SAN FRANCISCO – Ranolazine is being groomed as potentially the first drug to provide dual antianginal and glucose-lowering benefits in type 2 diabetic patients with coronary artery disease.

Results of the TERISA (Type 2 Diabetes Evaluation of Ranolazine in Subjects With Chronic Stable Angina) trial presented by Dr. Mikhail Kosiborod at the annual meeting of the American College of Cardiology have established the first part of the sought-after demonstration of dual benefit.

The second step in winning an expanded indication for ranolazine (Ranexa) specifically in patients with type 2 diabetes and stable angina is to demonstrate that the drug also lowers fasting blood glucose and hemoglobin A_1c. Three ongoing phase III randomized clinical trials are addressing that issue, according to Dr. Kosiborod, a cardiologist at the Saint Luke’s Mid-America Heart Institute and the University of Missouri, Kansas City.

There is a compelling need for targeted, more effective therapies in patients with angina and type 2 diabetes. They often have more extensive and diffuse coronary artery disease (CAD) than do nondiabetic patients with CAD, and they have worse outcomes as well, including more repeat hospitalizations and higher health care costs, he observed.

TERISA was a randomized, double-blind, placebo-controlled trial in 927 patients with type 2 diabetes, coronary artery disease, and stable angina with symptoms despite treatment with one or two other antianginal agents. The trial was conducted in 105 centers in 14 countries.

The target dose of ranolazine was 1,000 mg twice daily in this 8-week trial. The primary outcome was the average number of anginal episodes during weeks 2-8 as captured by patients using a novel electronic diary with daily entries. Participants had a mean diabetes duration of 7.5 years and a baseline HbA_1c of 7.3%.

From a baseline anginal frequency of 6.7 episodes/week, the ranolazine group improved to 3.8 episodes/week. The control group averaged 4.3 episodes/week, demonstrating the profound placebo effect commonly noted in angina clinical trials. The half-episode per week advantage in the ranolazine group, compared with placebo was highly significant (P = .008).

The secondary endpoint in TERISA was change in weekly use of sublingual nitroglycerin. From a baseline mean of 4.3 doses/week, it improved to 1.7 episodes/week in the ranolazine group and 2.1 episodes/week in controls. Once again, the between-group difference was significant.

Ranolazine was extremely well tolerated, said Dr. Kosiborod. The only side effects that were more common than in the placebo arm were dizziness and nausea, each affecting fewer than 4% of patients on ranolazine.

Dr. Kosiborod highlighted two intriguing TERISA subgroup analyses. One showed that ranolazine’s antianginal effect was greater among patients with higher baseline HbA_1c values. The potential mechanism is under study. If confirmed in other clinical trials, this finding would suggest that ranolazine is particularly beneficial in type 2 diabetic patients with angina and suboptimal glucose control.

Another prespecified subgroup analysis revealed that ranolazine was significantly more effective than placebo at all study sites except for selected locations in Russia. When the Russian sites were excluded from the study analysis, the average number of weekly anginal episodes in the ranolazine group dropped from 3.8 to 3.1.

"There’s a very active investigation underway to find out what was going on at those Russian sites that created a geographic difference in outcome," according to Dr. Kosiborod.

Discussant C. Michael Gibson, professor of medicine at Harvard Medical School, Boston, said he’d really have like to have seen data on the duration as well as the number of anginal episodes. Objective measurement of total ischemic burden, as by Holter monitoring, is particularly important in diabetes patients because they have notoriously poor anginal warning systems.

Dr. Kosiborod replied that he and his coinvestigators opted to go with change in the number of anginal episodes as a more clinically meaningful, patient-centered outcome.

"I would say the reason we prescribe antianginal medications is based upon patient symptoms, not how long they can go on the treadmill or what their Holter monitor looks like," he added.

Dr. Miguel A. Quinones, cochair of the ACC conference and chairman of the department of cardiology at Methodist Hospital, Houston, commented that ranolazine’s 0.5 episode/week greater decrease in angina episodes than with placebo is a rather modest effect. Dr. Kosiborod was quick to respond that it’s in the same ballpark as has been shown in studies of percutaneous coronary intervention to improve angina, a widely accepted form of treatment.

Simultaneously with Dr. Kosiborod’s presentation at the San Francisco conference, the TERISA findings were published online (J. Am. Coll. Cardiol. 2013 [doi:10.1016/j.jacc.2013.02.011]).

TERISA was sponsored by Gilead Sciences. Dr. Kosiborod reported serving as a consultant to Gilead and several other pharmaceutical and medical device companies. Dr. Gibson reported having financial ties to numerous pharmaceutical and device manufacturers, but not Gilead. Dr. Quinones reported having no relevant industry relationships.

TERISA targets diabetes as potential new market for ranolazine