Background <p>This study aimed to evaluate the effectiveness and safety of quadruple combination therapy (metformin, DPP4 inhibitors, SGLT2 inhibitors, and sulfonylurea) in patients with high HbA1c at initial diagnosis or those who failed to achieve treatment goals.</p> Methods <p>This retrospective study included 412 diabetic patients treated with quadruple therapy at Uijeongbu St. Mary’s Hospital from January to December 2023. These patients were first diagnosed with diabetes or, due to suboptimal glycemic control, the attending physician recommended insulin therapy, but the patient refused. Patients were divided into an initial treatment group (group A) and a subsequent treatment group (group B). HbA1c levels, side effects, and regimen changes were monitored at 3- and 6-month post-treatment. Factors associated with achieving HbA1c &lt; 7% were analyzed using logistic regression.</p> Results <p>For the total population, with quadruple therapy, the mean HbA1c decreased by -12.0 ± 15.5% from baseline, with 23.5% achieving HbA1c &lt; 7% at 3 months. At 6 months, HbA1c decreased by 10.6%, with 21.6% achieving HbA1c &lt; 7%. Group A achieved significantly greater HbA1c reductions at both 3 and 6 months than group B (-38.1% vs. -9.9%, <i>P</i> &lt; 0.001). At 6 months, 54.5% of patients in group A achieved HbA1c &lt; 7% compared to 18.9% in group B. Factors positively influencing HbA1c reduction included younger age, shorter diabetes duration, and initial treatment group. Minimal side effects were reported.</p> Conclusions <p>Quadruple oral hypoglycemic therapy may be a safe and effective option for patients with type 2 diabetes who refuse insulin, particularly in newly diagnosed individuals. While less effective in long-standing diabetes, it can serve as a transitional approach to improve glycemic control and promote future treatment adherence.</p> Clinical trial number <p>Not applicable.</p>