Combination Therapy for Patients with Type 2 Diabetes: Repaglinide in Combination with Metformin

Robert G Moses


Expert Rev Endocrinol Metab. 2010;5(3):331-342. 

In This Article

Chemistry & Mode of Action

Repaglinide, S(+)2-ethoxy-4(2((3-methyl-1-(2-(1-piperidinyl) phenyl)-butyl) amino)-2-oxoethyl) benzoic acid, is chemically unrelated to the oral SU-based insulin secretagogs and has a molecular formula of C27H36N2O4 (Figure 1).[103] Repaglinide binds to the sulfonylurea receptor-1 in the β-cell membrane at a site distinct from the SU binding site.[30,46] Binding at Kir6.2/sulfonylurea receptor-1 closes ATP-dependent K+ channels, leading to β-cell depolarization and opening of calcium channels. The resulting increased calcium influx induces insulin secretion.[47] The stimulation of insulin secretion from β-cells by repaglinide differs from SUs in the following ways: repaglinide binds to a unique receptor site on the cell membrane separate from the SU receptor site;[30,46] unlike glibenclamide, repaglinide does not have an effect on exocytosis independent of its KATP action[31] and does not inhibit insulin biosynthesis;[48] unlike SUs, repaglinide overcomes the metabolic stress induced by dinitrophenol, making it a superior option in normalizing glucose-induced insulin release in metabolically stressed pancreatic islets.[49]

Figure 1.

Repaglinide and metformin.
Reproduced from [103].

Metformin (N,N-dimethylimidodicarbonimidic diamide) is not chemically or pharmacologically related to any other classes of oral antihyperglycemic agents and has a molecular formula of C4H11N5 (Figure 1).[103] Metformin reduces hyperglycemia by a number of mechanisms: suppressing hepatic gluconeogenesis; improving insulin sensitivity by increasing peripheral glucose uptake and utilization by activating membrane-bound glucose transporters GLUT-1 and GLUT-4 and improving nonoxidative glucose disposal and glycogen synthesis; and decreasing fatty acid oxidation and increasing splanchnic glucose turnover.[33] Metformin reduces fasting hyperglycemia by decreasing hepatic gluconeogenesis and increasing concentration of glucagon-like peptide-1.[50] By increasing peripheral glucose uptake, metformin may decrease cardiovascular complications.[51]


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