Background <p>In low- and middle-income countries, sulfonylureas are commonly prescribed due to cost-effectiveness. However, data comparing their real-world impact, especially when used alone versus in combination with metformin, remain limited.</p> Objective <p>This study aimed to assess the effectiveness of glipizide and glipizide plus metformin in individuals with type 2 diabetes (T2D) using real-world data.</p> Methods <p>Data was obtained from 11,949 individuals with T2D who were prescribed either glipizide or glipizide+metformin and had at least one follow-up within 1 year at a tertiary diabetes care centre in India. The primary outcome was the change in glycated hemoglobin (HbA1c) levels from baseline to follow-up. Secondary outcomes included changes in fasting plasma glucose (FPG), postprandial glucose (PPG), body mass index (BMI), and estimated glomerular filtration rate (eGFR).</p> Results <p>The mean age of participants was 56 ± 11 years, 59% (<i>n</i> = 7008) were male, and the mean diabetes duration was 10.2 ± 8 years. In the glipizide group (<i>n</i> = 6034), HbA1c decreased from 8.8% to 7.9% (<i>p</i> &lt; 0.001), FPG decreased by 16 mg/dL (<i>p</i> &lt; 0.001), and PPG decreased by 29 mg/dL (<i>p</i> &lt; 0.001). In the glipizide + metformin group (<i>n</i> = 5915), HbA1c levels declined from 8.9% to 7.8% (<i>p</i> &lt; 0.001), and FPG and PPG declined by 23 mg/dL and 44 mg/dL, respectively (<i>p</i> &lt; 0.001). BMI remained stable in the glipizide group, while a reduction of 0.2 kg/m² was observed among overweight/obese individuals in the glipizide + metformin group. The use of glipizide and glipizide + metformin effectively improved glycemic control without adverse anthropometric changes. C-peptide levels were preserved across all treatment groups, demonstrating sustained β-cell function. HbA1c reductions were observed consistently across all eGFR categories. Furthermore, as glipizide plus metformin is one of the least expensive antidiabetic drugs in India (₹1460/year [$16.87]) it can help improve accessibility to treatment even among those in lower socio-economic statuses.</p> Conclusions <p>Glipizide as monotherapy or in combination with metformin, significantly improved glycemic control even in those with decreasing renal function, with no adverse effects on weight and with preservation of β-cell function. While long-term studies are needed to assess the sustainability of these benefits, glipizide can be considered a cost-effective therapeutic option for T2D in low- and middle-income countries.</p>