Association of Low Fasting Glucose and HbA1c With Cardiovascular Disease and Mortality

The MESA Study

Morgana Mongraw-Chaffin; Alain G. Bertoni; Sherita Hill Golden; Nestoras Mathioudakis; Dorothy D. Sears; Moyses Szklo; Cheryl A.M. Anderson


J Endo Soc. 2019;3(5):892-901. 

In This Article

Abstract and Introduction


Trials of intensive glucose control have not improved cardiovascular disease (CVD) risk in populations with type 2 diabetes; however, in the general population, reports are inconsistent about the effects of maintaining lower glucose levels. Some speculate that low glycemic values are associated with increased glycemic variability, which is in turn associated with higher CVD risk. It has also been suggested that fasting glucose and hemoglobin A1c (HbA1c) in the lower ranges have a different relationship with CVD and mortality. In 4990 participants from the Multi-Ethnic Study of Atherosclerosis, we used logistic regression to investigate associations of low fasting glucose (<80 mg/dL) and HbA1c (<5.0%) from baseline and averaged across follow-up with incident CVD and mortality over 13 years. We used normal glycemic ranges (80 to <100 mg/dL and 5.0 to <5.7%) as references and analyzed glycemic levels with visit-matched covariates. We adjusted for potential confounding by age, sex, race/ethnicity, education, income, smoking status, body mass index, total cholesterol level, cholesterol medications, high-density lipoprotein cholesterol, and hypertension. Low baseline glucose and HbA1c were positively, but not significantly, associated with mortality, whereas low average fasting glucose and HbA1c were strongly and significantly associated with incident CVD [glucose OR, 2.04 (95% CI, 1.38–3.00); HbA1c OR, 2.01 (95% CI, 1.58–2.55)] and mortality [glucose OR, 1.93 (95% CI, 1.33–2.79); HbA1c OR, 2.51 (95% CI, 2.00–3.15)]. These results were not due to type 2 diabetes or medication use. Glucose variability did not explain CVD risk beyond average glucose levels. Chronic low fasting glucose and HbA1c may be better indicators of risk than a single low measurement.


Once questioned as an intermediate condition, impaired fasting glucose (100 to <125 mg/dL) has now been shown to confer cardiovascular disease (CVD) risk even though it is below the diabetic range (≥126 mg/dL).[1] Similarly, there is now evidence that low blood glucose levels [<80 mg/dL fasting or hemoglobin A1c (HbA1c) <5.0%] without reported clinical hypoglycemia may also indicate metabolic dysregulation and confer increased risk for CVD or mortality.[2–10] It remains unknown whether low glucose itself places some individuals at risk or whether low glucose is a marker for glycemic variability, which has consistently been associated with CVD events and mortality in those with type 2 diabetes.[11–14] Research on hypoglycemia has predominantly been focused on iatrogenic hypoglycemia resulting from glucose-lowering therapy in type 2 diabetes. The unexpected findings about the failure of intensive glucose control interventions in type 2 diabetes to prevent CVD events and the possibility that such interventions may even increase mortality have heightened the uncertainty around lower glucose values in individuals without type 2 diabetes as well.[15] Few studies have investigated the relationship of low fasting glucose or HbA1c with CVD outcomes in the general population.[6,16,17] Similarly, few have investigated whether glucose variability is associated with CVD outcomes beyond a single measurement.[11,12,14,18]

Increasing evidence supports the need to study CVD outcomes in the population of individuals who consistently have fasting and/or average glucose levels in the lower ranges.[2,3,6,7,16,17] Thus, we sought to determine whether low fasting glucose (<80 mg/dL), low HbA1c (<5.0%), or glycemic variability (coefficient of variation) are associated with incident CVD and all-cause mortality in individuals without type 2 diabetes in the Multi-Ethnic Study of Atherosclerosis (MESA). Following up on prior work in MESA on fasting glucose at baseline and CVD[19] and based on previous evidence of a J-shaped association,[2,3,20–22] we hypothesized that low HbA1c would be similarly associated with all-cause mortality. Extending this work, our primary hypothesis was that glycemic levels averaged over follow-up would be stronger predictors of CVD and mortality than baseline measurements alone. We further hypothesized that higher glycemic variability would be associated with increased risk for CVD and all-cause mortality, independent of fasting glucose or HbA1c level. Finally, we hypothesized that these associations would differ by age, sex, and race/ethnicity. Our interest in heterogeneity is based on prior literature suggesting that the relationship between other risk factors, mainly obesity, and CVD is stronger in younger individuals,[23] and the knowledge that the distribution of glucose is generally lower in women than in men,[24,25] and the likelihood of hypoglycemia higher.[26]