Good evening from San Francisco! Two things tonight.

News just in that Roche has purchased start up disposable pump manufacturer Medingo for $160 million plus up to $40 million in bonus payments. While this is a far cry from the close to $4.3 billion Medtronic paid for Minimed (including MRG) back in the day (2001), or the ~$900 million Roche paid for Disetronic a couple of years later (2003), this is a very fast exit for Medingo, particularly given the technology remains largely untested in humans. Given that J&J paid just over $500 million for Animas, a high-margin pump on the rise that had already amassed market share over 5%, the $160 million seems a very good deal for Medingo management. That was the main difference compared with both other deals - MiniMed in 2001 still owned the market for pumpers; Disetronic was a clear #2 at that time. The timing for Medingo launch has been delayed and is now said to be by 2012. We do very much see increased Roche activity in diabetes technology as a major positive. We are very curious about the margin structure for the company and also about regulatory approvals (the acquisition is subject to approvals - the company already has US approvals). More info to follow as we learn more!

Second, our notes from the second and final day of the Clinical Diabetes meeting are below and detailed views attached. There were some very strong speakers but less new information and fewer new insights on day #2 overall in our view. Among other talks, we found quite interesting listening to Dr. Zach Bloomgarden on new drug classes, CDE Jane Seley on insulin pen and pump use in the hospital, and Dr. Lori Laffeel on the motivation for initiating/discontinuing pump therapy and basal/bolus dosing strategies, focusing on pediatric populations.

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Clinical Diabetes Technology Meeting—6^th Annual Conference

April 9-10, 2010; San Antonio, TX Day #2 Full Notes Draft

Executive Highlights

The second day of the 6^th Annual Clinical Diabetes Technology meeting in San Antonio, Texas focused on technologies for diabetes therapy. The nearly 300 attendees arrived eager to hear discussions on long-standing debates and hot-topics such as tight glycemic control in the hospital and optimal A1c targets in type 2 diabetes. Dr. Vigersky and Dr. Ward offered valuable insights on the treatment of type 2 diabetes, one through the lens of appropriate A1c targets and the other through an examination of the importance of insulin kinetics and post-prandial glucose control. Drs. Fahy and Korytkowski addressed the challenges to achieving good glycemic control in the intensive care unit and how the definition of good control in the hospital is still quite controversial. During the morning session we also thoroughly enjoyed a very timely review of type 2 diabetes drug safety, delivered by Dr. Gabbay, and a stellar overview of new drugs for type 2 diabetes by Dr. Bloomgarden. Educator Jane Jeffrie Seley discussed practical consideration in using insulin pens and insulin pumps in the hospital, while Stacie Haller-Wich complimented with a discussion of outpatient use of insulin pens and pumps, and Dr. Laffel probed the topic of fine-tuning insulin dosing on an insulin pump. The day was rounded out by discussions on prevention of weight gain and type 2 diabetes by Dr. Williamson and Dr. Lustig. Below we feature full notes from very valuable day of learning.

