Diabetes mellitus is one of the many risk factors for cardiovascular disease (CVD), and poor glycemic control worsens the risk of CVD. CVD is known to be the major cause of death in diabetics.¹ Among CVD patients with diabetes, chronic angina is a major problem. Patients with diabetes often have diffuse coronary artery disease not amenable to revascularization therapy and suffer from chronic angina. Diabetic patients also have a greater incidence of heart failure from diastolic dysfunction.² A drug that can simultaneously target both chronic angina and diabetes and improve the diastolic function would be very useful.³

Ranolazine was FDA approved in 2006 for its use in chronic angina as a first-line agent for concomitant use with other anti-anginal drugs. It is a selective inhibitor of cardiac late sodium channels. Blockage of these late sodium channels results in decreasing the intracellular Na⁺ and Ca⁺², which leads to improved myocardial relaxation and diastolic function and improved myocardial blood flow leading to its anti-anginal and anti-ischemic properties. This mechanism of action was also observed in tissues other than cardiac muscles, such as pancreatic islets. The effect on pancreatic islet alpha cells causes the reduction in glucagon release. The other proposed mechanisms of its anti-diabetic actions are the preservation of beta cells and increasing insulin delivery to tissues. These mechanisms of actions are yet to be proved and extensively studied.⁴

Several studies have demonstrated the efficacy of ranolazine in chronic antianginal therapy including patients with incomplete revascularization after percutaneous coronary intervention. The MARISA (Monotherapy Assessment of Ranolazine in Stable Angina) and CARISA (Combination Assessment of Ranolazine In Stable Angina) trials clearly demonstrated the improvement in exercise capacity in a patient with chronic angina on ranolazine therapy, including patients with diabetes. The ERICA (Efficacy of Ranolazine in Chronic Angina) trial clearly demonstrated a decrease in the incidence of anginal episodes with ranolazine.

Ranolazine has been shown to improve control of diabetes. Four large published trials have shown that there is a statistically significant reduction in HbA1C in diabetics on ranolazine without side effects of hypoglycemia. The two trials CARISA and MERLIN-TIMI 36 (Metabolic Efficiency with Ranolazine for Less Ischemia in Non-ST Elevation Acute Coronary Syndromes- Thrombolysis in Myocardial Infarction 36) demonstrated 1.2% absolute decrease in A1C in diabetic arm compared to placebo with an oral dose of 1000mg twice daily.¹ Another trial on glycemic effects of ranolazine monotherapy in diabetics showed that there was a decline in HbA1C levels by 0.56% at 24 weeks of therapy and more patients achieved goal A1C compared to placebo.¹ Many trials are being conducted to study the effect of ranolazine in combination with oral hypoglycemics. One such study found that patients on ranolazine and metformin did not achieve a significant (-0.37% in the metformin plus ranolazine group vs -0.20% in the metformin group) level of A1C reduction. The reason for this was attributed to halving the metformin dose (in the ranolazine arm 500 mg instead of 1000 mg).¹ The TERISA (Type 2 Diabetes Evaluation of Ranolazine in Subjects with Chronic Stable Angina) study published in 2013 evaluated the efficacy of ranolazine in chronic angina. This trial found that diabetics on ranolazine had decreased use of sublingual nitroglycerin and reduced anginal episodes compared to placebo. A recent small pilot study was done to demonstrate its effect on insulin resistance, which showed significant decrease in insulin resistance measured in HOMA-IR units (decrease in ranolazine arm from 3.01 to 2.8 compared to 3.0 to 2.8 in the control group).⁵ These results make ranolazine seem like a very promising therapeutic option in the management of diabetes in patients with coronary artery disease (CAD). The fact that diabetes contributes to risk factors for adverse outcomes in CAD adds more weight to this point.

The role of ranolazine in diastolic dysfunction is still evolving and small trials have demonstrated benefits but large multicenter studies have yet to prove its efficacy in this condition. Ranolazine has been shown to improve diastolic function in patients with coronary artery disease by increasing the regional peak filling rates and regional wall lengthening during isovolumic relaxation period.⁶ It has also been shown to decrease pulmonary capillary wedge pressure and left ventricular end diastolic pressure in patients with heart failure with preserved ejection fraction.⁷

More data is needed to ascertain ranolazine's possible mortality benefits and hypoglycemic side effects. Conducting large randomized multicenter trials could be considered to investigate its use in diabetics without angina as it is not FDA approved for use in type 2 diabetes mellitus (T2DM). No trials have conducted to study the effect of ranolazine in preventing micro and macro vascular complications due to T2DM. The effect of ranolazine in diabetics on insulin is under investigation.

To conclude, ranolazine is shown to have promising effect on glycemic control and improvement in angina symptoms in diabetic patients, but more data is needed. There is also a possible role of ranolazine in the treatment of congestive heart failure in patients with diabetes and diastolic dysfunction, and hopefully future studies will shed light on this possible indication.

References

1. Greiner L, Hurren K, Brenner M. Ranolazine and its effects on hemoglobin A1C. Ann Pharmacother 2016;50:410-5.
2. From AM, Scott CG, Chen HH. Changes in diastolic dysfunction in diabetes mellitus over time. Am J Cardiol 2009;103:1463-6.
3. Kosiborod M, Arnold SV, Spertus JA, et al. Evaluation of ranolazine in patients with type 2 diabetes mellitus and chronic stable angina: results from the TERISA randomized clinical trial (Type 2 Diabetes Evaluation of Ranolazine in Subjects With Chronic Stable Angina). J Am Coll Cardiol 2013;61:2038-45.
4. Banerjee K, Ghosh RK, Kamatam S, Banerjee A, Gupta A. Role of ranolzaine in cardiovascular disease and diabetes: exploring beyond angina. Int J Cardiol 2017;227:556-64.
5. Caminiti G, Fossati C, Battaglia D, Massaro R, Rosano G, Volterrani M. Ranolazine improves insulin resistance in non-diabetic patients with coronary heart disease. A pilot study. Int J Cardiol 2016;219:127-9.
6. Hayashida W, van Eyll C, Rousseau MF, Pouleur H. Effects of ranolazine on left ventricular regional diastolic function in patients with ischemic heart disease. Cardiovasc Drugs Ther 1994;8:741-7.
7. Maier LS, Layug B, Karwatawska-Prokopczuk E, et al. RAnoLazIne for the treatment of diastolic heart failure in patients with preserved ejection fraction: the RALI-DHF proof-of-concept study. JACC Heart Fail 2013;1:115-22.

Keywords: Acute Coronary Syndrome, Angina, Stable, Blood Pressure, Coronary Artery Disease, Diabetes Mellitus, Type 2, Heart Failure, Hypoglycemia, Hypoglycemic Agents, Insulin, Insulin Resistance, Metformin, Myocardial Infarction, Myocardium, Neurofibromin 2, Nitroglycerin, Percutaneous Coronary Intervention, Pulmonary Wedge Pressure, Risk Factors, Metabolic Syndrome

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