Positive Antihyperglycemic, Metabolic Effects With Ranolazine in Patients With Diabetes

The antianginal drug ranolazine has demonstrated positive antihyperglycemic and metabolic effects in patients with uncontrolled hemoglobin A1C (HbA_1c) and therefore may be useful in patients with chronic stable angina pectoris and diabetes mellitus, according to a literature review published in the American Journal of Cardiology.¹

With the growing prevalence of obesity, the incidence of patients presenting with both coronary artery disease and diabetes is on the rise.¹ In addition,  patients with concomitant diabetes and cardiovascular disease have been found to have a reduced life-span and greater mortality from acute coronary syndromes.^2,3 Ranolazine is one of several antianginal drugs that reduce the symptoms of ischemic heart disease and, although not well understood, also has antihyperglycemic effects potentially through inhibiting glucagon secretion, increasing insulin secretion, and preserving pancreatic beta cell function.^4-10

To evaluate the antihyperglyemic and positive metabolic effects of ranolazine in patients with diabetes, the investigators searched MEDLINE from 2000 to October 1, 2016 using the terms ranolazine, antihyperglycemic, diabetes, cardiology, and antianginal, and identified 5 randomized controlled trials and one retrospective study.^1,11-16 They found that ranolazine demonstrated efficacy as an antihyperglycemic agent when used as monotherapy or in combination with traditional diabetes therapies. There was between a 0.48% and 0.70% absolute reduction in HbA_1c with use of ranolazine in patients with diabetes, which is comparable with second-line oral antidiabetic agents. Ranolazine also has a relatively mild adverse event profile.

While future research is still needed, ranolazine may have a niche in the management of this high-risk population. The investigators concluded that, “with the lowering of HbA_1c ranolazine could potentially offer significant benefits in the diabetic population with angina through positive disease state management as well as decreasing healthcare related costs.”

References

1. Gilbert BW, Sherard M, Little L, Branstetter J, Meister A, Huffman J. Antihyperglycemic and metabolic effects of ranolazine in patients with diabetes mellitus [published online November 28, 2017]. Am J Cardiol. doi:10.1016/j.amjcard.2017.11.021
2. Franco OH, Steyerberg EW, Hu FB, Mackenback J, Nusselder W. Associations of diabetes mellitus with total life expectancy and life expectancy with and without cardiovascular disease. Arch Intern Med. 2007;167:1145-1151.
3. Donahoe SM, Stewart GC, McCabe CH, et al. Diabetes and mortality following acute coronary syndromes. JAMA. 2007;298:765-775.
4. Rodbard HW, Blonde L, Braithwaite SS, et al; AACE Diabetes Mellitus Clinical Practice Guidelines Task Force. American Association of Clinical Endocrinologists medical guidelines for clinical practice for the management of diabetes mellitus. Endocr Pract. 2007;13(suppl 1):1-68.
5. Hammond DA, Smotherman C, Jankowski CA, et al. Shortcourse of ranolazine prevents postoperative atrial fibrillation following coronary artery bypass grafting and valve surgeries. Clin Res Cardiol. 2015;104:410-417.
6. Aldakkak M, Camara AK, Heisner JS, Yang M, Stowe DF. Ranolazine reduces Ca2+ overload and oxidative stress and improves mitochondrial integrity to protect against ischemia reperfusion injury in isolated hearts. Pharmacol Res. 2011;64:381-392.
7. Timmis AD, Chaitman BR, Crager M. Effects of ranolazine on exercise tolerance and HbA1c in patients with chronic angina and diabetes. Eur Heart J. 2006;27:42-48.
8. Chisholm JW, Goldfine AB, Dhalla AK, et al. Effect of ranolazine on A1c and glucose levels in hyperglycemic patients with non-ST elevation acute coronary syndrome. Diabetes Care. 2010;33:1163-1168.
9. Ning Y, Zhen W, Fu Z, et al. Ranolazine increases b-cell survival and improves glucose homeostasis in low-dose streptozotocin-induced diabetes in mice. J Pharmacol Exp Ther. 2011;337:50-58.
10. Dhalla, AK, Yang M, Ning Y, et al. Blockade of Na⁺ channels in pancreatic α-cells has antidiabetic effects. Diabetes. 2014;63:3545-3556.
11. Page RL 2nd, Ghushchyan V, Read RA, Hartsfield CL, Koch BR, Nair KV. Comparative effectiveness of ranolazine versus traditional therapies in chronic stable angina pectoris and concomitant diabetes mellitus and impact on health care resource utilization and cardiac interventions. Am J Cardiol. 2015;116:1321-1328.
12. Lamendola P, Nerla R, Pitocco D, et al. Effect of ranolazine on arterial endothelial function in patients with type 2 diabetes mellitus. Atherosclerosis. 2013;226:157-160.
13. Pettus J, Mcnabb B, Eckel RH, et al. Effect of ranolazine on glycemic control in patients with type 2 diabetes treated with either glimepiride or metformin. Diabetes Obes Metab. 2016;18:463-474.
14. Timmis AD, Chaitman BR, Crager M. Effects of ranolazine on exercise tolerance and HbA1c in patients with chronic angina and diabetes. Eur Heart J. 2006;27:42-48.
15. Morrow DA, Scirica BM, Chaitman BR, et al; MERLIN-TIMI 36 Investigators. Evaluation of the glycometabolic effects of ranolazine in patients with and without diabetes mellitus in the MERLIN-TIMI 36 randomized controlled trial. Circulation. 2009;119:2032-2039.
16. Eckel RH, Henry RR, Yue P, et al. Effect of ranolazine monotherapy on glycemic control in subjects with type 2 diabetes. Diabetes Care. 2015;38:1189-1196.