Diabetes, ADVANCE, ACCORD and the Timely Perspective of Dr. Gauss

If you are a regular reader of the Disease Management Care Blog, you already know about ACCORD. This randomized prospective study of tight versus not so tight blood glucose control among persons with diabetes showed an unexpectedly increased death rate associated with tight control. While the preliminary results initially appeared online, the New England Journal of Medicine has now published a full report. The mean A1c was 6.4% in the tight control group and was 7.5% in the not-so-tight control group. While there was a non-statistically significant decline in heart attack, stroke and cardiovascular death in the group with the lower A1c, the death rate was statistically higher: these patients were less likely to have a stroke or heart attack, but it if it did happen, it was more likely to be lethal.

At about the same time ACCORD was announced, there was another study called ADVANCE that was also randomized and prospective and also designed to test the merits of tight versus not so tight blood glucose control. It differed, however, in that patients were initially started on a drug called ‘glicazide.’ In ACCORD, docs were able to choose the drugs. In ADVANCE, there was no difference in death rates between the two groups but the tight control group had fewer kidney complications. The rate of heart attack and stroke between the two groups was not different.

If you are confused by the contrasting results, welcome to the club. As Dr. Cefalu points out in his accompanying editorial, there were differences in the rate at which patients achieved their targeted A1c levels, the medications used,the duration of follow-up and the degree of weight gain. Whether one some or all account for the confusion will be answered in future studies.

The DMCB preferred to focus on the what-does-this-mean-for-diabetes-guidelines commentary by Drs. Krumholz and Lee. Wondering if the differing medications had much to do with the disparate ACCORD and ADVANCE outcomes, they have two recommendations:

1. Treatment targets (for example, the American Diabetes Association recommends an A1c of 7%) need to be paired with recommendations on how to get there. Some drugs may be better than others.

2. Treatment targets need to be tailored to an individual patient’s risk. For example, ADVANCE tells us that an increased pre-existing burden of cardiovascular disease may warrant avoiding tight blood glucose control.

The DMCB cannot disagree with these eminent editorialists, but humbly offers an additional population-based point of view that contrasts with the ‘guideline-ish’ one-patient-at-a-time perspective of Drs. Krumholz and Lee. By the way, the pic above is of Herr Professor Gauss, of population-distribution fame. He'd probably appreciate what follows.

Assuming that an A1c target of 6.4% results in a distribution of A1cs around a mean, it is possible that persons to the left will have an even higher rate of harm. Imagine, then, that docs serving a population in a network are successful in achieving an average state-of-the-art A1c 7%. Assuming there is a distribution around THAT mean, the result is that there will be a fraction of patients that are being exposed to a low A1c, some as low as 6.4%, which ACCORD tells us results in a greater rate of lethal heart attack and stroke.

This potential for an increased risk of harm for some persons in a population-based A1c that otherwise 'looks' good at 7% can be addressed one of two ways:

1) move the curve to the right (say to a mean A1c of 7.5%). Before you blanch at this apostasy, consider that there are other diabetes treatment recommendations that have a more flexible approach to the A1c.

2) narrow the distribution around that mean, so there are fewer persons with low blood glucoses.

Either way, fewer patients are exposed to harm. While the first strategy means there will be patients to the right of the mean with higher A1c, the ‘harm ratio’ of the left versus the right of an A1c strategy of 7.5% is unclear. Of the two approaches, a narrower distribution is probably better.

Either way, the DMCB suspects savvy population-based approaches to care, backed up by the right kind of registries, patient education, disease management and physician incentives (among other things) can result in a better ‘distribution’ of A1cs with fewer deaths than the one-on-one approach advocated by the editorialists.