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Where does intensive glucose control stand now, given the study results presented at ADA?
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The term intensive glucose control needs to be redefined in a way that intensive would include HbA1c between 6.5 and 7 rather than 6 or <6.5, or for that matter, normalization. The ADA guidelines should still be adhered to.
I wasn’t surprised by the ADVANCE and VA Diabetes Trial data, but I was a little surprised by the ACCORD findings presented at the ADA. What surprised me was that the deaths were higher and, as someone who was involved with this very early on, the concern was always on nocturnal hypoglycemia, or hypoglycemia in general.
In my opinion, the reason the mortality rate was higher in the low glucose control group in ACCORD was that the lower aggressive glucose control group had a much higher incidence of nocturnal hypoglycemia. This would result in substantial increases in sympathetic tone and early morning increases in BP, all of which would have contributed to higher cardiovascular risk. It had more to do with the timing of the medications and how glucose was controlled rather than the levels. Based on these findings, the message we have is that lower is not necessarily better. When we carefully look at the data, is clear that aggressive glucose control, while it does contribute to reduced mortality, it is far more important for reducing morbidity — specifically blindness, neuropathy, peripheral vascular disease, etc.
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The VA Diabetes Trial did not have an intensive arm, but findings did show clear reductions in morbidity. You can’t put the ADVANCE trial in the same context as ACCORD because intervention was at a much earlier time in the disease course. Obviously, aggressive BP and glucose control in that group given in early times of disease would have a far better effect.
From the moment that we have a diagnosis of diabetes one should institute aggressive management to achieve the current recommended guidelines that are irrefutable, HbA1c <7, BP <140 and lipid management and LDL in the double digits. If you achieve all of those things, plus take a low dose aspirin a day, the data are very solid that this is the most you can do to reduce cardiovascular risk.
George Bakris, MD, is Professor of Medicine and the Director of the Hypertensive Diseases Unit Section of Endocrinology, Diabetes and Metabolism University of Chicago-Pritzker School of Medicine and is an Endocrine Today Editorial Board Member.
The current recommendations from the ADA are a goal of <7 with individual therapy perhaps <6 if it can be obtained without a lot of risk. The AACE has a goal of <6.5.
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The ACCORD data showed a potential for harm with intensive glucose control and neither the ADVANCE nor the VA Diabetes Trial showed benefits. Regarding the results presented at the ADA, the absence of benefit wasn’t a total surprise; on the other hand, the fact that ACCORD, ADVANCE and VA Diabetes Trial showed no benefit is a little bit discouraging. The increase in mortality in ACCORD was a real surprise; no one expected harm. The other thing that sort of stunned me was that people focused on the fact that the primary composite for CVD was down about 10% and sort of ignored that cardiovascular mortality was significantly increased.
These findings are somewhat damaging for a diabetologist. One of the questions that is very interesting is what is this due to, and the answer is not completely clear. Some people believed there were signals for hypoglycemia. The ACCORD investigators said there was more hypoglycemia and it seemed to have been associated with mortality, but on the other hand they said it doesn’t explain the excess mortality.
There are other important glycemic control trials that haven’t been reported that we need to keep in mind. One of them is ORIGIN, which is being conducted in new diabetics and a few IGT patients comparing insulin to placebo. If it turns out insulin is beneficial, that will be somewhat informative. The other trial that is interesting is the BARI-2 trial, which is in patients with coronary heart disease, those who seem to be most at risk in ACCORD, comparing two different treatment strategies (metformin plus rosiglitazone vs. insulin plus short-acting insulin). That may also be important because there should be a big difference in hypoglycemia between the two groups and that should inform whether hypoglycemia might be important.
Current guidelines should take account all of these new research findings. My guess, however, is that the recommendations are probably not going to change, although they should have some caveats about the recommendations for lower HbA1c goals.
Steven M. Haffner, MD, is Professor of Internal Medicine at The University of Texas Health Science Center and is an Endocrine Today Editorial Board Member.