what we're reading January/February, 2007
If 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 here.) 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 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," various authors, Diabetes Forecast, January 2007. (This article can be accessed free online here.) 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.
"Why Is There More Cardiovascular Disease in Diabetes?" Daniel L. Lorber, Practical Diabetology, December 2006. (The website for this magazine is www.practical-diabetology.com, but the article itself is not available online.) We like Practical Diabetology because it's straightforward, actionable, and smart — but, be warned, it's for physicians. This article examines how diabetes relates to cardiovascular disease. Cardiovascular disease signifies problems with the heart, veins, or arteries and includes bad events like strokes and heart attacks. Lately, its relationship with diabetes has received broad acknowledgement. The details of the relationship aren't fully clear, but we do know that three quarters of diabetes-related deaths are related to cardiovascular disease. We know that while the incidence of heart disease in the US generally has decreased by 25%, it has increased by 23% in women with diabetes. Not surprisingly, diabetes can impair blood vessels. "The vascular endothelium" refers to the lining of our blood vessels, and Dr. Lorber tells us that, rather than a passive lining, the vascular endothelium is actually like an active organ all by itself. In other words, through hormones and secretions, it actually does something. It actively inhibits clotting, irregular growths, and spasm-like constrictions. A diseased endothelium doesn't just seem not to do these things, but it seems to do the opposite, encouraging clots, spasms, and so on. Though it is sometimes hard to separate the chronic hyperglycemia of diabetes with the other risk factors in type 2 diabetes (like unhealthy lipids or high blood pressure), it appears that hyperglycemia itself actually diminishes the vascular endothelium's ability to do its job. A very large and famous trial in diabetes, the Diabetes Control and Complications Trial (DCCT), showed that early control of hyperglycemia in people with type 1 produced a 42% reduction in cardiovascular events in the long term. Also, there is a five-fold increased risk for cardiovascular disease between ages 20 and 39 in people with type 1 relative to the non-diabetic population. Since people with type 1 don't necessarily have the classic risk factors, both statistics support the idea that hyperglycemia itself is bad for the vascular system. Dr. Lorber also discusses the relationship of hypertension (or high blood pressure), dyslipidemia (more "bad" cholesterol and less "good" cholesterol), and inflammation (a hot research area), with cardiovascular risk. Risk factors seem to be synergistic, meaning the risk of having two is more than the risk of having one plus the risk of having the other. But this article isn't just bad news — it's a call to doctors (and you!) to be vigilant about heart disease, not only by controlling glycemia but also by looking out carefully for other risk factors.
The bottom line: Chronic hyperglycemia seems harmful to blood vessels, which are active organs in preventing heart disease. Not only should glycemia be controlled to reduce the risk of heart disease, but everyone with glucose intolerance (type 1s, type 2s, or pre-diabetics) should be vigilant about the other cardiovascular risk factors like high blood pressure and poor cholesterol levels.
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 (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 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.)
ADA/EASD Algorithm for Type 2 Diabetes
In August 2006, the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) published a joint consensus statement on glucose management in type 2 diabetes. The statement includes a new treatment algorithm for doctors and nurses, which emphasizes four main points:
- Achieving and maintaining normal glycemic levels
- Initiating therapy with lifestyle intervention and metformin therapy
- Rapid addition of more medications for patients over glycemic target
- Early initiation of insulin therapy when needed
The statement focuses on A1c as the measure of glycemic control. While A1c is certainly the gold standard for monitoring therapy, we couldn't help but wonder whether glycemic variability will be used in the future. Certainly, the algorithm is forward-looking to recommend immediate therapy at diagnosis for type 2 patients — metformin is the standard therapy recommended, probably because it is relatively inexpensive and there are many years of demonstrated safety. If patients do not meet the A1c <7% goal on metformin alone, a second oral drug should quickly be added, either a sulfonylurea or a thiazolidinedione (TZD). Rather than suggesting the addition of a third oral drug for patients who are still not at goal, the algorithm recommends insulin therapy. Insulin can be effectively used with an insulin sensitizer such as metformin or a TZD. Although many new drugs have recently become available for type 2 diabetes, the algorithm only recommends metformin, sulfonylureas, TZDs, and insulin, citing issues with cost, efficacy, and lack of data for all other drugs. It is true that Byetta and Symlin had been on the market for less than two years when this statement was drafted, but both doctors and patients have found these drugs so helpful that we believe it would have been useful to include them anyway as alternatives. The oft-changing environment reflects the extent to which the therapeutic landscape is changing so rapidly. Since this statement was published, yet another new class of drugs has entered the market, in the form of Merck's sitagliptin (Januvia), the first DPP-4 inhibitor.
The bottom line: The ADA/EASD recommends that doctors make faster and more aggressive therapy adjustments to help type 2 patients meet and maintain A1c goals. Earlier initiation of insulin therapy is advised. Their therapy algorithm does not recommend use of the new incretin class of drugs, but we tend to think that looking forward, Byetta as well as Symlin will become an increasingly important part of the treatment of type 2 diabetes.
(Nathan D. M. et al. "Management of hyperglycaemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy." Diabetes Care. Aug 2006. 29(8):1963-1972.)