We sort of punted on covering obesity in our latest DCU, because we thought we'd rather do a whole issue on it (next month, August's issue) rather than cover only sketchily what happened at ADA and still be pressed for space. We also wanted our issue to cover two other meetings in June besides ADA - first, the Endocrine Society, which started yesterday in boston with a bang (diabetes and obesity are just a part of this meeting, but a growing part) and the bariatric surgery meeting, which starts in san francisco this tuesday.
So just a word on boston goings - on ... not to be believed, but it looks like the american heart association and the american diabetes association are coming together on the subject of metabolic syndrome. hurrah! we were wondering how long they could stay tied to their opposing views (this is reductive, but basically the ADA was against the use of metabolic syndrome as a descriptor of a specific condition, while the AHA was for it). we always sided with the AHA, simply because doctors don't always have time to spell things out and that as such, some patients will be more driven to act when they hear something a little more dramatic - like being told they have metabolic syndrome - as opposed to JUST understanding (and maybe blowing off) that they have to take a pill for hypertension, a pill for high cholestoral, etc.
Metabolic syndrome (such as it is, with its four different definitions) has also become synonymous with pre-diabetes and we know that name is definitely having an impact on patients - as it, people do NOT want it! now, true, we haven't exactly seen a reduction yet, but we do think people will work harder to get rid of anything with diabetes in the title versus just knowing they have this or that defect (lipids, blood pressure etc) so - while we don't favor treating with fear in isolation (i.e., scaring people with something called metabolic syndrome) we do favor educating people that unless they act in a big way, they'll move quickly from pre-diabetes to diabetes. To boot - obesity is part of most definitions of metabolic syndrome, and anything that prompts PCPs to take out the tape measure and put it around bellys - that's a good thing (you can even do this at home - if you have a waist measure over 30 inches for women or 40 inches for men, that's positive for one symptom of MS - usually you need three to quality...others center on lipids and hypertension).
A debate yesterday at the endocrine meeting "Controversies in Endocrinology: Impact and Management of the Metabolic Syndrome" certainly did make clear that both organizations want to work to reduce conversion of pre-diabetes to diabetes even if there is still disagreement over semantics. the release below basically says that tomorrow there will be a press release from AHA and ADA explaining how they will work together on the metabolic syndrome front. While we don't know exactly what tomorrow's press release from both organization's will bring, we do think that everyone will win, because apparently "cardio-metabolic risk" will become a more official term for both organizations. that probably can't be a bad thing, even if the biggest winner is sanofi!
we agree with Dr. Jay Skyler, who implied in our DCU interview this month (the full interview is posted on our website www.closeconcerns.com) that we should get OVER semantics and just address the problem - we applaud the gist, and hope it happens. in the meantime, we will be watching both the pharmacologic and the surgery fronts with great interest. we believe rimonabant, pramlintide, TZDs, and GLP-1 all will be examined closely in terms of pharmacologic potential and believe that a majority will in time become actual therapies. while the FDA looks to be a very long way from approving anything to treat metabolic syndrome, we would expect to see first a label for pre-diabetes, namely impaired glucose tolerance. of course, then, reimbursement will be the next hurdle! The surgery front (gastric banding to full on surgery) is less clear to us, but given the multi-faceted problem obesity presents, from our perspective, the more solutions, the better. and in terms of surgery, given how much diabetes is downright resolved with surgery, we think reimbursement there is a no-brainer in many cases.
Here's to the multiple winners.... and even though we're not yet sure about rimonabant safety (but still look for FDA approval shortly), good for Sanofi for getting made official this cardiometabolic risk terminology they've now been bandying about for years... (see our November 14 blog from the AHA for more on Sanofi, which we've copied below the Endocrine Society release)
New Perspective Emerges on Metabolic Syndrome
Sunday June 25, 11:39 am ET
Leaders of the American Diabetes Association and the American Heart Association Announce Joint Letter at ENDO 2006, Annual Meeting of The Endocrine Society
BOSTON, June 25 /PRNewswire/ -- Though they have markedly different opinions on the controversial Metabolic Syndrome, leaders of the American Heart Association and the American Diabetes Association announced at the annual meeting of The Endocrine Society that they will co-publish a statement on Monday expressing a desire for the organizations to work together on the topic of "cardio-metabolic risk."
