Experts On One Accord: Studies Not as Advanced as Hoped
As you may have heard, the results of two major clinical trials, ACCORD and ADVANCE, were presented at the annual American Diabetes Association conference held this year in San Francisco from June 6-10. Now that a few months have passed and the dust has settled, we wanted to talk about the takeaways from these discussions about the ADVANCE trial and the ACCORD trial, – we didn't agree with all the headlines!
The aim of both trials was to test the theory that tight control of blood glucose levels can help reduce heart disease through a combination of oral therapies and/or insulin. As you probably know, heart disease is a major concern in the diabetic community since cardiovascular failures account for two-thirds of deaths in those with type 2 diabetes. In general, the results of these two studies were unexpected. Although ADVANCE showed reductions in microvascular complications (eye, kidney, or nerve disease), contrary to expectations, both studies failed to show a significant benefit of intensive glucose control on cardiovascular outcomes such as heart disease and strokes.
But, when you "peel the onion" and talk to the experts, you find that many doctors at this stage say that the trials may not have taught us that much about the "average" patient out there. It is important to keep in mind, they say, that the patient populations in both studies are unique and not representative of the diabetic community as a whole. Patients were generally older (over 60 years old) with a long history of type 2 diabetes and heart conditions - 30% of patients in the ADVANCE trial and 50% of patients in the ACCORD trial have known cardiovascular disease. Therefore, the results of these two studies are probably less applicable to those with no previous history of heart conditions, type 1 diabetes, and newly diagnosed diabetes. Looking back, it may have been better to test patients who weren't at such high risk – because now that we have the outcomes, we can really only apply them to high-risk patients.
The ACCORD Trial
Some background. ACCORD assessed the effects of intensive glucose control in reducing cardiovascular events in patients with type 2 diabetes. Patients were assigned to one of two treatments: in the intensive treatment, the target was near-normal blood glucose levels (an A1c around 6%) and in the control ("conventional") treatment, the target blood glucose levels were higher (7.5% A1C). However, in February 2008, participants in the intensive arm were switched to standard treatment following safety concerns. The primary concern was the higher death rates in the intensive treatment arm. Participants in the intensive treatment were 22% more likely to experience a heart failure with a death rate of 1.4% vs. 1.1% in the standard arm. Along with cardiovascular death, participants in the intensive treatment arm also had a higher incident of arrhythmia (irregular heart beats) and heart failures. Though the ACCORD investigators have performed a range of analyses to determine the cause of the increased mortality, they have yet to discover anything of significance. However, one possible explanation centers on the fact that participants did experience a rapid drop in A1c from 8.3% to 6.7% in only four months. This may have been too short a timespan for such a large A1c drop. This and other possible explanations are still under investigation but most agree that the findings can really only be applied to high-risk patients. An additional confounder may have been weight gain - 30% of patients in the ACCORD study gained 10 kg (22 pounds) or more during the study (patients in ADVANCE did not gain weight) due to treatments that can cause significant weight gain, including Avandia, sulfonylureas, and insulin. Could the weight gain have caused the cardiovascular problems? Maybe, but it will never be known for sure.
I hate to even suggest this, but what if the cure never comes? What if long-term clinical human trials go on indefinitely into the future with no hope in sight? What if cinnamon is just cinnamon? What if cactus juice is just cactus juice and reptile saliva just reptile saliva? And what if the BCG drug is a vaccine for tuberculosis and nothing more? I have this terrible feeling I’ll be an old man with a long grey wizard’s beard and a walking cane made out of...