Published Online
on April 6, 2009

A more recent version of this article appeared on April 21, 2009

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Submitted on January 4, 2008
Accepted on January 30, 2009

Evaluation of the Glycometabolic Effects of Ranolazine in Patients With and Without Diabetes Mellitus in the MERLIN-TIMI 36 Randomized Controlled Trial

David A. Morrow MD, MPH^*, Benjamin M. Scirica MD, MPH, Bernard R. Chaitman MD, Darren K. McGuire MD, Sabina A. Murphy MPH, Ewa Karwatowska-Prokopczuk MD, PhD, Carolyn H. McCabe BS, Eugene Braunwald MD, for the MERLIN-TIMI 36 Investigators

From the TIMI Study Group, Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, and Harvard Medical School, Boston, Mass (D.A.M., B.M.S., S.A.M., C.H.M., E.B.); Saint Louis University School of Medicine, Saint Louis, Mo (B.R.C.); University of Texas Southwestern Medical School, Dallas (D.K.M.); and CV Therapeutics, Palo Alto, Calif (E.K.-P.).

^* To whom correspondence should be addressed. E-mail: dmorrow{at}partners.org.

Background—Ranolazine is a novel antianginal shown in an exploratory analysis in patients with diabetes mellitus and chronic angina to be associated with a decline in hemoglobin A_1c (HbA_1c). We designed a prospective evaluation of the effect of ranolazine on hyperglycemia as part of a randomized, double-blind, placebo-controlled outcomes trial.

Methods and Results—We compared HbA_1c (percentage) and the time to onset of a 1% increase in HbA_1c among 4918 patients with acute coronary syndrome randomized to ranolazine or placebo in the MERLIN-TIMI 36 trial. Ranolazine significantly reduced HbA_1c at 4 months compared with placebo (5.9% versus 6.2%; change from baseline, -0.30 versus -0.04; P<0.001). In patients with diabetes mellitus treated with ranolazine, HbA_1c declined from 7.5 to 6.9 (change from baseline, -0.64; P<0.001). Diabetic patients were more likely to achieve an HbA_1c <7% at 4 months with ranolazine compared with placebo (59% versus 49%; P<0.001) and were less likely to have a 1% increase in HbA_1c (14.2% versus 20.6% at 1 year; hazard ratio, 0.63; 95% confidence interval, 0.51 to 0.77; P<0.001). Moreover, ranolazine reduced recurrent ischemia in diabetic patients (hazard ratio, 0.75; 95% confidence interval, 0.61 to 0.93; P=0.008). Notably, in patients without diabetes mellitus at baseline, the incidence of new fasting glucose >110 mg/dL or HbA_1c 6% was reduced by ranolazine (31.8% versus 41.2%; hazard ratio, 0.68; 95% confidence interval, 0.53 to 0.88; P=0.003). Reported hypoglycemia did not increase with ranolazine (P=NS).

Conclusions—Ranolazine significantly improved HbA_1c and recurrent ischemia in patients with diabetes mellitus and reduced the incidence of increased HbA_1c in those without evidence of previous hyperglycemia. The mechanism of this effect is under investigation.

Key words: angina • coronary disease • diabetes mellitus • hemoglobin A_1c

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