The dipeptidyl peptidase-4 (DPP-4) inhibitor saxagliptin in combination with metformin has been suggested to significantly improve glycaemic control compared to either monotherapy in type 2 diabetes (T2D). In addition, metformin and other DPP-4 inhibitors have been shown to protect against ischemic injury in clinical and experimental studies. We therefore hypothesised that chronic treatment with saxagliptin monotherapy may protect the T2D heart against myocardial infarction. Moreover, in combination with metformin, an enhanced effect may be achieved. Goto-Kakizaki (GK-a model of T2D) rats received, via oral gavage, either saxagliptin (30 mg/kg/day), metformin (300 mg/kg/day),metformin & saxagliptin (300 mg/kg/day & 30 mg/kg/day) or vehicle (water) for 2 weeks. Blood glucose was measured before and throughout the treatment. Rats were subjected in vivo to 30min ischaemia/120min reperfusion. The infarct was quantified using TTC staining and expressed as a percentage of the myocardium at risk (I/R%). Both saxagliptin and metformin alone reduced myocardial infarct size (I/R%: 24.7 ± 1.4% with saxagliptin, 18.7 ± 2.5% with metformin, versus 44.6 ± 2.2% with vehicle; P < 0.05: N ≥ 6/group). However, no additive protection was observed when the two agents were co-administered (I/R%: 28.1 ± 3.2% with saxagliptin/metformin combination vs 44.8 ± 4.0% with vehicle). Interestingly, neither treatment (monotherapies/combination therapy) reduced blood glucose significantly following the 2-week treatment. (Before and after treatment, blood glucose in mmol/L: saxagliptin, 9.1 ± 0.5 to 8.3 ± 0.7, metformin, 9.4 ± 1.0 to 8.2 ± 0.3 and combination, 10.7 ± 0.3 to 7.6 ± 0.4). This study highlights the infarct-limiting effect of chronic saxagliptin treatment. The data also suggest that the cardioprotective mechanism of saxagliptin may be similar to that of metformin as these drugs did not manifest additive protection when co-administered. Interestingly, the infarct-limiting effects of these agents seem to be independent of their glucose-lowering properties.