Abstract
BackgroundThe dipeptidyl peptidase-4 (DPP-4) inhibitors Sitagliptin and Vildagliptin lower blood glucose by augmenting endogenous levels of glucagon-like peptide-1 (GLP-1), an incretin which also confers cardioprotection. As such, we hypothesized that treatment with DPP-4 inhibitors are also cardioprotective.MethodsIn ex vivo experiments: Male Sprague–Dawley rats were randomized to receive by oral gavage either Vildagliptin (20 mg/kg/day), Sitagliptin (100 mg/kg/day), or water for 2 weeks. Excised hearts were Langendorff-perfused with buffer containing either 5 mmol/L or 11 mmol/L glucose and subjected to 35 minutes ischaemia/120 minutes reperfusion. In in vivo experiments: Male young Wistar and Sprague–Dawley rats, middle aged Wistar and Goto-Kakizaki diabetic rats were randomized to receive by oral gavage either Sitagliptin (100 mg/kg/day), or water for 2 weeks. Rats were then subjected to 30 minutes ischaemia/120 minutes reperfusion and infarct size ascertained.ResultsTwo weeks pre-treatment with either Vildagliptin or Sitagliptin reduced ex vivo myocardial infarction (MI) size in hearts perfused with buffer containing 11 mmol/L glucose but not 5 mmol/L glucose. This effect was abolished by Exendin 9–39 (GLP-1 receptor antagonist) and H-89 (PKA antagonist). Treatment of perfused hearts with native GLP-1 was also glucose-sensitive, reducing MI size, at glucose concentrations 7, 9, and 11 mmol/L but not at 5 mmol/L. Finally, Sitagliptin reduced in vivo MI size in middle aged Wistar (7-8 mmol/L glucose) and Goto-Kakizaki (9-10 mmol/L glucose) rats where blood glucose was elevated, but not in young Wistar (5 mmol/L glucose) or Sprague–Dawley (5 mmol/L glucose) rats, where blood glucose was normal.ConclusionsWe find that chronic treatment with DPP-4 inhibitors reduced MI size, via the GLP-1 receptor-PKA pathway, in a glucose-dependent manner. Glucose-sensitive cardioprotection of endogenous GLP-1 in diabetic patients may in part explain why intensive control of serum glucose levels has been associated with increased cardiovascular risk.
Highlights
The dipeptidyl peptidase-4 (DPP-4) inhibitors Sitagliptin and Vildagliptin lower blood glucose by augmenting endogenous levels of glucagon-like peptide-1 (GLP-1), an incretin which confers cardioprotection
Differences were considered significant when P < 0.05. Both Sitagliptin and Vildagliptin pre-treatment reduced myocardial infarct size ex vivo in a glucose-dependent manner There was no difference in the area at risk or haemodynamic variables between the treatment groups
Vildagliptin pre-treatment reduced myocardial infarct size in hearts perfused with buffer containing 11 mmol/L of glucose (34.4 ± 4.1% with Vildagliptin versus 52.9 ± 5.2% with control: P < 0.05:N ≥ 6/group) but not 5 mmol/L glucose (53.2 ± 4.8% with Vildagliptin versus 52.6 ± 7.2% with control: P > 0.05:N ≥ 6/group) (Figure 2B)
Summary
The dipeptidyl peptidase-4 (DPP-4) inhibitors Sitagliptin and Vildagliptin lower blood glucose by augmenting endogenous levels of glucagon-like peptide-1 (GLP-1), an incretin which confers cardioprotection. We hypothesized that treatment with DPP-4 inhibitors are cardioprotective. Coronary heart disease (CHD) is the leading cause of death in diabetic patients. Patients with diabetes are two to three times more likely to develop CHD, and experience worse clinical outcomes following an acute myocardial infarction [1,2,3], coronary angioplasty [4], and cardiac bypass surgery [5,6,7]. The reason for the worse cardiovascular outcomes in diabetic patients is currently unclear. Novel cardioprotective strategies are required to improve clinical outcomes in diabetic patients with CHD
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