When a single agent no longer works
EugloPlus offers option for type 2 diabetes unresponsive to monotherapy
Patients with type 2 diabetes who no longer respond to treatment with a single drug stand to benefit from a combination drug for blood-glucose management.
"The combination of glibenclamide and metformin (EugloPlus) represents a rational approach in the therapy of type 2 diabetic patients no longer responsive to low doses of monotherapy," said Dr. Roland Heintz, associate professor at Louis Pasteur University and University of Strasbourg in France. Speaking before a scientific symposium organized by Roche Philippines, Heintz explained how each drug works when administered individually and together.
Glibenclamide, a sulfonylurea, increases pancreatic ß-cell insulin release. It blocks the adenosine-triphosphate-sensitive potassium channels of the ß cells, allowing increased insulin secretion. To a minor degree, it increases the sensitivity of peripheral tissue to insulin. Because of this, high doses of sulfonylurea could put a patient at risk of hypoglycemia, which does not happen with metformin, Heintz pointed out.
Metformin, a biguanide, primarily improves peripheral sensitivity to insulin, with a minor effect on pancreatic ß-cell insulin secretion. It increases peripheral uptake of glucose in skeletal muscle and fat while decreasing gluconeogenesis in the liver. As a result, less insulin is needed to produce the same glucose-lowering effect.
Glibenclamide is completely metabolized by the cytochrome P450 system (specifically CYP2C9) in the liver, yielding two major metabolites contributing to its clinical efficacy. Patients with the CYP2C9*1*3 allele are poor metabolizers. In these individuals, glibenclamide clearance is slowed down by 58 percent, and the elimination half-life is increased by 2.5 percent. This lengthens the drug's antihyperglycemic effect and increases the risk for hypoglycemia.
Both glibenclamide and metformin, said Heintz, compare favorably with other agents in their respective drug classes. Compared with other sulfonylureas, glibenclamide has the lowest transport rate through the human placenta, and does not appear to be excreted in human breast milk.
Because glibenclamide and metformin are metabolized by different pathways, they do not interfere with each other's actions. These remarkable contrasting pharmacologic and pharmacokinetic profiles of glibenclamide and metformin offer interesting therapeutic possibilities.
The Tosi Study
Heintz presented the results of a randomized, double-blind study comparing the efficacy of combination glibenclamide and metformin with either agent alone. For the first six months, the patients were randomized into three groups receiving glibenclamide, metformin, and glibenclamide-metformin (EugloPlus). For the next six months, subjects receiving monotherapy were switched to EugloPlus, while half of those on combination were switched to metformin and the other half to glibenclamide.
Results showed greater decreases in both the fasting plasma glucose and glycosylated-hemoglobin (HbA1c) levels among patients on combination therapy than with either glibenclamide or metformin alone. Ten percent of patients on metformin mono-therapy achieved the desired HbA1c of 6.3 percent. With the addition of glibenclamide, 52 percent achieved the goal.
"If you look at glucose, it's similar," Heintz said. "Seventeen percent were reaching the criteria after administration of metformin alone, and you increase the percentage by 49 percent if you give the combination."
The same trend is observed for glibenclamide. With monotherapy, 17 percent of patients achieved the desired HbA1c and fasting-plasma-glucose levels. With the addition of metformin, this increased to 24.5 percent and 52 percent. But the opposite effect was seen when patients on combination were switched to either drug alone.
"The combination treatment with low doses of each antidiabetic agent is more effective than each of these drugs alone in improving the glycemic control in type 2 diabetic patients no longer responsive to low doses of monotherapy with sulfonylureas or metformin," stressed Heintz.
A rational approach
"Normally, when you start [treating] a patient with type 2 diabetes, you will start with monotherapy," said Heintz. "If your treatment has no effect, you start to increase the dose.... By increasing the dose, naturally, you risk side effects."
It's a risk, according to Heintz, that doctors can avoid by using the one-pill, fixed-dose glibencla-mide-metformin (EugloPlus) combination.
"The combination treatment with low doses of the antidiabetic agents is well tolerated and no increase in adverse events of the combination as compared to the monotherapy was observed in this clinical study," concluded Heintz. "If you use the fixed combination, you can start orally with low dose ... much lower than if you use monotherapy."
M
|