Despite their differences of opinion, both organizations are working together to prevent heart disease, stroke and diabetes, said Robert H. Eckel, president of the American Heart Association, a physician and professor at the University of Colorado.
Eckel presented alongside John Buse, vice president of the American Diabetes Association in a debate at The Endocrine Society annual meeting entitled "Controversies in Endocrinology: Impact and Management of the Metabolic Syndrome."
The two organizations represented by Buse and Eckel clearly still have differing viewpoints on the Metabolic Syndrome, as articulated last year in a paper published by the American Diabetes Association, "The Metabolic Syndrome: Time for a Critical Appraisal."
The Metabolic Syndrome is loosely defined as a cluster of medical conditions -- including obesity, high blood pressure, high LDL cholesterol (and low HDL) -- that increase the risks of diabetes and cardio-vascular disease.
The American Heart Association, according to Eckel, supports identifying and treating the syndrome through lifestyle modifications and other treatments.
But the American Diabetes Association, Buse said, believes that the definition of the syndrome is poor, and that risk prediction of cardiovascular disease is also poor. Further, he said there is little benefit to treating the syndrome as a whole rather than identifying and treating the various components.
The letter, to be released Monday, uses the term "cardio-metabolic risk," new terminology which Buse said may signify a new way of describing and therefore treating the condition known as Metabolic Syndrome.
The debate also included representatives of the FDA and the pharmaceutical industry.
Founded in 1916, The Endocrine Society is the world's oldest, largest, and most active organization devoted to research on hormones, and the clinical practice of endocrinology. Today, The Endocrine Society's membership consists of over 12,000 scientists, physicians, educators, nurses and students in more than 80 countries. Together, these members represent all basic, applied, and clinical interests in endocrinology. The Endocrine Society is based in Chevy Chase, Maryland. To learn more about the Society, and the field of endocrinology, visit our web site at www.endo-society.org.
AHA Musings - Drugs and more drugs and more on FIELD
So we keep talking about how cardiology is becoming so much more focused on endocrinology and diabetes ... welllll, that's sort of true, but we believe it's a bit less apt than we had thought, based on a wild search about drugs on the exhibit floor, where we lived the following:
Kelly: "Hi, are you giving any information about Pargluva here?"
Medical Rep (irritated): "Absolutely not!"
Kelly: "Hi, are you giving any information about Byetta?"
Rep (confused): "By-what?"
Rep (mystified): "By-ate-a?"
Kelly (incredulous): "Yes, Byetta! You know your amazing new drug, the GLP-1?"
Rep (sad): "I don't know about it." (Turning to another rep ... "Do you know about - what is it called? - Byetta?"
Second rep (enthusiastic): "Oh yes! That's doing great! But we don't have it here. That's not our division."
Kelly (questioning): "But aren't cardiologists moving into diabetes? Don't you have a big diabetes division? How can you not have Byetta here?"
First Rep: "Yeah! How can we not have Byetta here? Here, can you fill out this comment card and we'll get you some info .... let me swipe your badge!"
Overweight doctor from Cornell, joining the conversation: "How about Symlin!"
First Rep: "Sim-lin? What's Sim-lin?"
Second Rep: "Sim-lin? What's Sim-lin?"
Kelly: "Hi, are you giving any information about Avandia here?"
Rep (on it): "YES! Please go see this film and then I'll answer all your questions! This is a very important area for us."
