The FDA does it again.
“We all do still wonder if tight control earlier after diagnosis is most beneficial. After an individual has had diabetes for a prolonged time, the horse is out of the barn, so to speak, and tight glucose control is not as effective.” These comments come from Dr. Sherita Golden of John Hopkins.
According to a position statement published in the January 2009 issue of Diabetes Care entitled “Intensive Glycemic Control and the Prevention of Cardiovascular Events: Implications of the ACCORD, ADVANCE, and VA Diabetes Trials”; “As is the case with microvascular complications, it may be that glycemic control plays a greater role before macrovascular disease is well developed and a minimal or no role when it is advanced.”
Just last week the New England Journal of Medicine published “Glucose Control and Vascular Complications in Veterans with Type 2 Diabetes”; which concluded “Intensive glucose control in patients with poorly controlled type 2 diabetes had no significant effect on rates of major cardiovascular events, death, or microvascular complications.”
Why then is the Food and Drug Administration (FDA) asking drug companies to conduct extensive and expensive studies that “should demonstrate that the therapy will not result in an unacceptable increase in cardiovascular risk.” According to the FDA’s new guidance “Sponsors should ensure that phase 2 and phase 3 clinical trials are appropriately designed and conducted so that a meta-analysis can be performed at the time of completion of these studies that appropriately accounts for important study design features and patient or study level covariates. To obtain sufficient endpoints to allow a meaningful estimate of risk, the phase 2 and phase 3 programs should include patients at higher risk of cardiovascular events, such as patients with relatively advanced disease, elderly patients, and patients with some degree of renal impairment. Because these types of patients are likely to be treated with the antidiabetic agent, if approved, this population is more appropriate than a younger and healthier population for assessment of other aspects of the test drug’s safety.”
This portion of the new guidelines seems to be a direct contradiction to the position statement in Diabetes Care which states “However, subset analyses of ACCORD, ADVANCE and VADT suggest the hypothesis that patients with shorter duration of type 2 diabetes and without established atherosclerosis might reap cardiovascular benefit from intensive glycemic control. Conversely, it is possible that potential risks of intensive glycemic may outweigh its benefits in other patients, such as those with a very long duration of diabetes, known history of severe hypoglycemia, advanced atherosclerosis, and advanced age/frailty.”
Looking at the results of VADT more closely the researchers noted “Interventions such as lifestyle changes, control of blood pressure and lipids, and antiplatelet therapy can reduce the development, progression and complications associated with type 2 diabetes. Glucose control may reduce microvascular complications, but not cardiovascular complications. Even with microvascular complications, blood-pressure control has a greater effect than glucose control. In patients with advanced type 2 diabetes, the unanswered question is whether glucose control independently reduces cardiovascular complications.” The researchers noted; “For now, appropriate management of hypertension, dyslipidemia, and other cardiovascular risk factors appears to be the most effective approach to preventing cardiovascular morbidity and mortality.”
The lead VADT investigator Dr. William Duckworth stated; “One of the things we wanted to do was reduce or eliminate as many controllable risk factors as we possibly could. We treated blood pressure and lipids very intensely and got those down to very good numbers. We also had the patients on aspirin and encouraged diet and exercise – all the things you’re supposed to do- and once that was done, I was not surprised that glucose lowering had no additional effect.”
Over the weekend Diabetic Investor spoke with several respected endocrinologists and researchers to get their reaction to the new FDA guidelines. Like Diabetic Investor they see the new guidelines as an over-reaction by the FDA to the Avandia controversy. Additionally they believe the requirement to study new drugs in a high risk patient population will yield little benefit and may actually lead to greater confusion. About the only thing this will do is increase the incidence rate of adverse cardiovascular events as these patients are called high risk for a reason.
As happens too often with the FDA they are putting the cart before the horse. There is little, if any, evidence based medicine that concludes that antidiabetic drugs actually caused these adverse cardiovascular events. There is even less evidence that shows that these patients who were already classified as high risk and therefore more likely to experience an adverse cardiovascular event, that these events could be prevented. As Dr. Golden correctly stated and Dr. Duckworth, reinforced once the damage has been done limiting adverse cardiovascular events goes well beyond glucose control.
Looking over the new guidelines the FDA appears to be viewing diabetes in a vacuum failing to understand that while diabetes is part of the problem it is not the sole reason why patients experience adverse cardiovascular events. This is exactly the same logic that leads the agency to issue its ill-advised statement on Byetta and pancreatitis. Rather than look at establish evidence based medicine that shows that patients with diabetes are at a higher risk for developing pancreatitis and that Byetta users actually had a lower incidence rate than the overall diabetes population, they chose to react first and think later.
While researchers can have honest disagreements on the benefits of tight glycemic control there is almost universal agreement that diabetes is the enemy and the sooner it’s treated after diagnosis the better. These researchers also agree that physicians in the real world must aggressively treat all factors facing the patient which goes beyond glycemic control. The fact is for the majority of patients diabetes is not their only issue but one of many. Ignoring cholesterol levels, high blood-pressure, hypertension and obesity isn’t just stupid it’s criminal. This would be like a physician encouraging a smoker to smoke more even though every reasonable person knows that smoking causes lung cancer.
Looking over the new guidelines and all available evidence it’s obvious to Diabetic Investor that the agency didn’t put much thought into what impact these guidelines would have not just on drug development but existing therapy options. The implication is that there is a link between the drugs used to treat diabetes and adverse cardiovascular events, when no such link has been clearly established.
What the facts, backed by years of research, tell us is that poorly controlled diabetes leads to numerous adverse events and not just adverse cardiovascular events. There is no dispute that patients who achieve control have fewer diabetes related complications. There is also no dispute that nearly 75% of patients are not reaching control.
Instead of looking at the facts the FDA has chosen a path that will increase the time and cost of developing new treatments. The FDA has chosen to ignore evidence based medicine. Unfortunately what they have done is implemented new guidelines that could actually do more harm than good. Sadly, this is par for the course when it comes to the FDA.
The bottom line is the FDA is more concerned with covering their collective butts than following their stated mission. Once again they are attempting to appease members of Congress who know even less about diabetes. They ignore input from respected and experienced diabetes researchers just because they may have done research that was funded by a company working in the diabetes space. Yet they are willing to listen to so-called “independent cardiologists” just because they don’t work with drug companies. One day someone will have to explain to Diabetic Investor why researchers who have worked with or for drug companies are tainted and those who haven’t are geniuses.
When it comes to the FDA and these new guidelines Barbara Tuchman said it best; “Wooden-headedness consists of assessing a situation in terms of preconceived, fixed notions while ignoring or rejecting any contrary signs. It is acting according to wish while not allowing oneself to be confused by the facts.”
