AACE Patient Safety - Editorials

Patient Safety in Diabetes Care and Intensive Glycemic Therapy

In June 2008, the results of both the ADVANCE and ACCORD studies became public. The results were published in the New England Journal of Medicine (NEJM) on June 12, 2008, presented at the American Diabetes Association (ADA) meeting, and widely discussed in the public media as well. The two trials, ADVANCE and ACCORD, are clearly landmark trials, both because of the high quality of the studies, and the importance of the results. Yet, the two show what appears to be conflicting conclusions.

The ADVANCE trial, a multi-center RCT study with 215 centers in 20 countries, involving 11140 patients with Type 2 Diabetes, compared the results of intensive glycemic management between an experimental group of 5,571 patients receiving therapy with a goal of an A1C of 6.5%, and achieved that goal with a median A1c of 6.5%. The authors concluded that the goal was achievable, safe, and beneficial.

The primary outcome of combined macrovascular and microvascular events was 18.1% in the experimental group, and the standard therapy group had a major outcome of 20.0% over the five year average study period.

The major benefit in reduction of complications was a reduction of nephropathy, 4.1% intensive vs. standard 5.2%, with a hazard rate of 0.79 and a P = 0.006. In contrast, there was a nonsignificant reduction in major macrovascular events with a hazard ratio of 0.95, p = 032. They did also note that severe hypoglycemia was more common in the intensive – control group (2.7% to 1.5%, hazard ratio 1.86, p = 0.001)

But the results of the ACCORD trial were strikingly different. As is now widely known, the safety committee of ACCORD concluded that the excess of deaths noted in the intensive therapy group was sufficiently alarming to require the cessation of the study for safety reasons. 257 patients in the intensive group died, compared to 203 in the standard group. The hazard ratio was 1.22, p = 0.004. They noted, however, that the primary outcome of macrovascular event was less frequent in the intensive group, 352 vs. 371 in the standard therapy group (hazard ration 0.9, p = 0.16). Also noted was a lower number of non-fatal myocardial infarctions in the intensive group.

Moreover, subgroup analysis suggested a clear benefit for intensive therapy among patients with an A1c <8.0% at baseline, and with patients with no previously documented cardiovascular disease.

There has been, so far, far too little attention paid to the fact that we do not yet have data from a very important sub-study embedded within the ACCORD, the ACCORD-MIND study, which is a careful and detailed analysis of the cognitive and emotional changes noted in the study patients, both during the 3.5 years of the intensive glycemic phase and continuing until 2010.

In contrast, the ADVANCE Trial did report that there was a nonsignificant risk reduction of cognitive decline of 2% in the intensive therapy group, but the most detailed analysis and data is likely to be found in the results of the ACCORD-MIND study, and that is not yet available.

But why should the ACCORD-MIND data be so important? Because most of the therapy in both the ACCORD and ADVANCE trials is prescribed by the research team, but actually administered by the patients themselves.

Until we know that the patient was as capable as they should be of doing what is asked of them accurately and in a timely fashion, we cannot exclude the possibility that the discordance between the macrovascular outcomes of two studies, ACCORD and ADVANCE, reflects a less-than-perfect way good strategies were either prescribed or administered.

To be certain, the patients in both arms of both studies, overall had lower death rates than what would be expected from previous epidemiologic data. The patients were certainly not placed in harm’s way. The ACCORD investigators were correct to stop the intensive therapy arm of the study, but we have insufficient data to be sure why the results were what they were in ACCORD. It is still plausible that the strategy used for all may have worked for the right patient. Moreover, the strategy of intensive glycemic control may still work if the method of implementation is optimized by adapting more closely to the emotional and cognitive characteristics of the patient.

We look forward to further studies to answer the questions raised by the findings of the ADVANCE, ACCORD, and VADT trials.