Association of long-term visit-to-visit variability of HbA1c and fasting glycemia with hypoglycemia in type 2 diabetes mellitus

Abstract

Background: Self-management of blood glucose levels to avoid hypoglycemia is vital for patients with type 2 diabetes mellitus (T2DM). The association between specific metrics of glycemic variability (glycosylated hemoglobin A1c [HbA1c] and fasting plasma glucose [FPG]) and severe hypoglycemia has not been fully studied in patients with T2DM.

Methods: In this post hoc analysis, patients with established T2DM with a high risk of cardiovascular disease were included in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) study. The Cox proportional hazards model was used to investigate the relationship between glycemic variability and hypoglycemia requiring medical assistance (HMA) and hypoglycemia requiring any third-party assistance (HAA). The prognostic value of HbA1c/FPG variability for our predefined outcomes was compared using Harrell's C method.

Results: After adjusting for confounders, each increase in HbA1c variability of 1 standard deviation (SD) indicated a higher risk of HAA (hazard ratio [HR]: 1.10; 95% confidence interval [CI]: 1.03-1.16; P < 0.01) and HMA events (HR: 1.11; 95% CI: 1.03-1.20; P < 0.01). Meanwhile, each increase in FPG variability of 1 SD increased the risk of HAA (HR: 1.40; 95% CI: 1.31-1.49; P < 0.01) and HMA events (HR: 1.46; 95% CI: 1.35-1.57; P < 0.01). Meanwhile, models, including FPG variability, had better prognostic value for our predefined outcomes than HbA1c variability (P < 0.01).

Conclusions: Increased visit-to-visit variability in HbA1c and fasting glycemia is associated with a greater risk of severe hypoglycemic events in T2DM patients. FPG variability is a more sensitive indicator than HbA1c variability.

Trial registration: http://www.clinicaltrials.gov. Unique identifier: NCT00000620.

Keywords: HbA1c variability; Severe hypoglycemia; comparative analysis; fasting glycemia variability; type 2 diabetes mellitus.

Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Copyright © 2022 Long, Tang, Huang, Liu and Xing.

Figures

Figure 1

Quartiles of HbA1c/FPG variability and rate HAA/HMA Events a Function of Baseline HbA1c/FPG. (A, B) FPG (Fasting Plasma Glucose) and FPG variability, Q1 is defined as a FPG mean located in first quartile, Q2 located a FPG mean in second quartile, Q3 a FPG mean located in third quartile and Q4 a FPG mean located in a fourth quartile; (C, D) HbA1c (hemoglobin A1c) and HbA1c variability. Q1 is defined as a HbA1c mean located in first quartile, Q2 a HbA1c mean located in second quartile, Q3 a HbA1c mean located in third quartile and Q4 a HbA1c mean located in fourth quartile.

Figure 2

Association of predicted HAA/HMA event and HbA1c/FPG variability (A) Association of FPG variability and HAA event; (B) Association of FPG variability and HMA event; (C) Association of HbA1c variability and HAA events; (D) Association of HbA1c variability and HMA event. Hazard ratios are indicated by solid lines and 95% CIs by areas between two dotted lines. (Reference point is the lowest value for each curve) The Reference knots were placed at the 5th, 35th, 65th, 95th, centiles of HbA1c/FPG variability distribution. HbA1c/FPG variability were adjusted using model 2.

Figure 3

Hazard ratios per one standard deviation increase in the HbA1c/FPG variability for the predefined endpoints. Each stratification was adjusted for all factors in model 2 (fasting plasma glucose, plasma glucose control strategy, age, race, female, history of cardiovascular disease, education, depression, cigarette, duration of diabetes, alcohol, body mass index, low-density lipoprotein, high-density lipoprotein, glomerular filtration rate, HbA1c), except for the stratification factor itself. HAA, hypoglycemia requiring any third-party assistance; HMA, hypoglycemia requiring medical assistance; HbA1c, Hemoglobin A1c; FPG, Fasting plasma glucose.