A DREAM Fulfilled
Our team sat captivated in Copenhagen in September as we witnessed a major event in diabetes research: the long-awaited results of the DREAM (Diabetes Reduction Assessment with Ramipril and Rosiglitazone Medication) trial. With diabetes expected to rise in epidemic proportions from the 200 million affected today to 333 million by 2025, prevention is seen as the single greatest hope to curb this worldwide public health crisis. Prevention was exactly what the DREAM trial tested.
Type 2 diabetes is a progressive disease, which means that it typically becomes more severe over time. Another famous trial, the UKPDS (United Kingdom Prospective Diabetes Study) proved this conclusively. Those affected by diabetes usually begin with impaired fasting glucose (IFG), a pre-diabetic state in which blood glucose levels are slightly higher than normal but not high enough to be classified as diabetic, or impaired glucose tolerance (IGT), a similar and often overlapping condition in which the body does not produce quite enough insulin to lower blood sugar after meals. Over time, a majority of type 2 diabetes patients will require insulin to control their blood glucose. TZDs (or thiazolidinediones) are oral drugs that have been used to treat type 2 diabetes since the late 1990s; they reduce insulin resistance, one of the two major defects defining diabetes; the other is a reduction in insulin secretion. Because insulin resistance begins early in pre-diabetes, it was hoped that treating this early manifestation of diabetes in people with pre-diabetes might stave off their progression to diabetes. In other words, the question the trial was testing was whether treatment with TZDs in people at risk for diabetes could actually prevent diabetes.
On September 15, 2006, the DREAM researchers presented three-year data at the Copenhagen congress of the European Association for the Study of Diabetes (EASD). The DREAM trial studied ramipril and rosiglitazone. Rosiglitazone is a TZD with the trade name Avandia. Ramipril is not a TZD, but rather an ACE inhibitor, a class of drugs used treat high blood pressure. We focus our discussion here on the rosiglitazone arm, which had the most interesting results. Half of the over 5,000 subjects in the trial, already at risk for diabetes, were given rosiglitazone while the other half were given placebo.
The study showed that treatment with rosiglitazone reduced the incidence of diabetes by 62%; only 10.6% of the patients on rosiglitazone developed type 2 diabetes compared to 25.0% of the placebo patients. This is a very meaningful result – statistically significant, as the scientific lingo goes! Perhaps just as meaningfully, rosiglitazone also increased the likelihood of returning to normal glucose by 70%! However, the bad news is that there was also an increased risk of adverse events – the scientific terminology for unforeseen complications – for patients taking rosiglitazone. The adverse event, in this case, was congestive heart failure. During the study, 14 of the rosiglitazone patients (or 0.5% of them) developed congestive heart failure (CHF) compared to only two of the placebo patients (or 0.1%).
All of these numbers are complicated, aren't they? We asked noted endocrinologist Dr. Bernard Zinman of the University of Toronto, a member of the DREAM Trial steering committee, for a little help putting the numbers in context. He told us to think about the trial in the following way: for every 1,000 patients treated with rosiglitazone, 240 will return to normal glycemia from impaired fasting glucose (IFG), 144 patients who would have progressed to diabetes will not, and the attendant risk is that four patients might develop congestive heart failure. In that context, we think the results of the trial might eventually be considered landmark. While there was extensive clinical concern over the adverse events, our view was if you could actually prevent as awful a disease as diabetes for 144 people out of a thousand (and push another 240 people out of 1000 back from the brink), the risk of congestive heart failure for a handful might be worth it as we look for ever better ways to treat this complication. Congestive heart failure is serious, no doubt – but how valuable to be able to prevent or turn back diabetes for hundreds of every thousand?
Despite the exciting results, Avandia or Actos, the other TZD, are not yet approved to treat pre-diabetes and it is a big question how long such an approval would take. Issues surrounding congestive heart failure and several other complications will likely need to be addressed more carefully. In our view, weight gain was also a notable negative associated with taking rosiglitizone. Patients on rosiglitazone gained 0.67 kg per year, or about 3.5 kg after five years. Researchers stressed that subjects who gained weight maintained a consistent waist to hip ratio, which might mean that some visceral fat, or "bad" fat around the middle, was dropped in favor of subcutaneous fat, or "good" fat on the butt and legs. We doubt many patients will really care about what kind the fat is, though! We see a lot of irony in the notion that doctors may ultimately be asking patients to take medication that will cause them to gain weight and might cause heart failure in order to prevent a disease that they don't yet have. On the other hand, we also believe there may be other drugs to counteract the weight gain – more on that to follow in a future column.
Even if TZDs do win earlier than expected approval for the prevention of diabetes, they may not be reimbursed straightaway. DREAM did not do a cost-effectiveness study on prevention therapy, the results of which would be a factor for reimbursement. Additionally, it is hard to know from the three-year data whether TZDs can really prevent diabetes or just delay it and for how long. For these reasons, the results are not immediately going to change clinical decision-making by doctors, but they are still a very exciting first step.
The DREAM trial was the first of many trials assessing possible therapies for the prevention of diabetes. As the diabetes epidemic continues to grow, the DREAM study shows that our approach to the disease is evolving. We now have data that support treating patients as early as possible and indicate that it may be possible to change the underlying physiology of the disease. If further research confirms and refines these findings, the future of diabetes could well be changed. We believe that in the coming years, the underlying conclusion of the UKPDS – that diabetes is always a progressive disease – may come under fire. With optimal therapy, it may be… or it may not.
And what is congestive heart failure anyway? And how should we think about congestive heart failure? Congestive heart failure occurs when stiffness or weakness of the heart leads to a back up of fluid in the lungs and extremities. Patients might experience fatigue and shortness of breath with exertion or even at rest, depending on the severity. In severe cases, the lower blood output can cause brain damage or kidney dysfunction. Luckily the researchers reported that when patients with congestive heart failure were taken off rosiglitazone, their heart function returned to normal. This means at least that there was not permanent damage.
Kelly Close is Editor-in-Chief of diaTribe, an electronic newsletter that helps people learn about new ways to manage diabetes better. diaTribe focuses on new drugs, devices and research. diaTribe is free and available online at www.diatribe.us.
NOTE: The information is not intended to be a replacement or substitute for consultation with a qualified medical professional or for professional medical advice related to diabetes or another medical condition. Please contact your physician or medical professional with any questions and concerns about your medical condition.
As I mentioned in an earlier post, one of the benefits that made it cost-effective for me to go with the real healthcare (HSA) plan rather than the phony (HRA) plan is that my company is now covering "preventative" medicines at $0 copay. The formulary for these, as stated by CVS/Caremark (my pharmacy benefits provider), covers all test strips, lancets, and control solutions. I dutifully get my doctor to write up prescriptions for all of my testing needs, submit...