ADA opens! On the device side, everyone’s talking about Abbott MARD of 12.8% while on the drug side, everyone wonders, s-l-o-w-l-y, but catching on – how many more people are going to delay going on insulin? And how long will this last?
• ADA has started with a vengeance! SO many people have descended on Washington DC it is unbelievable. You can tell it’s a very international meeting, too, because there are lots of cigarettes …
• SO, for today, we’re going to go backwards. The first corporate symposia were tonight and things were truly really something. Our team has been talking a lot about what we care the most about learning, and basically, it’s four words – incretins, continuous monitoring, and VRAI (very rapid acting insulin).
• Did we say handy? Oh. Just kidding. It was actually maniacal. Both programs began at 7, and if you weren’t there at 6:30-6:45, with pre-registration in hand, you were SO left behind! It was like a rock concert - if you think you can’t imagine a rock concert at a Hyatt hotel, you’re probably wrong. They had the velvet ropes, the bouncers, everything. First, when you walked in the Hyatt, you saw signs, you saw people running, you followed them, one level down. CROWDED. But you hadn’t seen anything yet. Then, you got to the roped off area. You had to be approved to go down to the next level. If you arrived at 6:55 or later, forget it. You were not even close to being let in, had you signed up or not!
• Abbott’s program on continuous monitoring was truly inspired, with accuracy data out of this world.
• Novartis, meanwhile, put on a very credible program, and while they didn’t blow away anyone with DPP4 data, the deal with this market? You don’t have to blow anyone away. Okay to not so great drugs do pretty well (Meridia and Xenical have nearly $1 billion in combined sales, remember, and these drugs are so sub-optimal, it’s not true), and good drugs will be blockbusters, since the market itself is so flipping huge (Actos and Avandia have over $4 billion in combined global sales, despite all the weight gain, edema, and oh, um, congestive heart failure fears). True blockbusters – no one even knows how big they’ll be. Right now, we’d put Byetta in that category. Byetta is pretty much the talk of the town here. Sit down at any table, and you hear, “And I’ve/she’s/they’ve/he’s lost 40 pounds!” Person beams. “Yes, I/they/she/he love(s) it.” Why? More enthusiasm. “What’s not to love?” What do I mean? What rock are you under? “Oh, well, it’s easy. And so good. I/my patient/my niece, my grandmother/my kid … was able to go off Lantus. Yep. Did I mention it was easy? And how much weight I’ve/she’s/they’ve/he’s lost? 40/20/50 pounds. It’s a whole new world for me/him/them/her.”
• “And my/her/his insurance pays for it! Not that they have to. I’d/she’d/they’d/he’d buy it out of pocket.”
• Right, back to Novartis. Jim Gavin, the most respected of the very respected, chaired the program. Is there anyone who doesn’t deeply respect and deeply like this man? Doctors want all their least compliant-we-mean-adherent patients to go to him, CDEs all want him to speak to their training classes, investors all want to chummy up to him, writers all (yes) want to interview him. So he started it off, and Novartis got points right off the bat for being cool enough to persuade Dr. Gavin to chair the program. Then, Dr. Dan Drucker spoke on “Incretin Action: New Concepts Underlying Physiological Control of Glucose Homeostasis,” Dr. Steven Kahn spoke on “Current Clinical Data: What Have We Learned a Year Later?”, Dr. Gavin asked “Why Do Current Type 2 Diabetes Treatments Fall Short?” and then the panel, led by Dr. Gavin, participated in “Ask the Experts: How Will Incretin-Based Therapies Be Integrated Into the T2DM Treatment Paradigm.”
• So, first, Abbott. Abbott also had a terrific expert panel, led by Dr. Bruce Bode, and including Dr. Richard Weinstein, and Dr. Richard Bergenstal. The evening started off with a poignant piece that is SO Abbott Diabetes Care, where graphs showed where we are going – with a CGM profile over some episodic tracings, indicating that we are missing lots of hyper and hypoglycemia in type 1 patients. The next slide, “What we are working to achieve” showed a world with no diabetes.
• The next segment explained why accurate continuous glucose monitoring systems are needed: One, two, three, punch: 1) intensive management reduces risk for microvascular and macrovascular complications; 2) glycemic variability is an added risk for heart disease, inflammatory damage to cells, and increased prevalence of depression; and 3) intensive management comes at a price; increased in incidence and fear of hypoglycemia, hypoglycemic unawareness. The slide, ended, plaintively, that new tools are needed to enable patients to achieve glycemic targets without increasing risk of hypoglycemia. (Round of applause.)
• Next slide – this detailed Dr. Bode’s brilliant 2005 Diabetes Care study, a multi-center, prospective study (albeit observational) that showed how 101 users (60% type 1 and 40% type 2) used FreeStyle Navigator for 21 days, when data was masked to subjects – subjects, meanwhile, were testing nine times per day, but in euglycemia only 28% (#)$@&$#*$) of the time. How upsetting is THAT! Forget it! From a patient perspective – testing ten times a day is a lot. Most insurance won’t cover it, and if it only gets us to 28% anyway …?
