Incretin-based therapies: new treatments for type 2 diabetes in the new millennium

Figures & data

Table 1 Actions of incretins on the defects in glucose handling, βcell function, and energy intake in type 2 diabetes patients

Defects in type 2 diabetes	Actions of incretins
Impaired glucose-stimulated insulin secretion and lack of postprandial biphasic response	Restoration of glucose dependent insulinotropic effect and first phase response
Hyperglucagonemia	Suppression of glucagon secretion
Defective hypoglycemia counter-regulation	Glucagon secretion, and loss of insulinotropic effect, when plasma glucose is low
Reduced βcell mass and insulin content	Increased synthesis of proinsulin, possible increased β-cell mass or differentiation of islet precursor cells into β-cells
Accelerated βcell apoptosis	Possible inhibition of toxin-induced β-cell apoptosis
Normal, retarded or accelerated gastric emptying	Slowing of gastric emptying
Hypercaloric energy intake, obesity	Suppression of appetite/increased satiety, weight loss

Table 2 Comparison of GLP-1 agonists and DPP-4 inhibitors

	GLP-1 agonists	DPP-4 inhibitors
Currently marketed	Exenatide (short-acting and long-acting release), liraglutide	Sitagliptin, vildagliptin
Mode of action	GLP-1 receptor agonist, resistant to degradation by DPP-4	Inhibits degradation of GLP-1 → increases endogenous GLP-1 level
Usage	+ metformin ± SU ± TZD	+ metformin and/or TZD and/or SU
Administration	Subcutaneous injection (pen)	Oral (tablet)
Reduction in HbA1c	∼1% to 1.5%	∼0.5% to 1%
B-cell function	Possibly improved	Possibly improved
Extraglycemic benefits	↓ BP	↓ BP (sitagliptin)
	↓ Cholesterol, LDL, TG, ↑HDL	↓ Cholesterol, LDL, TG, ↑HDL
	↑ Left ventricular function, arterial vasodilation (GLP-1 infusion)
Hypoglycemia	very low risk	very low risk
weight	Reduction	Neutral
GI adverse effects	Frequent (∼35% to 50%, dose-dependent and usually self-limited)	Uncommon
Gastric emptying	Slowed (greatest effect with exenatide)	No effect
Other adverse effects	Pancreatitis	Nasopharyngitis, upper respiratory tract infection, headache; elevated liver enzymes (vildagliptin)

Abbreviations: BP, blood pressure; HDL, high-density lipoprotein; LDL, low-density lipoprotein; SU, sulfonylureas; TG, triglycerides; TZD, thiazolidinediones.