The effects of glycated hemoglobin and body mass index on the relationship between the hemoglobin glycation index and the hypoglycemia risk: a moderated mediation analysis

Aim: To explore the relationship between the hemoglobin glycation index (HGI) and the hypoglycemia risk, and the potential effect of glycosylated hemoglobin (HbA1c) and body mass index (BMI) on this relationship. 

Methods: This is a prospective observational study. A total of 1,203 type 2 diabetes mellitus (T2DM) patients were included. Linear regression was used to establish an equation by which to calculate the HGI. Logistic regression models were employed to explore the association between the HGI and hypoglycemia. A moderated mediation approach was taken to detect the effect of body mass index (BMI) and HbA1c on the association between HGI and hypoglycemia.

Results: During the follow-up period (median 34.73 months), 344 patients developed hypoglycemia. The relationship between the HGI and hypoglycemia was significant [odds ratio (OR), 95% confidence interval (CI) = 1.255 (1.089-1.446), P = 0.001] after adjusting for potential confounders. Compared to the low-HGI group, the risk of hypoglycemia in the high-HGI group was significantly elevated [OR (95% CI) = 1.603 (1.167-2.201), P = 0.006]. Trend tests suggested that the risk of hypoglycemia increased significantly from the low- to the high-HGI group (P = 0.003). A significant mediation effect of HbA1c was observed along the path HGI→Hypoglycemia (coefficient = 0.128, 95% CI = 0.140-0.247, P = 0.008) and a significant moderation effect of BMI was observed along the path HGI→HGI*BMI→HbA1c (coefficient = 0.019, 95% CI 0.004-0.040, P = 0.022), suggesting that HbA1c served as a mediator and BMI as a moderator of the relationship between the HGI and hypoglycemia.

Conclusion: The HGI was significantly associated with the risk of hypoglycemia in T2DM subjects. Moderated mediation analysis demonstrated that the association between the HGI and hypoglycemia was mediated by HbA1c and moderated by BMI. Interventions targeting HbA1c and BMI may mitigate the risk of hypoglycemia in T2DM patients.