Drugs to prevent diabetes? Drug companies can still DREAM.
Imagine designing a clinical study where patients at high risk of getting diabetes will be instructed in ways to improve their diet and exercise regimens and will be randomly assigned to receive one of two drugs or placebo on top of those recommendations.
Now, imagine that you believe that one of those drugs, a thiazolidinedione, will prevent over 20% of study subjects from developing diabetes during three years of follow-up. You also believe that it will cause modest weight gain in most users, it will cause some patients to develop edema and very few to develop CHF. Finally, you know almost for certain that no “hard outcomes” (i.e. microvascular or macrovascular diseases related to dysglycemia) treatment effects will be seen, given the low risk of such events at baseline.
You design the study and pitch it to those in charge of the money (executives at Sanofi-Aventis, GlaxoSmithKline and King Pharmaceuticals and the Canadian Institutes of Health, to be specific). What do you tell them will be the advantages of funding such a study?
If you are Salim Yusuf or Hertzel Gerstein of McMaster University this scenario was probably close to reality. If anything, Profs. Yusuf and Gerstein might have pitched a much greater reduction in incident diabetes with rosiglitazone, one of the two drugs included in the DREAM study, published late last week in advanced online versions of the Lancet and the NEJM (the other drug was the ACE inhibitor ramipril). [see dream-rosi; dreamlanceteditorial; dream-ramipril; dreamnejmeditorial] GSK sells rosiglitazone as Avandia.
I’m actually having trouble imagining how the good doctors convinced GSK to co-fund this large study. Surely, everyone involved must have imagined how even a spectacular reduction in incident diabetes would be received by the academic medical community, regulators and third-party payers.
Well…the results were spectacular. Rosiglitazone clearly and convincingly reduced the rate of incident diabetes by nearly two-thirds in high-risk patients, compared with lifestyle instruction alone. So, how were they received? In short, the study results are not going to win over any skeptics. Here’s the party line from Jaakko Tuomilehto and Nicholas Wareham, from the Department of Public Health, University of Helsinki and MRC Epidemiology Unit, Elsie Widdowson Laboratory, Cambridge, respectively. The U.S. concensus is unlikely to differ very much.
Overall, despite the impressive risk reduction for progression to diabetes, the lack of data on long-term benefits and side-effects, and the high cost of therapy, mean that health-care funders are unlikely to see rosiglitazone as an appropriate agent for individuals with impaired glucose regulation but low absolute cardiovascular risk. Unfortunately, the greater benefits in higher risk individuals would have to be balanced against the likely increased risk of heart failure.
Surely, the above sentiments are no surprise to the investigators. Surely, they are of no surprise to GSK.
You might reasonably wonder why, then, this study was conducted, given that the “success” of rosiglitazone was unlikely to alter treatment practices, even if the “benefits” of therapy, as evidenced by the primary endpoint of incident diabetes (and death), was clear and convincing.
Well, I for one am interested in the effects of TZDs on beta cell function and would like to see whether long-term treatment in this population can delay or prevent microvascular complications and progression of atherosclerosis. These questions might be addressed by additional analyses and further study during the next phase of the DREAM trial. In particular, we’re likely to get a good sense of the effects of rosi on atherosclerotic plaque progression, thanks to a subset of subjects who had annual carotid ultrasonography. I’m less sanguine about the ability of the study to answer these other important questions.
Preventing diabetes with anything but lifestyle intervention is going to be a tough sell for any company that attempts it. An ideal preventive would dramatically reduce the risk of developing not just progression of dysglycemia but also the vascular complications related to such progression. Short of this demonstration, which might be too much to ask of any single drug-development program, a drug therapy would have to reduce the risk of developing diabetes to an extent greater than that achievable by intensive lifestyle modification alone (i.e. by more than 50-60% compared with routine lifestyle instruction), with evidence of superior adherence to therapy and minimally increased risk helping to make the case. Perhaps these hurdles are more than any single drug can deliver. Or perhaps not.
If the theory that diabetes progresses via gradual impairment of beta cells is correct, it is arguably realistic to think that a drug with prescriber-friendly characteristics is within our sights. Perhaps long-acting exenatide or the emerging DPP-IV inhibitors will be the first such drugs. We won’t know until the studies are done. Can you imagine how those studies will be pitched?
