ADVANCE and ACCORD and A1C   (February 16, 2008)

Last week, I commented on the ACCORD diabetes trial (ACCORD AND A1C), which surprised experts when there were an unexpected finding that trying to lower A1C below 6 in people with T2DM and cardiovascular disease resulted in a higher death rate. The reason for the increased death rate is not clear: see my earlier story for more details.

Since then, AACE (American Association of Clinical Endocrinologists) has reviewed the ACCORD trial, and recommended "We encourage doctors to individualize the A1c target goals on patients with Type 2 diabetes at higher risk. An A1c target of 6.5% or less is useful for many, including patients with Type 1 diabetes, and probably Type 2 patients at lower cardiovascular risk, but this goal is clearly not appropriate for all type 2 patients."

And AADE (American Association of Diabetes Educators) also commented after ACCORD that they "would like to caution the diabetes community against changing blood glucose monitoring treatment recommendations based solely on the findings of the ACCORD study."

But this week, it has been reported that another acronymous diabetes trial (ADVANCE, Action in Diabetes and Vascular disease: PreterAx and DiamicroN MR Controlled Evaluation) found the reverse: in the ADVANCE study, involving 11,140 high-risk patients with type 2 diabetes, results from an interim analysis did not show evidence of an increased risk of death among those patients receiving intensive treatment to lower blood glucose. Dr. Rory Collins, who chaired the ADVANCE data monitoring and safety committee, said the ADVANCE results were based on more than twice as much data and similar levels of glucose control as in the ACCORD study. There's a press release from the ADVANCE trial on-line [reproduced at Preliminary findings from the largest-ever study of treatments for diabetes provide no evidence that intensive treatment to lower blood glucose (sugar) increases risk of death]. The ADVANCE trial was funded by the National Health & Medical Research Council of Australia and Servier, the manufacturer of a sulfonylurea drug for diabetes, gliclazide. The trial also included an investigation into more intensive blood-pressure lowering, which was reported previously.)

So we've now got opposite results, and a dilemma: should we believe one or the other or both (or neither!)? Well, there's simply not enough data about the surprising results from ACCORD to decide what happened. We're all awaiting further results being released, as well as the results of yet another study of the same sort later this year.

Reuters quotes Dr. Denise Simons-Morton, project officer for ACCORD at NHLBI as saying "There are some differences between the ACCORD and the ADVANCE studies. We will need to communicate about the data with each other to understand what those differences are... The data I would like to see are exactly what drugs people were on, what were the mortality rates."

And if diabetes docs were confused about what to recommend to their patients after looking at ACCORD, they're now in a tizzy after learning of ADVANCE. A commentary from the American Diabetes Association pretty well sums things up: "The American Diabetes Association believes that the information from ADVANCE is very important and further magnifies the uncertainty over whether intensive glucose control may harm some people with diabetes. Of note, the studies were not identical, and it is unclear whether their differences can explain the discrepancy in results. ADA eagerly awaits the full reports from ACCORD and ADVANCE..." ADA's recommendation: "In the meantime, the American Diabetes Association continues to advise most people with diabetes to strive for an A1C... of less than 7 percent, but as always stresses individualization of treatment goals. People with type 2 diabetes who have existing CVD or multiple CVD risk factors should consult with their health care team about their treatment goals."

Dr. James Dove, president of the American College of Cardiology, said to Reuters "Until we know more about these two trials and the patient populations, we will be doing things as we had been doing them in the past."

The LA Times quotes Richard Kahn, chief scientific and medical officer of the ADA, as saying "I think the message is 'Don't do anything until we get this sorted out'."

And my advice will remain exactly the same as it was last week, before the somewhat reassuring ADVANCE results were released:

1) All patients on super-tight-control diabetes programs (especially type 2 patients) where A1C is being forced below 6.0 should be reassessed for cardiovascular disease by their physicians. And if there's evidence of heart or blood vessel disease, and/or hypertension and/or hyperlipidemia, the level of control might be loosened to allow the A1C to float up to 7.0 or perhaps slightly higher. And if not already on aspirin and other preventative tools for cardiovascular disease (such as smoking cessation), such tools should probably be started.

2) All patients with type 2 diabetes and A1C below 6.0 and known heart or other cardiovascular disease should have their diabetes program rechecked -- and if they are prone to hypoglycemia, the level of control should probably be loosened to allow the A1C to float up to 7.0 or higher. And maybe even if not prone to hypoglycemia, the control should be loosened.

3) And anyone with diabetes whose A1C is still 8.0 or above should continue to work to lower the A1C to the range of 7.0-7.9, and perhaps lower, and should be under the care and close supervision of a highly-skilled diabetes team. After all, it's very clear that blood sugar control reduces complications resulting from diabetes including eye, kidney, and nervous system diseases in people with both type 1 and type 2 diabetes.