VO L U M E 1 • I S S U E 2

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in this issue
From the Editor .............. 1 Feel the excitement Test Drive ........................ 1 Our highs and lows while trying out Symlin Diabetes Dialogue ......... 3 Talking to two diabetes’ titans, Dr. Irl Hirsch, endocrinologist extraordinaire (and type 1 patient!), and Arnold Donald, the new JDRF CEO Learning Curve ............... 7 A DPP-What? A closer look at Januvia, a new kind of drug Logbook.......................... 9 A story of bigotry on a radio show Profile.............................. 11 Caps off to this intensive manager, Phil Southerland Conference Pearls .......... 13 Around the world with your doctors NewNowNext ................ 16 Don’t miss it! What We’re Reading ...... 17 Cutting through the information clutter Trial Watch ...................... 19 Step into cutting edge trials

research and product news for �������������������������������������������������� people with diabetes from the editor
helps lower blood sugars after meals, but it makes some patients nauseous the first few months. Others, however, feel euphoric, experiencing a “post-sex buzz.” The potential side effects of this prescription drug are, shall we say, conflicting. As our Test Drive column describes, we tried the drug ourselves. It’s called Symlin, a synthetic derivative of the hormone amylin, which is secreted by the beta cells to control glucose levels. We hope you’ll read about our experience. We’re excited about our second issue of diaTribe, and we’re grateful to readers for their feedback – please always feel free to let us know what stories appeal to you and what you want to see more of (write kelly@diatribe.us). We want to cut through the clutter to give you great information on new products and breakthrough research that can improve your life. Back to the issue! Our Learning Curve story describes Merck’s big-splash introduction of Januvia, the latest incretin product that helps the body secrete insulin and could pave the way for earlier, more aggressive therapies in type 2 diabetes because it seems easy to take – check it out. We have not one but two outstanding Dialogues: one is with the new president of the JDRF, Arnold Donald, who gave us his first in-depth interview; the second is with top endocrinologist Dr. Irl Hirsch, who shares his incisive thoughts on new products and therapies. Dr. Hirsch’s brother, James S. Hirsch, is our LogBook columnist, who writes a must-read story about the bigotry he encountered while doing a radio talk show in Iowa. Seriously unbelievable. And I thought I was into intensive management - a Profile on Phil Southerland and his beloved bike team by dynamite blogger Amy Tenderich shows us one way to be supremely intensively managed. Finally, we traveled to Cape Town, South Africa, last month to attend the International Diabetes Federation and we returned with the highlights in our Conference Pearls. We have all that and much more. We hope you enjoy the issue. — Kelly L. Close

It

test drive
The bottom line: Our verdict on Symlin: Fabulous-Though-Can-Be-Difficult-At-First. Read on… If you have diabetes, you already know that your pancreas has difficulty producing insulin. What you may not know is that your pancreas also has trouble producing another hormone, called amylin, which also plays a role in regulating blood sugar. Amylin is insulin’s less well-known cousin, but it is now stepping out of the shadows with the availability of a new amylin-like product on the market.
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Symlin was approved for people with type 1 and type 2 diabetes in March 2005 and is manufactured by Amylin Pharmaceuticals.

diaTribe staff
Editor in Chief Kelly L. Close Managing Editor James S. Hirsch Contributers Daniel Belkin Michael Chen John Close Cindy Glass Rashad Jaeger Jenny Jin Amy Tenderich Design Gina Wilson

diaTribe advisory board
Dr. Bruce Bode, M.D. Dr. Nancy Bohannon, M.D. Dr. Zachary Bloomgarden, M.D. Dr. Bruce Buckingham, M.D. Dr. Wendell Cheatham, M.D. Dr. Irl Hirsch, M.D. Jeff Hitchcock Dr. Lois Jovanovic, M.D. Dr. Francine Kaufman, M.D. Dr. Aaron Kowalski, Ph.D. Dr. William H. Polonsky, Ph.D. Dr. Howard Wolpert, M.D. Gloria Yee, R.N., C.D.E.

Called Symlin (pramlintide), this drug is actually a synthetic derivative of amylin and, like insulin, works to replace or supplement amylin in the body. Symlin has proven to be quite controversial so far, with patients claiming side effects that range from a “post-sex buzz” to intense initial nausea. I am always excited to learn about new therapies and was among the first to try this one. Three years ago, when the product was still being tested, I enrolled in a six-month clinical trial for Symlin. Symlin was approved for people with type 1 and type 2 diabetes in March 2005 (my trial was part of the approval process) and is manufactured by Amylin Pharmaceuticals (which is currently riding high on the success of Byetta, which we covered in last month’s Learning Curve). I had heard some good things about Symlin, namely, that it helped lower post-prandial blood glucose levels. Mine are always too high, which has been very frustrating. Although my A1c has long been around 6.5%, I had always suspected that many of my hypoglycemic experiences stemmed from correcting high blood sugars (especially post meal), and those lows, rather than actually good control, were what kept my A1c scores low. It made sense to me that the “quality of A1c” should be considered as well as the numerical value, and mine didn’t seem great, so I was looking for help. I had also heard that Symlin prompted some weight loss, which was intriguing. Before I describe my experiences with Symlin, a bit of science: In people without diabetes, the same beta cells that make insulin also produce amylin. However, people with type 1 don’t make either amylin or insulin because their beta cells have been destroyed. Amylin is usually released in conjunction with insulin – especially after eating – because it helps the body maintain flatter blood sugar profiles. It does this in three ways: by slowing gastric emptying (allowing sugar to enter the bloodstream more slowly), making people feel full more quickly and thus eat less, and inhibiting post-meal secretion of glucagon, a hormone that makes the liver release extra sugar into the bloodstream. Like insulin, Symlin is an injected drug, but while different types of insulin have different peak effects and timing of dosage, Symlin is specifically designed to affect glucose levels after eating – which is why it is taken only before meals containing at least 30 carbs or 250 calories. Thus, during the clinical trial I took Symlin at each meal along with my insulin. It looks a lot like insulin (but in a much smaller bottle) and is handled in much the same way. The FDA advises you not to mix insulin and Symlin, so I took a separate shot alongside my pre-meal insulin pump boluses. Over the years, I have become better at taking my boluses at least 15 minutes before eating, and I found that leaving some time between Symlin and eating also worked well because I felt full earlier in the meal. I also tried using Symlin in a pump, which worked fine. However, wearing two pumps (and a continuous glucose monitor) took up a bit too much real estate, so I eventually went back to taking Symlin shots. While I was pumping it, though, Symlin worked extraordinarily well and my blood glucose was actually significantly more predictable than with just shots. Plus, I lost an extra two pounds. I’m not sure if this was a direct effect or not, but I wish pumps with two reservoirs were available! Dosing was a little complicated. At first I took a fixed dose of Symlin for each meal and cut back my bolus insulin by 50%, just as the manufacturer instructs. But this proved too steep a reduction, and my blood glucose went too high. After adjustments, I figured out that I actually only needed to reduce my insulin by about 25%. Alternately, I could not reduce my insulin at all, but just “extend” it by delivering small boluses with the insulin pump over 3-4 hours. Using these tactics, I was able to titrate doses of Symlin and insulin to control my post-prandial blood sugar.
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Once I figured out the dosing, I could reliably reduce blood glucose scores one hour after meals by 50 mg/dL (2.8 mmol/L) or more,

compared to what my pre-Symlin score would have been.