• Boom, boom, boom, rapid-far – that was the perfect opening, and it set up very well the data presentation (for the first time) from two major clinical studies, a multi-center in-patient accuracy study (n=58; 5 days) where Abbott’s Freestyle Navigator (FSN) was compared to venous blood using a lab reference (YSI) and a multi-center home use study (n=138; 41 days) showing performance in a home-use setting, compared to capillary blood using a standard blood glucose monitor.
• First, the accuracy data rocked. 82% of the data in the accuracy study landed in the Clarke Error Grid zone A, pretty much unheard of for continuous. (98% was in zones A and B, but that matters less.) This covered n=20,362 data points. And the most excellent part? 82% of hypoglycemic (<70 mg/dL) were detected as well (n=170) – typically there is so little hypoglycemia to discuss in their studies – not this one – glucose and insulin challenges were included. There were 9% false alarms on the hypoglycemia end and 12% of the hyperglycemia end – well within the clinically acceptable range, we think.
• It’s worth noting that mean and median absolute relative difference are both important to note – mean was 12.8% and median was 9.3%. Whew! (The median ART of the Freestyle Fash, by the way, was ~ 5%.”
• Performance was equivalent between arm and abdomen, over five days, during the day and during the night.
• Interesting, glucose rate of change at times of venous sampling indicated that 75% of the time, the rage of change of the subjects’ glucose was between -1 and +1 mg/dL/minute. That was surprising to us. Everyone always talks about how much variability there is in the blood glucose of type 1 patients. This implies otherwise – that most of the time, we’re pretty stable, right? No! -1 to +1 mg/dL/minute is huge – that means our blood glucose could go between 50 and 170 mg/dL in any hour. That’s not exactly stable. We wish the arrows would actually reflect more like 0.5 and +0.5 mg/dL/minute – that would mean blood glucose might go between 70 mg/dL and 130 mg/dL – that’s more like it! Now that’s stable.
• On the home use study – this one is great. First off, accuracy – not quite as good as in the previous study, but still very strong. 77% of data points landed in the A zone (99% in the A plus B, not that that matters), mean absolute relative difference (MARD) hit 14.4%, with median absolute relative difference at 11%. Second, the ease of use – 97% of all subjects found the device easy to apply to the skin, and 80% found the insertion to be no more painful than a fingerstick. There were 96-97% success rates for insertions (incredible), 89% calibration success rates, and 83% of sensors reached the 5-day limit. Last, in terms of clinical utility, there was a 47% reduction in time spent <55 mg/dL, 19% less time spent between 55 and 80 mg/dL, 6% more time spent at 81-140; 8% more time spent in 141-240 (this wasn’t intuitive to us) and a 19% reduction in time spent over 240 mg/dL.
• Last, and most importantly, in terms of patient satisfaction, these results were quite stirring: 1) 95% found blood glucose value changes easy to understand; 2) 94% felt the information from the system helped users better understand blood glucose levels; 3) 89% found the system easy to learn; and 4) 80% found the system easy to carry around. Worryingly, only 46% found waiting ten hours for the system to show real data as acceptable – this is too bad, since most of the systems have issues at the start – even if they don’t actually have a ten-hour delay, they do have “noise” or other issues that make the first day basically kind of a wash. Tough if less than half find this acceptable – this is the status quo for now, and it’s true basically on all the systems, from what we understand.
• The adverse events, 15 in all, were mostly benign, except one episode of severe hypoglycemia – the subject did recover. Two were “itching at insertion site” and twelve were “transient events not related to the clinical study.”
• Enough of symposia! How about the sessions?
• Hypoglycemia in Early Diabetes, with Drs. Tim Jones and Patrick Boyle, was excellent. Dr. Jones from the Perth Children’s Hospital in Perth, Australia, spoke on “Pediatric Diabetes and Hypoglycemia” to open up this session. He chose three case studies, all children, and made some prescient key points and conclusions:
• Management outcomes in pediatric diabetes depend on both HbA1c and hypoglycemic episodes, and these in turn affect psycho-social development and the quality of life of both the patient and the family. We were fascinated to learn that the excessive fear of such events led to inappropriate treatment quite often.
• In the early 1990s the mean A1c of pediatric patients treated in Perth was 10.5-11%, whereas in the next ten years it dropped to 8%. The rates of severe hypoglycemia, however, were high in the early 1990s and since then they have actually increased, undoubtedly due to more intensive management. “This is something to work on.”
• One question that comes up is whether seizure and coma events cause lasting damage – we assumed yes. In looking at 170 T1DMs at onset Dr. Jones showed that in those with seizures (N=25) the IQ was lower after a few years than those without (80 control, 65 with diabetes but no seizures). All had similar IQs at diagnosis. But on memory and intelligence tests and cross-social studies there was no difference between the three groups. Therefore nothing concrete can be concluded on the issue. Our complete guess is that hypoglycemia is just not great for cognitive function. How can it be?
