OBJECTIVES: To evaluate the association between saxagliptin and cardiovascular risk in patients with type 2 diabetes mellitus (T2DM). METHODS: Literature searches were performed in PubMed, CENTRAL, and ClinicalTrials.gov. In addition, reference lists of included studies were cross-checked for relevant studies. RCTs (≥24 weeks) that compared saxagliptin against placebo, or active antidiabetic drugs in adult patients (≥18 years) with T2DM, and reported cardiovascular outcomes were included. RESULTS:  Of 26778 (19 trials) treated patients (mean±SD HbA1c 8.2±0.8%, age 56±10.11 years, BMI 30.2±4.9 kg/m2), 14649 received saxagliptin once daily and 12129 received comparators. There was no significant difference between saxagliptin 2.5mg and placebo on myocardial infarction (MI) [2.5mg: odds ratio (OR) 0.22, 95% confidence interval (CI) 0.04 to 1.31, 3 trials, n=1083], cardiovascular mortality (OR 0.80, 95% CI 0.25 to 2.54, 2 trials, n=886), acute MI (OR 0.46, 95% CI 0.10 to 2.05, 4 trials, n=1239), congestive-heart failure (OR 0.23, 95% CI 0.03 to 2.09, 2 trials, n=749) and angina pectoris (OR 0.33, 95% CI 0.05 to 2.08, 4 trials, n=1412) at week 24. Similar findings were observed on MI (OR 0.61, 95% CI 0.19, 1.96, 6 trials, n=2762), cardiovascular mortality (OR 0.95, 95% CI 0.22, 4.17, 4 trials, n=1287), acute MI (OR 0.51, 95% CI 0.19, 1.37, 7 trials, n=2488), congestive-heart failure (OR 0.95, 95% CI 0.21, 4.22, 2 trials, n=741) and angina pectoris (OR 0.70, 95% CI 0.20, 2.51, 6 trials, n=2010) between saxagliptin 5mg and placebo at week 24. However, at week 24, the odds of heart failure with saxagliptin (5mg) was 1.8 times higher than placebo (OR 1.78, 95% CI 1.27 to 2.50, 4 trials, n=17796). CONCLUSIONS: Evidence suggests no increased risk of cardiovascular MI/mortality/congestive-heart failure/angina-pectoris with saxagliptin 2.5/5mg in T2DM patients. However, limited evidence suggests that saxagliptin 5mg is associated with increased risk of heart failure among T2DM patients.