Background: Antihypertensive agents like Angiotensin-Converting Enzyme Inhibitors (ACEIs) andAngiotensin-Converting Enzyme Blockers (ARBs) are commonly indicated for patients with bothhypertension and diabetes. However, the effect of these agents on blood sugar level or glycatedhemoglobin (HbA1c) is still controversial. This study aims at investigating the short, and long term effects of ACEIs and ARBs on blood sugar level and HbA1c of a group of streptozocin (STZ)-induced NIDDM rats when given in combination with Glimepiride (antidiabetic drug fromSulfonylureas group).Methods: Diabetes mellitus (DM) was induced in 100 Wistar albino adult male and femalelaboratory rats above 8 weeks old, and weigh between 250-300 gm by the administration ofStreptozocin 75% α-anomer. Two weeks later, the 100 rats were then randomized into four groups(25 rats each). Group one was the untreated control group (received placebo only), while othergroups (II, III, and IV) were treated by Glimepiride only, Glimepiride plus ARB (Candesartan), andGlimepiride plus ACEI (Enalapril) respectively. HbA1C levels were measured at baseline (pretest/directly after randomization) to ensure that there was no significant difference between studygroups at the baseline, post-test (after two weeks), and delayed-post-test (12 weeks afterrandomization/ 10 weeks after post-test) to measure short and long-term changes in the studygroups.Results: There was no significant difference (p-values >0.05) between the four groups (groups I, II,III, and IV) in the HbA1C mean level at the beginning of this study (two-weeks after randomizationand injection of STZ) (mean = 7.62 ±SD = 0.41, 7.72 ±SD = 0.48, 7.66 ±SD = 0.47, and 7.52 ±SD =0.51respectively). However, two weeks later, treated groups (groups II, III, and IV) showedmoderate reduction of HbA1C mean level compared to the untreated (placebo) group I, that wassignificant in groups III, and IV, and insignificant in group II (mean =7.43±SD 0.54, 6.97±SD 0.33,6.72±SD 0.26, and 7.71 ±SD 0.44 respectively). Furthermore, treated groups (groups II, III, and IV)showed significant dramatic reduction of HbA1C mean level when compared to the untreated group(group I) (mean = 6.22 ±SD 0.51, 5.24 ±SD 0.62, 5.22 ±SD 0.13, and 7.62 ±SD 0.42respectively).Overall, treated groups showed significantly lower HbA1C level than placebo groups.Moreover, Glimepiride + Enalapril combination showed a stronger hypoglycemic effect than theGlimepiride + Candesartan combination at post, and post-delayed tests, however, these differenceswere not significant.Conclusion: The addition of either ACEIs like Enalapril, or ARBs like Candesartan toSulfonylureas like Glimepiride to in NIDDM patients will synergize its anti-diabetic effect in NIDDMsubjects, and might increase the possibility of hypoglycemia. Caution and/or dose adjustmentshould be considered upon using these agents together in patients with hypertension along withdiabetes.