CV Risk and HbA1c: Search Continues for Key Cut Points, Subgroups

Shelley Wood

June 24, 2013

CHICAGO, Illinois — Five years after the release of the Action to Control Cardiovascular Risk in Diabetes (ACCORD) and ADVANCE studies, some physicians are still searching for some cut-and-dried answers to the question of what level of HbA1c lowering yields the most benefit and the least risk.

And while new guidance on this topic was issued last year, a host of presentations here at the American Diabetes Association (ADA) 2013 Scientific Sessions point to the fact that diabetologists and cardiologists are by no means 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 HbA1c 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 dosed 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.

Glycemic "Burden"?

In one of the studies presented here today, Dr Gregory Nichols (Kaiser Permanente Center for Health Research, Portland, OR) showed an analysis of the concept of "glycemic burden," essentially trying to use 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 HbA1c 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 A1c," he concluded.

What's more, other covariates such as age, systolic BP, cholesterol, presence of CAD or heart failure--all these well-established risk factors--were much better predictors of a CVD hospitalization than all of the different HbA1c measures, with one exception, he said. An HbA1c "ever rising above 7%" was found to be a powerful predictor of CVD. "If a patient ever went above [an HbA1c of] 7%, that increased their risk of a CVD hospitalization by 39%, relative to those who never did."

As such, "an A1c ever rising above 7% as a predictor of CVD may have important clinical ramifications for newly diagnosed patients."

Different Range for Different Subgroups

Other presentations used previously published series to look at specific groups, asking the question as to whether different HbA1c 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 HbA1c levels >6.5% in NHANES III and followed patients for 7.5 years for rates of deaths and CVD deaths. This analysis, presented by Dr Fangjian Guo (University of Alabama, Birmingham), 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: "Stringent glycemic control (HbA1c <6.5%) may not increase risks for all-cause mortality or CVD mortality, but A1c levels in diabetics should not exceed 7.5%. However, for women and Mexican Americans, more stringent goals for HbA1c 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 HbA1c 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.

Whether Glucose Control Matters

Speaking with heartwire , Dr Craig J Currie (Cardiff University, Wales), who was not involved in any of these studies, appeared to shrug off some of the findings, pointing out flaws such as study size, their post hoc nature, or the use of single HbA1c measurements.

"The diabetes community doesn't like to hear that glucose control isn't important in the scheme of things, and this seems to be some backlash [against that notion]."

Currie is "pretty confident"--and has published data to support his views--"that a U-shaped association" does exist for HbA1c.

"We're really looking at a plateau, between 7% and 8.5%, a plateau where it really makes no difference at all whether you are going to get hospitalized with a CV event or you're going to die. In terms of the range, risk goes up below 7% and increases above 8.5%."

Currie does not, however, recommend regular testing of HbA1c, although he acknowledged the debate will go on.

"I think the best thing is to not worry too much about it, it's not that important, at least in terms of CVD. For microvascular disease, that's a different kettle of fish, but if you asked the people in this room, 90% would say HbA1c is really important, and an epidemiologist would say, who really cares?"

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