December 2-6, 2013; Melbourne, Australia Day #1 Highlights – Draft

Executive Highlights

Greetings from Melbourne, Australia and Day #1 of IDF’s 2013 World Diabetes Congress! In particular, today’s program featured notable satellite symposia from Abbott, BI/Lilly, and Novo Nordisk. The day began with Novo Nordisk, the clear marketing champion of the conference – no attendee could miss the company’s compelling signs plastered all around the Melbourne airport and Convention Center (“How do we change diabetes if we don’t understand it?” “Diabetes is changing the world; how can we change diabetes?”). The stadium-sized plenary room for Novo Nordisk’s symposium provided lots of interesting tidbits, including a slew of controversial remarks from the influential Dr. Steven Nissen (Cleveland Clinic, Cleveland, OH). See immediately below for our top 10 highlights from Day #1 and the appendix for our full coverage of Dr. Nissen’s talk and ensuing panel discussion. We also heard plenty on the cardiovascular outcomes trial front, especially how Dr. Nissen would characterize himself vis-à-vis industry and regulators; why the FDA’s 1.3 and 1.8 cardiovascular risk cutoffs are arbitrary; and speakers’ views on whether increased hospitalization for heart failure is a DPP-4 inhibitor class effect. Lastly at the Novo Nordisk symposium, we continued to hear enthusiasm for the company’s GLP-1 agonist/basal insulin combination product, IDegLira, with Drs. Bernard Zinman, Chantal Mathieu, and Luigi Meneghini all characterizing it as the preferred method by which to initiate (!) insulin. This reinforced our view that so much therapy will be combination in form ten years from now (perhaps sooner, but definitely by that point) and that monotherapy may be mostly used in titration but not so much for long stretches for patients.

On the technology side, Abbott reprised its much-discussed EASD symposium on the Ambulatory Glucose Profile (AGP) and Flash Glucose Monitoring (our report from that day is our most widely read of this 2013). The content and speakers were nearly identical, and again, we heard plenty of “wows” from the audience at the thought of a 14-day sensor with no fingerstick calibration. As at EASD, Abbott very clearly positioned Flash Glucose Monitoring as a replacement for BGM, and with the advantage of collecting continuous glucose data for retrospective analysis using the AGP. We will be most interested to see how reimbursement works out for this device (in the best case, the studies will show powerful A1c reduction combined with less hypoglycemia and more time in target zone), as well as whether longer and larger studies confirm the sub-10% MARD seen in the first 12-patient feasibility study.

The BI/Lilly symposium was headlined by the announcement of a new 26-country, 17,000-participant survey developed in partnership with the IDF. The project has a tight focus: “What do people with type 2 diabetes experience in their early conversations with physicians?” This is a provocative question on many levels and we so look forward to what we will learn from both sides. Undoubtedly, the answers will vary dramatically across the world and we salute BI/Lilly for taking on this important initiative.. Other highlights from the day included Dr. Merlin Thomas (Baker IDI Heart and Diabetes Institute, Melbourne, Australia) on the value of fixed-dose combinations and a talk on elderly patients with diabetes from Dr. Brian Frier (University of Edinburgh, Scotland).

The day concluded with the Congress’ official Opening Ceremony in which the inimitable Sir Michael Hirst (IDF President) gave an impassioned talk about the state of diabetes, noting the shadow it is casting across every part of the globe and emphasizing it is no longer only a health issue but also a work issue, affecting society in untold ways. A special highlight of the opening was the procession of the IDF’s 140 Young Leaders in Diabetes from across the globe – there were 70 in Dubai and it is wonderful to see the growth in this spectacular program for the under-30 group of extraordinarily diverse patient leaders across the world.

Below you will find our top 10 highlights from Day #1, followed by a complete write-up of Dr. Steve Nissen’s presentation and panel discussion highlights from the three aforementioned symposia.

Top 10 Highlights

1) Dr. Steve Nissen (Cleveland Clinic, Cleveland, OH) had harsh words regarding the FDA’s recent decision to remove the restrictions on GSK’s Avandia (rosiglitazone). He stated that the decision was less about the science, and more a bureaucracy wanting to make a problem go away (in this case, the problem being the agency’s failure to appropriately notify the medical community and the public in a timely fashion after learning in 2005 that rosiglitazone was associated with an increase in cardiovascular adverse events). By saying that there was never a problem with the drug in the first place, Dr. Nissen suggested, the FDA effectively eliminates the grounds for criticism of its initial inaction. He argued that reanalyzing an old trial and coming to new conclusions (as was done with the re-adjudication of the RECORD study for rosiglitazone) is not good science, and he generally did not seem confident in rosiglitazone’s safety. Regardless of the agency’s recent decision, Dr. Nissen noted, the reality is that only a few thousand patients are currently on rosiglitazone, and the drug’s relevance will continue to fade (on this much, we would agree). 

2) Dr. Nissen described his role in the creation of the FDA’s CV guidelines for anti-diabetic agents as proposing a compromise between the need to ensure a candidate’s safety and to get new agents to the market quickly. Dr. Nissen characterized a pre-approval exclusion of a hazard ratio of 1.8 as being a relatively easy threshold to reach (i.e., requiring few CV events) such that it is not too cumbersome for industry, while the post-approval requirement for excluding a hazard ratio of 1.3 more strongly ensures a drug’s safety.

3) Dr. Nissen also remarked that the FDA’s selection of hazard ratio thresholds of 1.8 (pre-approval) and 1.3 (post-approval) had “no science behind it.” Instead, he asserted that these selections were based on an estimation of what would be a tolerable amount of risk for an anti-diabetic agent. In this case, we believe that the policy would be well served by allowing the threshold to be adjusted to based on an agent’s efficacy – benefit/risk analyses should be just that: analyses considering both an agent’s benefit and risk.

