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.
Song S, Cai X, et al. • Drug design, development and therapy • 2026
Folic acid use was significantly associated with lower new-onset diabetes risk and improved long-term glycemic status in CHD patients, particularly at 0.8 mg/day and cumulative dose >140 mg.
Key Findings
Results
Folic acid therapy was significantly associated with lower new-onset diabetes risk in CHD patients after propensity score matching.
Multivariable Cox regression showed HR: 0.749; 95% CI: 0.586–0.957; P=0.021 for FA users vs non-users
The multicenter propensity score-matched analysis yielded 2440 patients for analysis (1:4 matching ratio)
During a median follow-up of 3.35 years, 510 incident cases of diabetes were recorded
Association was significant both before and after propensity score matching
Results
Among dose-stratified analyses, the 0.8 mg/day folic acid group showed the greatest reduction in new-onset diabetes risk.
HR for the 0.8 mg/day group: 0.637; 95% CI: 0.453–0.897; P=0.010
The 0.8 mg/day group also demonstrated a more favorable long-term HbA1c trajectory compared to other dose groups
Dose-stratified analyses compared multiple daily dose levels of folic acid
This dose-specific finding suggests a non-uniform benefit across different dosing regimens
Results
Folic acid demonstrated a cumulative dose effect, with diabetes risk-lowering benefits becoming more evident when cumulative dose exceeded 140 mg.
Restricted cubic spline analysis was used to examine the dose-response relationship between cumulative FA dose and diabetes risk
Risk-lowering benefits became 'more evident' beyond the 140 mg cumulative threshold
This finding suggests a threshold or progressive cumulative effect rather than a purely linear relationship
Results
Repeated glycated hemoglobin (HbA1c) measurements indicated that folic acid use was associated with improved long-term glycemic control trajectories.
Repeated HbA1c measurements were used to assess long-term glycemic trajectories across the follow-up period
The 0.8 mg/day group showed a particularly more favorable HbA1c trajectory
Kaplan-Meier curves were used to compare cumulative diabetes risk between FA users and non-users
Improved glycemic trajectories were observed in addition to reduced incidence of new-onset diabetes
Methods
The study population consisted of CHD patients recruited from multiple centers, with propensity score matching used to minimize baseline imbalance between folic acid users and non-users.
Patients were categorized as FA users or non-users, followed by 1:4 propensity score matching
Final matched analysis included 2440 patients
Median follow-up was 3.35 years
Multivariable Cox regression models were used to evaluate associations of FA use and daily dose with diabetes risk
The observational study design was noted as a limitation requiring cautious interpretation of findings
Background
The study was motivated by the established link between elevated homocysteine and cardiovascular disease, with the rationale that homocysteine-lowering therapy via folic acid might also reduce diabetes risk.
Elevated homocysteine has been 'consistently linked to cardiovascular disease development and progression'
Whether homocysteine-lowering therapy reduces diabetes risk and improves glycemic status in CHD patients was described as 'unclear' prior to this study
Folic acid is a recognized homocysteine-lowering agent and was the intervention studied
The study focused specifically on CHD patients as the target population
What This Means
This research suggests that taking folic acid supplements may help reduce the risk of developing diabetes in people who already have coronary heart disease (CHD). The study followed 2,440 CHD patients over a median of about 3.35 years and found that those who took folic acid were about 25% less likely to develop new-onset diabetes compared to those who did not take it. The researchers used a statistical technique called propensity score matching to make the two groups as comparable as possible at the start of the study, reducing the chance that other factors explained the difference.
The benefits appeared to depend on the dose. Patients taking 0.8 mg of folic acid per day had the largest reduction in diabetes risk (about 36% lower risk) and also showed better long-term blood sugar control as measured by HbA1c, a standard marker of glycemic status. Additionally, the total accumulated amount of folic acid taken over time mattered: once patients had taken more than 140 mg total, the protective effect became even stronger, with roughly a 52% lower risk of developing diabetes. This suggests that longer-term and higher cumulative use of folic acid may be more beneficial.
This research is notable because folic acid is inexpensive and widely available, and is already used in some cardiovascular patients to lower levels of homocysteine, an amino acid linked to heart disease. The findings raise the possibility that folic acid could serve a dual purpose in CHD patients by also helping to prevent diabetes. However, the authors caution that because this was an observational study rather than a randomized controlled trial, the results should be interpreted carefully, and further research is needed to confirm whether folic acid truly causes a reduction in diabetes risk.
Song S, Cai X, Li X, Cui P, Zou Z, Liu Y, et al.. (2026). 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.. Drug design, development and therapy. https://doi.org/10.2147/DDDT.S631127