Hemoglobin A1C Levels Strongly Linked to Subsequent Mortality in Diabetes

Hemoglobin A1C (A1C) levels are strongly associated with subsequent mortality in both men and women without a previous diabetes diagnosis, according to the results of the largest study to date of A1C levels and subsequent mortality risk, reported in the June issue of Diabetes Care. In those without known diabetes at baseline, a 1% increase in A1C level was associated with a 16% increase in mortality rate. See publishers comment.

"Only a few prospective studies have examined the associations between A1C among subjects initially free of diabetes and subsequent risk of mortality," write Naomi Brewer, MMedSci, from the Centre for Public Health Research, Massey University in Wellington, New Zealand, and colleagues. "Each of these studies found associations with subsequent mortality. A1C levels have also been associated with mortality in patients with type 1 diabetes and nondiabetic chronic kidney disease and with incident cardiovascular disease."

The goal of this study was to evaluate the association between A1C concentration and mortality rate in a population. From 1999 to 2001, participants were offered A1C testing during a Hepatitis Foundation screening campaign for hepatitis B.
Of 47,904 participants, A1C was less than 4.0% in 142 participants, 4.0% to less than 5.0% (reference category) in 12,867, 5.0% to less than 6.0% in 30,222, 6.0% to less than 7.0% in 2669, and 7.0% or higher in 1596 participants. In addition, 408 participants had a previous diagnosis of diabetes.

During follow-up, there were 815 deaths. For participants without a previous diagnosis of diabetes, HRs for all-cause mortality steadily increased from the A1C reference category to the highest category (≥ 7.0%; HR, 2.36; 95% confidence interval [CI], 1.72 - 3.25). In addition, A1C was associated with mortality from circulatory, endocrine, nutritional, metabolic, and immune diseases as well as from other and unknown causes. Although mortality rate was also increased in participants with a previous diagnosis of diabetes, this was only partially explained by their increased A1C levels.

"This is the largest study to date of A1C levels and subsequent mortality risk," the study authors write. "It confirms previous findings that A1C levels are strongly associated with subsequent mortality in both men and women without a prior diabetes diagnosis."

"The excess mortality risk was from a range of causes but was particularly strong for endocrine, nutritional, and metabolic and immunity disorders and for cardiovascular disease," the study authors conclude. "However, A1C levels only partially accounted for the excess mortality risk in participants with a previous diagnosis of diabetes."

Because A1C level is not affected by recent meals and can be measured without a fasting blood sample, it is a reasonable option for preliminary screening for undiagnosed diabetes. A1C is also linked to low birth weight and other risk factors for cardiovascular disease and diabetes.

Although only a few prospective studies have looked at the relationship between A1C in adults without diabetes at baseline and subsequent mortality risk, these have shown associations with subsequent mortality as have studies in patients with type 1 diabetes, nondiabetic chronic kidney disease, and incident cardiovascular disease.

In those without known diabetes at baseline, a 1% increase in A1C level was associated with a 16% increase in mortality rate.
HRs for A1C level and overall and cause-specific mortality rates were very similar in men and women.
Mortality rate was also increased in participants with a previous diagnosis of diabetes, but this was only partially explained by increased A1C levels.
A1C level was associated with mortality from circulatory, endocrine, nutritional, metabolic, and immune diseases as well as from other and unknown causes.
Of 47 deaths in the "endocrine, nutritional and metabolic and immunity disorders," category, 38 were from diabetes.
A1C level was also strongly associated with mortality from diseases of the circulatory system, particularly ischemic heart disease.
There were weaker associations with deaths from cancer and other and unknown causes.
The investigators concluded that these findings confirm previous findings that A1C levels are strongly associated with subsequent mortality in both men and women without a diagnosis of diabetes at baseline and that the excess mortality risk was strongest for endocrine, nutritional, and metabolic and immunity disorders and for cardiovascular disease.

Practice Pearls:

In participants without a previous diagnosis of diabetes, there was a dose response for increased all-cause mortality with increasing level of A1C.
A1C was associated with mortality from circulatory, endocrine, nutritional, metabolic, and immune diseases as well as from other and unknown causes, with HRs very similar in men and women. Excess mortality risk was strongest for endocrine, nutritional, and metabolic and immunity disorders and for cardiovascular disease.

Diabetes Care. 2008;31:1144-1149.

Publishers Comment: We continue to see that elevated A1c levels above normal are related to all-cause mortality, especially in those with diabetes. Yet in a number of studies that tried to aggressively to lower A1c’s to normal ranges failed to show a reduced risk of cardiovascular disease. Could that be due to the fact that they were not even able to get the A1c’s close to normal? Or that their diets were so high in carbohydrates that it was impossible to get their A1c’s to normal even with massive amounts of medications?