4) Several panelists during Novo Nordisk’s morning session on basal insulin therapy suggested that IDegLira might become the preferred approach for initiating (!) insulin therapy. Dr. Chantal Mathieu (Katholieke Universiteit Leuven, Leuven, Belgium) pressed that IDegLira is a physiological choice since it addresses both fasting and postprandial hyperglycemia. Dr. Luigi Meneghini (University of Miami, Miami, FL) noted that IDegLira could be particularly powerful for people not at control at baseline, given its dramatic efficacy. Furthermore, Dr. Bernard Zinman (University of Toronto, Toronto, Canada) highlighted that IDegLira could end up as the best drug to use after metformin, particularly if an HCP is planning on an injectable agent anyways. Likewise, Dr. Gregory Fulcher (University of Sydney, Sydney, Australia) asserted that any time an HCP considers using liraglutide, he or she should think about whether IDegLira might be an even better option. However, Dr. Mathieu warned that it might be challenging to convince payers and general practitioners to use an injectable combination therapy such as IDegLira early in the natural history of type 2 diabetes. She also wondered if some would question the approach of exposing patients to two agents in the disease’s early phases.

5) Dr. Nissen and Dr. Thomas Engstrøm (University of Copenhagen, Denmark) suggested that DPP-4 inhibitors – as a class – might increase the risk for congestive heart failure (CHF). As a reminder, SAVOR (the CVOT for BMS/AZ’s Onglyza) found that the agent was associated with a significantly elevated risk for hospitalization due to heart failure. Additionally, EXAMINE (the CVOT for Takeda’s Nesina) detected a non-significant trend towards an elevated risk for heart failure hospitalization. Dr. Nissen commented that meta-analyses that indicate CHF risk is a DPP-4 inhibitor class effect are “working their way into publication now.” He characterized the roughly 25% increase in risk as “probably real” and something HCPs should be taking into account when making treatment decisions. Similarly, Dr. Engstrøm’s “gut feeling” is that heightened CHF risk might be a class effect. Neither knew what the mechanism might be; however, Dr. Engstrøm remarked that some believe it could be an interaction between DPP-4 inhibitors and ACE inhibitors. Interestingly, despite the heart failure signal, Dr. Nissen described the DPP-4 inhibitor class as safe with regards to cardiovascular adverse events as a whole, although he noted that it certainly does not seem that they will prove to be cardioprotective. This conclusion falls in line with the sentiments expressed by SAVOR investigators who presented a sub-analysis of the heart failure findings at AHA 2013 Day #2. The heart failure risk appears to be real (SAVOR was a very large, rigorously adjudicated RCT, and the hospitalization for heart failure risk increased with increasing baseline BNP levels [a biomarker for risk of heart failure]), but the elevated risk of heart failure was not accompanied by an elevated risk of death or the trial’s composite MACE endpoint.

6) Abbott’s afternoon symposium focused on the Ambulatory Glucose Profile (AGP) and Flash Glucose Monitoring System. While the presentations and speakers were very similar to those given at EASD (pages 4-12 here), it was great to see the company’s continued focus on this exciting technology. Mr. Steven Scott (Division Vice President R&D, Abbott Diabetes Care, Alameda, CA) capped off the session with a presentation on Abbott’s new Flash Glucose Monitoring concept – as at EASD, the talk very clearly positioned it as a replacement for BGM for a “broad population” of patients with diabetes, though also as a product intended to overcome some of the limitations of CGM (cost, lack of reimbursement, data interpretation challenges). The system will be factory calibrated and wearable for 14 days – we heard plenty of wows from fellow audience members when this slide came on screen. As a reminder, to see the real-time glucose value, glucose trend arrow, and eight-hour trend graph on the Flash system, the reader is scanned over the sensor patch, which allows wireless collection (via RFID) and display of the glucose data on the color touchscreen reader device (many more details here). Mr. Scott showed the same accuracy data from the 12-patient study first presented at EASD – an overall MARD of 8.5% vs. YSI reference glucose and 93% of points in Zone A of the Parkes consensus error grid. He did not mention the 14-day sensor data shown at DTM 2013, which found a higher MARD of 13.9% in a 62-patient study (though hardware and algorithms were different in the two studies). We also heard no mention of any new trials, the CE Mark status, or if the product is still expected to launch in 2H14 in Europe.

• In seeing this presentation on Flash Glucose Monitoring for the second time, we were reminded of its potential to help patients with diabetes. In short, we think the system has the potential to “democratize” continuous glucose data and bring it to many more patients with diabetes. According to Abbott’s introductory slide, CGM currently has just 3% penetration – the footnote cited BBC, 2011 T1D Exchange data, dQ&A 4Q11 data , and Abbott Diabetes Care category revenue estimates. Given that this data is two years old, penetration is certainly higher now, approaching 10% of the type 1 diabetes population in the US. In a sense, the Flash system is also forced adherence, since patients don’t have to physically do anything to gather 14 days of continuous glucose data (aside from simply wearing the sensor patch). As we noted in our original report, this could be particularly appealing to patients and HCPs that have not embraced CGM for whatever reason, especially type 2s that are not at goal. Greater availability of continuous data could help HCPs make more informed treatment decisions, titrate therapy better, and overcome clinical inertia.
• As always, we were also reminded that cost and reimbursement will be critical factors in this product’s success. Abbott presumably plans to show significant clinical benefit to obtain reimbursement that is preferable to BGM. We believe the company is in a position to do that, especially if studies of the Flash system incorporate the Ambulatory Glucose Profile in a clinical setting and workflow. Being able to show much more about “time in zone” and “time in hypoglycemia” etc. should be particularly valuable.

7) During the Novo Nordisk symposium, there was explicit support for use of CGM to better characterize the glycemic impact of insulin degludec. In dissecting the results observed in trials of the new insulin, Drs. Athena Philis-Tsimikas (Scripps Health, La Jolla, CA) and Gregory Fulcher (University of Sydney, Australia) both used similar language: “If we had CGM data we could get more information…” and “A CGM in some of these studies would help determine what is happening exactly.” As we noted in our Closer Look report on the use of CGM in drug trials, this is a topic that we expect to get much more attention in the coming years from companies and regulators, especially now that newer generations of CGM are much more accurate.