I remember getting some real rushes as I learned how to use Symlin. I would have 4050 carbs (eight or nine sushi rolls, plus a beer!), check an hour after eating, and my meter would say 110-120 mg/dL (6.1-6.6 mmol/L). What a result! I had pretty much given up eating sushi before Symlin. Once I figured out the dosing, I could reliably reduce blood glucose scores one hour after meals by 50 mg/dl (2.8 mmol/L) or more, compared to what my pre-Symlin score would have been. After working hard on my dosing, I did see some reductions in hypoglycemia – mainly because I wasn’t chasing after-meal highs and then accidentally going too low (the “roller coaster’’ effect). But initially, I actually had more lows because the combination of Symlin plus fast-acting insulin reduced my blood glucose very quickly. I could go down by 50 mg/ dl (2.8 mmol/L) in less than 15 minutes! This improved after I realized that if I spread out my bolus (using the square wave or extended bolus function on my pump), I could match the action of insulin and Symlin better. I also knew some people who adopted the strategy of taking insulin after they ate, so they would already know how much their appetite had been reduced. — For more on Symlin, go to www.diatribe.us/testdrive - you’ll see our specifics on nausea, weight loss, and our bottom line.

dialogue
Patients trust him because they know they are talking to an expert and a peer – Dr. Hirsch has had type 1 since he was a child.

Irl B. Hirsch, MD
Irl B. Hirsch, MD, an internationally-recognized diabetes expert and former ADA Clinician of the Year, is a professor of medicine at the University of Washington School of Medicine and Medical Director of the Diabetes Care Center at the University of Washington Medical Center. Patients trust him because they know they are talking to an expert and a peer – Dr. Hirsch has had type 1 since he was a child. He discussed with us the importance of “glycemic variability,” the risks and rewards of continuous glucose monitors, and the latest on new products. Kelly: Dr. Hirsch, thanks so much for discussing your current views on diabetes research and treatment. Today we’d like to start by asking you about your focus on glycemic variability. You have said that too much emphasis is placed on A1c control and not enough on keeping all blood glucose values as close to normal as possible. It seems this view is finally starting to move into the mainstream among doctors and nurses. What prompted your initial interest in this area? Dr. Hirsch: When we started downloading data about 10 years ago, I realized that our gold standard of A1c wasn’t enough, and I also realized that looking at simple averages didn’t give me the whole picture. I saw that I could get much more meaningful information by evaluating standard deviations [glycemic variability from normal glucose levels]. It all started with an amazing software program from LifeScan that had time-specific standard deviations. I realized that I could look at a download and see who was making smart choices about insulin dosing, who was testing more between meals, and who was in optimal control. I think that a lot of people are embarrassed about the pizza and the beer that they had on Saturday night, and they don’t want their doctor to see that 435 blood sugar . . . [but] I see the 400 plus blood sugar when I do the downloads, and that’s good data for me. When
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I think that a lot of people are embarrassed about the pizza and the beer that they had on Saturday night, and they don’t want their doctor to see that 435 blood sugar… [but] that’s good data for me.

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I see a standard deviation that’s way out of whack, when I see certain times of day when the averages are either too high or too low, I can focus on that. When you have such limited time for office visits as we do, you need to learn how to analyze and counsel as optimally as possible. Kelly: But what made you believe that glycemic variability was important for a patient’s overall control? Dr. Hirsch: It started with a report from the DCCT study group in 1995. As you recall, patients in the intensive therapy arm were mostly taking mealtime regular insulin and basal with NPH or Ultralente. They were doing a better job than the conventional group of matching prandial insulin with their food intake. But at any given level of A1c, the intensive therapy group had 40% to 60% less risk of developing complications. Kelly: Let’s talk about continuous glucose monitoring. Some health care professionals and researchers worry that it provides the patient with too much blood glucose information. Do you feel real-time continuous monitoring is ready for prime time, particularly in light of questions regarding calibration and analysis? Dr. Hirsch: First of all, nobody really has ever taught health care professionals—much less patients—what to do with the information. We’re in the early days. If you have a continuous graph, what do you do with the glycemic profiles, especially if you are a patient? That is, you may see your current blood glucose is 95 and you know that a half hour ago your glucose was 135, and now you’re getting ready to eat, and now you would normally give 8 units for what you’re eating but your blood sugar is dropping quickly. How much less insulin do you take? How do you change the lag time? You know, usually you take your rapid-acting insulin, you wait a few minutes before eating—eating nothing may be dangerous in this case.

Kelly: How do you think the monitors actually perform? Dr. Hirsch: We need to all remember they are first generation and they will all improve. Obviously, they are not yet perfect, but for people who understand how to use trends in addition to SMBG, our initial experience has been great. For me, I can’t wear the Medtronic as for some reason I get inflammation with their sensor. In my Star1 study, no one had that problem, so I must be unusual in that regard. Clearly, no one has software for the data as good as the Medtronic Carelink, but to be fair, I haven’t really had enough experience with the Abbott software to make a good comparison. DexCom does not have all of the bells and whistles literally, but for me that is a good thing. I look at my sensor constantly, so having it alarm all day would just be an annoyance. The arrows one gets with the Abbott and Medtronic are great benefits, and hopefully we will see something similar in the future from DexCom. For me, and as my wife will agree – I won’t sleep or leave the house without wearing it, whichever one it is. Kelly: Both Byetta and Symlin are generating a lot of interest for type 1 and 2 patients respectively. How widely are you prescribing these new drugs and what has your experience been? Dr. Hirsch: Quite a bit for both. Symlin is tricky as we have learned that only those sophisticated with their insulin use it long-term. The three-times daily dosing with the old fashioned syringe is a turn-off for some, but those who do well with it don’t want to come off of it. A lot of these patients need a lot of hand-holding the first month or two, so providers need to know about that. Byetta seems to cause more nausea than Symlin, and
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For me, and as my wife will agree – I won’t sleep or leave the house without wearing a continuous glucose monitor, whichever one it is.

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most of us have had great success using it with basal insulin . . . but new type 2 patients when talking about what drug to start often decide to take Januvia simply because they don’t want to deal with the shot or shots and the hassle of keeping it cool. Kelly: Exubera made a big media splash when it was introduced, but patient interest and acceptance appear to be mixed at best. What is your view of this drug and on inhaled insulin more broadly? Dr. Hirsch: Inhaled insulin may be great for some patients, but it obviously doesn’t appear the market is ready. My take is that the insulin will need to be easier to administer than the Exubera is, and the insulin will require some type of pharmacokinetic/ phamacodynamic advantage. That is why I think both the Lilly preparation and the Mannkind insulin will do better. Kelly: For all the tools and technology that we have, patient motivation is still critical for effective management. How do you motivate your patients? If you had advice for motivated patients out there who want to do better, what would that be? Dr. Hirsch: This is very difficult. I feel I spend a lot of my time as a cheerleader. Some patients do better when family members are involved (and some do worse!). Some do better when writing things down, while others seem to be motivated more with weekly downloads. The biggest problem I see (probably worse in Seattle) are those patients who fail due to depression. Mental illness is a huge problem which often gets overlooked by both patients and physicians. If I see a college graduate, or maybe someone with less education but has done well with a pregnancy, and we download the meter and I see less than two checks daily, my first guess is I am dealing with depression, often not yet diagnosed. So this is a huge issue, and the reason we have a psychologist and psychiatrist in our clinic. When the depression is adequately treated, many (but not all) of these patients do better. Kelly: We so appreciate your time. Thank you again and all the very best to you from me and the readers of diaTribe. — For more answers from Dr. Hirsch, including his thoughts on when type 2 patients should go on insulin, important recent trials, and his concerns about the endocrinologist shortage, please check our website at www.diatribe.us/dialogue/.

The biggest problem I see (probably worse in Seattle) are those patients who fail due to depression. Mental illness is a huge problem which often gets overlooked by both patients and physicians.

