Evaluation of the glycometabolic effects of ranolazine in patients with and without diabetes mellitus in the MERLIN-TIMI 36 randomized controlled trial.
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.


RESULTS
We compared HbA(1c) (percentage) and the time to onset of a > or =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 > or =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) > or =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.
TIMI Study Group, Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA. dmorrow@partners.org
David A
DA
Morrow
Benjamin M
BM
Scirica
Bernard R
BR
Chaitman
Darren K
DK
McGuire
Sabina A
SA
Murphy
Ewa
E
Karwatowska-Prokopczuk
Carolyn H
CH
McCabe
Eugene
E
Braunwald
D000083:Acetanilides / Q000494:pharmacology / Q000627:therapeutic use*; D054058:Acute Coronary Syndrome / Q000188:drug therapy* / Q000453:epidemiology; D000368:Aged; D001786:Blood Glucose / Q000187:drug effects*; D002317:Cardiovascular Agents / Q000494:pharmacology* / Q000627:therapeutic use; D048909:Diabetes Complications / Q000188:drug therapy; D003920:Diabetes Mellitus / Q000097:blood / Q000188:drug therapy*; D004311:Double-Blind Method; D005260:Female; D005951:Glucose Tolerance Test; D006442:Glycated Hemoglobin / Q000032:analysis*; D006801:Humans; D006943:Hyperglycemia / Q000188:drug therapy / Q000517:prevention & control; D008297:Male; D024821:Metabolic Syndrome / Q000188:drug therapy; D008875:Middle Aged; D010879:Piperazines / Q000494:pharmacology / Q000627:therapeutic use*; D011446:Prospective Studies; D000069458:Ranolazine; D012008:Recurrence
D000083:Acetanilides; D001786:Blood Glucose; D002317:Cardiovascular Agents; D006442:Glycated Hemoglobin; D010879:Piperazines; D000069458:Ranolazine