Folic Acid Therapy is Associated with a Lower Risk of Incident Diabetes and Better Glycemic Status in Patients with Coronary Heart Disease: Findings from a Multicenter Propensity Score–Matched Analysis

Shuaiwei Song,1,* Xintian Cai,2,* Xiyang Li,3,* Penghui Cui,4 Ziliang Zou,5 Yazhe Liu,6 Kaiyu Wang,7 Shengqin Li81Department of Endocrinology and Metabolism, Shanghai Tenth People’s Hospital, School of Medicine, Tongji University, Shanghai, 200072, People’s Republic of China; 2Heart, Lung and Vessels Center, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, Sichuan, People’s Republic of China; 3Cardiovascular Medicine Center, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, People’s Republic of China; 4Department of Cardiology, Changzhi People’s Hospital, Changzhi, People’s Republic of China; 5Department of Cardiology, Sixth Affiliated Hospital of Kunming Medical University, Yuxi, Yunnan, People’s Republic of China; 6Department of Cardiology, Yunyang County People’s Hospital, Yunyang, People’s Republic of China; 7Department of Critical Care Medicine, The Quzhou Affiliated Hospital of Wenzhou Medical University, Quzhou People’s Hospital, Quzhou, Zhejiang, People’s Republic of China; 8Emergency and Critical Care Center, Department of Emergency Medicine, Zhejiang Provincial People’s Hospital (Affiliated People’s Hospital), Hangzhou Medical College, Hangzhou, Zhejiang, People’s Republic of China*These authors contributed equally to this workCorrespondence: Kaiyu Wang, Department of Critical Care Medicine, The Quzhou Affiliated Hospital of Wenzhou Medical University Quzhou People’s Hospital, Quzhou, Zhejiang, People’s Republic of China, Email [email protected] Shengqin Li, Emergency and Critical Care Center, Department of Emergency Medicine, Zhejiang Provincial People’s Hospital (Affiliated People’s Hospital), Hangzhou Medical College, Hangzhou, Zhejiang, People’s Republic of China, Email [email protected]: Although elevated homocysteine has been consistently linked to cardiovascular disease development and progression, whether homocysteine-lowering therapy reduces diabetes risk and improves glycemic status in patients with coronary heart disease (CHD) remains unclear. This study investigated whether folic acid (FA) therapy and different treatment doses were associated with reduced new-onset diabetes risk and improved long-term glycemic control in CHD patients.Methods: The multicenter study used a propensity score–matched design. Patients with CHD were categorized as FA users or non-users, followed by 1:4 propensity score matching to minimize baseline imbalance, ultimately yielding 2440 patients for analysis. During a median follow‑up of 3.35 years, 510 incident cases of diabetes were recorded. Multivariable Cox regression models evaluated the associations of FA use and daily dose with diabetes risk. Kaplan–Meier curves compared cumulative diabetes risk between groups. Repeated glycated hemoglobin (HbA1c) measurements were used to assess long-term glycemic trajectories, and restricted cubic spline analysis examined the dose–response relationship between cumulative FA dose and diabetes risk.Results: Multivariable Cox regression analyses showed that FA use was significantly associated with lower new-onset diabetes risk in CHD patients before and after matching (HR: 0.749; 95% CI:0.586– 0.957; P=0.021). Dose-stratified analyses indicated that the 0.8 mg/day group had the greatest risk reduction and a more favorable long-term HbA1c trajectory (HR: 0.637; 95% CI:0.453– 0.897; P=0.010). FA also showed a cumulative dosage effect, with risk-lowering benefits becoming more evident when cumulative dose exceeded 140 mg (HR: 0.478; 95% CI:0.351– 0.650; P< 0.001).Conclusion: FA use was significantly associated with reduced new-onset diabetes risk and improved long-term glycemic status in CHD patients, particularly at 0.8 mg/day and cumulative dose > 140 mg. These findings suggest that FA may have a potential role in diabetes prevention among CHD patients, although this should be interpreted cautiously given the observational study design.Keywords: folic acid, coronary heart disease, diabetes, homocysteine, glycemic status