The first question was, am I the right person, number one. I am a corporate person and so, am I the right person? That wasn’t self-evident to me.

Arnold W. Donald
Arnold W. Donald seems an improbable selection to lead the Juvenile Diabetes Research Foundation. An African-American who has spent his entire career in corporate America, Donald is now the president and chief executive officer of a non-profit organization that – given the demographics of type 1 diabetes – has principally been run by and for Caucasians. While Donald has participated in many diabetes fundraisers, he has relatively little personal or family experience with the disease. And while the JDRF headquarters is in New York, Donald lives in St. Louis. Nevertheless, Donald’s corporate career has dovetailed with diabetes. He has a degree in mechanical engineering as well as an MBA; he joined the Monsanto Company in industrial chemical sales in 1977 and steadily climbed through the ranks. In 2000, he organized investors to buy Monsanto’s sweetener business, which included Equal and is sold extensively to people with diabetes. The Merisant Company was formed, and Donald
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became its chief executive, a position he held for three years. He was the company’s chairman when the JDRF hired him last year, replacing Peter Van Etten. What’s undeniably appealing about Donald, 51, is his excellent track record: he’s been an extremely successful executive and has won countless honors during his time in corporate America for leading and managing. To boot, he is also one of St. Louis’s top civic leaders, sitting on no fewer than 18 boards (corporate and nonprofit). The JDRF has few peers in the world of fundraising. Since its founding in 1970, it has distributed more than $1 billion for diabetes research, and is currently at $612 million in its ambitious five-year campaign to raise $1 billion, which ends in 2009. But for all its fundraising success, the JDRF has not been able to achieve what it originally set out to do 37 years ago: cure diabetes. That challenge now falls to Arnold Donald. When I recently spoke to Donald at the JDRF offices in St. Louis, he had been on the job for less than a year. He struck me as extraordinarily focused and determined but also very much at ease, a man who’s very comfortable in his own skin. I’m confident he’ll be embraced by all segments of the organization (volunteers, staff, scientists) and by the diabetes community at large. After our wide-ranging, two-hour-plus interview, I can easily say Donald is one of the most engaging and persuasive leaders I’ve met. He is helping the JDRF make evolutionary changes – funding research for continuous glucose sensors; providing venture capital for start-up companies; even demanding that names of donors and volunteers are correctly spelled in letters. But his first and foremost priority is to “find a cure fast.”

“ “

When I first started as a volunteer [at the JDRF], I was like a lot of people. I didn’t have any connection with type 1.

Kelly Close: You actually started in the organization years ago as a volunteer. Can you describe what your reaction was to the JDRF when you first came to it? Arnold Donald: When I first started as a volunteer, I was like a lot of people. I didn’t have any connection with type 1. I started off. I was 23. I was running the United Way campaign for Monsanto, which was a very active participant, and St. Louis was one of the largest United Way campaigns in the country. So it was a big deal, and Monsanto always took upand-coming executives and gave them that leadership role, and I was one of those. Kelly: Okay. Mr. Donald: One of the agencies with the campaign was JDRF. That was my first exposure. Then many years later, I ended up being involved in the low calorie, highintensity sweetener business. The Equal brand and NutraSweet products. Obviously those products are used extensively by people with diabetes, and so we were very active with both the ADA and JDRF. I headed up the national walk campaign for the American Diabetes Association. I was the chair of the Gala here in St. Louis at JDRF. I chaired a walk here for JDRF. Kelly: That’s considerable exposure. Mr. Donald: Through all that, I just got to know a number of people who had diabetes and for a few years went through their lives with them as a friend and saw what these organizations were accomplishing and especially JDRF, the research focus, which is more my cup of tea. I just grew close and passionate about it and continued to be involved, even when I left the sweetener business. It’s been almost three or four years ago now. Kelly: How specifically did this opportunity come up?

I just got to know a number of people who had diabetes and for a few years went through their lives with them as a friend and saw what these organizations were accomplishing…

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T2

This article may be of particular interest to those with type 2 diabetes.

Mr. Donald: I stayed involved, my wife and I, because of the friends we have, and then I had a fundraiser at my house. We built a new home, and it’s a bit of an interest here in St. Louis; and so we had a high-end fund raiser for a limited number of people and some dignitaries and what have you, and Peter Van Etten, who was my predecessor at JRDF, was there, and you know the rest of the story. Kelly: What did you think when you were deciding whether to take the position? Mr. Donald: The first question was, am I the right person, number one. I am a corporate person and so, am I the right person? That wasn’t self-evident to me. Kelly: Really? Mr. Donald: And I still feel I need to prove that to myself every day because if I think that I’m not making the kind of difference that needs to be made, then my first priority is to get out of the way and help find someone who will, because this is about finding the cure. Kelly: Certainly. Mr. Donald: And so the question was, do I even have the right set of skills? And am I the right person? After asking myself that and talking with Peter Van Etten and with other leaders within JDRF, I thought, I really want to make a difference. What better way to spend a disproportionate amount of my time than doing this, and I was lucky enough to be in a position where I felt psychologically, financially, that I could afford to do this versus continuing to accumulate wealth. So that’s what I did. Kelly: I see. Can you discuss how you see your job and what your responsibilities are? Mr. Donald: Practically speaking, I’m here to unleash the latent potential that exists in our incredible volunteer and donor base. That’s my goal, and how that turns out in practical terms is simply, first and foremost, to find a cure fast. That’s what we’re here to do. Kelly: Find a cure fast? Mr. Donald: Find a cure fast. Now, fast is a relative term. But basically what we want to do is get to a cure faster than it would have happened if we hadn’t worked on it. Kelly: We’re looking forward to everything you’ll accomplish at JDRF! Thanks so much again. — For more of Mr. Donald’s comments, including his thoughts on the JDRF road map, the focus of his work, the nature of past and upcoming investments, and how the JDRF is trying to fill non-traditional gaps, please go to www.diatribe.us/dialogue.

Find a cure fast. Now, fast is a relative term. But basically what we want to do is get to a cure faster than it would have happened if we hadn’t worked on it.

learning curve
Nearly 20,000 prescriptions were written during the first week of 2007

T2 Novel Class of Treatments
By Cindy Glass

Merck Launches New Type 2 Drug as First in

Merck is one of the country’s largest pharmaceutical companies, so the FDA’s approval of the company’s first diabetes drug brings a major player into the field. Late last year, the FDA gave its blessing to a much-anticipated oral drug for type 2 patients called Januvia (diaTribe subscribers received this news via our “news alert” system that day). Granted, the
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name sounds like an obscure planet in the solar system or perhaps a new-age rock band, but Januvia is the first agent in a novel class of diabetes treatments that we believe can significantly improve care if they are taken early in the progression of the disease. Minimal side effects are a major benefit. The potential impact is obvious: only 33% of type 2 patients who are on medication are considered to be “at goal,” so any drug that enhances control could find a large market. Merck has the marketing and financial muscle to give its new product every chance for success – and it’s off to an excellent start. Within eight days of the approval, Merck had contacted 70,000 physicians, stocking many of them with free samples; the company has targeted 100,000 doctors for its initial outreach. Meanwhile, Merck’s januvia.com website had 60,000 hits in the first three weeks, and a January report from pharmaceutical tracking firm IMS showed that nearly 20,000 prescriptions were written during the first week of 2007. This is far fewer – on a week-to-week comparison – than the 500,000-plus prescriptions written for Actos and Avandia combined, but it’s far more than the well under 1,000 prescriptions for Exubera (inhaled insulin) and quite respectable compared to 50,000 prescriptions written for Byetta. Moreover, a similar product by Novartis is also under review by the FDA. The drug’s name has an intergalactic connotation as well – Galvus. Whatever they’re called, these products could be of great importance to diabetes.