8) Dr. Mark Cooper (Baker IDI, Melbourne, Australia) introduced a 17,000-participant, 26-country survey, which will investigate “early conversations” about type 2 diabetes between patients and HCPs. Developed by BI/Lilly and IDF, this survey will address four main questions:

• How can early conversations be improved by providing appropriate information?
• What do patients recall from these early conversations when they were diagnosed or when a new medication was added?
• What elements of early type 2 diabetes conversations are associated with patient well being and other self-reported outcomes?
• What solutions will support even better conversations?  We commend IDF and BI/Lilly for taking such an active role in such an important topic – we hope that the study’s large and global scope will illuminate ways to optimize conversations across both clinics and cultures.

9) Dr. Merlin Thomas (Baker IDI Heart and Diabetes Institute, Melbourne, Australia) gave a strong overview of the value of fixed-dose combinations (FDC), highlighting literature on their adherence advantages. He presented a 2012 meta-analysis (Han et al., Curr Med Res Opin) showing that use of an FDC improved A1c by 0.5% compared to the co-administered dual therapy – presumably due to better adherence – (“that’s as good as adding another agent”). Dr. Thomas also presented an interesting 2003 survey (Grant et al., Diabetes Care) of individuals with type 2 diabetes. Importantly, the major reason patients did not take their therapy was side effects (58%), followed distantly by difficulty in remembering doses (23%), cost (8%), and other reasons (11%). Of concern, only 23% of patients who had side effects reported the problem to their primary care physician. (We thought this was compelling data, though were also disappointed to see it dates back to 2003 – we surely think cost would come up higher in a more recent survey now that reimbursement is a greater stress upon the entire system. We also think side effects would be less of an issue given the entry of GLP-1 agonists, DPP-4 inhibitors, and SGLT-2 inhibitors since the data was collected – all classes with more benign side effect profiles than many of the traditional agents, particularly SFUs and TZDs.  Lamentably, Dr. Thomas’ remarks only mentioned DPP-4 inhibitor/metformin combinations – given BI/Lilly’s focus on SGLT-2 inhibition with empagliflozin, we hope to hear more in the future on SGLT-2/DPP-4 inhibitor FDCs.

10) Dr. Brian Frier (University of Edinburgh, Edinburgh, Scotland) reported striking statistics on the prevalence of type 2 diabetes among the elderly and inpatients. For instance, the 2011 NHANES dataset found that 26.9% of people 65 years and older had diabetes – a rate he called “staggeringly high.” In England’s 2012 National Diabetes Inpatient Audit, people with diabetes occupied 15% of inpatient beds (though not all of those people were admitted for their diabetes) and 84% of inpatients with diabetes were admitted as an emergency (as opposed to a planned surgery, etc.). This is particularly important when considering the impact of type 2 diabetes in the elderly, as the median age of an inpatient with diabetes was 75 years. Additionally, the median length of stay for a patient with diabetes was eight nights, and a 40% of people with diabetes experienced at least one medication error while in the hospital. Perhaps the scariest statistic he presented was that those who were victim to a medication error were twice as likely to have a severe hypoglycemia event (~14% vs. 7%). Certainly food for thought on how much there is to improve in the hospital setting – this is another area where we think CGM can make a real difference for patient outcomes and reducing burden on nurses.

Detailed Discussion and Commentary

Corporate Symposium: Cardiovascular Disease and Special Populations: Is There a Role for GLP-1? (Sponsored by Novo Nordisk)

The History of Cardiovascular Disease Trials in Diabetes and Overview of Ongoing Trials

Steve Nissen, MD (Cleveland Clinic, Cleveland, OH)

Dr. Steve Nissen gave an engaging presentation on cardiovascular outcomes trials for diabetes drugs, which was fairly similar to his very well-attended talk at this year’s EASD. He began by decrying the “gluco-centric” viewpoint that has ruled the diabetes community in past decades, which has lead to a dearth of rigorous CV outcomes data on antihyperglycemic drugs. He cited the PPAR agonists muraglitazar and rosiglitazone as examples of drugs that lower glucose but seem to be associated with increased cardiovascular risk. He suggested that the 2008 FDA CV guidance (for which he was a guiding force) struck the appropriate balance between bringing new treatments to patients in a timely fashion while ensuring CV safety and elucidating agents that may even be cardioprotective. He did, however, express misgivings regarding the FDA’s application of the guidance with regards to Novo Nordisk’s ultra long-acting basal insulin candidate Tresiba (insulin degludec), which, as an insulin, was intended by the 2008 FDA advisory committee to be exempt from the pre-approval CVOT requirement. In Dr. Nissen’s view, Tresiba is safe, and was the victim of an overly aggressive FDA. Turning to the recently released cardiovascular outcomes data for the DPP-4 inhibitors Onglyza (saxagliptin) and Nesina (alogliptin), Dr. Nissen stated that the Onglyza and Nesina appear to be safe with regards to cardiovascular safety as a whole, although he characterized the heart failure signal seen with Onglyza as robust. Dr. Nissen touched upon this subject, as well as the FDA’s recent removal of restrictions on rosiglitazone, in more detail during the session’s excellent panel discussion.

