BOSTON, MA — The addition of ranolazine (Ranexa, Gilead Science), an agent approved in the US for first-line use in angina or as an add-on therapy to other antianginal agents, significantly lowered HbA1c levels in type 2 diabetes patients when used as a monotherapy or when added to the sulfonylurea glimepiride[1].

When ranolazine was added to metformin, however, there was no effect on HbA1c levels, report investigators.

"The absence of effect on HbA1c in the add-on to metformin study may relate to the metformin dosing," lead investigator Dr Robert Eckel (University of Colorado, Denver) said when he presented the findings of the trial during the American Diabetes Association (ADA) 2015 Scientific Sessions.

The metformin dose was halved in the arm in which it was used in combination with ranolazine, because the latter decreases the renal clearance of metformin, he explained.

Ranolazine was approved as an antianginal agent in 2006, but post hoc analyses of various angina trials suggested the drug might be effective in diabetic patients, not only for its role in eliminating angina but also for its ability to lower HbA1c levels.

In 2013, the Type 2 Diabetes Evaluation of Ranolazine in Subjects With Chronic Stable Angina (TERISA) study showed that the drug reduced episodes of stable angina in diabetes patients already receiving one or two antianginal drugs. Ranolazine also led to less use of sublingual nitroglycerin.

And in that study, the first prospective international randomized controlled study focusing specifically on angina in patients with diabetes, the benefits of ranolazine appeared more prominent in patients with higher rather than lower HbA1c levels.

This latest phase 3 trial was therefore designed to determine the safety and effectiveness of ranolazine for glycemic control, said Eckel.

Good Results as Monotherapy, Added to Glimepiride

The study presented by Eckel included patients with type 2 diabetes mellitus and a baseline HbA1c level ranging from 7% to 10%.

In the first arm of the study, where ranolazine was tested as monotherapy in 465 patients, treatment with ranolazine 1000 mg twice daily reduced HbA1c levels 0.56% compared with placebo by 24 weeks. Fasting plasma glucose levels were also significantly reduced in the ranolazine-treatment arm.

By the beginning of week 12 in the monotherapy study, "there was about a 50% increase in the number of patients who achieved an HbA1c less than 7% while on ranolazine," said Eckel.

Regarding the potential mechanism, he said they also observed a significant reduction in fasting and 3-hour postprandial glucagon levels.

In another arm, patients were treated with glimepiride 4 mg during an initial qualifying period. After the run-in phase, 215 patients were randomized to ranolazine 1000 mg twice daily on top of the sulfonylurea, while 216 patients were randomized to glimepiride plus placebo.

Like the monotherapy study, the addition of ranolazine reduced HbA1c levels 0.5% compared with placebo at 24 weeks, as well as reducing fasting plasma glucose levels. Nearly twice as many patients in the glimepiride/ranolazine arm achieved HbA1c levels less than 7% compared with the glimepiride arm alone, said Eckel.

As for safety, nausea, headache, dizziness, and constipation were more common in the ranolazine arm, and there were four patients who developed hypoglycemia, in the monotherapy trial.

Effects Blunted When Used With Metformin

In the metformin arm of the study, patients were treated with metformin 1000 mg twice during the run-in phase of the study. If they were randomized to treatment with ranolazine, the metformin dose was decreased to 500 mg twice daily, whereas patients randomized to metformin plus placebo remained on the 1000-mg dose of metformin.

The 500-mg dose was selected so that patients in this arm ended up with similar serum metformin levels to those in the placebo/ranolazine-treatment arm, due to the effect of ranolazine on metformin clearance.

"Keep in mind that the gut is where is metformin works, and ultimately the reduction in dose [used in the trial] may have a significant impact on HbA1c and fasting glucose levels," Eckel observed.

In conclusion, he said, "We can say with relative confidence that ranolazine was very well tolerated, with a very low incidence of hypoglycemia," and no cases of severe hypoglycemia were seen.

While the patients were well matched in the three studies, "it should be pointed out that the age was a bit higher in the add-on studies, as was the duration of type 2 diabetes," added Eckel. "That's because patients were often pretreated with normal agents prior to entrance into the study."

Will Ranolazine for Glycemic Control Be Commercially Viable?

But with no Food and Drug Administration (FDA) indication for ranolazine for glycemic control in patients with diabetes, Dr Eric Peterson (Duke Clinical Research Institute, Durham, North Carolina), who was not involved in the latest study of ranolazine, told heartwire the challenge for the company will be demonstrating safety to the agency. After the issuance of new agency guidelines in December 2008, any new diabetes drug must prove it does not cause cardiovascular harm.

"The issue here is that if you needed to do a trial demonstrating cardiovascular safety, it would need to be quite large," said Peterson. "These trials run in the tens of thousands of patients. To get that indication, you have to be pretty sure that there's a safe market to make that an economically wise decision."

Peterson added that there are already a number of existing drugs in different classes that reduce HbA1c levels and do not increase the risk of cardiovascular events. "If you had a drug that would show cardiovascular benefit, then you'd have a potential blockbuster," said Peterson, speculating on the possible role for ranolazine in diabetes. "But drugs that show a similar degree of safety as we're seeing now are going to be hard to beat."

The study was funded by Gilead Sciences. Eckel reports consulting fees from Amylin Pharmaceuticals, Esperion, Janssen, Novo Nordisk, Foodminds, Isis Pharmaceuticals, Regeneron/Sanofi, and Vivus. He receives research funding from Esperion, Janssen, and ISIS Pharmaceuticals.

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