Incretins can stimulate insulin from the weakened beta cells of type 2 patients – and that’s where Januvia comes in.

See www.diatribe.us/ learning-curve.php for in-depth 2006 article on Byetta, another incretin-based therapy

A DPP-what? Januvia is part of an emerging class of “incretin-based” therapies, the most popular of which is Byetta, which over 500,000 people are now taking. Incretins are “gut hormones” our bodies use to digest and process our food. Among other things, the incretins help the body’s metabolism by increasing insulin production and slowing food absorption – both of which should work to reduce glucose levels. But incretins have a problem: secreted by the endocrine cells of the intestine, they only survive in the blood for one to two minutes before they are obliterated by an enzyme called dipeptidyl-peptidase 4, or DPP-4. This doesn’t represent a problem for nondiabetics. They don’t need the incretin boost because their beta cells can produce enough insulin to carry the load. Incretins aren’t critical for type 1 patients either because their beta cells have already been destroyed – you can’t pump water from a dry well. But incretins can stimulate insulin from the weakened beta cells of type 2 patients – and that’s where Januvia comes in. Januvia is a so-called DPP-4 inhibitor. It blocks the DPP-4’s search-and-destroy function, giving the grateful incretins a longer life – hopefully, to recharge the beta cells. This allows patients to regulate their glucose levels better, because the incretins trigger insulin secretion by the beta cells and impede glucose production by the liver. So, what’s wrong with the treatments we already have? Currently, physicians have the following pharmaceutical choices as the first line of attack for type 2 diabetes: • sulfonylureas, which can cause hypoglycemia, weight gain, and GI (stomach) distress • metformin, which can cause GI distress • TZDs, which can cause weight gain, swelling, and congestive heart failure • insulin, which can cause weight gain and hypoglycemia All of these options can involve unpleasant, if not dangerous, side effects, so it’s no surprise that primary care doctors might delay needed drug therapy and choose to emphasize diet and exercise instead, although it is dispiriting because as a result, many patients don’t get treatment when their A1c levels first stray above 7, to 7.5, 8 or even higher. But many believe (including us) that we will soon enter a new era of diabetes care.
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Companies have long been encouraging earlier, more aggressive therapies – and leading doctors have advocated the same – but the existing drugs have made that approach difficult (patients typically aren’t excited to pay $3-4/day or more to gain weight, for example). Incretin therapy, on the other hand, makes that type of intervention easier.

Januvia is considered a very “clean” drug: no weight gain, no hypoglycemia, no gut troubles, no heart problems, and no swelling. In other words, no reason for patients to stop taking the drug.

DPP-4 [inhibitors] will be perfectly suitable for first, second, and third [line therapy], and if physicians take the 6.57% A1c goal seriously, most type 2 patients will need multiple agents to achieve it.

What makes Januvia different? The major advantage of Januvia (and other DPP-4 inhibitors) is its favorable “tolerability” profile, which means it’s easy to take and has few side effects. Januvia is considered a very “clean” drug: no weight gain, no hypoglycemia, no gut troubles, no heart problems, and no swelling. In other words, no reason for patients to stop taking the drug. These are also important considerations for physicians, some of whom are reluctant to prescribe drugs whose side effects will cause patients to call them with complaints. And the dosing for Januvia is easy. It’s taken orally once a day. While Januvia doesn’t cause weight gain, we should point out that unlike Byetta, it won’t cause weight loss either. The study data indicate that Januvia, taken as monotherapy, reduces A1c scores on average by between 0.6% and 1%; taken in combo therapy with metformin, the reduction increased to 2.1%. These numbers suggest both clear opportunities and limits for Januvia. The drug should be very beneficial for patients with A1c’s at 7.5% or lower, who could use the product – probably in combination therapy – to stay at or close to their A1c target. This requires early intervention, but “glycemic success” helps motivate patients and could curb the debilitating progression of the disease. As Dr. Zachary Bloomgarden, Clinical Professor of Medicine at Mount Sinai, told us, “DPP-4 [inhibitors] will be perfectly suitable for first, second, and third [line therapy], and if physicians take the 6.5-7% A1c goal seriously, most type 2 patients will need multiple agents to achieve it.” However, once a patient exceeds, say, 8.0%, more aggressive therapy will be needed. Januvia simply doesn’t have enough glucose-lowering benefits to get these patients to target on its own. In fact, it could even impede necessary care by allowing patients to avoid more intrusive therapy; namely, insulin. Dr. Irl Hirsch, professor of medicine at the University of Washington, said, “The problem is in the typical patient with the very high A1c, the hypoglycemia benefit may not be all that important and, like the TZDs, these [DPP4 inhibitors] may be used as yet another procrastinator for those who need insulin.” There is also uncertainty about long-term safety. Only about 1,100 patients have been treated for more than a year with Januvia, though more studies on DPP-4 inhibitors are underway. We know of 43 studies right now involving about 6,700 patients, 70% of them on Januvia. One point of known caution: because Januvia clears mostly through the kidneys, patients with kidney problems need different dosing and should take periodic tests (ask your doctor if he or she doesn’t suggest it) to ensure that Januvia is having no damaging effects. At just over $4 per pill, Januvia isn’t cheap. Merck, along with its competitors in this category, will have some reimbursement hills to climb, especially for patients who want to take it as a first-line drug. We are intrigued by Merck’s decision to price below $5 a day. This price seems designed to attract support from insurers and HMOs, even though it is still pricier than generics like metformin and the sulfonylureas, which cost pennies per pill. Regardless, Januvia’s price is a reminder that new diabetes drugs and technologies almost always cost more than what they’re trying to replace.

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logbook
The Risks and Rewards of a “Genetically Flawed Child”
Jan Mickelson at 1040 WHO told his morning listeners that I was a genetically flawed individual...
By James S. Hirsch

In Mickelson’s view, I did a bad thing when my wife and I decided to start a family.

The bias against diabetes comes easily, perhaps because the disease is chronic (“they’re incurable”) or perhaps because type 2 diabetes is closely linked to obesity (“they’re lazy”).