• Dr. Nissen began by emphasizing the “knowledge gap” regarding the cardiovascular impact of antidiabetic drugs. In his mind, this lack of data is especially disappointing given that oral antidiabetic drugs have been used for approximately half a century. He attributed that absence of information to the regulatory and medical community’s “gluco-centric” mindset: the “irrational” belief that lowering blood sugar by any means will produce a reliable reduction in outcomes. Attempts to challenge the gluco-centric view, such as the UGDP study group’s finding that tolbutamide was associated with substantially increased mortality, have generally attacked. As a result, sponsors stopped conducting long-term cardiovascular outcomes trials, leading to a dark age devoid of robust CV data for diabetes. During the 1970-80s, diabetes patients were not seeing anywhere near the same level of improvement in coronary heart disease mortality as nondiabetic individuals (risk actually increased by 11% in female diabetes patients; Gu et al., JAMA 1999). Major outcomes trials failed to support the theory that antihyperglycemic agents reduced CVD — Dr. Nissen characterized metformin’s positive results in the obese patient subgroup in UKPDS (upon which the drug’s status as a first-line therapy is largely based) as not very robust.
• Dr. Nissen believes that muraglitazar (BMS/AZ’s PPAR-alpha/gamma dual-agonist that the company discontinued after phase 3 trials in 2006 due to CV safety concerns) and rosiglitazone provided a wake-up call regarding the potential cardiovascular risks of diabetes therapies. Muraglitazar demonstrated powerful glucose-lowering effects during clinical testing and was close to approval, but a Cleveland Clinic analysis headed by Dr. Nissen found that the drug was associated with a significant increase in multiple CV composite endpoints. Dr. Nissen found a great deal of fault with the FDA’s handling of rosiglitazone (GSK’s Avandia). In his view, the drug’s demonstrated effect of raising LDL cholesterol should have forced a pre-approval outcomes trial. He characterized the FDA’s decision to approve the drug even though clinical data demonstrated a relative risk of 1.8 (not statistically significant, but trending towards significance) as irresponsible. Even when a GSK internal analysis of all studies on rosiglitazone found a 31% statistically significant increase in ischemic CV risk, the FDA did not react strongly enough, in Dr. Nissen’s view. 
  
  • Dr. Nissen noted that pioglitazone (Takeda’s Actos) appears to have, if anything, a slight cardioprotective effect. He stated that the difference relative to rosiglitazone is likely due to the two drugs’ different effects on lipids: rosiglitazone raises triglycerides, while pioglitazone decreases triglycerides (and appears to raise LDL cholesterol less than rosiglitazone). The overarching lesson from the TZD class is that two drugs with seemingly similar mechanisms can have different effects on cardiovascular morbidity and mortality.
• A central regulatory dilemma for diabetes drugs was how to balance the need to bring new agents to patients in a timely fashion and the need to ensure CV safety. The solution that Dr. Nissen suggested to the FDA became the agency’s 2008 CV guidance requirement for pre-approval CV outcomes data. The result of this guidance, in his mind, is the betterment of science for clinicians and patients (while that much may be true, the haphazard implementation of the CVOT requirement can also be seen as an immense new barrier for the development of diabetes drugs that threatens to stifle innovation and any additional risk-taking in the field). Dr. Nissen emphasized that there are currently around 100,000 patients enrolled in CVOTs for diabetes drugs, providing a “spectacular opportunity” to learn more about the CV (and other) effects of diabetes drugs.
• While Dr. Nissen expressed confidence in the 2008 FDA CV guidance, he expressed misgivings about certain instances of its application by the FDA. Notably, he stated that he was “disturbed” by the FDA’s poor application of the guidance with regards to Novo Nordisk’s basal insulin candidate Tresiba (insulin degludec). He noted that clinical trial data was essentially neutral with regards to MACE, but instead of accepting that finding, the FDA re-analyzed the data using a number of different definitions. Echoing a quote he delivered at EASD, Dr. Nissen remarked that “If you torture the data, eventually it will confess,” suggesting that the FDA went looking for an issue. Notably, he also emphasized that the advisory board for the 2008 CV guidance exempted insulin from the pre-approval CVOT requirement, as insulin is an endogenous natural compound. The fact that European and Japanese authorities approved Tresiba, in his mind, casts an added shadow over the FDA’s decision. We continue to be very surprised by the Tresiba delay at FDA and have seen more and more negative downstream effects of the decision.
• Turning to incretin therapies, Dr. Nissen reminded the audience that both SAVOR-TIMI 53 (for BMS/AZ’s Onglyza [saxagliptin]) and EXAMINE (for Takeda’s Nesina [alogliptin]) were about “as neutral as any study can be” with regards to their primary CV endpoint. However, he characterized the signal for hospitalization for heart failure seen in SAVOR as fairly strong. Notably, despite this signal, he stated that it is reasonably safe to assume that DPP-4 inhibitors are neutral for CVD and are safe overall, although they do not appear to be cardioprotective as was initially hoped. With five CVOTs underway for GLP-1 agonists, Dr. Nissen forecast that we will learn a great deal about the class in coming years, and expressed hope that the class may prove cardioprotective.

Panel Discussion Highlights

Q: We received many questions about the FDA’s recent announcement regarding the reversal of restrictions on rosiglitazone. What is your opinion? Were you wrong before or was the FDA wrong?

Dr. Steven Nissen (Cleveland Clinic, Cleveland, OH): The FDA seems to be unable to get its act together. This decision was more about the FDA than it was about the science. The agency had known about the risk since around 2005, when they were informed by the company that rosiglitazone increased CV events, but it failed to warn the public. Subsequently, the agency has spent much of the last seven to eight years trying to explain what happened. They think that the best they can do is to say that there was never a problem to make the problem go away. The reality is that the drug won’t be used much moving forward. It’s down to around 3,000 patients worldwide. I do not expect that anybody is going to start using it again. This was more about the bureaucracy wanting to make a problem go away. You can’t reanalyze an old clinical trial and come to new conclusions.

Dr. Eduard Montanya (University of Barcelona, Barcelona, Spain): I have to tell you that there were many, many questions on this issue. I think your point was clear enough.

Q: What about the increase seen in heart rate that has been presented; what are the possible implications of that?

Dr. Thomas Engstrøm (University of Copenhagen, Copenhagen, Denmark): We know that GLP-1 RAs are present numerously in the sinus nodes. That would be the most logical explanation for the increase in heart rate. We don't know about the long-term effect of this. In the trials it appears to not be a big problem; however, as cardiologists we know that a long-term increased pulse could be problematic, but this is usually seen when heart rate is increased by more beats than that seen with GLP-1 RAs.

Q: Can you comment further on the effects of the GLP-1 receptor in the heart?