Highlights

• Robert Gabbay, MD, PhD (Pennsylvania State University, Hershey, Pennsylvania) tackled a topic that has been of enormous interest in the past year—diabetes drug safety in type 2 diabetes. After giving a brief overview of the new (2008) FDA cardiovascular (CV) risk assessment requirements, he went on to review several specific drugs, commenting on safety concerns that have arisen. In his discussion on sulfonylureas, he highlighted concerns about hypoglycemia and weight gain, and focused on CV concerns that plagued older versions of the drug but do not appear to be an issue with newer sulfonylureas. Moving on to metformin, Dr. Gabbay covered the CV benefits associated with metformin (a 39% reduction in myocardial infarction in UKPDS) and recent data suggesting there should not be concern over congestive heart failure or lactic acidosis. On TZDs, Dr. Gabbay discussed class-wide concerns such as fluid retention, congestive heart failure, and osteoporosis, before moving on to agent-specific concerns surrounding rosiglitazone (GSK’s Avandia). GLP-1s, once believed to be relatively side effect free, have recently raised concern over pancreatitis and safety problems in patients with renal insufficiency. Another major concern with these drugs (at first believed to be exclusive to liraglutide but has not been ruled out as a class-effect) is the c-cell carcinomas observed in rodents, but this issue has not yet been observed in humans. In closing, Dr. Gabbay turned to the well-known cancer scare with insulin in type 2 patients, originating from a set of retrospective studies published in Diabetologia in late 2009. After discussing these concerns and methodological problems with the retrospective studies, he emphasized that most large randomized controlled trials do not support an increased risk for cancer with the use of insulin. A poll of the audience revealed they are most concerned about the safety of rosiglitazone and the TZD class in general, and have the lowest concern over the incretin class.
• Zachary Bloomgarden, MD, FACE (Mt. Sinai Medical Center, New York, New York) delivered a whirlwind tour of novel technologies in development for the treatment of diabetes and obesity, focusing on the efficacy and safety profiles. He began by reviewing the effects of two therapies, FDA-approved rapid-acting bromocriptine (VeroScience’s Cycloset) and salsalate, which have demonstrated modest improvements in glycemic control. He continued to discuss other classes of drugs in the pipeline, such as glucokinase activators (GKA) and glucagon receptor agonists; notably, Dr. Bloomgarden highlighted the adverse side effect profile of Merck’s GKA candidate MK-0599 and we look forward to further information on the safety profile of GKA products. Dr. Bloomgarden also touched on Biodel’s VIAject and the potential of intradermal administration of insulin to substantially increase the rapidity of insulin action. As we understand it, BD is currently researching the pharmacokinetics/pharmacodynamics of intradermal insulin infusion in phase 1 studies. Finally, Dr. Bloomgarden raced through the advantages and disadvantages of several drug classes, including SGLT2 inhibitors, PTP1-B inhibitors, PPAR “pan” agonists, and SIRT1 activators.
• W. Kenneth Ward, MD (Oregon Health and Science University, Portland, Oregon) focused on the effects of postprandial hyperglycemia, its effects on cardiovascular mortality, and novel ultra rapid-acting insulins with an earlier onset than currently available insulins. He began by reviewing the recent discovery of insulin’s release from beta cells in healthy individuals; large amounts of insulin are stored in secretory granules with c- peptide and amylin. Before delving into the kinetics of insulin, he emphasized the risk associated with excessive postprandial hyperglycemia, citing the DECODE and STOP- NIDDM trials. Finally, he discussed the mechanisms of late-stage ultra rapid-acting insulins VIAject (Biodel) and Afrezza (MannKind). As a reminder, the FDA is currently reviewing VIAject and has issued a complete response letter for Afrezza (MannKind is expected to request a meeting with the agency to discuss the next steps).
• Brenda Fahy, MD, FCCP, FCCM (University of Kentucky, Lexington, Kentucky) delivered a comprehensive review of the top-line issues at play in the debate over tight glycemic control in the ICU. She focused her discussion on the work of Dr. Greet Van den Berghe in Leuven, NICE SUGAR, relevant meta-analyses, and the work of Dr. Tony Furnary in Portland. The inconsistency in results between these different studies is well known, and there remains a high level of confusion over what glycemic targets are appropriate in the ICU. Dr. Fahy’s take-home message was that hypoglycemia needs to be carefully considered (as all the tight glycemic control studies have shown increased hypoglycemia in the tightly controlled patients, regardless of ultimate outcome). She went on to suggest it may be appropriate to have different glycemic targets for different patient populations (echoing sentiments we have been hearing from other distinguished speakers in the last year). Dr. Fahy closed by suggesting that newer technology could help HCPs achieve better glycemic control in the ICU while avoiding hypoglycemia, namely CGM – this echoed opinions heard at all major conferences of late. She also hopes that this new technology allows new studies to explore the most appropriate application of tight glycemic control in different patient populations. During her talk, Dr. Fahy polled the audience about what they believe to be the target blood glucose range with the lowest associated mortality and the results revealed that there is considerable variation in currently held beliefs on this topic. While 38% of the audience believed 90-140 mg/dl would be associated with the lowest mortality, 27% believed 70-100 mg/dl would be, and 25% believed 140-180 mg/dl to be associated with the lowest mortality. Dr. Fahy remarked that the answer to this question largely depends on which author or study you are reading. We note that several observational studies, while not randomized controlled trials, suggest a J-shaped curve for mortality, implying that 140-180 mg/dl may engender elevated risk for death compared to a lower target range, especially if hypoglycemia is not increased. 
• Mary Korytkowski, MD (University of Pittsburgh, Pittsburgh, Pennsylvania) reviewed multiple studies evaluating the safety and efficacy of tight glycemic control in the inpatient and outpatient settings. She attempted to explain why no other study of tight glycemic control in the hospital has been able to replicate the results of Dr. Van den Berghe’s Leuven I study. After describing the recommendations from the AACE-ADA consensus statement on inpatient glycemic control, she delved into the RABBIT-2 trial, which compared sliding scale insulin (SSI) to a basal/bolus regimen in non-surgical insulin-naïve patients with type 2 diabetes admitted to a noncritical care unit. She concluded by reiterating the glycemic targets of 140-180 mg/dl for the majority of critically ill patients and 100-180 mg/dl for the majority of noncritically ill patients and stated that prolonged monotherapy with SSI is inappropriate.
