Background: Different studies have indicated that thiazide diuretics can increase the risk of developing type 2 diabetes (T2D). Therefore, in this study, we investigated whether switching from hydrochlorothiazide (HCTZ) to amlodipine resulted in ameliorating different cardiovascular and metabolic measures in hypertensive patients with or without T2D. Methods: This study [Diuretics and Diabetes Control (DiaDiC)] was a 6-week, single-blind, single-center randomized controlled trial. The first 20 normal glucose-tolerant, 20 prediabetic, and 20 T2D consecutive patients were randomized to continue the previous antihypertensive treatment with HCTZ (12.5-25 mg/day) or to switch from HCTZ to amlodipine (2.5-10 mg/day). The primary endpoints were the absolute change in 7-day continuous subcutaneous glucose monitoring (CSGM) glycemia, serum uric acid concentrations, and endothelial function [measured as flow-mediated dilation (FMD)]. Other secondary endpoints were investigated, including changes in glycated hemoglobin (HbA(1)c), glycemic variability from 7-day CSGM, and the estimated glomerular filtration rate (eGFR). Results: Amlodipine treatment was associated with a significant reduction in HbA(1)c (P = 0.03) for both 7-day CSGM glycemia (P = 0.01) and glycemic variability (coefficient of variability %: HCTZ +3%, amlodipine -2.8%), and a reduction in uric acid concentrations (P < 0.001), especially in participants with T2D or prediabetes. Following amlodipine treatment, a significant increase in both eGFR (P = 0.01) and FMD (P = 0.02) was also observed. Conclusions: This study demonstrates that the replacement of HCTZ with amlodipine has several metabolic and cardiovascular beneficial effects. However, further intervention studies are necessary to confirm the clinical effects of thiazides, especially in diabetic people and in those at risk of diabetes.