Dr. Martin Haluzik (Charles University, Prague, Czech Republic): I think it’s a very interesting question that hasn’t been rigorously studied yet. Regarding the pattern of heart rate, we don’t really know yet. As we speak, we are conducting a small trial on exenatide, linagliptin, and liraglutide looking at changes in heart rate and blood pressure. Hopefully we will have some answers soon. Regarding the receptors, I think there has been some confusion regarding expression for receptors in different organs due to lack of specific antibodies. It appears that there are receptors in the vasculature and myocardium, but less than we originally thought. It is indeed in the atrium and AV node, so the pathways may go in that direction.

Dr. Richard Pratley (Sanford Burnham Medical Research Institute, Orlando, FL): The one thing that I was going to comment on was that initially people thought that the increased heart rate could be a reflex to a decrease in blood pressure; however, further evidence has suggested that it is a direct effect.

Q: Lets clarify the new rules for the FDA approval of drugs; why were the hazard ratios of 1.3 and 1.8 selected?

Dr. Nissen: First of all, there is no science behind it; it was a question of what amount of risk would be tolerable. Many people thought that given all of the problems we had seen with these drugs, we should require a full outcome trial prior to approval. I proposed the 1.8 rule as a compromise. I wanted us to bring drugs to the market in a timely fashion but also knowing about their safety. We know that ruling out a 1.8 risk is not very precise but that it is better than nothing as long as you then have the 1.3 ruled out later. Its important on the industry side, since getting say 122 events in a clinical trial is relatively easy but getting 620 events takes a long time. The idea was to get the drugs to the market but make sure that they are safe.

Q: Can you talk about the results of SAVOR-TIMI 53, particularly the heart failure finding?

Dr. Nissen: Although it was seen primarily in one of the trials [SAVOR], there was a trend in the other [EXAMINE]. There are meta-analyses working their way into publication now indicating that it is a class effect, the roughly 25% increase in risk for hospitalization for heart failure with these drugs. I cannot tell you why; I do not understand the mechanism. It’s probably real, and it’s something that should be taken into account when taking patients with impaired cardiovascular function.

Q: Thomas, do you think that the cardiovascular heart failure hospitalizations might be a class effect?

Dr. Engstrøm: Maybe. I have heard some thoughts about a possible explanation – it might be that there is some interaction with ACE inhibitors. I think that it is probably too early to say, but my gut feeling is that it might be a class effect.

Q: Do you think that the drugs’ different kinetics could result in different cardioprotective effects?

Dr. Haluzik: I definitely think that the potency at the receptor site is important. This difference between the different analogs could have an impact.

Corporate Symposium: Basal Insulin Therapy – Combining to Target (Sponsored by Novo Nordisk)

Panel Discussion Highlights

Q: IDegLira – where are you going to use it?

Dr. Bernard Zinman (University of Toronto, Toronto, Canada): We are at a time when the interaction between a basal insulin and a GLP-1 is being understood and represents a tremendous clinical opportunity. There are people who are on large doses of insulin and not doing well; there, adding a GLP-1 is clearly a very valuable thing. I think that IDegLira might end up being the preferential insulin to start people with type 2 diabetes on. With IDegLira, you have made that insulin more effective and removed two of the things we don't like about insulin – weight gain and hypoglycemia. It is remarkable that that ratio works very well with the vast majority of individuals. It might be that the company will produce other ratios. Or maybe we have just been lucky that the ratio chosen might be the sweet spot. I think we need to do more studies to determine that.

Q: Why is this not the product you would use after metformin?

Dr. Zinman: It might very well be. We need more data. We need the results from DUAL 2. It may very well turn out to be the best product after metformin, particularly if you are going for an injectable.

Dr. Chantal Mathieu (Katholieke Universiteit Leuven, Leuven, Belgium): I fully agree. When we saw data on IDegLira for first time, we were blown away. For us endocrinologists and diabetologists it makes sense to want to treat the islet dysfunction in its entirety. I also believe that IDegLira may be the best way to start basal insulin. That being said, regardless of what we feel, we will have to convince non-specialists and payers to introduce an injectable combination therapy early on. Some might ask why we want to expose patients to two pharmacological agents in the beginning. But it really makes sense –from a pathophysiological standpoint it’s a logical combination to use early in the progression of the disease.

Dr. Zinman: Greg pointed out that in some of the studies that are treat to target both arms get the same A1c results of 7.0%. That is what we expected here, but with IDegLira we ended up with an A1c of 6.4%. That means that a vast majority of people were now at target. It means that a vast majority of people reached target and that they had less hypoglycemia and weight gain.

Dr. Jiten Vora (University of Liverpool, Liverpool, UK): It is the caliber of the change that blows you away.

Q: Any other comments about IDegLira?

Dr. Luigi Meneghini (University of Miami, FL): If you look at the statistics in terms of when insulin is started, it is often at the high 8% and low 8% A1c range, so I could see a therapy that could bring down A1cs by around 2% as an effective way to get to target for most individuals who are not properly controlled.

Dr. Vora: Given the data in terms of weight and hypoglycemia is this is a fire and forget therapy, or a primary care therapy?

Dr. Meneghini: I don't think anything is a fire and forget therapy but it clearly offers advantages.

Dr. Thomas Pieber (Medical University Graz, Graz, Austria): I think it’s attractive to have two different pharmacological modes of action combined into one injection. It lowers fasting plasma glucose as well as postprandial glucose. The idea to use it quite early is something we should consider.

Dr. Gregory Fulcher (University of Sydney, Sydney, Australia): I think it will change how we do things. We are moving towards sparing our patients hypoglycemia for a long period of time. You can argue where you are going to do it, but if you are going to introduce an injectable why not have it be IDegLira? You have the added advantage of getting to target, less weight gain, less hypoglycemia. So I would think that anytime that you are considering liraglutide, you should be looking at IDegLira at that point of time.

Q: Why might we be seeing more of a reduction in fasting plasma glucose with insulin degludec?

Dr. Athena Philis-Tsimikas (Scripps Health, La Jolla, CA): It’s interesting that this was noted in most, if not all of the studies. When you think about A1c, the contributors to A1c include hypoglycemia, fasting plasma glucose, and postprandial glucose. You might think that perhaps postprandial levels were higher in the trials, and that fasting plasma glucose levels were lower. If you look at the published data, the postprandial glucose levels were generally the same between groups, so it doesn’t look like that is the reason. Hypoglycemia rates were lower with insulin degludec, so perhaps that contributed to balancing out the A1c as well. When trials are done you often have more questions than when you started. This is something to explore further. Remember, we didn’t have glucose time points during the middle of the study. If we had CGM data we could get more information, and those studies are in progress.

