Despite its efficacy in diabetes management, concerns about potential cardiovascular injury associated with alogliptin have limited its widespread use. This study investigated whether sustained, once-weekly low-dose alogliptin provides greater efficacy with fewer adverse effects than daily administration. Type 2 diabetes was induced in rats using a high-fructose, high-fat, high-salt diet for three weeks, followed by streptozotocin (STZ) injection. Diabetic rats were then allocated into three groups: diabetic, S Alogliptin (weekly administered sustained alogliptin preparation), and F Alogliptin (daily administered standard fast-acting alogliptin). Postprandial blood glucose levels and body weight were monitored. Cardiovascular hemodynamics, cardiac enzymes, lipid profile, HOMA-IR, oxidative stress, and quantitative histopathological changes in the ventricles, aorta, liver, and skeletal muscle were evaluated at study end. S alogliptin provided superior postprandial glycemic control over 40 days and improved metabolic parameters, including reduced bodyweight gain, triglycerides, HOMA-IR, and leptin, with increased adiponectin compared with F Alogliptin. More alleviation in cardiac dysfunction was observed in S alogliptin versus F alogliptin as manifested by reductions in cardiac enzymes, as well as improved hemodynamics (contractility index, pulse pressure, and dicrotic notch pressure). This was accompanied by more alleviation by S alogliptin in tissue inflammation and damage as evidenced by reductions in heart malondialdehyde (MDA) and histopathological examination of ventricles, aorta, liver, and skeletal muscles. Conclusion Overall, S Alogliptin achieved superior glycemic control and greater mitigation of metabolic and cardiovascular complications of diabetes than F Alogliptin.