CHICAGO – A novel delayed-release formulation of oral metformin holds the promise of making the drug work for the many patients with type 2 diabetes who are unable to take generic metformin because of renal insufficiency or GI intolerance.

The key to this development was the discovery that metformin’s primary site of action isn’t the circulation, it’s the lower bowel – specifically, the gut enteroendocrine L-cells. Metformin plasma exposure is not required for the drug’s glucose-lowering effects, Dr. Ralph A. DeFronzo asserted at the annual scientific sessions of the American Diabetes Association.

The investigational proprietary delayed-release formulation of metformin, known as NewMet, is designed to minimize the drug’s bioavailability. The delayed-release tablet bypasses the highly absorptive upper bowel, instead delivering the medication to the distal small intestine, where metformin is poorly absorbed into the circulation and enteroendocrine L-cells are concentrated. Metformin’s glucose-lowering effects are now thought to result from the drug’s stimulation of the L-cells to release gut hormones, including glucagon-like peptide-1 (GLP-1) and peptide YY, said Dr. DeFronzo, professor of medicine and director of the diabetes division at University of Texas Health Science Center at San Antonio.

He presented a proof-of-concept study demonstrating that metformin’s glucose-lowering effect is dissociated from plasma drug levels. The randomized, double-blind, crossover study involved 24 patients with type 2 diabetes. After being withdrawn from oral diabetes therapy for 2 weeks, they received in random order 5 days of commercially available, immediate-release metformin at 1,000 mg twice daily; delayed-release metformin at 1,000 mg twice daily; and delayed-release metformin at 500 mg twice daily. Each 5-day treatment period was separated by a 9- to 12-day washout.

Each of the two dosing regimens of delayed-release metformin proved as effective as conventional metformin. They reduced fasting and postprandial plasma glucose levels as well as the 10-hour glucose area under the curve to the same extent as that of immediate-release metformin, without changing the insulin area under the curve. In other words, 1,000 mg/day of delayed-release metformin was as effective as was standard full-dose conventional metformin at 2,000 mg/day. Yet plasma metformin exposure was reduced by 45% with delayed-release metformin at 1,000 mg twice daily and by 57% by the investigational agent at 500 mg twice daily. Both the conventional and delayed-release formulations of metformin increased GLP-1 and peptide YY levels to a similar extent.

Delayed-release metformin was better tolerated. Unlike conventional metformin, it did not cause any nausea or vomiting, since it was not yet released in the upper bowel. However, both immediate- and delayed-release metformin were associated with a 10%-15% incidence of diarrhea, a side effect of metformin in the lower bowel.

It appears that when a patient is on full-dose conventional metformin, about half of the dose is absorbed into the circulation from the stomach, while the other half continues downstream to the lower bowel, where it actually exerts its therapeutic effects, according to Dr. DeFronzo.

Conventional metformin is contraindicated in patients with renal insufficiency. That’s because once metformin is absorbed into the circulation, it gets cleared by the kidney. If renal function is impaired, the drug accumulates and can cause lactic acidosis due to metformin-induced liver toxicity.

Delayed-release metformin should sidestep this problem because the plasma levels are so much lower than with the conventional drug. That was suggested in a separate study presented at the ADA meeting by Mark Fineman, Ph.D., senior vice president for research and development at San Diego–based Elcelyx Therapeutics Inc., which is developing NewMet. He presented a model designed to predict plasma metformin concentrations that would result if type 2 diabetes patients with varying degrees of renal impairment were to take delayed-release metformin. The results suggested no increased risk of lactic acidosis at 1,000 or 2,000 mg/day. And a study is now underway to see if 800 or 600 mg once daily can provide the full effect seen at 500 mg twice daily in Dr. DeFronzo’s study, Dr. Fineman said in an interview.

Metformin is recommended in ADA treatment guidelines as the initial drug of choice for patients with type 2 diabetes. It is the most commonly prescribed medication for type 2 diabetes in the world. Yet roughly 40% of patients don’t take it due to renal insufficiency or GI intolerance. Moreover, many patients on metformin are unable to take full-dose therapy because of limited tolerability. These are the patient populations where delayed-release metformin could be a boon.

Dr. Fineman said Elcelyx is now in discussions with the FDA about the requirements for marketing approval, which are likely to be abbreviated since NewMet is a new formulation of an approved drug.

"We’ll need to do a phase III program to show that in non–renally impaired people delayed-release metformin works just as well as regular metformin, maybe better, and then we’ll do studies in renally impaired patients to show what the efficacy is," he said.

Dr. DeFronzo is a clinical adviser to Elcelyx.

bjancin@frontlinemedcom.com

New metformin formulation broadens candidate population