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

Abstract

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 for calculating 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 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 groups (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.

Keywords

Hemoglobin glycation index / hypoglycemia / HbA1c / BMI / mediation / prospective study

References

[1] González-Vidal T,Gutiérrez-Hurtado A.Hypoglycemia in patients with type 2 diabetes mellitus during hospitalization: associated factors and prognostic value.Diabetol Metab Syndr2023;15:249 PMCID:PMC10694969

[2] Heller SR,Oates SK.Hypoglycemia in patient with type 2 diabetes treated with insulin: it can happen.BMJ Open Diabetes Res Care2020;8:e001194 PMCID:PMC7299018

[3] Wang Y,Hu X.Association between hemoglobin glycation index and 5-year major adverse cardiovascular events: the REACTION cohort study.Chin Med J2023;136:2468-75 PMCID:PMC10586840

[4] Pan L,Cheng B,Wang B.Association between hemoglobin glycation index and mortality in critically ill patients: a retrospective cohort study.J Health Popul Nutr2025;44:249 PMCID:PMC12254999

[5] Zhao M,Cheng Y.Hemoglobin glycation index and mortality risk in metabolic dysfunction-associated steatotic liver disease patients: a novel U-shaped association.Sci Rep2025;15:1465 PMCID:PMC11718243

[6] Hempe JM,Myers L,Buse JB.The hemoglobin glycation index identifies subpopulations with harms or benefits from intensive treatment in the ACCORD trial.Diabetes Care2015;38:1067-74 PMCID:PMC4439529

[7] Shi F,Wang Z,Fang C.Association of hemoglobin glycation index with all-cause and cardiovascular mortality in patients with diabetes or prediabetes and comorbid cardiovascular disease: a population-based cohort study.Sci Rep2025;15:20696 PMCID:PMC12216783

[8] Ernesti I,Cipriani F.Impact of a very low-calorie ketogenic diet on metabolic and microbiota outcomes in post-bariatric patients and bariatric-Naïve individuals: a comparative pilot study.Diabetes Obes Metab2025;27:1950-9 PMCID:PMC11885101

[9] Wongwananuruk T,Chantrapanichkul P.Measures of serum markers HbA1c, HOMA-IR, HOMA-β, QUICKI and G/I Ratio as predictors of abnormal glucose tolerance among thai women with polycystic ovary syndrome.J Clin Med2025;14:1452 PMCID:PMC11900011

[10] Ning G.Diabetes and cancer: findings from the REACTION study: REACTION.J Diabetes2015;7:143-4

[11] American Diabetes Association Professional Practice Committee. 2. Classification and Diagnosis of Diabetes: Standards of Medical Care in Diabetes-2022.Diabetes Care2022;45:S17-38

[12] Solnica B,Sitkiewicz D.2024 Guidelines of the Polish Society of Laboratory Diagnostics and the Polish Lipid Association on laboratory diagnostics of lipid metabolism disorders.Arch Med Sci2024;20:357-74 PMCID:PMC11094830

[13] Hitz MP,Melnik N.Current and future diagnostics of congenital heart disease (CHD).Med Genet2025;37:95-102 PMCID:PMC11976401

[14] Tu Q,Hafiz N.Independent and joint associations of hypertension and depression with cardiovascular diseases and all-cause mortality: a population-based cohort study.J Hum Hypertens2025;Epub ahead of print:

[15] Hayes AF.An index and test of linear moderated mediation.Multivariate Behav Res2015;50:1-22

[16] Hempe JM.Variation in the hemoglobin glycation index.J Diabetes Complications2022;36:108223

[17] Hempe JM,Liu S.Standardizing the haemoglobin glycation index.Endocrinol Diabetes Metab2021;4:e00299 PMCID:PMC8502217

[18] Hempe JM,McCarter RJ Jr.High and low hemoglobin glycation phenotypes in type 1 diabetes: a challenge for interpretation of glycemic control.J Diabetes Complications2002;16:313-20

[19] Ghazaiean M,Zamanfar D.Risk factors for suboptimal glycemic control in pediatrics with type 1 diabetes mellitus: a cross-sectional study.Sci Rep2024;14:7492 PMCID:PMC10980686

[20] Klein KR,Marso S.Hemoglobin glycation index, calculated from a single fasting glucose value, as a prediction tool for severe hypoglycemia and major adverse cardiovascular events in DEVOTE.BMJ Open Diabetes Res Care2021;9:e002339 PMCID:PMC8614152

[21] Lin BS,Chen DR.Relationship between hemoglobin glycation index and risk of hypoglycemia in type 2 diabetes with time-in-range in target.World J Diabetes2024;15:2058-69 PMCID:PMC11525731

[22] Lipska KJ,Huang ES.HbA1c and risk of severe hypoglycemia in type 2 diabetes: the diabetes and aging study.Diabetes Care2013;36:3535-42 PMCID:PMC3816866

[23] Zhong VW,Cole SR.Proximal HbA1C level and first hypoglycemia hospitalization in adults with incident type 2 diabetes.J Clin Endocrinol Metab2019;104:1989-98

[24] Li J,Zhang L.Individualized coefficient of variability cut-off values for reducing the risk of hypoglycemia in Chinese type 1 diabetes mellitus (T1DM) patients.Chin Med J2024;137:244-6 PMCID:PMC10798686

[25] Shabestari M,Barbieri S,Heshmati-Nasab P.Predictive factors of hypoglycemia in type 2 diabetes: a prospective study using machine learning.Sci Rep2025;15:18143 PMCID:PMC12104344

[26] Min Ko M, Kit Lee W, Chang Ang L, Goh SY, Mong Bee Y, Ming Teh M. A Cross-Sectional study on risk factors for severe hypoglycemia among Insulin-Treated elderly type 2 diabetes Mellitus (T2DM) patients in Singapore.Diabetes Res Clin Pract2022;185:109236

[27] Jiang J,Pan Y.Relationship of obesity to adipose tissue insulin resistance.BMJ Open Diabetes Res Care2020;8:e000741 PMCID:PMC7254100

[28] Wu WC,Chen SC.Progression of insulin resistance: a link between risk factors and the incidence of diabetes.Diabetes Res Clin Pract2020;161:108050