• The first case concluded that in preschool-age children it is preferable and often necessary to relax A1c goals because then most hypoglycemic events can be avoided. This surprised us. Great, yes, to avoid hypoglycemia, but at what cost to long-term complications? Besides, continuous monitoring should help us avoid hypoglycemia and stay in tight control.
• The second case showed that in hypoglycemic events that occur soon after diagnosis many T1DMs fail to produce adequate glucagon counter-regulation in the first few months after diagnosis. That’s not good. Also, monitoring children’s exercise soon after diagnosis is crucial as the hypoglycemic effects of exercise are often demonstrated hours later, overnight.
Dr. Patrick Boyle, from the University of New Mexico in Albuquerque, spoke on “Hypoglycemia in Early Type 2 Diabetes.” We strive to listen to Dr. Boyle whenever possible – he’s a star, and he doesn’t go out of his way to give so many talks, so this was an extra, true bonus. He discussed first and foremost the need to tailor therapies to individual patients. His talk also focused on some new therapeutic combinations, with the goal of reducing hypoglycemic events. One conclusion was that incidence of hypos in patients with type 2 treated with Metformin OR sulfonylurea is much much lower than those treated with insulin.
But when you look at type 2s on insulin (looking at A1c, age, BMI, sex, years with diabetes) the only difference between those who do and don’t have hypos is BMI. Patients with a smaller BMI have more hypoglycemia. This was, if not counter-intuitive to us, at least confusing.
• Dr. then assessed the differences between Glargine (Lantus) and NPH (usually, we clal this “the dreaded NPH”) therapies and the related efficacy of switching to wider Glargine use. Both were equally effective at A1c maintenance, but NPH produces more hypoglycemic events: 5.1/yr versus 3.0/yr on Glargine – so 40% less with Lantus. On the other hand, the rate of severe episodes was about the same: seven patients reported nine events on NPH and 9 patients reported 14 events on glargine. Surprisingly, he concluded that since there is really no difference in the rate of severe events (those most likely to cause complications), there is no really convincing reason to switch to Glargine therapy. We would switch, personally!
• He also used case studies to recommend the oral combination of Metformin, Pioglitazone, and Exenatide—he’s found it very effective in treating T2DMs.
• Additionally, he cautioned the audience to consider the unique lifestyle of elderly patients when adjusting medication: they eat larger meals earlier typically and therefore often go low in the evening and night.
• Dr. Boyle concluded but sharing some thoughts on other risk factors that are not initially obvious. He shared that in ambulance calls for Type 2 hypoglycemic events, recent alcohol consumption was the largest contributing factor.
On that note, we’ve got our continuous monitor on, and we’re going to have a Guinness!
POSTSCRIPT: Preview for tomorrow – get rested now! (five can’t miss sessions at 8 am alone…)
• Early morning – and what is amazing that these are PACKED even at 5 am! Eli Lilly is hosting a session on inpatient insulin therapy (Hyatt), GSK on tight glycemic control (Hyatt), and Takeda is hosting on on the beta cell in type 2 diabetes – “examining tomorrow’s breakthrough today.” We think this alludes to DREAM and ADOPT, which will be introduced at EASD and IDF in 2006.
• Can we say inflammation is a buzzword? Indeed. Don’t miss oral abstracts – “Inflammation, Obesity, and Insulin Resistance” at 8 am, in Room 144.
• “Current Issues – Leveraging the clinical potential of GLP-1 – Two perspectives.” 8 am, Ballroom AB.
• “Tools for Managing Patients with Difficult Clinical Challenges” – 8 am, Room 202.
• Oral abstracts, “Glucose Monitoring and Insulin Resistance” (who put those two together?), 8 am, Room 147.
• “Endocannabinoids – Good potential obesity targets” – 8 am, room 146
• More controversy on Metabolic Syndrome – even I don’t want to go to this, I just want to read our review – Renaissance, Grand Ballroom Central/South, 10:15 am
• Symposium on “How Important are Maternal Glucose Concentrations to Pregnancy Outcomes in Women with Diabetes?” 10:15, room 144
• Oral abstracts on Insulin Delivery – Biodel gives its talk here – we so cannot wait to hear more on VRAI (that’s what we have christened this super-fast rapid acting insulin) 10:15, room 146
• Ooooh, at the SAME time… oral abstracts on pharmacologic treatments – incretin mimetics, DPP-4 inhibitors, and PKC beta inhibitors – Ballroom AB, at 10:15. Yes, they were smart to put out the ballroom for this one! (Note to other presenters in other sessions: don’t feel badly, it’s hell to go up against this one.)
• Obesity treatments – behavioral vs pharmacologic vs surgical – Ballroom C, 10:15.
• The changing face of diabetes care delivery – 2006” – we have heard that this one will include data from LA, where Byetta was added to the LA County formulary – brilliant.
• One nighttime symposia – Novo’s on insulin analogs at the Hyatt – looks good – integrating evidence into practice. Dr. Robert Ratner and Dr. Malcolm Nattress will co-chair Dr. Martin Abrahamson of Joslin and Dr. Philip Raskin of the University of TX Southwestern (we learned earlier today that he had the lowest DCCT A1C score, or something like that – more on that tomorrow!)
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