Type 2 diabetes (T2D), the most common form, is marked by insulin resistance and β-cell failure. β-cell dysfunction under high-glucose-high-lipid (HG-HL) conditions is a key contributor to the progression of T2D. This study evaluates the comparative effects of 10 nM semaglutide, 10 nM tirzepatide, and 1 mM metformin, both alone and in combination, on INS-1 β-cell maintenance and function under HG-HL conditions. INS-1 cells were pretreated for 2 h with single doses of metformin (1 mM), semaglutide (10 nM), tirzepatide (10 nM), or combinations of 1 mM metformin with either 10 nM semaglutide or 10 nM tirzepatide, followed by 48 h of HG-HL stimulation. The results indicate that combining 1 mM metformin with either 10 nM semaglutide or 10 nM tirzepatide significantly enhances the effects of 10 nM semaglutide and 10 nM tirzepatide on HG-HL-induced apoptosis and dysregulated cell cycle. Specifically, the combination treatments demonstrated superior restoration of glucose-stimulated insulin secretion (GSIS) functionality compared to 1 mM metformin, 10 nM semaglutide, and 10 nM tirzepatide.