Dr. Fulcher: I think that the same question has been asked with the premixed studies. You can come up with a more theoretical explanation with premixed insulins where you could have a balancing out of many factors – lower nocturnal hypoglycemia, improved FPG, etc. – to get the same A1c. A CGM in some of these studies would help determine what is happening exactly.

Q: What about using IDegAsp (insulin degludec/insulin aspart) in type 1 diabetes?

Dr. Fulcher: I think that the positioning of IDegAsp is largely as insulin for patients with type 2 diabetes. That’s fairly clear. However it does help in type 1 to have more tools at your disposal in terms of insulin delivery. I’m sure there will be type 1 diabetes patients for whom we may want to use IDegAsp. Overall, I think that basal-bolus or insulin pump therapy are preferred options for type 1 diabetes, but the odd type 1 diabetes patient may find this useful. I think there is data being gathered and analyzed in the type 1 diabetes population so we’ll know more soon.

Dr. Zinman: I agree that this is not as much for type 1 diabetes. In type 1 you want to modify basals and premeal boluses; having them together would be a burden.

Q: The other question that comes up is IDegAsp being taken three times a day – for example in countries that have three large meals a day – how would you handle this situation?

Dr. Fulcher: If I was in that situation and I had a patient who had pretty good control but there was a mid-day meal that was less than ideal, then I might add in insulin aspart at the time of that meal rather than adding basal insulin. For me the attractiveness in that situation would be to go down having additional aspart for that third meal.

Q: Can you comment on the definition of hypoglycemia at 3.1 mmol/l (~56 mg/dl) for the study, rather than 3.9 mmol/l (~70 mg/dl)?

Dr. Philis-Tsimikas: Don’t forget that these were clinical trials, and the targets were 4 to 4.9 mmol/l (~72 to 88 mg/dl). To have a hypo definition of 3.9 mmol/l doesn’t leave you much room to differentiate between hypoglycemia and reaching target, which is why 3.1 mmol/l was used. That same definition has also been used in past studies, making it better for consistency. A consistent definition also allows meta-analyses to be conducted. Counterregulatory hormones kick in around that levels, and symptoms are clear at that level, so that’s a level that makes sense for clinical trials.

Q: In terms of meals some people inject their insulin in relation to meals rather than a set time.

Dr. Meneghini: The flexibility of meals is ingrained in a basal bolus approach. I would be curious with a mixed insulin if you could maybe adjust the time at which you inject IDegAsp, for example, if you are having the largest meal during the week at dinner but at lunch on Sunday. I think you could.

Q: How do boluses need to be handled when type 1 diabetes patients are on insulin degludec?

Dr. Mathieu: In type 1 diabetes, there are still some learning points in terms of how we need to handle bolus insulin. In studies in type 1 diabetes patients it is clear that there was an increased risk of confirmed hypoglycemia at the beginning of the studies when patients switched to insulin degludec. From reanalysis of the data, it seems that there was an especially high risk for hypoglycemia after the morning bolus. We are planning studies with Novo Nordisk to see what we should do in type 1 diabetes patients regarding the morning bolus. Should we decrease it when we switch to degludec? In type 1 diabetes, we need to think differently about short-acting insulins when we use insulin degludec as our basal. That’s still a learning curve, and hopefully we will be able to study that more.

Dr. Zinman: I agree with Chantal 100%. In the old day, we did not have that and the basal replacement was related to the prandial insulin.

Dr. Philis-Tsimikas: There was no difference in severe hypoglycemia, however, in case that was a question in anyone’s mind.

Q: Can you comment on the nausea seen with IDegLira?

Dr. Zinman: I think what was remarkable about IDegLira is the low incidence of nausea. Because you’re dosing based on the insulin half of the compound, as you saw from the dose schedule, the increases are pretty slow. The increase in liraglutide is slower than the titration for liraglutide monotherapy, resulting in less nausea. It’s good learning for using liraglutide in clinical practice; maybe we should be titrating liraglutide more slowly in some patients.

Corporate Symposium: Modern Management of Type 2 Diabetes: Experts’ Perspectives (Sponsored by BI/Lilly)

Panel Discussion Highlights

Q: In the armamentarium of drugs, where would you put an SGLT-2 inhibitor in the treatment paradigm?

Dr. Vlado Perkovic (George Institute for Global Health, Sydney, Australia): It’s an exciting class of agents. But we need to be careful. We don’t yet have data on the impact on major clinical outcomes that we’re trying to generate benefit for – cardiovascular, renal, and others. Other safety questions need to be addressed in larger studies. I would put them behind metformin, and probably behind DPP-4 inhibitors. Down the track, it’s possible that they might be second-line or third line, but that remains to be seen.

Dr. Juliana Chan (Chinese University of Hong Kong, Hong Kong, China): I believe in early aggressive treatment. These new classes reduce A1c without hypoglycemia. That is a golden moment to treat people earlier and safely. I would like to see these new drugs being used earlier.

Q: Should HCPs ever consider initially introducing fixed-dose combinations?

Dr. Merlin Thomas (Baker IDI, Melbourne, Australia): Absolutely, yes. There are real opportunities to increase compliance by using a fixed-dose drug. One phrase that Dr. Ralph DeFronzo (University of Texas Health Sciences Center, San Antonio, TX ) says is: “We’re treating diabetes; we’re not treating A1c levels.” Diabetes is a complex disorder with multiple pathologies, including not only changes in beta cell functions, but also changes in hepatic functions, which are sensitive to treatment with metformin. We should be treating diabetes with a combination approach tied to pathogenesis rather than tied to a reduction in A1c levels. We’re starting to see a movement toward that type of thinking as HCPs are coming in with combination therapies that don’t cause hypoglycemia or weight gain and are easy to use. Combination therapies are beneficial because they are easy to use and don’t require intensive management.

