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American Diabetes Association 67th Scientific Sessions (Chicago, June 22-26, 2007)

In late June, diaTribe sent our team to Chicago to attend the 67th Annual Scientific Sessions of the American Diabetes Association. Referred to simply as 'ADA,' this meeting is the biggest in diabetes; this year over 11,000 researchers, doctors, educators, nurses, dieticians, and other professionals gathered to present new scientific data, hear from clinical thought leaders, and generally expand the knowledge base in diabetes. We came back from the grueling five-day meeting exhausted but newly optimistic about ongoing work in diabetes care as well as the many exciting new drugs and products that we expect to become available within the next few years. See below for our ADA pearls!

Pumps, patches, and ports – new insulin delivery technologies for type 2s are just around the corner.

One interesting trend this year was the large number of small companies working on new insulin-delivery technologies that may provide affordable alternatives to injections within the next few years. The h-Patch is a disposable insulin patch pump for type 2s being developed by Valeritas (www.Valeritas.com); this device would be simpler to use than traditional insulin pumps. Each h-Patch lasts a day, after which it is discarded. The patches infuse a fixed basal rate of insulin but also have the ability to deliver additional units as needed for meals. We think this technology has the potential to make it easier for type 2s to go on basal-bolus insulin therapy although it would not be appropriate for type 1 patients because each pump uses a standard basal rate that patients are unable to change. Alternatively, insulin ports are another way of getting around injections; these are similar to the infusion sets used for insulin pumps, removing the need to give many daily injections; patients would only need to pierce their skin every few days when it came time to change the port. We believe this would also be very useful for patients interested in using Symlin (see our Learning Curve on Symlin in diaTribe #3) to reduce their post-meal blood glucose levels but who don’t want to take more shots per day.

What to do about Avandia? An expert panel weighs in.

More than four thousand doctors packed into an enormous auditorium to hear from Cleveland Clinic cardiologist Dr. Steven Nissen, the author of the original paper that started the Avandia controversy. As readers probably saw in the popular press, this paper suggested that Avandia, an insulin sensitizer commonly used for type 2 diabetes, increases the risk of heart attack by 43%. Other expert panelists at this symposium included Dr. Philip Home, a well-known UK researcher; Dr. John Buse, the highly regarded president of the American Diabetes Association; Dr. David Nathan of Harvard Medical School; Dr. Barry Goldstein of Thomas Jefferson University; and moderator Dr. Richard Kahn of the American Diabetes Association. The panel was not able to answer the question of whether Avandia is actually harmful – we simply do not have rigorous clinical trial evidence to decide one way or the other – but Dr. Kahn did pose a very interesting three-part question to his colleagues: “What would you do with 1) a patient who is not on Avandia, 2) a patient who is in good glycemic control on Avandia, and 3) a patient who is not in good control on Avandia?” Dr. Buse led the panelists in recommending that 1) someone who isn’t taking Avandia yet should be started on one of the many alternative medications available, 2) someone who is doing well on the drug should remain on it until we know more about it, and 3) someone who isn’t doing well on Avandia should be evaluated for therapeutic intensification and possibly discontinuation of the drug.

An FDA panel met July 30 to deliberate on the controversy and on August 14, a black box warning was issued for Avandia as well as Actos, a drug from the same class (called thiazoladinediones). The warning emphasizes that the drugs may cause or exacerbate heart failure, especially in certain patient populations. Both drugs will, however, remain on the market – this warning doesn’t address heart attack risk, the issue originally raised by Dr. Nissen. We believe all patients should make sure their healthcare team is watching out for “safety first” – if you have not recently, we encourage you to “check in” with your healthcare team to make sure you are on optimal therapy. If your A1c is over 7 and your therapy has not changed in more than six months, your doctor or educator may wish to optimize your routine – they will be the best judge, but as always, it is very important for you to follow your own progress and to manage your diabetes to the best of your abilities.

A new paradigm for continuous glucose monitoring (CGM): Improving A1c without increasing hypoglycemia.

One of the most important trials presented this year was the STAR 1 study, the first randomized controlled trial to compare continuous glucose sensor-augmented pump therapy against traditional insulin-pump therapy without CGM. Dr. Irl Hirsch from the University of Washington gave a brisk presentation to a packed auditorium of more than a thousand professionals. The trial enrolled 138 adults and adolescents with type 1 diabetes; all were already using insulin pumps. These participants were randomized into two groups. One began wearing the Medtronic Paradigm 522/722 pump, which can be used with a real-time CGM sensor. Continuous glucose data were displayed in real time on their pump screens. The other group went on the Paradigm 715 smart pump, a standard insulin pump without CGM. After six months, A1c dropped from 8.5% to 7.8% in both groups, but only the CGM group was able to do so without an increase in hypoglycemia.

