ACCORD and ADVANCE again   (June 10, 2008)

Several months ago, I wrote about two diabetes trials: ACCORD and ADVANCE. Both studies involved people who have both type 2 diabetes and high risk of cardiovascular disease, but they came to opposite conclusions about whether tight control of blood glucose was harmful in these patients.

ACCORD surprised experts when it was announced that patients in the tight-control part of the study (aiming for A1C below 6.0) had more deaths than patients in the standard-treatment group (aiming for A1C between 7 and 7.9). This unexpected finding generated a lively discussion amongst endocrinologists: were the problems in the intensive group actually due to hypoglycemia, and if not, to what? There was no answer at the time, but it was expected that when more information from the study was available, it might answer the questions.

The following week, another study, ADVANCE, released the results of an interim analysis of their patients. In this study, researchers found the reverse: the 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. Again, it was anticipated that further results would be available soon.

Well, additional information has now become available. The New England Journal of Medicine has just published two articles: Effects of Intensive Glucose Lowering in Type 2 Diabetes (the ACCORD results) and Intensive Blood Glucose Control and Vascular Outcomes in Patients with Type 2 Diabetes (the ADVANCE results).

So, what's new? Sadly, not much to help clarify whatever resulted in the disparate results announced previously.

The ACCORD authors state "Our findings indicate that a comprehensive, customized, therapeutic strategy targeting glycated hemoglobin [A1C] levels below 6.0% increased the rate of death from any cause after a mean of 3.5 years, as compared with a strategy targeting levels of 7.0 to 7.9% in patients with a median glycated hemoglobin level of 8.1% and either previous cardiovascular events or multiple cardiovascular risk factors."

They speculate that "the higher rate of death in the intensive-therapy group may be related to factors associated with the various strategies. These factors include but are not limited to differences in the achieved glycated hemoglobin level of 6.4% in the intensive-therapy group, as compared with 7.5% in the standard-therapy group; in the magnitude of the reduction in glycated hemoglobin levels in the two study groups; in the speed of the reduction in glycated hemoglobin levels, with reductions of approximately 1.4% in the intensive-therapy group and 0.6% in the standard-therapy group within the first 4 months after randomization; in changes in drug regimens and in the rate of hypoglycemia; in adverse effects due to an undetected interaction of the various drug classes used at high doses; or in some combination of these or many other possibilities, perhaps in combination with the clinical characteristics of the patients in the study." In other words, they don't know what caused the excess number of deaths.

They conclude "our study has identified a previously unrecognized harm of intensive glucose lowering in high-risk patients with type 2 diabetes mellitus and high glycated hemoglobin levels. This harm may be due either to the approach used for rapidly lowering glycated hemoglobin levels or to the levels that were achieved."

The ADVANCE publication reported a different conclusion: that "a strategy of intensive glucose control ... that lowered the glycated hemoglobin [A1C] value to 6.5% yielded a 10% relative reduction in the combined outcome of major macrovascular and microvascular events, primarily as a consequence of a 21% relative reduction in nephropathy." In other words, forcing the A1C down does help decrease the risk of diabetes blood vessel complications, both large-vessel problems (stroke and heart attack) and small-vessel problems (kidney and eye damage), but most of the effect was on decreased kidney disease (a form of microvascular disease). Addressing the results seen in the ACCORD study of increased deaths, the ADVANCE authors indicate that their data showed "no significant effects of the type of glucose control on... death from cardiovascular causes ... or death from any cause..."

So the disparity continues, and there's no clear reason why there were excess deaths in the tight-control part of the ACCORD trial. Various experts are implicating weight gain, the use of multiple drug combinations and perhaps even getting blood sugar too low, too fast. And an editorial in the NEJM points out that "Both trials showed that targeting glycated hemoglobin levels that are below currently accepted standards in high-risk patients with type 2 diabetes did not have a beneficial effect on cardiovascular disease."

Now, the important point for patients with type 2 diabetes, and for their physicians: Does the information from these two studies result in any new recommendation for where to aim the A1C?

A second NEJM editorial suggests "the most appropriate target for glycated hemoglobin should remain 7%, though lower individualized targets may be appropriate when the focus is primary prevention of macrovascular disease. When glycated hemoglobin values under 7% are the goal, clinicians will need to balance the incremental benefit of a reduction in microvascular events with the increased rates of adverse events..."

So, I think my previous recommendations are still appropriate:

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.