Effect of ranolazine on A1C and glucose levels in hyperglycemic patients with non-ST elevation acute coronary syndrome

Abstract

Objective: We determined the relationships between glycemia at randomization, concurrent antidiabetic therapy, and change in A1C and fasting plasma glucose (FPG) in patients with diabetes receiving standard treatment for diabetes and randomized to ranolazine or placebo within the MERLIN-TIMI-36 (MERLIN) study. Ranolazine is a novel first-in-class drug approved for treating angina pectoris.

Research design and methods: Randomization and 4-month glycemic and antidiabetes drug usage data from MERLIN were analyzed using Spotfire and SAS version 9.1 software.

Results: In patients with diabetes and A1C of >or=8-10% at randomization (n = 171), there was an absolute A1C reduction in the ranolazine group of 1.2% (95% CI -1.4 to -1.0), and the placebo-adjusted (n = 182) decrease in A1C by ranolazine was 0.59% (95% CI -0.99 to -0.20, P < 0.001). In patients with FPG of 150-400 mg/dl at randomization, ranolazine (n = 131) compared with placebo (n = 147) reduced FPG by 25.7 mg/dl (95% CI -43.3 to -8.1, P = 0.001). When changes in either A1C or FPG were correlated to A1C or FPG at randomization, the slopes were significantly steeper for ranolazine than placebo (A1C, P = 0.046; FPG, P < 0.001), indicating that lowering of A1C and FPG by ranolazine is related to hyperglycemia at randomization. Ranolazine, compared with placebo, was not associated with serious hypoglycemic events, associated with significant changes in concurrent antidiabetic therapy, or dependent on a history of angina.

Conclusions: Ranolazine, when added to concurrent antidiabetes treatment, lowers FPG and A1C in patients with cardiovascular disease and poorly controlled diabetes.

Trial registration: ClinicalTrials.gov NCT00099788.

Figures

Figure 1

Relationship between glycemia at randomization and lowering of A1C and FPG by ranolazine in patients with a history of diabetes. A: In a cell means model, with parameters for combinations of treatment, A1C category, and diabetes, the placebo-adjusted effect of ranolazine on A1C was −0.28% (95% CI −0.55 to 0.003, P = 0.045) for patients with A1C 6 to <8% and −0.59% (−0.99 to −0.20, P < 0.001) for patients with A1C ≥8–10%. B: In a cell means model, with parameters for combinations of treatment, FPG category, and diabetes, the placebo-adjusted effect on FPG for these patients was 6.8 mg/dl (95% CI −8.8 to 22.3, P = 0.677) for patients with FPG <150 mg/dl and −25.7 mg/dl (−43.3 to −8.1, P = 0.001) for patients with FPG ≥150–400 mg/dl. Changes in A1C and FPG at month 4 are summarized by mean, associated 95% CI, and number of patients (n). C: Relationship between A1C at randomization and the change in A1C at month 4. The slope for placebo was −0.31 (95% CI −0.41 to −0.21), R = 0.26 and n = 558. For ranolazine, the slope was −0.44 (−0.53 to −0.36), R = 0.41 and n = 508. The slopes were significantly different (P = 0.045). D: Relationship between FPG at randomization and the change in FPG at month 4. The slope for placebo was −0.55 (95% CI −0.64 to −0.46), R = 0.54 and n = 328. For ranolazine, the slope was −0.81 (−0.89 to −0.73), R = 0.76 and n = 310. The slopes were significantly different (P < 0.001). Least squares regression was performed by Graphpad Prism 5.0, and the best-fit line and 95% CI for the fit are shown for each group. Similar results were obtained using an ANCOVA model with a term for treatment, A1C or FPG at randomization, and the interaction of treatment.

Figure 2

Effect of concurrent antidiabetes drug treatment on patients treated with ranolazine reaching an A1C goal of ≤7%. Patients with a history of diabetes who were hyperglycemic at randomization (A1C >7%) were grouped by drug treatment. These patients were reexamined at 4 months and categorized as responders if A1C was ≤7%. OR for hyperglycemic patients in each group to reach an A1C ≤7% was calculated using a logistics analysis model (SAS software, Cary, NC). Data are plotted as OR (95% CI). Ins, insulin.