University of Virginia mathematician Dr. Boris Kovatchev nicely summed up this finding when he said that we should think of CGM’s primary benefit as the ability to reduce hypoglycemia; this in turn allows patients to intensify therapy and reduce A1c and long-term complications. We note, however, that to everyone’s surprise, in STAR 1 there were actually more episodes of severe hypoglycemia in the CGM group than in the control group (11 vs. 3). In case your doctor might note this or might seem otherwise unenthusiastic about the study results – it is key to know that Dr. Hirsch attributed this result to unique problems that occurred at one of the study sites rather than to the use of CGM itself. STAR 1 was the first of three major trials that Medtronic is sponsoring to show the benefits of continuous glucose monitoring. The trial was at least in part intended as a ‘practice’ study to help the research investigators prepare for the current STAR 3 trial. STAR 3 is the largest of Medtronic’s CGM trials – the yearlong trial was expanded recently to 550 patients - and will likely also be the most important one in helping convince insurance companies to pay for CGM. Unlike STAR 1, it will compare sensor-augmented therapy against multiple daily injections (MDI) of insulin guided by fingerstick glucose values – it is comparing against MDI rather than “standard” pump therapy because MDI is still the way most type 1 patients take insulin.

For Byetta enthusiasts who wish they could take fewer injections, next-generation incretin therapies are on the way.

The next big drugs in the GLP-1 class to which Byetta (exenatide, made by Amylin/Lilly) belongs will be liraglutide (Novo Nordisk) and Byetta LAR (Amylin/Lilly), which stands for Byetta long-acting release. Both are expected to be on the market around 2009 – see this issue’s What We’re Reading for more details on how they work. Liraglutide will be a once-daily injection with a fine needle, while Byetta LAR will be a once-weekly injection with a slightly wider needle. Just before ADA began this year, Novo Nordisk released some intriguing data from a large six-month trial for liraglutide. In this trial, liraglutide produced a 0.2% greater A1c drop than Lantus insulin in patients not achieving A1c goal on metformin and/or sulfonylureas. Oral medications like metformin and sulfonylureas are rarely enough to keep type 2 patients at A1c goal for more than a few years, after which insulin therapy becomes necessary. However, in the future it may become common practice for patients who have stopped responding to oral medications to try a GLP-1 drug like Byetta or liraglutide before going on insulin.

Unlike insulin, which causes weight gain, GLP-1 drugs are associated with weight loss, though the actual amount of weight change varies greatly among individuals. Dr. John Buse, ADA president, presented new data showing that patients in the original phase 3 Byetta trials who continued taking Byetta for three more years continued to lose weight and maintain the same A1c drop that they had after six months of Byetta treatment. Amylin/Lilly stated they expect to release the results of ongoing phase 3 study of Byetta LAR – we’ll update you when they do!

Why Janumet may be better than Januvia.

Researchers from Merck, which makes both of these drugs, presented some interesting data that suggest metformin and Januvia (sitagliptin) may have synergistic mechanisms of action. Januvia belongs to the DPP-4 inhibitor class of drugs, which work by inhibiting the action of the DPP-4 enzyme, which breaks down GLP-1. The net result is that it works by increasing the level of active GLP-1 in the bloodstream by about two-fold (Byetta effectively raises GLP-1 levels considerably more, which is why it produces different effects than Januvia). Metformin is one of the oldest diabetes drugs on the market, but its mechanism of action remains somewhat of a mystery. This year, researchers revealed that metformin also raises levels of GLP-1 in the bloodstream by about two-fold, but while Januvia works to prevent the breakdown of active GLP-1, metformin seems to increase the total production of GLP-1. Thus, when taken together (i.e., Janumet), the two drugs produce an additive effect on GLP-1, increasing levels by about four-fold. This may account for why Janumet produces a more robust A1c drop than either metformin or Januvia alone. The ADA recommends metformin as first-line therapy for type 2 diabetes, followed by either a sulfonylurea (generic), a thiazolidinedione (Actos or Avandia), or basal insulin (Lantus or Levemir). At the time of the recommendation, Januvia was not yet approved by the FDA, but these new data suggest that Januvia might not be a bad idea for combining with metformin in patients who don’t reach A1c goals on metformin alone.

No one is safe from hyperglycemia, especially during pregnancy.