Q: Do you think we should have longer studies of SGLT-2s – lasting a few years – to address the increase in UTIs?

Dr. Perkovic: Those studies are certainly underway, so we will get the data. The excess of UTIs is very clear. The important thing to remember is that about 5% of people with diabetes got UTIs even without taking an SGLT-2. That went up modestly to 6-7% with these agents. If you have a patient who is struggling to treat UTIs, you might want to make sure you get that under control. But most people won’t get a UTI.

Q: There is data that shows that DPP-4 inhibitors provide more benefit in Asian patients. How convinced are you by these results? How good is the evidence, and why do Asian patients do better with DPP-4 inhibitors?

Dr. Chan: There is emerging data from trials that examine inter-ethnic differences in pathology; in normal subjects with normal glucose tolerance, Asian patients have higher glucose excursions even within the normal range. They have higher insulin resistance and a lower beta cell mass to overcome it. Looking at a meta-analysis of many trials, DPP-4 inhibitors seem to have multiple effects.

Q: Could you change the molecular structure of SGLT-2s to be more site specific? That could lower the side effect profile and make them more selective for glucose.

Dr. Perkovic: As a clinical researcher, I have no idea.

Dr. Thomas: Dr. Ralph DeFronzo wrote a very exciting review in Diabetes Care on why SGLT-2s don’t cause 100% inhibition. He argues that it has to do with changes in the availability of the drug at the site in the proximal tubule. Some is internalized, and it may be possible to get even better SGLT-2 inhibition. You are absolutely right. They are currently working on better ways to inhibit SGLT-2. But what we have right now are the promising first line of agents. Phlorizin was like the first Apple computer. Now we have newer versions with dapagliflozin and canagliflozin.

Q: Do you think that when you make a fixed-dose combination with metformin you will use XR rather than regular? Would this improve compliance?

Dr. Thomas: XR means that patients would only have to take this pill once daily, which could be beneficial. However, this is the biggest tablet your patient will ever have to swallow, and, typically, patients don’t like it. Smaller tablets are better – the size tends to be alarming to a lot of patients. There are pluses in terms of timing, but there are minuses in terms of size. There are no head-to-head studies saying that one is better than the other. You do need to make sure you do a careful dose titration of metformin, however, because if a patient develops GI side effects, you lose the opportunity to use a really great drug. Using XR might increase exposure to more complications.

Corporate Symposium: Improving Cardiovascular Outcomes: An Essential Aim of Type 2 Diabetes Management (Sponsored by BI/Lilly)

Panel Discussion Highlights

Q: Diabetes is second major risk factor for cardiovascular events. Why is it so hard to prove that treating diabetes improves cardiovascular risk? Why is it so hard to prove the safety of these drugs, and why do these studies fail to show the benefits of these drugs?

Dr. Karin Jandeleit-Dahm (Baker IDI, Melbourne, Australia): It’s true that it’s hard to show a correlation with cardiovascular disease. As I showed, the thresholds for macrovascular are a little higher than they are for microvascular risk; however, in a more recent trial, it has become evident that there are a range of pathways for patients with high glucose levels that ultimately lead to cardiovascular complications.

Dr. Michael Lehrke (University of Munich, Munich, Germany): I think the way cardiovascular studies are driven by the FDA is just based on how the FDA wanted to do it. This is unfortunate because the trials require a lot of investment, and they still go for too short of a time. It takes a while for diabetes drugs to prove cardiovascular benefit; in that sense, these studies are really unfortunate. However, in the future there will be additional cardiovascular endpoints. Right now, studies go for 18 months – these don’t really prove long-term benefits.

Dr. Juliana Chan (Chinese University of Hong Kong, Hong Kong, China): Epidemically they are related, but clinically there is not a correlation between pure blood glucose lowering and beneficial effects on CV risk. Perhaps new trials will deliver a story that lowering glucose will benefit CV risk.

Corporate Symposium: Flash Glucose Monitoring and Ambulatory Glucose Profile (AGP): Expanding the Glucose Story Beyond A1c (Sponsored by Abbott)

Panel Discussion Highlights

Dr. Richard Bergenstal (International Diabetes Center, Minneapolis, MN): A MARD under 10% is remarkably good. When I read the original paper, the MARD was around 13% in the first study, but the most recent data has this value under 10%. What’s happening there? How is it getting better, and what is the real number?

Mr. Steven Scott (Division Vice President R&D, Abbott Diabetes Care, Alameda, CA): The first study was a feasibility study; it was not meant to be a prospective study to look at calibration. We did a retrospective analysis of the calibration. The second study used a sensor that was optimized. Essentially, the first study did not use the optimized sensor, and there was no prospective analysis.

Q: I’m only asking because there are a number of different manufacturers and they all have different reports. But already in this meeting, you’re producing data in different ways.

Dr. Roger Mazze (International Diabetes Center, Minneapolis, MN): You’re making an interesting observation. From a development perspective, we want to see one simple form that everyone agrees to. When we had this expert meeting, some of the manufacturers were holding back and saying variability in reporting was good. I could not see any positive in it. We’re taking them slowly step-by-step. From our side, we do a lot of research. They’ll standardize first in publications, and hopefully all the manufacturers will accept a standard view.

Q: Can we do an AGP from SMBG data for the 97% of our patients that aren’t on CGM?

Dr. Bergenstal (International Diabetes Center, Minneapolis, MN): We do have AGP for SMBG. It’s just connecting the dots with a nice smooth line. But we could make it for someone who is a good tester and tests throughout the day. You would need several months of data. But we will start to see a similar set of displays for SMBG.

Q: In the development of the AGP, there were a number of elements that included the plot and the day-by-day view and the quantitative data. The last three speakers didn’t use those elements – they only showed the plot. Is the AGP all of those elements, or just the visual plot?

