Background: While cardiovascular disease (CVD) polypills have demonstrated significant benefits in preventing CVD events by managing CVD risk factors and improving patient adherence, their effects on blood glucose levels, an important risk factor for CVD, remain unknown. Methods: We analyzed data from the PolyIran-Liver trial, which involved 1,508 participants aged 50 and above. Of these, 787 were randomly assigned to receive a polypill (consisting of aspirin, atorvastatin, hydrochlorothiazide, and valsartan), while 721 received usual care as the control group over a five-year period. The aim was to determine whether there were any significant differences in fasting blood sugar (FBS) levels between the two groups at baseline, middle, and end of the study. The data analysis focused on three subgroups: participants with diabetes, those with metabolic syndrome (MetS) but without diabetes, and participants without diabetes or MetS. Results: Of the total studied population, with a mean age of 59±6.7 years, 328(22%) were identified with diabetes, 371 (25%) with MetS but without diabetes, and 809 (54%) without diabetes or MetS. We observed a trend of rising FBS levels until month 30, followed by a subsequent decline at month 60. Participants in the polypill group exhibited lower FBS levels than the control group at both time points, with statistically significant differences in all three subgroups at month 30 and in the MetS-without diabetes at month 60 (mean difference: -9.3 mg/dl, 95% CI: 13.9 to -4.6). Conclusion: The polypill used in this study may have the potential to delay the onset of diabetes in patients with MetS more effectively than in the general population. However, its beneficial effects on the blood sugar levels of diabetic individuals require further investigation.