HbA1c Variability and Risk of All-Cause Mortality and Cardiovascular Events

Study assesses effect of variable glycemic levels on risk of vascular complication in patients without diabetes.

Glycemic management by patients with diabetes is often assessed via hemoglobin A1C. This value will give a roughly 3-month average of the individual’s blood glucose level. Typically, if a patient’s A1C is below their goal, their diabetes is considered to be well-managed. However, recent studies have indicated that there may be a correlation between high glycemic variability and micro- and macrovascular complications. These findings suggest that, in patients with diabetes, glycemic variability may increase vascular risk to a similar degree as sustained elevations in blood sugar. While this correlation has been established in patients with diabetes, it is unknown if glycemic variability in patients without diabetes will increase the risk of vascular complications. Therefore, the aim of this study is to assess the effect of variable glycemic levels on risk of vascular complication in patients without diabetes.

Since the study researchers wished to determine if a correlation exists, a retrospective cohort was chosen as the study design. The primary outcome of the study was major adverse cardiovascular events (MACE), all-cause mortality, and type 2 diabetes diagnosis. These outcomes were compared against variability in A1C measurements. Data for the study was procured from the electronic patient records in the Danish National Patient Registry. Patients were considered for inclusion if they had 3 consecutive A1C measurements, roughly 1 year apart from each other (the 3rd A1C was considered baseline). Patient data was excluded if the patient was less than 18 or greater than 100 years of age, had an A1C of greater than or equal to 6.5% before baseline, or if a diagnosis of diabetes or vascular disease was made prior to baseline. Statistical significance was determined via analysis with the Cox regression model. Data was adjusted to account for known causative or risk-increasing factors for the primary outcome.

Of the 390,747 Danish patients who underwent A1C testing, 118,476 had 3 consecutive A1C values. Of those, 6,756 met the criteria for inclusion; therefore, their electronic health data were utilized in the trial. When the eligible participant’s data was analyzed, it revealed that 996 experienced MACE within a median follow-up of 6.3 years. These patients were also associated with a highly variable A1C. When assessed for significance, it was found that the individuals with variable A1Cs had a calculated hazard ratio of 1.09 (p = 0.002), for the development of MACE, when compared to those with more consistent A1Cs. Likewise, it was found that variable A1C also correlated to increased risk of all-cause mortality (hazard ratio of 1.13, p < 0.001). No statistically significant association was found between A1C variability and the development of type 2 diabetes (hazard ratio of 1.00, p = 0.935).

Prior to this study, little, if any, research had been conducted that focused on the effects of variable A1C in patients without diabetes. Thus, making this study fairly novel. The results of this study suggest that there is a correlation between high glycemic variability and increased incidence of major cardiovascular event and all-cause mortality in people who do not have diabetes.

While further study will be required to determine the true clinical significance of this finding, glycemic variability may prove to be a valuable predictive factor for major cardiovascular events in patients without diabetes.

Practice Pearls:

• Glycemic variability has been shown to increase the risk of vascular complication in patients with diabetes; however, little research has been conducted concerning this association in patients without diabetes.
• The results of this study suggest that, like patients who have diabetes, glycemic variability is associated with increased cardiovascular as well as all-cause mortality risk in patients without diabetes.
• While this may prove to be a valuable predictive factor for patients without diabetes, more research is necessary in order to determine the clinical significance of these findings.

References:

Ghouse J, Skov MW, et al., “Visit to Visit Variability of Hemoglobin A1c in People Without Diabetes and Risk of Major Adverse Cardiovascular Events and All-Cause Mortality.” Diabetes Cares, 2018, 2018, p. dc181396., doi:10.2337/dc18-1396.

Takao T, Matsuyama Y, Yanagisawa H, Kikuchi M, Kawazu S. “Association between HbA1c variability and mortality in patients with type 2 diabetes.” Journal of Diabetes Complications, vol. 28, 2014, pp. 494–499

Michael Zaccaro, Pharm. D. Candidate 2019, LECOM School of Pharmacy