Imeglimin for type 2 diabetes shows promise in small trial

SAN FRANCISCO – Imeglimin, the first in a new tetrahydrotriazine-containing class of oral glucose–lowering agents, markedly increased glucose-dependent insulin sensitivity and improved beta-cell function, a small randomized trial showed.

The agent, developed by Lyon, France–based Poxel, is currently in phase IIb development in the United States and Europe, regulates mitochondrial bioenergetics, and targets the liver, muscle, and pancreas, Dr. Michael Roden said at the annual scientific sessions of the American Diabetes Association. Imeglimin "has been shown to improve liver and muscle insulin sensitivity, and it is also efficient in untreated, metformin- or sitagliptin-treated type 2 diabetes without safety concerns," said Dr. Roden, director of the German Diabetes Center, Düsseldorf.

The aim of the current study was to examine the subacute effect of imeglimin on glucose-stimulated insulin secretion (GSIS) in vivo during hyperglycemic glucose clamp tests. The researchers enrolled 30 patients with type 2 diabetes who were either drug naive or on previous metformin monotherapy for at least 12 weeks. Their mean age was 61 years, their mean body mass index was 29.7 kg/m², and "they were reasonably well controlled at baseline, with a hemoglobin A_1c of 6.5%-7.5% at the first screening visit," Dr. Roden said.

After a 2-week metformin wash-out period, he and his associates compared imeglimin 1,500 mg twice daily for 1 week with placebo. A 90-minute hyperglycemic clamp was performed with administration of arginine at 45 minutes to assess the maximal response. The primary endpoint of the study was insulin secretion assessed by total insulin response given as the incremental area under the curve from 0 to 45 minutes as well as insulin secretion rate (ISR) calculated from C-peptide deconvolution. First-phase insulin sensitivity was defined as that which occurred in the first 8 minutes of administration while second-phase insulin sensitivity was defined as that which occurred after 25-45 minutes of administration.

Beta-cell glucose sensitivity was measured as the ratio of incremental ISR at steady state to mean incremental glucose levels during the same period, hepatic insulin extraction was measured by mathematical modeling from insulin and C-peptide concentrations, and insulin clearance was measured as a ratio of second-phase ISR and the corresponding area under the curve of insulin concentrations.

Dr. Roden reported that in drug-naive or metformin-treated patients with type 2 diabetes, imeglimin treatment for 7 days raised insulin response to glucose by 112% (P = .03), increased first-phase ISR by 110% (P = .034), increased second-phase ISR by 30% (P = .031), and improved beta-cell glucose sensitivity by 36% (P = .034). It also tended to decrease hepatic insulin extraction. "Imeglimin improves beta-cell function in humans, which may explain its glucose-lowering effect in longer-lasting trials," he said.

Poxel supported the study. Two of the study authors are employed by the company. Dr. Roden disclosed that he serves on advisory boards for Poxel.

dbrunk@frontlinemedcom.com

SAN FRANCISCO – Imeglimin, the first in a new tetrahydrotriazine-containing class of oral glucose–lowering agents, markedly increased glucose-dependent insulin sensitivity and improved beta-cell function, a small randomized trial showed.

The agent, developed by Lyon, France–based Poxel, is currently in phase IIb development in the United States and Europe, regulates mitochondrial bioenergetics, and targets the liver, muscle, and pancreas, Dr. Michael Roden said at the annual scientific sessions of the American Diabetes Association. Imeglimin "has been shown to improve liver and muscle insulin sensitivity, and it is also efficient in untreated, metformin- or sitagliptin-treated type 2 diabetes without safety concerns," said Dr. Roden, director of the German Diabetes Center, Düsseldorf.

The aim of the current study was to examine the subacute effect of imeglimin on glucose-stimulated insulin secretion (GSIS) in vivo during hyperglycemic glucose clamp tests. The researchers enrolled 30 patients with type 2 diabetes who were either drug naive or on previous metformin monotherapy for at least 12 weeks. Their mean age was 61 years, their mean body mass index was 29.7 kg/m², and "they were reasonably well controlled at baseline, with a hemoglobin A_1c of 6.5%-7.5% at the first screening visit," Dr. Roden said.