The results of the HAPO study were alarming for people both with and without diabetes. HAPO was the first study to ever look on a wide scale at pregnancy in women without diabetes. The investigators discovered that there were no cut-offs for increased risk when it came to glucose values. In other words, women with fasting plasma glucose values from 75 mg/dL to 100 mg/dL showed a linear relationship between glucose level and adverse pregnancy outcomes (note that 100 mg/dL is the cut-off for prediabetes and 126 mg/dL is the cut-off for diabetes). These included outcomes for the probability of the baby being large for gestational age (LFGA), rates of primary C-section, neonatal hypoglycemia in the newborn baby, and unusually high levels of insulin production. These findings are a reminder that we should all be striving for glucose levels as near to normal as possible, even before we reach diagnostic cut-offs for prediabetes and diabetes; to a certain extent, these cut-offs are only arbitrary values – especially during a pregnancy.

Too much glucose in the blood? Ask the kidneys to take a break to help out.

That is what researchers working on developing a new class of drugs called SGLT-2 inhibitors aim to do. The kidneys’ biggest job is to filter toxins from the blood. In doing so, a certain amount of glucose leaks out of the bloodstream and into the filtrate that eventually becomes urine. The reason valuable energy is usually not lost this way is because the SGLT-2 protein works tirelessly to pump the leaked glucose back into the bloodstream. SGLT-2 inhibitors would prevent this from happening. Researchers say that these drugs could stimulate the loss of up to 80 grams of glucose per day in the urine, or about 300 calories worth of sugar. In the process, they could reduce hyperglycemia and perhaps even promote some weight loss. Several companies are working on potential drugs in this class, including Bristol-Myers Squibb/AstraZeneca and GlaxoSmithKline. All of the candidate molecules are still in mid-stage development but we expect to learn more about this class in the coming years. The caveat: glycosuria, or glucose in the urine, is actually one of the side effects of extreme hyperglycemia and is responsible for polyuria (frequent urination, including in the middle of the night) and urinary tract infections – never a pleasant condition to deal with. It is not clear yet if SGLT-2 inhibitors would increase the frequency of urination and infections, but if so these drugs could turn out to be more trouble than they’re worth.

Think the relationship between blood glucose numbers and A1c is confusing? You are not alone.

We have always thought it was a little crazy that daily management of diabetes is performed using fingerstick blood glucose numbers (in units of mg/dl) but that our quarterly diabetes report cards comes back as an A1c value. So if my A1c is 7%, what does that say about my average blood glucose? An international trial is underway now to answer precisely that question. In the past there was no way of really finding how mean blood glucose (MBG) related to A1c because there was no way of calculating mean blood glucose based on a couple of fingersticks a day. However, the current trial utilizes continuous glucose monitoring technology to monitor volunteers’ glucose values over several months. Final results from this trial will be reported in Amsterdam in September. However, at ADA this year, Harvard endocrinologist Dr. David Nathan revealed that preliminary analyses show a good correlation between A1c and MBG. This is important because if there was too much variability between different individuals in the relationship between MBG and A1c, then it would not be possible to convert from one unit to the other. As it is, there is a movement underway to require laboratories to report MBG values alongside A1c values in the future. We ca not predict how fast this change will come, but within a few more years you may be seeing an average blood glucose number that you can recognize next to your A1c value when you go in for your quarterly checkups. (If you have not had a quarterly checkup in awhile – please pick up the phone now and make an appointment!)

Gene discovery is moving us toward personalized medicine.

There were several talks about the genetics of diabetes at this year’s ADA. It seems like nowadays geneticists are publishing papers on newly discovered genes linked to type 2 diabetes every few weeks. However, individual genes involved in diabetes tend to have only a subtle effect on risk, on the order of 10-20%. Even the most strongly associated gene, called TCF7L2, is associated with only a 37% increased risk of diabetes. In the aggregate, all of these genes do help predict an individual’s susceptibility to developing diabetes, but how useful are they in the clinic? As it turns out, not very – at least for now. That may well be a good thing - if type 2 diabetes were entirely genetic, we would have no hope of preventing it even if we could predict it using genetic tests, as is the case with Huntingdon’s disease. However, as the technology for gene sequencing improves, genetically guided medicine may become increasingly common. In 2002, a basic genetic screen of the human genome cost millions of dollars. These screens are called haplotype maps, or hap-maps, and they selectively look at common single-nucleotide polymorphisms (SNPs), the bits of DNA that vary from person to person. However, hap-map costs have been declining exponentially every year, to the point where genetic screens will be used routinely in our medical care to predict who will respond best to which diets, drugs, and other therapies, as well as which treatments to avoid. Instead of finding out what works for each patient through trial and error, doctors could refer simply to a lab test to pick out the best course of treatment.