Effectiveness of ranolazine in patients with type 2 diabetes mellitus and chronic stable angina according to baseline hemoglobin A_1c

Background Ranolazine reduces the frequency of angina and use of sublingual nitroglycerin (SL NTG) in stable angina patients with type 2 diabetes (T2DM). Because pre-clinical data suggest that myocardial late sodium current (I_NaL), the target of ranolazine, is increased by hyperglycemia, we investigated whether the efficacy of ranolazine was influenced by glycemic control. Methods TERISA was a multinational, randomized, double-blind trial of ranolazine vs. placebo in patients with T2DM and stable angina. Anginal episodes and SL NTG use were recorded daily in an electronic diary. Health status was evaluated at baseline and 8 weeks post-randomization using the Seattle Angina Questionnaire (SAQ). The interaction between baseline HbA_1c and treatment effect was tested across endpoints using analysis of covariance models, with HbA_1c as a continuous variable with restricted cubic splines. Results The study included 913 patients, with mean age 63.6 years, 39% women, mean T2DM duration 7.4 years, and mean HbA_1c of 7.3%. Heterogeneity of efficacy by HbA_1c was observed for the primary endpoint of angina frequency (P_interaction =.027), the key secondary endpoint of SL NTG use (P_interaction =.030), SAQ angina frequency (P_interaction =.001), and SAQ treatment satisfaction (P_interaction =.025) with greater efficacy of ranolazine in those with higher HbA_1c values, increasing continuously from HbA_1c levels >6.5%. Conclusion Among patients with T2DM and stable angina, the therapeutic benefits of ranolazine were greater in those with higher HbA_1c values. These data suggest that ranolazine is particularly beneficial in patients with stable angina who have suboptimally controlled T2DM.