Incretin mimetics and dipeptidyl peptidase 4 inhibitors in clinical trials for the treatment of type 2 diabetes

Expert Opin Investig Drugs. 2008 Jun;17(6):845-53. doi: 10.1517/13543784.17.6.845.

Abstract

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.

Method: 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.

Conclusion: 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.

Publication types

  • Review

MeSH terms

  • Adamantane / adverse effects
  • Adamantane / analogs & derivatives*
  • Adamantane / pharmacology
  • Adamantane / therapeutic use
  • Body Weight / drug effects
  • Clinical Trials, Phase III as Topic / statistics & numerical data
  • Diabetes Mellitus, Type 2 / blood
  • Diabetes Mellitus, Type 2 / drug therapy*
  • Diabetes Mellitus, Type 2 / enzymology
  • Dipeptidyl Peptidase 4
  • Dipeptidyl-Peptidase IV Inhibitors* / adverse effects
  • Dipeptidyl-Peptidase IV Inhibitors* / pharmacology
  • Dipeptidyl-Peptidase IV Inhibitors* / therapeutic use*
  • Double-Blind Method
  • Drug Therapy, Combination
  • Exenatide
  • Glucagon-Like Peptide 1 / pharmacokinetics
  • Glucagon-Like Peptide 1 / physiology
  • Glucagon-Like Peptide 1 / therapeutic use
  • Glucagon-Like Peptide-1 Receptor
  • Glycated Hemoglobin A / analysis
  • Humans
  • Hypoglycemia / chemically induced
  • Hypoglycemic Agents / adverse effects
  • Hypoglycemic Agents / pharmacology
  • Hypoglycemic Agents / therapeutic use*
  • Incretins / physiology*
  • Insulin / metabolism
  • Insulin / therapeutic use
  • Insulin Secretion
  • Nausea / chemically induced
  • Nitriles / adverse effects
  • Nitriles / pharmacology
  • Nitriles / therapeutic use*
  • Peptides / adverse effects
  • Peptides / pharmacology
  • Peptides / therapeutic use*
  • Pyrazines / adverse effects
  • Pyrazines / pharmacology
  • Pyrazines / therapeutic use*
  • Pyrrolidines / adverse effects
  • Pyrrolidines / pharmacology
  • Pyrrolidines / therapeutic use*
  • Randomized Controlled Trials as Topic
  • Receptors, Glucagon / drug effects
  • Sitagliptin Phosphate
  • Triazoles / adverse effects
  • Triazoles / pharmacology
  • Triazoles / therapeutic use*
  • Venoms / adverse effects
  • Venoms / pharmacology
  • Venoms / therapeutic use*
  • Vildagliptin
  • Vomiting / chemically induced

Substances

  • Dipeptidyl-Peptidase IV Inhibitors
  • GLP1R protein, human
  • Glucagon-Like Peptide-1 Receptor
  • Glycated Hemoglobin A
  • Hypoglycemic Agents
  • Incretins
  • Insulin
  • Nitriles
  • Peptides
  • Pyrazines
  • Pyrrolidines
  • Receptors, Glucagon
  • Triazoles
  • Venoms
  • Glucagon-Like Peptide 1
  • Exenatide
  • DPP4 protein, human
  • Dipeptidyl Peptidase 4
  • Vildagliptin
  • Adamantane
  • Sitagliptin Phosphate