical studies that support this?

A: There is a huge amount of interest in agents that affect the inflammatory pathway. This is where the thrust of lots of clinical trial work is happening. There are NCP1 antagonists, IL-1 and IL-6 antagonists that are currently in phase 2 trials. The focus of such research on the inflammatory process is on the interstitial tubules. In the next few years we’ll learn much more about this. This is the current state of research and there’s interesting data on anti-fibrotic mechanisms.

Q: Is there any difference in outcomes when you use ACE inhibitors or ARBs or are these equal in efficacy?

A: They are pretty much equivalent. No one has done an outcome studies, but short-term studies on albuminuria show that both classes are efficacious. ARBs are better tolerated in some patients over ACE inhibitors, and this just underscores my previous point that you should always be looking at the patient in front of you.

Q: How do you balance type 2 diabetes patients who have both autonomic neuropathy and hypotension?

A: What I tend to do, because these patients would have supine hypertension, is give the anti-hypertensive at night to lower supine BP for example losartan or other shorter duration agents so that there isn’t spillover in the morning. I don’t have a huge amount of evidence for that, but it’s a practical approach I take with my patients.

Special Lectures and Addresses: Kelly West Award for Outstanding Achievement in Epidemiology Lecture (Supported by an unrestricted educational grant from Merck)

Time to Retire “Microalbuminuria”--Early, Progressive Renal Decline Is the New Paradigm

Andrzej Krolewski, MD, PhD (Joslin Diabetes Center, Boston, MA)

Dr. Andrzej Krolewski’s research findings offer a new paradigm for detecting renal decline in type 1 diabetes patients at risk for nephropathy. He began by proposing a departure from microalbuminuria as a measure of progressive renal decline because of its lack of efficacy in detecting early progression of nephropathy, and instead offered alternative biomarkers that have shown great potential in early studies. Using data from the first and second Joslin Kidney Studies, Dr. Krolewski offered KIM-1 and TNFR1/TNFR2 as potential biomarkers with more accurate predictive ability than microalbumin. He concluded that improving glycemic control over a follow-up period of 12-15 years delayed the progression of end-stage renal disease (ESRD) by reducing the cumulative risk rate by up to 12% in contrast to poor glycemic control (p<0.001).

• Dr. Krolewski presented a new paradigm of nephropathy in type 1 diabetes described as “early progressive renal decline”. From the first Joslin Kidney Study, Dr. Krolewski found that urine albumin was not an accurate predictor of kidney function decline, as 10% of patients with normal albumin developed ESRD during the 6-10 years of follow-up. This form of nephropathy was identified as the primary form of nephropathy in patients with type 1 diabetes. Progression begins in patients with normal renal function (eGFR > 105 ml/min), and its onset represents a point of no return that leads to ESRD within 2-30 years. This unpredictability led to a need for new biomarkers beyond urine albumin in detecting early renal decline.
• The Joslin research group identified four potential markers, of which plasma KIM-1 and TNFR1/TNFR2 showed the most promise. KIM-1 was found to be an effective independent predictor of risk of progression of renal decline. A hypothesis for this improved predictive ability states that tubular damage and inflammation as detected by KIM-1 may play more important roles in early renal decline than glomerular damage as measured by microalbuminuria. In another study, over a follow-up period of up to 15 years, patients with the highest quartile of TNFR2 in the type 1 diabetes cohort with proteinuria were at significantly higher risk for developing ESRD in comparison to the other 3 quartiles (p<0.001, n=349). Dr. Krolewski noted that none of these proposed candidate proteins overlap with existing literature, thus reinforcing the call for an alternative paradigm.
• Improved glycemic control from any A1c baseline significantly slowed the progression of ESRD according to a study published this year by Skupien et al. Dr. Krolewski shared the results of this newly published study of a 349 member cohort from Joslin with type 1 diabetes that developed proteinuria. The patients had median ages of 38 years, eGFRs of 85 ml/min/1.73 m², 5-year pre-baseline A1c of 9.3%, and 5-year post-baseline A1c of 8.7%. The researchers assessed risk of ESRD based on a 5-year pre- and post-baseline of glycemic control. After 15 years of follow-up patients who began with poor glycemic control and sustained poor control had a cumulative risk rate of ESRD of over 40%, while patients that began with fair glycemic control and sustained it had a cumulative risk rate of about 22%. Remarkably, patients that began with poor control but demonstrated improvement in later years had a cumulative risk ratio of about 28%. A significant difference from the poor glycemic control group emerged as early as 5 years after follow-up, and became even more pronounced at 10 years (p<0.05, p<0.001, respectively). This data supports the implication that glycemic control slowed down early progression of renal decline independent of reno-protective drugs, and delayed onset of ESRD by 6-10 years. With markers such as TNFR1, early detection could lead to more targeted therapy to reduce the risk of developing ESRD in patients experiencing diabetic nephropathy.

-- by Melissa An, Eric Chang, Jessica Dong, Andrew Foley, Alex Ganninger, Sam Haque, Derek Pham, Katherine Sanders, Joe Shivers, Wilbur Song, Jenny Tan, Michelle Xie, and John and Kelly Close