Influence of Angiotensin Receptor Blocker (Candesartan) and Angiotensin-Converting-Enzyme Inhibitor (Enalapril) Combined with Glimepiride on Glycated Hemoglobin in Non-Insulin Dependent Diabetic Rats (NIDDM)

Background: Antihypertensive agents like Angiotensin-Converting Enzyme Inhibitors (ACEIs) and Angiotensin-Converting Enzyme Blockers (ARBs) are commonly indicated for patients with both hypertension and diabetes. However, the effect of these agents on blood sugar level or glycated hemoglobin (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 from Sulfonylureas group).

Methods: Diabetes mellitus (DM) was induced in 100 Wistar albino adult male and female laboratory rats above 8 weeks old, and weigh between 250-300 gm by the administration of Streptozocin 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 other groups (II, III, and IV) were treated by Glimepiride only, Glimepiride plus ARB (Candesartan), and Glimepiride plus ACEI (Enalapril) respectively. HbA1C levels were measured at baseline (pre-test/directly after randomization) to ensure that there was no significant difference between study groups at the baseline, post-test (after two weeks), and delayed-post-test (12 weeks after randomization/ 10 weeks after post-test) to measure short and long-term changes in the study groups.

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 randomization and 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) showed moderate reduction of HbA1C mean level compared to the untreated (placebo) group I, that was significant 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 0.42 respectively).Overall, treated groups showed significantly lower HbA1C level than placebo groups. Moreover, Glimepiride + Enalapril combination showed a stronger hypoglycemic effect than the Glimepiride + Candesartan combination at post, and post-delayed tests, however, these differences were not significant.

Conclusion: The addition of either ACEIs like Enalapril, or ARBs like Candesartan to Sulfonylureas like Glimepiride to in NIDDM patients will synergize its anti-diabetic effect in NIDDM subjects, and might increase the possibility of hypoglycemia. Caution and/or dose adjustment should be considered upon using these agents together in patients with hypertension along with diabetes.