Dr. Mazze: It’s meant to be all three components. When it was used in Germany with Oliver, it only had the AGP plot on it. As we’re developing what we’d like to consider a standard form – like an ECG – we’re defining the three elements. There was a group of 30 experts that met. Some wanted to go to a lower common denominator – mean and standard deviation. Others wanted a higher denominator – with time in hypoglycemia, etc. We compromised and have a top panel with one line of quantitative data, the AGP plot, and individual days at the bottom.

Q: Do you have any idea on whether or not you will make a version of the AGP for use with sensor-augmented pump therapy? It might be nice to have insulin data in addition to blood glucose data.

Dr. Mazze: We’ve produced many AGPs for pump patients. I’ve always felt that patient using pumps would benefit from an AGP by looking at glucose values before and after initiating pump or closed-loop therapies. An AGP for pump therapy is needed, but we don’t have enough experience with it yet. I think we need someone to develop it for us, or maybe we’ll need a co-developer. We work closely with a group over at the Mayo Clinic that is creating a closed-loop system. They are familiar with the AGP, so maybe they will look into developing something like that.

Dr. Howard Wolpert (Joslin Diabetes Center, Boston, MA): The AGP is not exclusive. It has its value in identifying trouble spots, but you can use other data representations to get answers to specific questions. If you put too much information on a single chart or representation, then the data gets complicated and difficult to interpret.

Q: I’m from Demark and am not too familiar with AGP. Can patients use the AGP? I don’t think this profile has any value if the patient can’t use it at home.

Dr. Mazze: Patients can use these profiles in the office – Dr. Schubert has shown us that. I don’t think there is any reason why patients cannot access their AGP at home and analyze it whenever they would like. There are patients would want to do this frequently, and there are patients who only want to do this once or twice a week. A simple, single view document would be great advance. Sometimes you can’t make a decision with too many elements.

Comment: Sometimes you can make a wrong decision with too little information.

Dr. Mazze: I think the CGM with AGP analysis has clarified more than it has confused. Additionally, you can research pages that go beyond the first AGP report, such as reports for sleep and weight. Even reports on individual events can be done, as well. Patients viewing the graphics themselves have been of enormous help; they are encouraged to identify their problems and identify what behaviors may be associated with the event.

Dr. Bergenstal: It seems like Denmark is moving where the US is moving. Work is being done between visits and not just at a patient’s visit with the HCP. The AGP is a key communication tool that can be used for remote analysis.

Dr. Ragnar Hanas (Sweden): Thank you very much for introducing this tool. I’d like to test AGP. My question is about the number of days – you showed three days vs. two weeks to predict the next month. Is it better to do two or four weeks?

Dr. Bergenstal: In Roy Beck’s paper that I showed, he did three months, and then went backwards. The one-month data didn’t add much more than two weeks.

Dr. Hanas: Two weeks could actually be better than four weeks, since life changes.

Dr. Bergenstal: Four weeks didn’t add much more than two weeks, and as you said, two weeks might be better because it’s more recent. The possibility of having a two-week sensor also brings this two-week ideal to reality. With sensors, we used to say, “I’ll get just a week of data. Or I’ll get three days and three days for six days.” The possibility of two weeks would be a remarkable advance.

Q: What are the different types of data being collected with the AGP vs. the Flash Glucose Monitoring sensor? Aren’t there flaws when you try to use the AGP with BGM data? Additionally, Dr. Mazze highlighted that CGM and AGP are not globally adapted because of accessibility issues. Why don’t we program the AGP into an app?

Mr. Scott: Accessibility is important, and we need a system that is viable to blood glucose monitoring. I agree that BGM is not going to provide enough comprehensive data to provide insight for treatment; that’s why we’ve come up with product that provides data for 14 days – we want this to replace BGM. Your other question addressed technology moving forward. The Flash Glucose Monitoring System is only introduction into this category. We will take this research concept and move forward with the times. There will be further application of this product concept more in line with your thoughts about apps.

Dr. Mezze: I have a point of clarification. If the device showed a single glucose reading of 147 because the reader was passed over the sensor, will this be the same reading one minute later?

Mr. Scott: When there is a newly available value, the reader will pull that value.

Dr. Mazze: There’s no difference in collection from the standard CGM, which is getting readings every 5 minutes?

Dr. Scott: Right.

Dr. Mazze: Within a framework of an hour, the measurement is essentially the same as CGM, but there is a big different because of the storage of the data.

Dr. Scott:  The sensor has limited storage, but the reader pulls from the sensor; the reader has no limitations on storage.

Dr. Mazze: We came up with the 14 days because we were challenged for researched purposes. We were looking for the minimum number of days that could be used for the predictive model. Patients with type 2 diabetes who come into the International Diabetes Center might be sent home for two weeks of monitoring, and then we would make a clinical decision. There needed to be a tool for patients with type 2 diabetes when you need a much more accurate picture in order to make sure the appropriate therapy is used; you can’t just use CGM with these patients. When you prescribe a GLP-1, you can tell after a week or two if it is not working; similarly, we can determine very quickly if patients are in danger of hypoglycemia when we put them on an insulin. The 14 days comes from our research and proved effective in two independent studies that showed that 14 days of data is predictive for up to three months with an 80-90% accuracy. You can’t predict to the next day with the current data. As for the app, we’re expecting you to develop that because some of us can’t even read the apps.

Q: What is the lag time with Flash Glucose Monitoring? And with the 14 days of sensor wear, is there a drop off in accuracy in the first one or two days and towards the end?

Mr. Scott: There is a one-hour startup for the sensor. We’re seeing very robust accuracy between day one and day 14. We feel that once the sensor is run through the one-hour startup, we have robust accuracy for the full 14 days. The physiological lag on CGM has been shown and discussed. People are talking about 8-15 minutes. It’s an interstitial fluid physiologic-based lag. Flash Glucose Monitoring will measure the interstitial fluid.

Dr. Wolpert: There was a recently published paper from the Mayo Clinic, where they measured interstitial fluid lag time using radiotracers. The physiologic lag time was only five to six minutes. With current CGM devices, what we’re seeing is software processing also introducing a lag.

-- by Adam Brown, Hannah Deming, Hannah Martin, Manu Venkat, and Kelly Close