Incretin mimetics and dipeptidyl peptidase 4 inhibitors in clinical trials for the treatment of type 2 diabetes.
BACKGROUND
Exenatide is an incretin mimetic, while sitagliptin and vildagliptin are incretin enhancers used as adjunctive therapy in patients with type 2 diabetes failing oral agents. Sitagliptin and vildagliptin can also be used as monotherapy in patients with type 2 diabetes uncontrolled by diet.


OBJECTIVE
To provide a critical review of clinical trials of exenatide, sitagliptin and vildagliptin.


METHODS
Review of Phase III clinical trials based on Medline search published up to April 2008.


RESULTS
The use of exenatide is associated with reduction in average hemoglobin A1c (HbA1c) levels of approximately 0.8% compared with baseline. The corresponding reduction with either sitagliptin or vildagliptin is 0.7%. The actions of incretin-based drugs predominantly target postprandial hyperglycemia. Treatment-related hypoglycemia is generally mild, and mainly occurs when used with sulfonylureas (SUs). Exenatide treatment leads to a mild weight loss of around 2 kg after 30 weeks, whereas sitagliptin and vildagliptin have generally neutral effect on weight. Sitagliptin and vildagliptin are well tolerated in trials lasting up to 52 weeks. Meanwhile, 5 - 10% of patients cannot tolerate exenatide due to adverse effects, mainly nausea and vomiting. The three drugs are limited by the lack of long-term safety and efficacy data, as well as by their high cost.


CONCLUSIONS
Exenatide, sitagliptin and vildagliptin are useful add-on therapy for type 2 diabetes that is suboptimally controlled on oral agents, particularly when there is concern about weight gain and hypoglycemia, or when postprandial hyperglycemia is the major cause of inadequate glycemic control. Sitagliptin and vildagliptin may be used as monotherapy in patients who cannot tolerate metformin or SU, and sitagliptin may be used as alternative to metformin in renal insufficiency.
Mikhail
Nasser
N
Endocrinology Division, Department of Medicine, Olive-View-UCLA Medical Center, 14445 Olive View Drive, Sylmar, CA 91342, USA. nmikhail@ladhs.org
D000218:Adamantane / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D001835:Body Weight / Q000187:drug effects; D017326:Clinical Trials, Phase III as Topic / Q000706:statistics & numerical data; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000188:drug therapy* / Q000201:enzymology; D018819:Dipeptidyl Peptidase 4; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D000077270:Exenatide; D052216:Glucagon-Like Peptide 1 / Q000493:pharmacokinetics / Q000502:physiology / Q000627:therapeutic use; D000067757:Glucagon-Like Peptide-1 Receptor; D006442:Glycated Hemoglobin / Q000032:analysis; D006801:Humans; D007003:Hypoglycemia / Q000139:chemically induced; D007004:Hypoglycemic Agents / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D054795:Incretins / Q000502:physiology*; D007328:Insulin / Q000378:metabolism / Q000627:therapeutic use; D000078790:Insulin Secretion; D009325:Nausea / Q000139:chemically induced; D009570:Nitriles / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D010455:Peptides / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D011719:Pyrazines / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D011759:Pyrrolidines / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D016032:Randomized Controlled Trials as Topic; D018027:Receptors, Glucagon / Q000187:drug effects; D000068900:Sitagliptin Phosphate; D014230:Triazoles / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D014688:Venoms / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D000077597:Vildagliptin; D014839:Vomiting / Q000139:chemically induced
D000218:Adamantane; D018819:Dipeptidyl Peptidase 4; D054873:Dipeptidyl-Peptidase IV Inhibitors; D000077270:Exenatide; D052216:Glucagon-Like Peptide 1; D000067757:Glucagon-Like Peptide-1 Receptor; D006442:Glycated Hemoglobin; D007004:Hypoglycemic Agents; D054795:Incretins; D007328:Insulin; D009570:Nitriles; D010455:Peptides; D011719:Pyrazines; D011759:Pyrrolidines; D018027:Receptors, Glucagon; D000068900:Sitagliptin Phosphate; D014230:Triazoles; D014688:Venoms; D000077597:Vildagliptin; C000593833:GLP1R protein, human; C042807:DPP4 protein, human