recently appeared on a radio show to talk about Cheating Destiny, my book on diabetes; I’ve had type 1 since I was a teenager. The following day, the talk show host, Jan Mickelson at 1040 WHO in Des Moines, Iowa, told his morning listeners that I was a genetically flawed individual. To be fair, he actually said that I was “a highly educated, highly functioning genetically flawed individual” – confirming that my master’s degree was indeed good for something. In Mickelson’s view, I did a bad thing when my wife and I decided to start a family. “I know the desire to reproduce from your own gene pool is almost overwhelming,” he said, “but what if you know that you have the shallow end of your own pool? If you are genetically flawed, just don’t reproduce. That’s just being a bad citizen.” Unfortunately, two years ago, our son, Garrett, was diagnosed at age 3 with type 1 diabetes. No one has informed him of any limitations or imperfections; but according to Mickelson, Garrett is a “genetically flawed child,” and my passing on the disease was “child abuse and an evil thing to do.” His comments, once downloaded on an audio link and emailed by diabetic patients around the globe, caused an outrage. Mickelson received a number of emails that compared him, unfavorably, to Hitler. To put out the storm, he immediately invited me back on his show, and he apologized, sort of. He conceded that he misrepresented the role of genetics in type 1 diabetes – he had said they played a “dominant role.” In fact, a child with a type 1 diabetic father has about a 7 percent chance of developing the disease; a child with a type 1 mother, about 2 percent. The genetic risks are much higher for children with parents who have type 2 diabetes: if both parents have type 2, the child has a 45 percent chance of developing it. But in our second interview, Mickelson reaffirmed his view that diabetic patients are “genetically flawed,” and he is still troubled that these individuals have children. He explained that what really bothers him are “welfare moms” who make tax payers support their children, and he believes this happens often with diabetic parents who have relatively high medical costs. Mickelson’s attack is a useful reminder that diabetic patients have long been the victims of discrimination, ignorance, and indifference. Lee Iacocca, whose wife, Mary, died from diabetes in 1983, said that in the auto industry, diabetic plant workers “were a cut above lepers” – and as The New York Times recently reported, patients still suffer workplace discrimination. Meantime, parents of diabetic children have to fight to ensure that schools provide legally mandated medical assistance, and insurers routinely reject coverage – or charge substantially higher premiums – for even well-controlled diabetic patients. The bias against diabetes comes easily, perhaps because the disease is chronic (“they’re incurable”) or perhaps because type 2 diabetes is closely linked to obesity (“they’re lazy”). No one, for example, would describe a woman with breast cancer or a senior citizen with Alzheimer’s as “genetically flawed,” despite those diseases being genetically based. At any rate, the claim that diabetics are intrinsically impaired is laughable on its face: Such diabetic luminaries as Thomas Edison, Jackie Robinson, and Ernest Hemingway exemplify genetic superiority, while those with the disease have fought in Iraq, won Olympic gold medals, and climbed Mount Everest. Despite those achievements, the question of whether diabetic patients should have children is still an area of legitimate debate. The claim that they shouldn’t is not new. Elliott
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The first year was tough – the daily insulin shots and finger pricks and the balancing of food and exercise, an elaborate scheme to keep your small child on this narrow glycemic precipice.

Joslin, America’s preeminent diabetes specialist in the first half of the 20th century, urged his patients not to marry other diabetics for just that reason. In my own case, I knew that treatment has improved dramatically since the days of Joslin, and that if either of our two children developed the disease, we would manage. But I can’t say I was entirely prepared for the event itself. When Garrett was diagnosed, I felt terrible guilt and condemned myself for helping to bring Garrett into the world. And the first year was tough – the daily insulin shots and finger pricks and the balancing of food and exercise, an elaborate scheme to keep your small child on this narrow glycemic precipice. Who needs a wacky talk show host to eviscerate you when you’ve already done it yourself? But Garrett surprised us. No, he doesn’t like his diabetes, and some days he still balks at his shots. But he’s accepted it and has already learned a great deal. When his school nurse recently tested his blood sugar and found it low, Garrett explained, “That’s my Daddy’s fault. He gave me too much insulin.” Garrett is now flourishing in kindergarten, beloved by teachers and friends and excelling as one of the best athletes on his soccer and basketball teams. And when I see him with friends or family, at school, or on the ball field or sleeping in his mother’s lap, I consider the question that has haunted me from the first and that Jan Mickelson reprised: Was it really a mistake to have Garrett? Of course not. He brings so much joy to so many people. If he were not around, the world would be a much smaller place.

profile
Cross-Country Challenge: Phil Southerland Bikes to Whip His Rivals and Defeat His Disease
Phil Southerland has accomplished what many people deemed impossible: leading a team of type 1 athletes to achieve a record time in the 3,000-mile Race Across America. By Amy Tenderich

hil Southerland is an energetic 24-yearold with a charmingly handsome grin and endearing southern accent. Diagnosed with type 1 diabetes as a 7–month-old, he has transformed his disease into a driving life force. Armed with a passion for competitive cycling, he’s accomplished what many people deemed impossible: leading a team of type 1 athletes to achieve a record time in the 3,000-mile Race Across America — completing the journey in 5 days, 16 hours, and 4 minutes. Southerland is not the only type 1 athlete to excel — his counterparts have won Olympic gold medals, climbed Mount Everest, and played professional sports — but Southerland has distinguished himself by working to raise hundreds of thousands of dollars for the cause and by becoming an inspirational speaker to young people with diabetes. “Phil is passionate about diabetes and controlling it, but he’s also a good supporter and is understanding about where you’re coming from,” says Joe Eldridge, the co-founder of the all-diabetic TeamType1 cycling team. Southerland may have saved Eldridge’s own life. When the two met in college at a bike race, Eldridge was in terrible control. But after Southerland starting making blood sugar bets with him (the loser had to buy dinner), Eldridge eventually got the message and began managing his diabetes more diligently. From this friendship, formed in 2004, came the notion of uniting diabetics through cycling. Southerland thought they should form an official racing team. Eldridge came up
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with name “TeamType1.” And they both adopted the motto “strive for 6.5,” referring to their A1c goals. Eldridge has dropped from over 10% to 5.8%, while Southerland himself maintains an A1c of around 5.5% and mean glucose levels in the mid-80’s.

If I have to check my blood sugar 20 times a day for the rest of life, then I’m okay with that, ” Southerland says. “It’s not that big a price to pay for eyesight.

Thank the Birthday Cake Southerland, who earns his living as an insurance rep, says his enthusiasm springs from his plucky single mother, Joanna, who juggled several jobs to support him and his brother. “She always said, ‘No matter what cards you’re dealt, you always have a great hand!’ And she helped me to have that same attitude.” His specific resolve to conquer diabetes can be traced to a birthday party when he was six years old: He wanted to eat birthday cake but didn’t want to take the requisite injection. “That’s fine,” his mother told him. “You can eat the cake, but you’ll go blind.” That shook him up so much he begged for the shot. “If I have to check my blood sugar 20 times a day for the rest of life, then I’m okay with that,” Southerland says. “It’s not that big a price to pay for eyesight.” Show Me the Money Southerland’s current efforts were kicked off by a college assignment to write a business plan. He found himself outside Starbucks at the Mall of Georgia with a clipboard, surveying people about whether they would donate money to an organization that provided tools to help diabetics effectively manage their disease (and therefore negate the risk of long-term complications). Mostly he was rebuffed, but then along came a guy who asked, “If I gave you money right now, what would you do with it?” Southerland had no intention of taking money on the spot, but the man insisted, pressing $400 cash on him and telling him to “get started.” “To this day, I have no idea why he did it,” Southerland says. “But I kept my promise and bought T-shirts and business cards to promote the idea.” While the group health management platform remains a long-term dream, what he has created is an organization (www.teamtype1.org) that now raises awareness and money for the Juvenile Diabetes Research Foundation (JDRF). Southerland’s personality was also critical in securing financial support for TeamType1. His endocrinologist, Dr. Bruce Bode, introduced him to executives at Abbott Laboratories, which became a sponsor. Southerland eventually managed to raise $400,000 from a variety of sponsors for the 2006 Race Across America, and he’s added additional sponsors for 2007, including Amylin Pharmaceuticals, Specialized Bicycles, Zip Wheels, and Hammer Nutrition. “He’s a salesman, for sure,” Eldridge says. “He’s extremely passionate about getting the word out about diabetes.” Smashing Records TeamType1 now consists of eight regular riders, including one woman, who collectively compete in 400-500 events throughout the year — from five-mile sprints, to Iron man triathlon events, to the 3,053-mile cross-country race. Southerland personally competes in about 60 events per year, training six days a week for up to six hours a day depending on the season. But the grueling Race Across America created unique challenges. Renowned worldwide cycling coach Rick Crawford donated his services at a deep discount but only had four months to get his glucose-challenged group ready. For his part, Southerland views blood sugar control not as an obstacle, but rather a puzzle to be solved. He’s learned the importance of keeping glucose levels steady by starting out in the 120-150 range and eating often, rather than starting out high (in the 200 range)
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If I gave you money right now, what would you do with it…?