After a 2-week metformin wash-out period, he and his associates compared imeglimin 1,500 mg twice daily for 1 week with placebo. A 90-minute hyperglycemic clamp was performed with administration of arginine at 45 minutes to assess the maximal response. The primary endpoint of the study was insulin secretion assessed by total insulin response given as the incremental area under the curve from 0 to 45 minutes as well as insulin secretion rate (ISR) calculated from C-peptide deconvolution. First-phase insulin sensitivity was defined as that which occurred in the first 8 minutes of administration while second-phase insulin sensitivity was defined as that which occurred after 25-45 minutes of administration.

Beta-cell glucose sensitivity was measured as the ratio of incremental ISR at steady state to mean incremental glucose levels during the same period, hepatic insulin extraction was measured by mathematical modeling from insulin and C-peptide concentrations, and insulin clearance was measured as a ratio of second-phase ISR and the corresponding area under the curve of insulin concentrations.

Dr. Roden reported that in drug-naive or metformin-treated patients with type 2 diabetes, imeglimin treatment for 7 days raised insulin response to glucose by 112% (P = .03), increased first-phase ISR by 110% (P = .034), increased second-phase ISR by 30% (P = .031), and improved beta-cell glucose sensitivity by 36% (P = .034). It also tended to decrease hepatic insulin extraction. "Imeglimin improves beta-cell function in humans, which may explain its glucose-lowering effect in longer-lasting trials," he said.

Poxel supported the study. Two of the study authors are employed by the company. Dr. Roden disclosed that he serves on advisory boards for Poxel.

dbrunk@frontlinemedcom.com

SAN FRANCISCO – Imeglimin, the first in a new tetrahydrotriazine-containing class of oral glucose–lowering agents, markedly increased glucose-dependent insulin sensitivity and improved beta-cell function, a small randomized trial showed.

The agent, developed by Lyon, France–based Poxel, is currently in phase IIb development in the United States and Europe, regulates mitochondrial bioenergetics, and targets the liver, muscle, and pancreas, Dr. Michael Roden said at the annual scientific sessions of the American Diabetes Association. Imeglimin "has been shown to improve liver and muscle insulin sensitivity, and it is also efficient in untreated, metformin- or sitagliptin-treated type 2 diabetes without safety concerns," said Dr. Roden, director of the German Diabetes Center, Düsseldorf.

The aim of the current study was to examine the subacute effect of imeglimin on glucose-stimulated insulin secretion (GSIS) in vivo during hyperglycemic glucose clamp tests. The researchers enrolled 30 patients with type 2 diabetes who were either drug naive or on previous metformin monotherapy for at least 12 weeks. Their mean age was 61 years, their mean body mass index was 29.7 kg/m², and "they were reasonably well controlled at baseline, with a hemoglobin A_1c of 6.5%-7.5% at the first screening visit," Dr. Roden said.

After a 2-week metformin wash-out period, he and his associates compared imeglimin 1,500 mg twice daily for 1 week with placebo. A 90-minute hyperglycemic clamp was performed with administration of arginine at 45 minutes to assess the maximal response. The primary endpoint of the study was insulin secretion assessed by total insulin response given as the incremental area under the curve from 0 to 45 minutes as well as insulin secretion rate (ISR) calculated from C-peptide deconvolution. First-phase insulin sensitivity was defined as that which occurred in the first 8 minutes of administration while second-phase insulin sensitivity was defined as that which occurred after 25-45 minutes of administration.

Beta-cell glucose sensitivity was measured as the ratio of incremental ISR at steady state to mean incremental glucose levels during the same period, hepatic insulin extraction was measured by mathematical modeling from insulin and C-peptide concentrations, and insulin clearance was measured as a ratio of second-phase ISR and the corresponding area under the curve of insulin concentrations.

Dr. Roden reported that in drug-naive or metformin-treated patients with type 2 diabetes, imeglimin treatment for 7 days raised insulin response to glucose by 112% (P = .03), increased first-phase ISR by 110% (P = .034), increased second-phase ISR by 30% (P = .031), and improved beta-cell glucose sensitivity by 36% (P = .034). It also tended to decrease hepatic insulin extraction. "Imeglimin improves beta-cell function in humans, which may explain its glucose-lowering effect in longer-lasting trials," he said.

Poxel supported the study. Two of the study authors are employed by the company. Dr. Roden disclosed that he serves on advisory boards for Poxel.

dbrunk@frontlinemedcom.com