The incretin system: glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors in type 2 diabetes.
Glucagon-like peptide 1 (GLP-1) is a gut-derived incretin hormone that stimulates insulin and suppresses glucagon secretion, inhibits gastric emptying, and reduces appetite and food intake. Therapeutic approaches for enhancing incretin action include degradation-resistant GLP-1 receptor agonists (incretin mimetics), and inhibitors of dipeptidyl peptidase-4 (DPP-4) activity (incretin enhancers). Clinical trials with the incretin mimetic exenatide (two injections per day or long-acting release form once weekly) and liraglutide (one injection per day) show reductions in fasting and postprandial glucose concentrations, and haemoglobin A1c (HbA1c) (1-2%), associated with weight loss (2-5 kg). The most common adverse event associated with GLP-1 receptor agonists is mild nausea, which lessens over time. Orally administered DPP-4 inhibitors, such as sitagliptin and vildagliptin, reduce HbA1c by 0.5-1.0%, with few adverse events and no weight gain. These new classes of antidiabetic agents, and incretin mimetics and enhancers, also expand beta-cell mass in preclinical studies. However, long-term clinical studies are needed to determine the benefits of targeting the incretin axis for the treatment of type 2 diabetes.
Drucker
Daniel J
DJ
Samuel Lunenfeld Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada. d.drucker@utoronto.ca
Nauck
Michael A
MA
D000218:Adamantane / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D058892:Adenosine Deaminase Inhibitors; D002986:Clinical Trials as Topic; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy*; D018819:Dipeptidyl Peptidase 4; D054873:Dipeptidyl-Peptidase IV Inhibitors; D004334:Drug Administration Schedule; D000077270:Exenatide; D052216:Glucagon-Like Peptide 1 / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000096:biosynthesis / Q000145:classification / Q000502:physiology* / Q000627:therapeutic use; D000067757:Glucagon-Like Peptide-1 Receptor; D006023:Glycoproteins / Q000037:antagonists & inhibitors*; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use; D000069450:Liraglutide; D009570:Nitriles; D010455:Peptides / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D011719:Pyrazines / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D011759:Pyrrolidines; D018027:Receptors, Glucagon / Q000819:agonists*; D000068900:Sitagliptin Phosphate; D014230:Triazoles / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D014688:Venoms / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D000077597:Vildagliptin
D058892:Adenosine Deaminase Inhibitors; D054873:Dipeptidyl-Peptidase IV Inhibitors; C000593833:GLP1R protein, human; D000067757:Glucagon-Like Peptide-1 Receptor; D006023:Glycoproteins; D007004:Hypoglycemic Agents; D009570:Nitriles; D010455:Peptides; D011719:Pyrazines; D011759:Pyrrolidines; D018027:Receptors, Glucagon; D014230:Triazoles; D014688:Venoms; D000069450:Liraglutide; D052216:Glucagon-Like Peptide 1; D000077270:Exenatide; C042807:DPP4 protein, human; D018819:Dipeptidyl Peptidase 4; D000077597:Vildagliptin; D000218:Adamantane; D000068900:Sitagliptin Phosphate