Combination Therapy for Patients With Type 2 Diabetes

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 K_ATP 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]

(Enlarge Image)

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]

Table 1. Oral pharmacological treatment choices for patients with Type 2 diabetes.
Therapeutic classes	Mechanism of action	Effects	Adverse events
Biguanides (e.g., metformin)	Decrease hepatic glucose production Decrease intestinal glucose absorption Increase glucose uptake by skeletal muscle and fat	Reduce blood glucose concentration Increase sensitivity to insulin Reduce blood lipid levels	Diarrhea, nausea, vomiting, lactic acidosis
Sulfonylureas	Stimulate pancreatic β-cell activity	Reduce blood glucose concentration Lowers risk of hypoglycemia than insulin	Hypoglycemia, weight gain, nausea, vomiting
Thiazolidinediones	Improve target cell response to insulin Decrease hepatic glucose output Increase insulin-dependent glucose uptake in skeletal muscle and fat	Reduce blood glucose concentration Beneficial alteration of blood lipid levels Possible beneficial effects on pancreas and cardiovascular risk factors	Alteration in liver function markers, detrimental cardiac effects, edema, weight gain
Meglitinides (e.g., repaglinide)	Stimulate glucose-mediated insulin secretion	Reduce blood glucose concentration Reduce postprandial glucose excursions Stimulates insulin secretion	Hypoglycemia, diarrhea, weight gain
α-glucosidase inhibitors	Inhibit pancreatic α-amylase and membrane bound α-glucosidase enzymes Inhibit intestinal disaccharide metabolism Delay glucose absorption	Reduce blood glucose concentration Reduce postprandial glucose excursions Levels out daytime glucose concentration Disperses calories over time Weight neutral	Abdominal pain, diarrhea, flatulence, elevated liver enzymes
Dipeptidyl peptidase-IV inhibitors	Inhibit peptide hormone metabolism by dipeptidylpeptidase-IV enzyme and enhancing biological activity of glucagon-like peptide-1	Reduce blood glucose concentration Reduce postprandial glucose excursions Weight neutral Possible beneficial effects on pancreas and insulin sensitivity Disease progression may have an impact on the effect of these agents	Hypoglycemia, upper respiratory tract infection, headache

Table 1. Oral pharmacological treatment choices for patients with Type 2 diabetes.

Therapeutic classes

Mechanism of action

Effects

Adverse events

Biguanides (e.g., metformin)

Decrease hepatic glucose production
Decrease intestinal glucose absorption
Increase glucose uptake by skeletal muscle and fat

Reduce blood glucose concentration
Increase sensitivity to insulin
Reduce blood lipid levels

Diarrhea, nausea, vomiting, lactic acidosis

Sulfonylureas

Stimulate pancreatic β-cell activity

Reduce blood glucose concentration
Lowers risk of hypoglycemia than insulin

Hypoglycemia, weight gain, nausea, vomiting

Thiazolidinediones

Improve target cell response to insulin
Decrease hepatic glucose output
Increase insulin-dependent glucose uptake in skeletal muscle and fat

Reduce blood glucose concentration
Beneficial alteration of blood lipid levels
Possible beneficial effects on pancreas and cardiovascular risk factors

Alteration in liver function markers, detrimental cardiac effects, edema, weight gain

Meglitinides (e.g., repaglinide)

Stimulate glucose-mediated insulin secretion

Reduce blood glucose concentration
Reduce postprandial glucose excursions
Stimulates insulin secretion

Hypoglycemia, diarrhea, weight gain

α-glucosidase inhibitors

Inhibit pancreatic α-amylase and membrane bound α-glucosidase enzymes
Inhibit intestinal disaccharide metabolism
Delay glucose absorption

Reduce blood glucose concentration
Reduce postprandial glucose excursions
Levels out daytime glucose concentration
Disperses calories over time
Weight neutral

Abdominal pain, diarrhea, flatulence, elevated liver enzymes

Dipeptidyl peptidase-IV inhibitors

Inhibit peptide hormone metabolism by dipeptidylpeptidase-IV enzyme and enhancing biological activity of glucagon-like peptide-1

Reduce blood glucose concentration
Reduce postprandial glucose excursions
Weight neutral
Possible beneficial effects on pancreas and insulin sensitivity
Disease progression may have an impact on the effect of these agents

Hypoglycemia, upper respiratory tract infection, headache

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

Chemistry & Mode of Action

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

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