There is a film, starting Della Reese and some of her friends with names like Fred and Millie. This is sort of well done, not on the Sanofi scale (see below), but they have a new little song "Get Rosi on board..." It has a nice ring to it and I might find myself singing it to Coco if I'm not careful. The whole film is brilliant at giving data that isn't WRONG exactly, but also isn't footnoted, and if it were, wouldn't be sourced from, say, a NEJM published study. There are statements from the narrator like "In another study, there was an A1C drop of 1.5%, in patients with A1Cs of 9% or higher. Then in another study, there was an A1C drop of 3%, where the baseline was 11.5% - dropouts were high, but it's much better to go on Avandia than up-titrate Metformin! 50% of patients got to goal! Yes, adding Avandia works on core defects - lowering insulin resistance and improving beta cell function ... "
After the film (which was packed for all three times I watched it), the reps came back, offered coffee commuter cups (with red "get Rosie on board" labels), and $30 coupons for a program called "I Can.." (see www.avandia.com - they are taking the DTC pretty seriously.) To top it off, they gave away Hershey's kisses. I took 10 and ate them on the spot, shooting up Symlin as I went .. "What's that?" the rep asked ...
Maybe it's just me, but it really seems like in a little bit here, we're going to start hearing a LOT about TZDs and prevention of diabetes. They are just gearing up...
ABBOTT: I went here before FIELD was announced (see previous post). They were happy and nice and told me FIELD slides would be up November 17 at www.lipidforum.com. They then offered some excellent espresso and biscotti. I asked them about mixing fenofibrate with a glycemic lowering compound and doing a combo drug ... "are you nuts?!" the rep asked. Score one for Abbott on that basis alone ... we talked about how combo drugs are overrated, how dosing is complex, how if the drug works it is fantastic, but if it doesn't, the doc gets a million calls ... I went by after and dejection abounded. I know it's not as positive as it would've been had it been a positive study, but I think either way, it's got to be good add-on therapy, no?
Kelly: "Hi, are you giving any information about inhaled insulin?"
Rep: "Go talk to the medical director - we're just reps."
Kelly: "Hi, are you giving any information about inhaled insulin?"
Medical director: "No, we're not really saying much about that."
Kelly: "Do you think it'll be approved soon?"
Medical rep: "Let me show you some data on Lipitor ..."
Kelly: "Hi, are you giving any information about Actos?"
Rep: "Why, yes! What can we tell you?"
Kelly: "Is it being used as first-line therapy?"
Rep: "Yes! And for pre-diabetes!"
Kelly: "Really? I hadn't realized that trial had come out yet. What did those results show!?!"
Rep: "Well, the trials aren't completed yet. We do not encourage use for pre-diabetes. But it is being used for that."
Kelly: "The ADA '03 DPP data was really powerful with Troglitazone, showing a 70% reduced progression to diabetes ... compared to much lower for Metformin and lifestyle ..."
Rep: "Yes, and you should see the follow up gestational data ..."
Kelly: "How's the edema and CHF?"
Rep: "Well, patients need to be chosen and followed appropriately ...they are seeing a lot fewer problems like that in pre-diabetes .. they are the younger, relatively healthier patients, of course ... now this drug is great in combo with Metformin ...."
Ironically, the Lilly reps _were_ at the Actos booth, since they co-market it for a bit longer ...
Kelly: "Hi, are you giving any information about Galida here?"
Kelly: "Nothing you can say about this dual PPAR?"
Rep: "We haven't been talking about dual PPARs much lately ..."
Kelly: "Because of the FD ..."
Rep (interrupting): "Yes. But check out our LDL/HDL ratio with Crestor .... "
The conversation then turned to another discussion of how combination therapy isn't as easy as it looks (dosing, mixes, etc.), which I buy, and then to personalized medicine, and the rep explained there was some kind of research ongoing to figure out which type of patient would actually benefit particularly from diet and exercise, etc - they felt more personalized medicine would revolutionalize lipids. I explained that I thought lipids had been revolutionalized ...."$26 billion category and all..." This rep felt some PCPs were seeing as many as 50-60 patients a day "a factory .. and would you want to be dealing with nausea phone calls....?"
Kelly: "Hi, are you giving any information about Acomplia here?"