• COL Robert Vigersky, MD (Walter Reed Army Medical Center, Washington, DC) skillfully addressed a topic that has a long and complex history: how tightly should we control type 2 diabetes? At the beginning of his discussion he suggested an apt subtitle for his talk would be “A Case for Individualization of Goals”. He went on to review the DCCT and EDIC data suggesting that microvascular benefits can be gained from intensive insulin control in type 1 patients and that there may be a legacy effect conferring long-term macrovascular benefits from early intensive glycemic control. Next, he reviewed data from the landmark randomized controlled trials that more directly address the issue of intensive control in type 2 diabetes: ACCORD, ADVANCE, and VADT. Dr. Vigersky summarized the three randomized controlled trials by suggesting that while there appears to be an improvement in microvascular complications with intensive control, there seems to be no improvement in death and there are conflicting results concerning macrovascular events. After discussing the formal recommendations published by the ADA, he offered the suggestion that it is ultimately best to individualize outpatient therapy based upon age, co-morbidities, duration of disease, and life expectancy. If only doctors and CDEs were reimbursed for the time it takes to do so …
• Lori Laffel, MD, MPH (Joslin Diabetes Center, Harvard University, Boston, Massachusetts) discussed the motivation for initiating/discontinuing pump therapy and basal/bolus dosing strategies, focusing on pediatric populations. She cited several challenges of pump therapy in children, including missed/late insulin boluses, infrequent blood glucose monitoring, device subject to failure, unrealistic expectations for “perfect” blood glucose, the potential for insulin “stacking,” etc. Not surprisingly, insulin omission was most common in pediatric patients who tested less frequently, used higher basal rates, and higher A1c levels (characteristics of less well-controlled individuals). In a study Dr. Laffel referenced, the major motivator for initiating pump therapy was glycemic control: 63% chose a pump for improved control, 43% for increased flexibility, 9% for fewer injections, 8% for food, 2% for camp (could pick multiple choices; unknown sample size). Over a four year period, 18% discontinued pump therapy (4-5% per year): 28% discontinued due to DKA, 28% due to diabetes burnout, 21% due to infusion site issues, 14% due to body image concerns, and 10% due to weight gain. Dr. Laffel ended her talk by reviewing the benefits of square-wave and dual-wave bolusing. 
• Jane Jeffrie Seley, MPH, MSN, GNP, BC-ADM, CDE (New York Presbyterian/ Weill Cornell, New York, New York) focused her talk on practical issues surrounding insulin pen and pump use in the hospital, offering valuable advice from her own experience in “error-proofing” her own hospital’s insulin delivery practices. She began by reminding the audience that many patients will go on insulin for the very first time in the hospital, often transforming a stressful event into a critical learning moment for the patient. Notably, insulin is the number one drug associated with error in the hospital (39% of medication errors in the hospital is associate with insulin). Seley went on to offer several helpful strategies to help reduce insulin error in the hospital. In the second half of her talk she covered the use of insulin pumps in the hospital, discussing strategies for dealing with patients coming into the hospital already using a pump and how to determine when a patient should be taken off of the pump. She closed with her mantra for insulin delivery: timing is everything—we must be very thoughtful about when meals are taken, when blood glucose is tested, and when insulin is delivered, regardless of what method of insulin delivery is being used.
• Stacie Haller-Wich, RD, LD, CDE (Diabetes & Glandular Disease Clinic, San Antonio, Texas) discussed the use of insulin pens and pumps in the outpatient setting, covering important practical issues for using these therapies. We found it significant that she agreed with comments from the previous day, noting that she wishes insulin pens would have more memory function and potentially even a simple bolus calculator to help patients in their carb counting. We think this might be difficult in the US where disposable pens are the norm and where there is a lot of sensitivity on the pricing front.
• Donald Williamson, PhD (Pennington Biomedical Research Center, Baton Rouge, Louisiana) discussed technology available for preventing weight gain and type 2 diabetes. He began with internet and online-based interventions. While these types of interventions have many advantages, it is very difficult to retain users and the intervention suffers from reduced utilization over time. Next he discussed digital photography methods that can be used to document food consumption; this information can be used to understand food selection and ultimately modify eating behavior. Computer Tracking Systems are another form of technology that can be used to help patients make healthier lifestyle choices. Remote data acquisition and feedback technology can be used as part of enhanced health behavior change programs—this would essentially manifest in the form of telemedicine, where patients can be monitored and coached on healthy behavior. In concluding, Dr. Williamson emphasized that most applications are still in the development phase and major improvements are expected in the coming years. In any event, he stressed, HCPs will continue to play a critical role in the success of these prevention technologies through encouraging patients to maintain utilization.
• Robert Lustig, MD (University of California, San Francisco, San Francisco, California) delivered an energetic and convincing presentation on the detrimental effects of fructose consumption on cardiovascular risk factors, diabetes markers, and obesity. As a reminder, sucrose (table sugar) is 50% glucose and 50% fructose. He explained how a “low fat” diet may be a misleading term since fructose is a carbohydrate metabolized “just like fat.” On an epidemiological level, he noted that fructose consumption has significant and steadily increased over the past 30 years, coinciding with the obesity epidemic. However, he described the mechanisms, in painstaking detail, by which fructose promotes elevated blood pressure, de novo lipogenesis, triglycerides, free fatty acids, VLDL, dyslipidemia, hepatic insulin resistance, obesity, oxidative stress, and CNS leptin resistance (promoting consumption). Interestingly, fructose is seven times more likely than glucose to form advanced glycation end (AGE) products. The American Heart Association (AHA) nutrition committee published an article on the “effects of sugars on cardiovascular disease and its risk factors” in 2009, recognizing the harmful effects of fructose and recommending a reduction in sugar intake from 22 tsp/day to 9 and 5 tsp/day for males and females, respectively. He concluded by labeling fructose an “alcohol without the buzz” and a dose-dependent chronic hepatotoxin that mechanistically explains the development of the metabolic syndrome.