BOSTON – Ranolazine, a drug licensed to treat angina, can lower glucose in people with type 2 diabetes, either as monotherapy or in combination with glimepiride, according to research presented at the annual scientific sessions of the American Diabetes Association.
But further studies will be needed to see if ranolazine (Ranexa, Gilead) can succeed as an add-on to metformin, researchers say.
Dr. Robert H. Eckel, the lead author of the ranolazine studies, said that a previous randomized trial in people with diabetes and coronary artery disease (n = 949) showed ranolazine to be effective in reducing attacks of angina (J. Am. Coll. Cardiol. 2013;61:2038-45).
A post hoc analysis from that trial suggested that ranolazine, a late sodium current inhibitor, also had potential as a glucose-lowering agent – something not seen with other antianginal drugs, said Dr. Eckel, the Charles A. Boettcher Endowed Chair in Atherosclerosis, Professor of Medicine in the divisions of endocrinology, metabolism, and diabetes, and cardiology, as well as professor of physiology and biophysics and program director, Adult General Clinical Research Center, University of Colorado Anschutz Medical Campus, Aurora.
The three phase III studies Dr. Eckel presented, all funded by the drug’s manufacturer, randomized adults with type 2 diabetes to ranolazine monotherapy vs. placebo (n = 465), to metformin plus ranolazine or placebo (n = 442) or to glimepiride plus ranolazine or placebo (n = 431). The trials lasted 24 weeks; all subjects had between 7% and 10% glycated hemoglobin at baseline (mean hemoglobin A1c 8%-8.1%).
Ranolazine, at the standard antianginal dose of 1,000 mg twice a day, performed well as monotherapy in reducing HbA1c; at week 12 the intervention group saw a 40% increase in the number of patients achieving HbA1c of 7% or below. In the treatment group, HbA1c dropped through 18 weeks and stayed constant through 24 weeks, with a mean change from baseline of –0.56% relative to placebo (P = .0001).
Added on to glimepiride 4 mg daily, ranolazine reduced HbA1c by 0.5% compared with placebo over a 24-week period (P < .001).
Problematically, however, the metformin study showed add-on ranolazine to have no effect on HbA1c over placebo, Dr. Eckel said in an interview. This finding was “bothersome,” he added, “because metformin is the number one drug used in patients with type 2 diabetes.”
Dr. Eckel pointed to the metformin dosing used in the study as the likeliest reason for the null funding. Metformin dose was reduced by half, to 500 mg twice daily, in the intervention group, because ranolazine is known to decrease metformin clearance in the kidney, and the Food and Drug Administration and investigators wanted to avoid the chance of metformin toxicity. In the placebo group, metformin was given at a standard dose of 1,000 mg twice daily.
However, the caution may have been unwarranted; studies are beginning to show that metformin may work differently than previously assumed. Rather than acting mostly in the liver, Dr. Eckel said, metformin may modify glucose-sensing L cell–activity in the gut and ultimately enhance glucagon-like peptide-1.
“That mechanism is still being defined, but the evidence is substantial and many people are on to the idea that metformin works indirectly in the liver because of its effects on L cell activity and GLP-1 secretion,” Dr. Eckel said.
Dr. Eckel said that ranolazine, which was well tolerated with little incidence of hypoglycemia, nonetheless appeared promising as an agent in people with coronary artery disease and angina along with type 2 diabetes. “It’s an obvious use of the medication,” he said, though he did not know whether the manufacturer would attempt to go forward with additional studies.
The research was funded by Gilead, the manufacturer of ranolazine. Dr. Eckel and three of his coinvestigators reported receiving no compensation from Gilead, while seven other investigators are employees of Gilead. Dr. Eckel disclosed past consulting fees and/or research funding from Amylin, Esperion, Janssen, Novo Nordisk, Foodminds, ISIS pharmaceuticals, Regeneron/Sanofi, and Vivus.