Things have been much easier now that he has a new continuous glucose monitor on his handlebars.

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Diabetics can do anything and everything that nondiabetics can do, but better – no offense!

with the expectation of plummeting. He recently completed a 320-mile ride from Atlanta to Tallahassee, FL — 16 hours — and never fell below 80 or rose above 140. “Blood sugar levels have a big effect on performance,” he says. “So sometimes, in the 45 minutes before a race, I might check five times. But I don’t check during riding: never have, never will.” Still, things have been much easier now that he has a new continuous glucose monitor on his handlebars. Through Dr. Bode, Southerland enrolled in a study of Abbott’s investigational FreeStyle Navigator continuous monitor, which uses a sensor/transmitter on the body and a wireless receiver to provide glucose readings every minute. The monitor also has alarms for highs and lows. “It’s fantastic,” Southerland says. “Every other year I’ve done this type of intense training, my blood glucose crashes, especially overnight. Now (using the Navigator) I can go to sleep and rest assured.” Energy sources of choice are Snickers bars (a favorite since Southerland was a kid) and Hammer Gel, a gooey energy supplement that contains maltodextrin, which allows it to absorb slowly, providing extended energy. By the end of the second day of the Race Across America, Southerland says he knew exactly how his blood sugars were affecting his ride. “If I was in the 150-180 mg/dL (8.3 – 10 mmol/L) range to start with, I could produce maximum power,” he says. “If I was at 120 (6.6 mmol/L), it was harder. If I was at 300 (16.6 mmol), it was also hard. And I wanted my (continuous monitor) arrow going in the right direction. If I was at 150, and the arrow was going straight down, I knew I needed to eat.” TeamType1’s victory, beating the 2nd place team by nearly an entire day, proved that “diabetics can do anything and everything that non-diabetics can do, but better — no offense!” Southerland says with a laugh. TeamType1 beat the Race Across America all-time corporate-team record by a full 19 hours. Southerland’s goals for the coming year are lofty yet simple: raise $210,000 for the JDRF (10 times the team’s 2006 contribution), and repeat his team’s cross-country victory – but this time, to “ride faster.” — Amy Tenderich is author of the popular web log www.diabetesmine.com, and coauthor of the new book, Know Your Numbers, Outlive Your Diabetes.

conference pearls
The 19th World Diabetes Congress (Cape Town, South Africa, December 3-7)

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…These countries’ emerging, industrialized economies…are bringing increased affluence but also the dark side of prosperity…

his winter we flew down to sunny Cape Town to attend the nineteenth official meeting of International Diabetes Federation (IDF). This conference, held only once every three years, drew over 12,000 clinicians, scientists, and other attendees. Diabetes isn’t easy for anyone to live with, but this meeting reminded us of how lucky we are, in the US, who have health insurance and access to the drugs and devices that make such a difference.

Diabetes is an international epidemic. Diabetes is a global epidemic, but its greatest impact right now is in fast-growing, developing countries – the most prominent being China and India, which have more diabetic patients than any other countries in the world. About 180 million people have diabetes worldwide, a number expected to at least double by 2030, according to the World Health Organization. China had about 21 million people with diabetes in 2000 (so, likely a few million more now), which is also expected to double by 2030. India had about 32
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million people with diabetes in 2000 and is expected to have 80 million (much more than double!) by 2030. These numbers compare to 15 million in the US, a number we typically perceive as sky-high. This crisis reflects these countries’ emerging, industrialized economies, which are bringing increased affluence but also the dark side of prosperity: sedentary lifestyles, high-caloric Western diets, and obesity.

Highlight on diabetes in children. In poor countries, children with diabetes are often not diagnosed until long after onset. Some die for want of a diagnosis, while others who are saved have severely shortened lives because insulin is too expensive or simply unavailable. Leading pediatric diabetes specialists Dr. Francine Kaufman and Dr. Henk-Jan Aanstoot spoke about the IDF theme for 2007: diabetes in children. We hope that passage of the UN Resolution for Diabetes will bring greater attention to this troubling area. Obesity is not the only cause of metabolic syndrome. While obesity, especially central obesity (fat around the stomach), undoubtedly has a role in the development of type 2 diabetes, many other factors contribute. Family history plays a big role in susceptibility to metabolic syndrome and diabetes. We also heard doctors talk about how stressful modern lifestyles and environments can activate our inflammatory responses to cause insulin resistance. Insulin resistance is one of the two “dual defects” of type 2 diabetes – the first defect is insulin secretion. In plain English, this means that type 2 patients tend to have two problems – one relates to insulin resistance and usually happens first; this means insulin can’t be properly or optimally processed. The second problem comes when the body has problems with insulin secretion; it doesn’t, in other words, produce enough. Obesity exacerbates both defects, so with the type 2 epidemic, it wasn’t a surprise to see such a big focus on obesity. After all, it is said that if excess weight (being overweight or obese) disappeared, over 80% of type 2 diabetes would disappear.

T2

Diabetes differs among ethnicities. Obesity and metabolic syndrome affect ethnic groups differently. Asians generally have more visceral fat (‘bad’ fat) than Caucasians, Africans, and Hispanics with the same BMI. Because visceral fat is associated with insulin resistance, this means that Asians tend to have a higher risk of developing diabetes at lower body weights. Asians are also more genetically prone to lose beta cell function, the other contributing factor in type 2 diabetes. The bottom line, though, is that people of every nationality, race, religion, age, and creed are increasingly at risk for diabetes as modern lifestyles – too much food, too little exercise – spread throughout the world.

T2

Diabetes drugs don’t last long enough by themselves. The results were released from a big study called “ADOPT,” which highlighted the fact that several common diabetes drugs stop working after a few years. The trial was designed to compare a thiazolidinedione (TZD), a sulfonylurea (SU), and metformin, when each was used by itself as the initial treatment in people with type 2. Though none of them performed outstandingly, the TZD did the best, followed closely by metformin and trailed at a distance by the SU. At four years, 40% of people on the TZD were at target A1c (below 7%), while 36% of people on metformin were at target, and only 26% of people on the SU were at target. The study confirmed what doctors generally know by now – that “monotherapy,” or taking only one diabetes drug, does not really work. “Combination therapy,” or taking more than one drug, seems much more effective. It produces fewer side

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effects as well – less weight gain on TZDs, fewer gastrointestinal side effects on metformin, and less hypoglycemia on SUs – because each drug does not need to be at its maximum dose.

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The Annual Meeting of the Obesity Society

The Obesity Society’s annual meeting has long been our favorite place to catch up on the basic science research behind this critical problem. While the FDA has not approved a new obesity drug since 1999, we came away feeling optimistic that promising new treatments are on the horizon.

Because obesity continues to be viewed as a lifestyle choice rather than as a medical condition, few insurers cover these drugs.

