More Conflicting Data
Last week we learned that the intensive treatment arm of the ACCORD study was being halted because of higher number of deaths than patients in the standard treatment arm. Diabetic Investor reported that another study Steno-2 came to an opposite conclusion; “After a mean of 13.3 years (7.8 years of multifactorial intervention and an additional 5.5 years of follow-up), there was an absolute risk reduction for death from any cause of 20% among patients with type 2 diabetes and microalbuminuria who received intensive therapy, as compared with those who received conventional therapy. The absolute risk of death from cardiovascular causes was reduced by 13% among those receiving intensive therapy. During the entire follow-up period, the rate of death among patients in the conventional-therapy group was 50%, a finding that underscores the poor prognosis for such patients in the absence of intensive treatment.”
This week we heard from the ADVANCE trial which involves 11, 140 high-risk patients with type 2 diabetes who were randomized to intensive or standard glucose-lowering treatments. Although the study is not yet completed the study felt compelled to issue a statement because of what happened with ACCORD. According to study director Dr. Anushka Patel of The George Institute, “with the data more than 99% complete and so we are confident that interim findings communicated here are a reliable guide to the final results.”
In a press release issued by the study, data safety and monitoring board (DSMB) chair, Professor Rory Collins of the University of Oxford said the data provided “no confirmation” of adverse mortality trend reported from the ACCORD study. Dr. Patel noted that only the DSMB has seen the data and ADVANCE investigators have not had access to the study results. “We do not know if the mortality results show a benefit for intensive glucose lowering or a neutral effect. But we understand there is no indication of harm.”
Dr. Patel went on to state; “There was probably a similar range of treatments used in the two studies, but there will be some differences. For example, ACCORD applied more stringent drug therapy to reach targets than we did, and there was probably more use of thiazolidinediones (TZD’s) in ACCORD than in ADVNACE.”
Based on this news several questions come to mind:
1. 1. Why didn’t the studies at least communicate with each other? Diabetic Investor understands that until each study was completed no hard data could be shared. However, when it’s a matter of life or death and your working with similar patient’s trying to achieve similar goals it does make sense. Working together after both studies are completed is fine yet Diabetic Investor doubts that family members of those who died are comforted by this after the fact analysis.
2. 2. Based on Dr. Patel’s statement regarding the use of TZD’s, one has to wonder why the ACCORD investigators continued to use a TZD particularly after the Nissen study was published. One reason could be that GlaxoSmithKline (NYSE: GSK) the makers of Avandia provided the drug free to the ACCORD study while Takeda the makers of Actos declined to participate.
3. 3. What will this conflicting data mean for drug makers and the Food and Drug Administration (FDA)? Lowering A1c has long been used by the FDA as the primary endpoint in measuring a drug’s effectiveness. Based on the ACCORD actions one could argue that if a drug is too good at doing its job of lowering A1c patients could be at risk. This would fly in the face of the conventional and long held belief that lower A1c levels are beneficial in preventing many of the long term complications associated with uncontrolled diabetes.
4. 4. How will physicians who actually treat patients with type 2 diabetes, who’ve been telling their patients from day one to take their medications and measure their glucose levels, react to this data? This is more of a conundrum when you consider the fact the over 80% of diabetes patients are treated by a primary care physicians and not a diabetes specialist. As a noted diabetologist told Diabetic Investor physicians need to look beyond A1c when treating their patients with diabetes and understand there are situations when aggressive treatment could do more harm than good. Simply put while there are numerous studies that document the benefits of tighter control, what applies generally does not always apply specifically. Lacking the time and knowledge base of a specialist the primary care provider may be ill-equipped to deal with nuisances of treating portions of their patient population.
5. 5. What will patients do? This is the most important question of all. While people in academia pontificate about the possible reasons why one study found one results and another study found a completely opposite result, patients are once again left to their own devices. The standard line is always patients should consult with their physician before making any changes in their treatment regimen. Someone needs to explain to Diabetic Investor what good it does a patient to speak with their physician when the physician is just as confused as the patient.
The sad fact is in the real world patients will use whatever excuse they can to stop taking their medications. As Diabetic Investor reported after the Avandia controversy broke reports from the field indicated that patients were taking matters into their own hands and stopped taking their medications. A truly horrifying event made more troubling by the fact that 75% of patients were already non-compliant with their therapy regimen BEFORE the Avandia controversy came to light.
Looking ahead Diabetic Investor is not optimistic that we will gain a better understand of why these differing results occurred. When all the data is published and reviewed it would be foolish to believe that a clear answer will emerge. Just as the Nissen meta-analysis was dissected and parsed, so too will be the data from ACCORD and ADVANCE.
The bottom line here is that patients will once again be the biggest losers. Patients want a simple answer to what should be a simple question; “Is the medication that I take every day of my life safe?” Given the conflicting data the patient might just begin to wonder if all the work they do every day to help reach control is worth it.
As researchers and academics debate the various study results Diabetic Investor is reminded of something Francis Bacon, the noted English philosopher, statesman, and essayist wrote way back in 1625; “To spend too much time in studies, is sloth; to use them too much for ornament, is affection; to make judgment wholly by their rules is the humor of a scholar.” The only problem here is that no one is laughing.