Drucker DJ. The biology of incretin hormones. Cell Metabolism 2006;3:153-165. Miller S, St Onge EL. Sitagliptin: A dipeptidyl peptidase IV inhibitor for the treatment of type 2 diabetes. Ann Pharmacother 2006;40:1336-1343.
BRIEF INTRODUCTION : T2DM Prevalent chronic healthcare disease with a significantglobal disease burden. Achieving specific glycemic goals substantiallyreduces morbidity & have made the effective treatmentof hyperglycemia a top priority. Intensive glycemic control has a powerful beneficialeffect on diabetes-specific complications. Development of new classes of blood glucose-lowering medications has increased the number oftreatment options.
DPP-4 Inhibitors : A Novelapproach in T2DM Management DPP 4 inhibitors inhibit the breakdown of Incretin peptide hormonesand increase the Incretin effect in patients with type 2 DM. Their development was based on observations that factorssecreted from gut participated in regulation of pancreatic endocrinesecretion.These gut factors were termed “Incretins”. Two Incretin peptide hormones have been identified inhumans,namely Glucose dependent insulin releasing polypeptide(GIP) and Glucagon like peptide -1 (GLP-1) Incretins are rapidly inactivated by dipeptidyl peptidase-4 (DPP-4).The DPP-4 inhibitors prolong the action of endogenous incretins,enhancing the first-phase insulin response.
Incretins and glycemiccontrolAdapted from 7. Drucker DJ. Cell Metab. 2006;3:153–165. 8. Miller S, St Onge EL. Ann Pharmacother 2006;40:1336-1343.ActiveGLP-1 and GIPRelease ofincretin guthormonesPancreasBloodglucosecontrolGI tract Glucagonfrom alpha cells(GLP-1)GlucosedependentAlpha cellsIncreased insulinand decreasedglucagonreducehepaticglucose outputGlucose dependent Insulinfrom beta cells(GLP-1 and GIP)Beta cellsInsulinincreasesperipheralglucoseuptakeIngestionof foodDPP-4enzymerapidlydegradesincretins
DPP – 4 Inhibitors in ClinicalPracticeA list of available and expected gliptins : Sitagliptin (Merck Sharp and Dohme Corp, approved as Januvia by US FDA in year 2006) Vidagliptin (Novartis, approved as Galvus by EU in year 2007) Saxagliptin (Bristol-Myers Squibb, approved as Onglyza by US FDA in 2010) Linagliptin (Boerhinger Ingelheim, approved as Tradjenta by US FDA in year 2011) Alogliptin (developed by Takeda Pharmaceutical Company Limited, approved for use in Japan) Dutogliptin (being developed by Phenomix Corporation) Gemigliptin (being developed by LG Life Sciences) Linagliptin has recently been approved in India. In clinical trials,most of these drugs have been shown to reduce HbA1c significantly when usedeither as monotherapy or in combination with Metformin, Sulphonylureas or a combination ofboth. They are also associated with lower rates of hypoglycemia and have also been shown to beweight neutral.
Advantages of Using DPP – 4Inhibitors As Monotherapy : Shown to be equally efficacious as compared to otherantidiabetic agents with added advantage of lesser incidence ofhypoglycemia and being weight neutral. As Initiation Therapy : Can be safely coupled with Metformin as an Inititaiontherapy as per the latest guidelines (ADA guideline) Insulin dose can be reduced if given with gliptins as a combination therapy. No significant drug – drug interaction with other drugs so can be givensafely with anti-hypertensives,anti-hyperlipidemics & antibiotics. Cardiac friendly profile :Studies suggest that DPP-4 inhibitors have acardiovascular friendly profile. Preclinical studies have suggestedendothelial benefit, anti-atherosclerotic effects and blood pressure loweringeffects.
Advantages of Using DPP – 4Inhibitors : Continued Safe in Hepatic Inefficiency : For patients with hepaticinsufficiency, except for vildagliptin, no dose adjustmentis necessary for gliptins. Safe in Renal Insufficiency :Linagliptin is safe in renalinsufficiency.Other gliptins can be used safely with doseadjustments. Well Tolerated in most people with not much significantadverse event profile.
Conclusion Need for newer medications in T2DMManagement. DPP - 4 Inhibitors offer a promising treatmentmodality in T2DM. Need for continued research to evaluate longterm safety and adverse event profile inpatients.
References Indian Journal Of Endocrinology &Metabolism 2011 Oct-Dec; 15(4): 298–308. www.Diabetesincontrol.com www.diabetesjournals.org www.qjmed.oxfordjournals.org