Society makes both weight loss and weight maintenance extremely difficult. In our current “obesogenic” environment, junk food is invariably cheaper than healthy food and people must schedule time to exercise because physical activity is so absent from our daily routines. Poor neighborhoods often lack grocery stores or safe places to exercise. Even when people do lose weight, both biological mechanisms and the pull of environmental lures make weight difficult to keep off. Low efficacy and reimbursement hamper use of current obesity drugs. Two prescription drugs are currently available for long-term weight management treatment: orlistat (Xenical) and sibutramine (Meridia). Both drugs cause about 5% loss of total body weight, which is enough to improve several medical measures of metabolic health but which, for many people, would not be very noticeable. In addition, the side effects can be quite unpleasant or downright worrisome: Xenical causes problems with oily stools and Meridia tends to raise blood pressure. Because obesity continues to be viewed as a lifestyle choice rather than as a medical condition, few insurers cover these drugs. Bariatric surgery is effective but invasive and expensive. Surprisingly, neither physical restriction of the stomach’s size nor mal-absorption of nutrients is the main cause of weight loss when people get gastric bypass surgery. While both do play a role in short-term weight loss, the most important change that occurs in people who get gastric bypass surgery is in the way their small intestines secrete gut hormones (a.k.a. incretins) in response to food. In the short term, these hormonal changes can reverse obesity-associated type 2 diabetes, even before patients begin losing weight! In the long term, surgery patients will feel full more easily and eat less, allowing them to keep off the weight in the initial months after surgery. The obesity pipeline is rich in neuroendocrine therapies. Rimonabant, a drug that reduces weight that is currently under review by the FDA, acts on the central nervous system to decrease appetite. Rimonabant seems slightly more effective than Xenical and Meridia, but side effect concerns include depression and anxiety – if you are interested in taking any new medicine, of course, always ask your doctor or healthcare team about side effects. Further down the road, but perhaps more promising, is the possibility of using incretin therapeutics to treat obesity. As we have discussed, both Byetta and Symlin are incretin hormones that cause weight loss when used for diabetes. Amylin, the maker of both drugs, is researching combinations of Symlin and another compound, leptin, as well as other hormones involved in appetite regulation. Results in rats have been promising, and although human immune systems are very different from those of rats, we look forward to seeing data on how these combinations work in humans.
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NewNowNext
NewNowNext is a new column in diaTribe about diabetic miscellanea that we think are interesting, urgent, or just plain fun.

If you’re not into jewelry, medical alert wallets may be the way to go makes for a quieter everyday For obvious reasons, people with diabetes statement, but it would be are encouraged to wear medical alert jewelry, sufficiently loud in an emergency. though sometimes they prefer carrying a medical information card in their wallet. This isn’t as conspicuous as a necklace or bracelet, but it may also be more difficult to locate. Now you can buy wallets with the medical alert symbol right on the front (medicalalertwallets.com). The quirky symbol, to us, has always been an enigma – it looks like a snake wrapped around a pen, which lies inside some kind of clover – but it’s not a bad design element. The wallet makes for a quieter everyday statement, but it would be sufficiently loud in an emergency. It also comes with a standard medical information card. The website sell all kinds of medical alert pouches, but our favorite is the “Travel Lite,” which seems ideal for those of us with cash flow problems.
The new medical alert wallet

New weight-loss drug may be worth the wait On April 26, the FDA will either approve a new drug for obesity called rimonabant… or they won’t. We do think it will be approved, however, with warnings about important side effects, and that although it is not for everyone, it has undoubtedly helped some patients in trials reduce cardiometabolic risk factors. “Cardiometabolic risk,” by the way, is a phrase increasingly used in diabetes. It describes the multi-faceted, overlapping risks for diabetes and cardiovascular disease faced by many people. So Rimonabant is a “cannabinoid receptor agonist,” which is a long way of saying that it reduces appetite. In a large, recent trial involving people with diabetes who were mostly not obese, rimonabant produced an average weight loss of 14.7 lbs (compared to 6.2 lbs on placebo, or dummy pill). It also reduced A1c by 0.5%, which is pretty good considering the fairly low average starting A1c of 7.9%. While this reduction isn’t on the scale of insulin, Byetta, TZDs, or even metformin, it’s a nice bonus – basically, rimonabant may not only be good for weight loss, but it also improves “cardiometabolic” health in general for at least some patients. The main concern with rimonabant is some strange side effects involving “depressed mood” – definitely a concern, and we imagine the FDA will want very strong warning labels, which makes a lot of sense to us. We’ll see what the FDA thinks come April, and report back then.

T2

This just in: women who intensively manage their diabetes may be divabetics…

According to one website, divabetics rule This just in: women who intensively manage their diabetes may be divabetics, and if you want a website that focuses on girl talk, recipes, and makeovers – and an organization that sponsors educational and social events for distaff diabetics – check out www.divabetic.org. It’s a combination of mypsace.com and The View and is a wonderful, boisterous addition to the diabetes community. We also note that its one sponsor is Novo Nordisk, which is light years ahead of its competitors in recognizing smart opportunities to reach customers.

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The HumaPen Memoir

promises to be the first pen of its kind.

Speak, Memory – a new, smart insulin pen Look out for a new “smart” insulin pen this February. It’s called the HumaPen Memoir – “memoir” because it records the time and amount of the previous 16 insulin doses. This promises to be the first pen of its kind – we love the idea of memory in a pen. It won’t be like a “smart” pump, because it can’t do math or suggest dosing (we believe that’s the best new feature in pumps in the last five years), but memory is certainly a first step. Certified diabetes educators say that thousands of patients have embraced the pen in Finland and the Netherlands, where it has been out for a year and a half. If the pen becomes popular here, it may even encourage more people to use insulin. — For more on what’s new, now, and next, head to www.diatribe.us/newnownext/.

what we’re reading

If
There are many [pump] options…and small variations can make a difference in your control. But how to choose?

you missed this column last time, we should explain: we barely have time to keep up with all the news in diabetes, so we assume it’s hard for you as well. This is why we suggest you take a few minutes to read below about our favorite pieces from the recent literature on diabetes. Not only do we monitor just about every patient magazine and newsletter out there, we also follow many scientific journals and identify the best, most relevant articles to highlight. Some of the pieces we bring to your attention this month can act as guides or resources for you. After all, as new treatments become available and possible treatment combinations multiply, you’ll want to stay abreast of all the developments and we think the articles below are fantastic resources to help you do so. Our favorite patient articles for this issue: ● “Go Ahead, Pick Your Pump: Which Pump is Right for You?” Gary Scheiner, Diabetes Self-Management, November/December 2006. (You can find this article online at http://www.diabetesselfmanagement.com/article.cfm?sid=11&aid=1695) With humor and detail, Gary Scheiner, a certified diabetes educator and author of one of our favorite books about diabetes, Think Like a Pancreas, gives us his enlightened view about which features are important in a pump and which are just “sales fluff.” There are many options – seven pump manufacturers, each with several models – and small variations can make a difference in your control. But how to choose? According to Mr. Scheiner, pumps don’t vary much in the warranty and support, training, computer connection, ease of use, backlight, and prolonged bolus delivery for slow-digesting foods. All of these features are pitched for “competitive edge,” but Mr. Scheiner says they don’t actually affect the user much. What does matter are the following: • Will the pump hold enough insulin to last you three days? Different models vary from holding 176 units to 300 units. • Will bolus-dose amounts work for you? Various models vary in their dosage increments and maximum amounts. • Is the clip convenient? This is more important than one might think! • How is unused insulin (often called “insulin on board”) treated? (Having “IOB” by the

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way is one of our favorite features of “smart” pumps, which came out in 2001 and which do all the calculations for you…) • Will you hear or feel the alarms? You might need to do a test run to figure this out. One warning: don’t turn payment or insurance information over to a rep before you make your final decision. In his article, Mr. Scheiner provides specific information about various pumps (Medtronic MiniMed, Animas, Cozmo, Insulet), but he also encourages you to do your own research and provides the pump manufacturers’ contact information as well as good pump review websites. He ends by not telling us what pump he’s using, explaining that any pump can be good or bad for you depending on whether or not it fits your individual needs. “After much research and deliberation, the pump I have chosen to wear at my side is none other than…” and there the article ends! The bottom line: This article will help you organize your thoughts on what’s important to you when you choose an insulin pump.

