(DCP084) ELECLAZINE: THE HIDDEN ANTIDIABETIC POTENTIAL?

Background: Few years ago, ranolazine, acting mainly by blocking late sodium channels (INa-L), was approved as an add-on therapy for treating symptomatic angina. Early clinical experience with ranolazine has shown that among its side effects, the drug causes dose-dependent reductions of both glycemia and glycated hemoglobin (HbA1c) in patients affected by chronic angina and type II diabetes. Interestingly, it was recently shown that the antidiabetic drugs empagliflozin, canagliflozin and dapagliflozin (all SGLT-2 inhibitors), while causing glycosuria, are also blocking INa-L, suggesting that this mechanism could also contribute to their antidiabetic action. Eleclazine is a recently developed drug that is selective and 8-times more potent than ranolazine to block INa-L. Although it has shown disappointing results in heart failure and arrhythmia trials, the potential antidiabetic action of eleclazine as a pure INa-L blocker has never been investigated. The objective was therefore to test the hypothesis that eleclazine has relevant antidiabetic effects in vivo in an animal model of Type II diabetes (T2D).

METHODS AND RESULTS: Sixteen-weeks old male Zucker Diabetic Sprague Dawley (ZDSD) rats (n=11) with overt T2D phenotype were used to test the in vivo effects of eleclazine on glycemia and glucose tolerance. The primary advantage of the ZDSD model is that it closely resembles human T2D, while having an intact leptin pathway. Seven ZDSD rats (n=7) were successively injected eleclazine 1 and 3 mg/kg daily for 10 days, at each dose. Effects of eleclazine were compared to those obtained in a control group of ZDSD rats (n=4) injected vehicle for the corresponding periods of 2 X 10 days. After 10 days of eleclazine at 1 and 3 mg/kg, oral glucose tolerance tests (OGTT) were performed and compared to those obtained in animals treated with vehicle. Eleclazine 1 and 3 mg/kg reduced glycemia in ZDSD rats during OGTT. Indeed, area under the curve (AUC) of glycemia X time was significantly reduced when compared to vehicle (p < 0.05). Weight of ZDSD rats treated with vehicle progressively and significantly declined over time when compared to rats treated with eleclazine 3 mg/kg (p < 0.05).

Conclusion: Eleclazine, by blocking the late sodium channels (INa-L), has hypoglycemic effects. Given that diabetes has long been associated with abnormal activation of INa-L, this is not coming as a surprise. On the other hand, eleclazine-mediated prevention of weight loss observed with aging and deterioration of T2D phenotype in ZDSD rats, could be explained by better utilization of glucose in drug-treated animals.