Rep (super nice): "Absolutely! See the booth over there? There's an excellent movie there about endocannabanoid systems. I can't even say it yet! But we're learning! Go ahead and watch it ... then let me know any questions you have! We'd love to help in any way possible."
Kelly: "ohhhh - I'll go watch it! When will Acomplia be approved?"
Rep (super nice): "April 2006 is what they're telling us! Go watch the movie, it's in 3-D, and fantastic! It doesn't have the word Acomplia in it, but it'll teach you a lot..."
Kelly: "OK thanks! oh and one other thing, how's Lantus doing?"
Rep: "Fantastic. We love selling this drug - it really changes people's lives."
Kelly: "Mm.. how do you think Levemir will do?"
Rep: "Oh please! Levemir is a glorified NPH!!!"
So I made my way over to the movie, "Exploring the ECS," which WAS in fast, fantastic. These guys don't skip a beat. Sanofi really knows how to market - even at 9 am, there were scads of people lined up grabbing at the 3-D glasses. The film (I can't believe I'm calling it that) was quite educational, and used lots of phrases like "appears to play a role" "seems to be linked" "apparently meaningful" etc. It reminds me of Wall Street days. Hedging is an excellent sport.
But, again, this was very well done ... it reviewed how a "newly discovered" physiologic system, the ECS (endocannabinoid system) plays a key role (see?) in glucose metabolism, lipid metabolism, and insulin resistance. CB1 receptors are found through the body - say, GI tract, brain, adipose tissue and skeletal muscle, for example, and they affect many processes. In the liver, CB1 activity is apparently associated with development of adiposity, dyslipidemia, and insulin resistance - all bad. In the brain, central CB1 activation influences feeding behavior and energy balance. This means satiety ... I really respect now anything that plays on satiety. I used to think it was sort of made up, but boy does Symlin work on satiety - almost sneakily, like I don't really notice it, but then I do ("wow I've eaten half my bacon cheeseburger and I'm not that hungry suddenly..."). I respect satiety, so it'll be interesting to see if that works with this drug.
Then, in adipose tissue, it is said, CB1 activation "appears to stimulate" lipogenesis and to inhibit adiponectin expression. What does adiponectin expression mean? Wellll, so as I understand it, adipose tissue used to be viewed as inert, but now it's seen as an active organ. Low adiponectin levels are commonly found in diabetics and those that are obese. Got it ... that's all we need to know, right ... CB1 activation is bad and adiponectin is good and there isn't enough adiponectin going on ... so we should be wary at the very least of adiponectin inhibition. Low levels of adiponectin, I then learned, are associated with high free fatty acids (FFA), low HDL, high triglycerides, and AND insulin resistance. In skeletal muscle, CB1 activity is associated GI motility and safety signalling. I have to check this out with all my smart connections in pharma, but this gives you an idea how the story is forming ...
I started remembering right about then how excited I got about this drug at ADA - doesn't it seem like, IF safety is established (the CNS questions are big) and for those that can get over side effects, that this should be mixed with Byetta? Byetta has all the glucose pieces that this doesn't have plus Byetta doesn't have insulin resistance and this doesn't have beta cell regeneration ... could be a mix, no? (We know Byetta doesn't necessarily have beta cell preservation or regeneration either - that is yet to be proven. We also are excited about Byetta with TZDs, which seems also complimentary - insulin resistance, potential beta cell regeneration from both, weight loss from Byetta offsetting weight gain from TZDs, potentially lower edema/CHF from combo due to lower dose TZD, etc.)
BMS/MERCK (second lap):
Kelly: "Hi, are you giving any information about Pargluva here?"
Rep: "Pargluva? We don't have a drug called Pargluva." (editor's note - kind of amazing, in hindsight...)
Kelly: "Hi, are you giving any information about LAF-237 here?"
Rep (cold): "No."
Kelly: "Hmm. How about Vildagliptin?"
Rep: "No, we're not talking about that one either."
Kelly: "Anything in diabetes?"
Rep: "No. This is a cardiology meeting!"
And on that note ....