The 2007 Resource Guide is a very useful, one-stop information guide that will be great to keep around all year.

● “The 2007 Resource Guide,” various authors, Diabetes Forecast, January 2007. (This article can be accessed online free at http://diabetes.org/diabetes-forecast/ 2007resourceguide.jsp.) The “Resource Guide” is special supplement to Diabetes Forecast that comes out every year and features comments on and comparisons of all the available products for managing diabetes. This is a very useful, one-stop information guide that will be great to keep around all year. It consolidates both basic and specific information in a readable, thorough, and organized format for easy reference. One of our favorite sections of the guide is “New Products,” which showcases devices, drugs, and supplies that have come out in the past year. For people with type 2, the section on different types of oral medications will be particularly useful – cleverly, it is titled “Class Action” to signify the many classes of medications now available. We were also thrilled to see a section on combination pills, which combine two drugs of different classes into single pills. Combination pills are growing as doctors become more disillusioned with monotherapy and enamored with “combination therapy.” For the patient, the single co-pay is also a nice bonus! The guide also discusses injectable drugs, like Byetta and Symlin, in the section on insulin. The bottom line: This is an excellent guide on the available treatment options for diabetes. See how your pump, oral medication, meter, or pen compares to others. — For other articles we liked this month, continue reading at www.diatribe.us/ whatwerereading/. WARNING! HARDER SCIENCE AHEAD!

Clinical Trials: ADOPT and CHICAGO Two important studies on thiazolidinediones (TZDs), a class of insulin sensitizers, were published in November and December of 2006. The two currently available TZDs are rosiglitazone (Avandia) and pioglitazone (Actos). While it isn’t correct to apply the study results of one drug to another drug, overall both TZDs seem to have the same mechanism of action and effects. The ADOPT trial was a five-year study that included 4,360 adults with newly diagnosed type 2 diabetes. The participants were randomized, or placed in separate groups, to receive either metformin, Avandia (rosiglitazone), or glyburide (a sulfonylurea). After five years, 40% in the Avandia group had an A1c <7%, compared to 36% in the metformin group and 26% in the glyburide group. This suggests that glyburide doesn’t last as long compared to Avandia. Patients also maintained A1c <7% the longest with Avandia

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Sulfonylureas are not a good choice for oral anti-diabetes therapy because they can cause weight gain and do not provide sustained glycemic benefits.

(60 months), followed by metformin (45 months) and glyburide (33 months). Thus, rosiglitazone provides more stable diabetes control than the other two drugs. However, Avandia also caused significant weight gain. Patients on the TZD gained 4.8 kg (10.5 lb) over five years, while those on metformin lost 2.9 kg (6.4 lb) and those on glyburide gained 1.6 kg (3.5 lb). Weight gain is clearly undesirable, and in previous studies Avandia has been linked to another cardiovascular complication, congestive heart failure, although in ADOPT, there was no difference shown. The CHICAGO study was a 72-week trial that included 462 adults with type 2 diabetes. The participants received either Actos (pioglitazone) or glimepiride, a sulfonylurea, to lower their fasting plasma glucose to <140 mg/dL (<7.8 mmol/L). The study was designed to look at the drugs’ effect on a commonly used marker of atherosclerosis (plaque on the arteries) called carotid intima-media thickness (CIMT). Increases in CIMT are associated with higher risk for cardiovascular disease. At the end of the study, mean CIMT decreased by 0.001 mm in the Avandia group but increased by 0.012 mm in the glimepiride group. If we accept that CIMT is a valid surrogate measure of cardiovascular risk, then these results are highly favorable for Avandia. However, the study was not big enough to measure cardiovascular risk directly, so we don’t actually know if risk was reduced. It’s possible that Avandia improves CIMT but does not affect the more important endpoint: cardiovascular disease. Still, the TZD did produce more sustained improvements in A1c than glimepiride and raised levels of HDL (good cholesterol) while glimepiride did not. The bottom line: TZDs produce more durable declines in A1c levels than metformin and sulfonylureas but cause significant weight gain and are more expensive. In their favor, they are also more beneficial to the vascular system than sulfonylureas and may reduce the risk of cardiovascular disease. Sulfonylureas are not a good choice for oral anti-diabetic therapy because they can cause weight gain and do not provide sustained glycemic benefits. Overall, monotherapy does not keep patients at goal very well, so the biggest takeaway is that combination therapy is essential in type 2 diabetes. (Kahn S. et al. “Glycemic durability of rosiglitazone, metformin, or glyburide monotherapy.” NEJM. 7 Dec 2006. 355(23):2427-2443. Mazzone T. et al. “Effect of Pioglitazone Compared With Glimepiride on Carotid Intima-Media Thickness in Type 2 Diabetes.” JAMA. 6 Dec 2006. 296(21):2572-2581.) — To learn about other recent and exciting studies, continue reading at www.diatribe. us/whatwerereading/.

trial watch
The benefit of enrolling in a clinical trial is easy access to new treatments, as well as the potential to contribute to all patients by helping test new treatments.

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elow we highlight several currently enrolling clinical trials in diabetes. The trials are phase 2 or 3 studies, which generally means that the products they are testing have already met safety requirements for use in humans. These trials tend to seek large numbers of people in order to evaluate a treatment for approval by the FDA, the federal agency that approves drugs and devices in the US. The benefit of enrolling in a clinical trial is easy access to new treatments, as well as the potential to contribute to all patients by helping test new treatments. Click the links provided to find out more about these trials and, if you’re interested, whether you can enroll. Use of the Paradigm 722 System to Improve Glycemic Control in Adult and Adolescent Subjects With Type 1 Diabetes (http://clinicaltrials.gov/ct/show/NCT00211510)
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This phase 3 study compares Minimed’s sensor-augmented pump with the regular 715 model pump. TYPE 1. Safety and Efficacy of Exenatide as Monotherapy (http://clinicaltrials.gov/ct/show/NCT00381342) This phase 3 study will evaluate Byetta in people who are using no other diabetes drugs. See last issue’s Learning Curve for more on what Byetta does and how it works! We believe strongly in earlier and more aggressive therapy and are excited to see this drug tested in those who haven’t yet taken other drugs, presumably early in the course of disease. TYPE 2. Effect of Liraglutide on Blood Glucose Control in Subjects with Type 2 Diabetes (LEAD-4) (http://clinicaltrials.gov/ct/show/NCT00333151) This phase 3 study will evaluate liraglutide in people already taking metformin or TZDs (Avandia or Actos). There are a number of liraglutide LEAD trials – if interested, do a search at http://clinicaltrials.gov. Liraglutide is a GLP-1 analog like Byetta. TYPE 2. Islet Cell Transplantation Alone in Patients With Type 1 Diabetes Mellitus: Steroid-Free Immunosuppression (http://clinicaltrials.gov/ct/show/NCT00306098) This phase 2 study will assess the long-term safety and function of islet cell transplants. Transplants will likely be reserved for those with very specific entry requirements – if you think you might be interested, we encourage you to read the background information. TYPE 1.

PEDIATRIC DIABETES SYMPOSIUM & KIDS KAMP! pre-register Saturday, March 3, 2007 — Admission is FREE! 415-353-9084 • lstiehl@diabetes.ucsf.edu • PARENTING THE CHILD WITH DIABETES •

Be an advocate for progress www.jdrf.org/advocacy

Conference and Expo July 11 – 15, 2007 www.childrenwithdiabetes.com

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diaTribe publishes information about diabetes products and research. This information is not a substitute for medical advice and should not be used to change treatment or therapy. diaTribe urges readers to consult with professional care providers in all matters relating to their health.