Fasting Glucose Level and the Risk of Incident Atherosclerotic Cardiovascular Diseases

CONCLUSIONS

In a large cohort of Korean men and women, we found that fasting glucose level was associated with higher risk for major CVD outcomes, increasing from a level of ∼90 mg/dL after controlling for other risk factors. The dose-response curves showed progressive increments in the HRs from this value at both higher and lower levels; the increased risk was greatest for stroke. The patterns of association were similar in men and women, but the associations were stronger in women.

Substantial evidence supports the biological plausibility of this finding. Experimental studies show that abnormal glucose metabolism impairs normal endothelial function, accelerates atherosclerotic plaque formation, and contributes to plaque rupture and thrombosis. Epidemiological studies provide complementary evidence. In the Rotterdam Study, among elderly participants with a fasting blood glucose <110 mg/dL and without diabetes, those with higher blood glucose levels had higher levels of arterial stiffness (20). The CATHAY study found that higher levels of glycemia (102–124 mg/dL) were associated with arterial endothelial dysfunction and intima-media thickening (21). In a biomarker study in Italy, a number of CVD biomarkers showed positive dose-response relationships with fasting glucose across three strata: <100; 100–109; and 110–125 mg/dL (22). Our study adds to the increasing evidence that IFG is an independent risk factor for incident CVD, including ischemic heart disease and stroke (7). In addition, the effects of other CVD risk factors may be enhanced by abnormal glucose metabolism (23–25).

In 1997, the American Diabetes Association Expert Committee introduced the IFG category, defined at the time as fasting plasma glucose level of 110 to 125 mg/mL or a 2-h value on the oral glucose tolerance test of 140–199 mg/dL (26). IFG is not a clinical entity in itself but is a risk category for development of diabetes and CVD (10). In 2003, the American Diabetes Association Expert Committee lowered the cut-point for IFG to 100 mg/dL to align the proportion of the population that would be included in the category using fasting glucose and the oral glucose tolerance test, and to indicate that glucose levels <110 mg/dL were predictive of diabetes development (26,27). Although previous studies also have identified an increased risk of CVD associated with IFG (100–125 mg/dL) (3,5,28,29), the size of KCPS provides a much more precise characterization of the up-turn in risk in relation to blood glucose level, placing it at ∼90 mg/dL. As a consequence, our findings support lowering the current American Diabetes Association IFG cut-off of 100 mg/dL, and they also open the possibility that low fasting glucose levels may identify people at increased risk for CVD.

Severe hypoglycemia in diabetes is known to increase risks of vascular events (30–32). Low fasting glucose levels in the nondiabetic population were associated with increased mortality in several studies (5,15). In our study, the lowest risk for CVD mortality occurred in the interval of 85–99 mg/dL, with a nadir at ∼90 mg/dL, suggesting that the range of fasting glucose levels associated with the lowest risk for CVD is narrow. In a prospective cohort study of >40,000 people, the lowest total mortality was associated with fasting plasma glucose of 79–109 mg/dL (15). In the study by Balkau et al. (33), the interval of lowest total mortality was 94–103 mg/dL, and in the DECODE study it was 81–90 mg/dL (34). The pooled analysis performed by the Emerging Risk Factors Collaboration described a nonlinear relationship between fasting glucose and coronary heart disease that had the same configuration as in the KCPS analysis (3). In the Atherosclerosis Risk in Communities (ARIC) study, Selvin et al. (35) found a J-shape relationship of glycated hemoglobin with risk for death attributable to coronary heart disease. Fasting blood glucose level <100 mg/dL was not associated with coronary heart disease death (35). Because different studies have used different categories for fasting glucose, further and perhaps pooled analyses of data from large studies should be performed using flexible models for dose-response analysis to confirm our findings of a narrow range of fasting glucose levels with lowest mortality.

The basis of the association between low fasting glucose levels and risk for CVD in people without diabetes is unclear. Wei et al. (15) hypothesized that long-term exposure to low fasting plasma glucose may serve as a risk factor for CVD mortality, perhaps through abnormal cardiac activity and thrombosis, particularly in patients with atherosclerosis. Tanne et al. (36) reported a J-shape relationship between fasting plasma glucose and incident ischemic cerebrovascular events in patients with preexisting atherothrombotic disease and suggested that hypoglycemia or rapid changes in plasma glucose may lead to elevations of counter-regulatory hormones, such as epinephrine and norepinephrine, and these increases induce vasoconstriction and platelet aggregation (36). In a pooled analysis of data from 97 cohorts involving people without vascular disease on enrollment, an increase in risk for vascular disease death was observed in those with blood glucose level <70 mg/dL on enrollment (7). The cohort of Tanne et al. (36) was comprised of patients with documented coronary heart disease. Because CVD risk factors and development of CVD are usually associated with metabolic abnormalities that increase fasting plasma glucose, additional studies need to be conducted to understand if low fasting plasma glucose levels are a consequence of impending disease (i.e., reverse causation) or if they have a role in precipitating acute CVD events.

Limitations of our findings need to be considered. First, single fasting glucose measurements are subject to substantial within-person variation and we did not perform 2-h glucose tolerance testing. Measurement error and between-study variability may have attenuated our results, adding to the identification of a narrow range of fasting glucose levels for optimal survival. Additionally, we measured serum glucose, not the currently recommended plasma glucose (37,38). However, because all measurements were of serum glucose, our findings should not be biased. Second, we lacked information on the evolution of fasting glucose levels and incidence of diabetes during follow-up, and we cannot identify if the increased risk associated with IFG depends on future evolution to diabetes or on other pathways. Third, we lacked data on other metabolic abnormalities associated with overweight and obesity and fat distribution. Fourth, the outcomes were obtained from admission records and death certificates. Because the outpatient records were not included, the incidence of CVD morbidity in our study may be lower than actual incidence.

With regard to generalizability of findings, the KCPS population differs from those of other investigations in several ways. Of course, participants were Asian and the population was also leaner than those in the other studies of blood glucose and CVD risk. The majority of males smoked, whereas only a few women smoked.

Fasting glucose is readily and widely measured for early detection and prevention of diabetes. Beyond risk for diabetes, it also conveys information about CVD risk. Additionally, the findings suggest that the optimal glucose level may be below the current cut-offs used to identify people at risk for CVD. Health care providers should recognize the J-shape relationship between fasting blood glucose and CVD risk in interpreting and communicating clinical data.