The aim of the present cohort study is the assessment of treatment failure rates in patients on monotherapy with metformin or insulin secretagogues, observed in a routine clinical setting. A cohort of patients without any pharmacological treatment was also observed. A retrospective observational cohort study was performed on a consecutive series of 2,020 type 2 diabetic patients receiving monotherapy with an oral agent (metformin or insulin secretagogue, n = 1,126) or drug-naive (n = 894). HbA1c and prescribed hypoglycemic therapy were recorded yearly. Patients were followed until death, change of residence, failure to treatment, or up to 48 months. The mean duration of follow up was 34.8 ± 18.0 months. In a Cox regression analysis, metformin was associated with a significant reduction, and insulin secretagogues with a significant increase, in the risk of failure to therapy during follow up. When duration of diabetes and baseline BMI were added to the model, insulin secretagogues, but not metformin, were still associated with increased risk of failure. In conclusion, insulin secretagogues are associated with increased failure rate in comparison with metformin. This difference could be due to detrimental effect of secretagogues, rather than to a beneficial action of metformin.