What Level of A1c Lowering Yields the Most Benefits and Least Risk?

Five years after the release of the ACCORD and ADVANCE studies, some physicians are still searching for answers….

While new guidance was issued last year, a host of presentations at the American Diabetes Association (ADA) 2013 Scientific Sessions point to the fact that diabetologists and cardiologists are not content with the evidence level so far.

Joint ADA/European Association for the Study of Diabetes(EASD) hyperglycemia guidelines published in 2012 concluded that clear-cut algorithms were less useful in the setting of glucose control. An HbA_1c of 7% is the "general" goal, but a higher target could be considered in patients with advanced cardiovascular disease, reduced life expectancy, or multiple medical problems, while a lower goal could be the aim in newly-diagnosed patients who are highly motivated. Most diabetologists have accepted that, with glucose, as with so many things in medicine, levels that are too low or too high put patients at risk.

In one study presented, Dr. Gregory Nichols, Kaiser Permanente Center for Health Research, Portland, OR, showed an analysis of the concept of "glycemic burden," using the "time in range" of 7% to 8.5% to better predict whether there is a threshold of glycemic burden above which CVD risk is markedly elevated.

His case-control analysis matched electronic medical records of diabetic patients from the Kaiser Permanente Northwest database who were hospitalized for a CV event with diabetics never hospitalized for CVD.

He and his colleagues found that HbA_1c levels at diagnosis and during the observation period were both associated with a modestly increased risk for CVD hospitalization, and that calculating "average monthly glycemic burden" was only slightly better at predicting CVD hospitalization.

"Glycemic burden is intuitively appealing, but it is not straightforward to calculate, and … was not a substantially better predictor of CVD risk than mean A_1c," he concluded.

What’s more, other covariates such as age, systolic BP, cholesterol, presence of CAD or heart failure — well-established risk factors — were much better predictors of a CVD hospitalization than all of the different HbA_1c measures, with one exception, he said. An HbA_1c "ever rising above 7%" was found to be a powerful predictor of CVD. "If a patient ever went above [an HbA_1c of] 7%, that increased their risk of a CVD hospitalization by 39%, relative to those who never did."

As such, "an A_1c ever rising above 7% as a predictor of CVD may have important clinical ramifications for newly diagnosed patients."

Other presentations used previously published series to look at specific groups, asking the question as to whether different HbA_1c ranges may confer different risks in subpopulations. Two such studies provided new data on the "Hispanic paradox" of glycemic control.

One looked at approximately 3500 participants with diagnosed diabetes or baseline HbA_1c levels >6.5% in NHANES IIIand followed patients for 7.5 years for rates of deaths and CVD deaths. Dr. Fangjian Guo, University of Alabama, Birmingham, presented the analysis, which found that the risk of all-cause mortality and CVD mortality appeared to rise after levels of 7.6% and 9.4%, respectively for the cohort as a whole. But of note, for both Hispanics and for women, the risk of all-cause mortality was also significantly increased in the 6.5%–7.5% range, something not seen for men, non-Hispanic whites, and non-Hispanic blacks.

Guo concluded: "Astringent glycemic control (HbA_1c <6.5%) may not increase risks for all-cause mortality or CVD mortality, but A_1c levels in diabetics should not exceed 7.5%. However, for women and Mexican Americans, more stringent goals for HbA_1c control may be warranted."

Another study, presented in poster form, also zeroed in on Hispanics, this time in the Veterans Affairs Diabetes Trial (VADT). Dr. Aramesh Saremi and colleagues compared risk of CVD with intensive HbA_1c lowering in Hispanics, non-Hispanic blacks, and non-Hispanic whites in VADT. They found that after adjustment for all of the usual CV risk covariates, Hispanic veterans randomized to intensive glycemic control had a significantly lower risk of CV events over a median of 5.5 years’ follow-up than Hispanics without intensive control — something that was not seen to a significant degree in the other ethnic groups.

These results, albeit post hoc, support the notion of a "Hispanic paradox" that requires further exploration, the authors conclude.

Practice Pearl:

• From the studies we see that every person is different and requires a goal that is unique to their health situation.

Presented at the American Diabetes Association (ADA) June, 2013 Scientific Sessions