The Effects of Ranolazine on Hemoglobin A1c in a Veteran Population

Diabetes mellitus (DM) is a risk factor for cardiovascular disease(CVD).^1-4 Death rates from heart disease are 2- to 4-times higher among adults with DM compared with those of adults without DM. In the US, it is estimated that 21.1 million adults have diagnosed DM, 8.1 million adults have undiagnosed DM, and 80.8 million adults have prediabetes.³ The American Heart Association has identified an untreated fasting blood glucose level < 100 mg/dL as a component of ideal cardiovascular health.³

Although the use of antidiabetic agents has been shown to reduce the risks of microvascular complications among patients with DM, a cardiovascular benefit has not been consistently demonstrated with all available agents, and some used in the treatment of DM are associated with cardiovascular harm.⁵ In addition, some cardiovascular medications may contribute to the development of DM or may mask the symptoms of hypoglycemia.⁶ Given the risk for CVD among patients with DM, a medication with utility in both DM and CVD could be beneficial.

Evidence for Use of Ranolazine

Ranolazine is indicated for the treatment of chronic angina.⁷ In clinical trials, ranolazine also was found to decrease hemoglobin A_1c (HbA_1c).^8-15 The possible mechanisms for lowering HbA_1c with ranolazine include preservation of pancreatic β-cells and an increase in glucose-dependent insulin secretion.⁶ The most common adverse effects associated with ranolazine include dizziness, headache, constipation, and nausea.⁷

Ranolazine has been shown to be efficacious and safe in the reduction of angina symptoms among patients with and without DM.^8-12 In addition to improving symptoms of angina, studies have demonstrated a reduction in HbA_1c among patients taking ranolazine.^9,13-15 In an open-label extension of the Combination Assessment of Ranolazine in Stable Angina (CARISA) trial, ranolazine 750 mg twice daily and 1,000 mg twice daily led to a greater reduction in HbA_1c when each was compared with placebo (-0.48% HbA_1c, P = .008; and -0.70% HbA_1c, P = .001, respectively).⁹

Among the 5,576 patients enrolled in the Metabolic Efficiency With Ranolazine for Less Ischemia in Non-ST-Elevation Acute Coronary Syndromes—Thrombolysis in Myocardial Infarction 36 (MERLIN-TIMI 36) trial with a baseline HbA_1c, ranolazine significantly reduced HbA_1c at 4 months when compared with placebo among patients with and without DM.¹³ In addition, patients with DM who were treated with ranolazine were more likely to achieve a HbA_1c < 7% at 4 months when compared with placebo (59% vs 49%; P < .001). Ranolazine was not found to increase the incidence of hypoglycemia.

A subgroup analysis of MERLIN-TIMI 36 evaluated the effects of ranolazine compared with those of placebo on fasting plasma glucose and HbA_1c in patients with moderate DM (HbA_1c ≥ 6% but < 8%, fasting plasma glucose < 250 mg/dL) and severe DM (A_1c ≥ 8%, fasting plasma glucose 150-400 mg/dL).¹⁴ A significant reduction in HbA_1c with ranolazine in addition to standard of care antidiabetes treatment was observed among both groups. The placebo-corrected decrease in HbA_1c in the moderate DM group was 0.28% (95% confidence interval [CI] -0.55 to 0; P = .045) and in the severe DM group was 0.59% (95% CI -0.99 to -0.20; P < .001).

In a trial designed to evaluate change in HbA_1c in patients taking ranolazine 1,000 mg twice daily compared with that of placebo, ranolazine led to a greater decrease in HbA_1c compared with that of placebo (placebo corrected change in HbA_1c -0.56%, P = .001).¹⁵ In addition, a higher percentage of patients achieved HbA_1c < 7% at 24 weeks in the ranolazine group compared with that of placebo (41.2% vs 25.7%; P = .001). No patient experienced severe hypoglycemia or had documented hypoglycemia in this study.

These trials suggest that ranolazine, in addition to decreasing anginal events, is potentially beneficial in achieving better control of DM. However, more studies are needed to determine this benefit. In addition, no trials have examined the 500-mg twice daily dose of ranolazine in HbA_1c reduction.

The purpose of this study was to evaluate the change in HbA_1c among veterans with DM after the initiation of ranolazine. The study compared the percentage of veterans achieving HbA_1c < 7% or < 8% after initiation of ranolazine with the baseline, to determine whether there is a dose-related change in HbA_1c among different ranolazine regimens and to determine whether there is a change in the incidence of hypoglycemia after the initiation of ranolazine.

Methods

This was a multicenter, retrospective study. The institutional review board and research and development committee for 3 Veterans Affairs medical centers (VAMCs) approved this study and waived informed consent. Additionally, this study was approved for access to national patient information through the Corporate Data Warehouse (CDW).