In this nationally representative sample, among adults aged ≥20 years, increasing GHb levels were associated with increased risk of all-cause mortality, heart disease, and cancer mortality. However, this association is mediated by the presence of diagnosed diabetes. Among adults with diagnosed diabetes, GHb ≥8% was associated with a 70% increased risk from all-cause mortality and a 150% increased risk from heart disease mortality. Among adults with diagnosed diabetes and GHb between 6 and 7% and 7 and 8%, there was no significant increased risk of all-cause mortality. However, there was a 90% increased risk for heart disease mortality for adults with diabetes and GHb between 6 and 7%. There was no significant association of GHb with mortality among adults without diagnosed diabetes.
Previous studies that have examined the association of hyperglycemia and mortality using fasting glucose or postchallenge glucose levels have also shown an increased risk of mortality with increasing glucose levels (2
). Hyperglycemia is also associated with an increased risk of incident CVD. A recent meta-analysis of >38 reports of hyperglycemia as a risk factor for CVD found an increased risk of CVD for all measures of hyperglycemia: fasting glucose, causal glucose, postchallenge glucose, and GHb level (1
). Few of the studies included in the meta-analysis were nationally representative, and some studies did not take diabetes status into account. GHb levels themselves have also been associated with an increased risk of incident disease including CVD among individuals with diabetes (23
) and colorectal cancer among individuals with and without diabetes (24
However, there is limited evidence on the association of GHb with mortality either among the diabetic population (25
) or the general population (3
). Among the diabetic population, one study showed that a 1% increase in GHb level corresponded to an increased risk of all-cause mortality, ischemic heart disease mortality, and diabetes mortality after adjustment for other risk factors (25
). Among the nondiabetic population, the results have been mixed (5
), with one study showing an increased risk among women but not in men after adjustment for potential confounders (8
Most previous studies have either analyzed GHb categorically or continuously, but few have examined the shape of the relationship of GHb with mortality (5
). Results presented from both the spline regression and the categorical analyses indicate that the association of GHb levels with mortality among the overall population and adults with diagnosed diabetes seems to differ. There seems to be a slight J-shaped relationship among the overall population, whereas there is a possible threshold effect in the diabetic population. This possible J-shape relationship was also observed in a study based in New Zealand (5
). These authors found that GHb levels >7 and <4% were associated with increased mortality compared with GHb levels of 4–5%, among adults without a diagnosis of diabetes (5
The American Diabetes Association recommends GHb of <7% for most individuals with diabetes (9
). These recommendations are also promoted by the National Diabetes Education Program (26
) and are based on evidence from randomized clinical trials showing that lowering GHb levels reduces diabetes microvascular complications (16
) including CVD (16
). The benefit of glucose control in preventing CVD in individuals with type 2 diabetes is still uncertain. Recently, three randomized clinical trials have addressed the question of whether lowering glucose levels in individuals with type 2 diabetes, measured by GHb, to the levels of adults without diabetes would reduce morbidity and mortality from CVD. The findings from these trials have, however, added uncertainty to this question (13
), with two studies finding an increased risk of mortality and one study finding no increased risk (13
). Our findings suggest that after taking into account other well-established CVD risk factors, lowering GHb <8% does not result in improvement in heart disease mortality. In fact, among adults with diabetes, there was an increased risk of heart disease mortality associated with GHb between 6 and 7%. Further studies are needed to determine treatment strategies for the prevention of CVD in individuals with diabetes.
There are two main limitations of our analysis. The first is that we had relatively few deaths from certain causes and were, therefore, unable to look at specific types of cancer or other causes. Based on the smaller sample size for the population with diagnosed diabetes and the smaller number of deaths from cancer, the study may have been underpowered to detect a significant increase in risk. The second limitation is that GHb was only measured at baseline, and we have no information on how changes in GHb may or may not have influenced a participant's risk of mortality.
Nonetheless, this study also has a number of strengths. First, NHANES III is the first nationally representative survey to measure GHb levels among adults and the first study to provide nationally representative estimates of the risk of mortality associated with GHb levels, and second, there was relatively little loss to follow-up for mortality.
In summary, we found that GHb of ≥8% was associated with a greater than twofold increased risk of all-cause mortality in the overall population and >60% increased risk for all-cause mortality among adults with diabetes. There was also a significant increased risk of heart disease overall and for adults with diabetes.