Ranolazine: An Established Anti-Anginal Drug with Emerging Antidiabetic Potential Supported by Preclinical and Clinical Evidence.

Abstract

Background: High blood glucose levels are a hallmark of Diabetes Mellitus (DM), which is classified as a metabolic disease. DM is closely associated with various Cardiovascular Disease (CVD) risk factors, and poor glycemic control is known to elevate the risk of developing CVD. Ranolazine, a novel anti-anginal medication, has demonstrated cardioprotective effects, making it an important agent in the management of heart-related complications in diabetic patients. The mechanism underlying the anti-ischemic effect of ranolazine primarily involves the blockade of the cardiac isoform of voltage-gated Sodium Channels (NaChs), specifically Nav1.5. By inhibiting the late Sodium Current (INa, late), ranolazine helps stabilize cardiac function and reduce ischemic episodes. Recent large Randomized Controlled Trials (RCTs) have shown that ranolazine significantly reduces levels of glycosylated hemoglobin (HbA1c), which is a critical marker for glycemic control. This dual action of ranolazine in improving both cardiac performance and glycemic control positions it as a valuable therapeutic option in the management of patients with DM and cardiovascular risk.

Objectives: This review aims to provide a comprehensive overview of the preclinical and clinical research concerning ranolazine's potential as an antidiabetic agent. By examining existing studies, we explore the drug's mechanisms of action, its impact on glycemic control, and its role in managing DM-related cardiovascular complications. Through the available data, we highlight the emerging evidence supporting ranolazine's use beyond its traditional role as an anti-anginal medication, as well as its promising implications for DM management.

Methods: Using the terms ranolazine, DM, beta-cells, alpha cells, and preclinical and clinical trials, an EMBASE search for English language articles was conducted from 1979 to 2024.

Results: Ranolazine has demonstrated a well-tolerated glucometabolic action and positively regulates glucose levels in individuals with DM. A meta-analysis has revealed that ranolazine effectively improves HbA1c levels without increasing the risk of hypoglycemia, offering significant advantages for patients with type 2 Diabetes Mellitus (T2DM) and stable angina. In addition to its effects on glycemic control, ranolazine has been shown to lower both baseline and postprandial glucagon levels in preclinical trials. This reduction in glucagon is associated with a decrease in hyperglycemia, suggesting that the blockade of Sodium Channels (NaChs) is integral to the glucose-lowering effects of ranolazine. Overall, these findings support the potential of ranolazine as a beneficial treatment option for managing glucose levels in diabetic patients, particularly those with concurrent cardiovascular conditions.

Conclusion: A novel approach for treating T2DM could involve selective Nav1.3 blockers, as ranolazine's unique mechanism of action distinguishes it from other approved antidiabetic medications. Targeting Nav1.3 channels may offer similar glycemic control benefits while minimizing side effects. This strategy could lead to innovative treatments that address both DM management and cardiovascular protection. Further research is needed to evaluate the efficacy and safety of these selective blockers in diabetic patients.