Background: The benefits of combination therapies in the management of type 2 diabetes are well-documented, while the comparative glycemic control and cardiovascular outcomes among the different combination options have not been studied well. The study aimed to compare glycemic control and risk of cardiovascular outcomes of metformin-insulin versus metforminsulfonylurea combination therapies in type 2 diabetes mellitus. Method: A comparative cross-sectional study was conducted in five tertiary level hospitals in Addis Ababa, Ethiopia. About 321 patients with type 2 diabetes mellitus who were on continuous treatment follow up on either metformin-insulin or metformin-sulfonylurea combination therapy were enrolled. Participants were interviewed and their medical records were reviewed to investigate medication efficacy, safety, and adherence. The primary outcome measure was glycemic control (reduction in glycated hemoglobin A1c) and the secondary outcome measures were composite cardiovascular outcomes (myocardial infarction, stroke, heart failure), microvascular complications (diabetic neuropathy, retinopathy, and nephropathy), treatment-emergent adverse events, changes in bodyweight, fasting blood sugar, systolic blood pressure, diastolic blood pressure and lipid profiles (low-density lipoprotein-cholesterol, highdensity lipoprotein-cholesterol, and triglycerides). Results: Of the total participants enrolled, 162 (50.5%) were those who received metformininsulin and 159 (49.5%) metformin-sulfonylurea combination therapies for a median of 48 months follow-up. Reduction of HbA1c was not different between the two groups, p = .912, with mean ± SD of -1.04 ± .96 % versus -1.02 ± 1.03%, respectively. Patients who received metformin-sulfonylurea are 4.3 times more likely to have achieved target HbA1c level compared to those who received metformin-insulin, p < .001 (AOR=4.31 [95% CI 1.79-10.32]). Risk of composite cardiovascular outcomes was higher in metformin-insulin group (40.5% versus 34.0%), p = .021. Co-morbidities, body mass index, systolic blood pressure, and HbA1c had a significant association with composite cardiovascular outcomes. Reductions of bodyweight, lipid profiles, and microvascular complications were different between the two groups, p < .05. Conclusion: High proportion of patients who received metformin-sulfonylurea achieved target HbA1c level and had less composite cardiovascular outcomes compared to those who received metformin-insulin. However, these findings have to be confirmed with randomized control trials to determine risks associated with insulin use, while efficacy is maintained as second-line treatment in patients with type 2 diabetes mellitus.