DPP-4 inhibitors are oral antidiabetic agents used in the treatment of type 2 diabetes. They share the suffix “-gliptin”, examples include sitagliptin, saxagliptin, vildagliptin, linagliptin, and alogliptin. This article outlines their mechanism of action, key pharmacokinetic parameters, cautions and contraindications, side effects, and clinically significant drug interactions. Mechanism Of Action DPP-4 inhibitors increase the amount of incretin hormones available. The enzyme dipeptidyl peptidase 4 (DPP-4) rapidly hydrolyzes gastrointestinal incretin hormones, rendering them inactive. Incretin hormones include glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). They are released throughout the day, increasing at mealtimes, and have several functions: Stimulate the production and secretion of insulin in response to eating (glucose-dependent insulin secretion) GLP-1 enhances the sensitivity of alpha cells to glucose, resulting in more glucose-appropriate glucagon secretion Slow digestion and decrease appetite Thus, DPP-4 inhibitors indirectly enhance insulin release, suppress glucagon secretion, and improve glycaemic control. Drawn in Inkscape by Ilmari Karonen based on w:Image:Incretins and DPP 4 inhibitors.jpg from http://casesblog.blogspot.com/2006/11/dpp-4-inhibitors-for-treatment-of.html (uploaded by author) Fig 1: mechanism of action of DPP-4 inhibitors Key Pharmacokinetic Parameters The table below describes the key pharmacokinetic parameters for DPP-4 inhibitors: Drug Clearance Half-life Time to peak (Tmax) Metabolism by CYP enzymes Sitagliptin Primarily renal 12.4 hours 1-4 hours CYP3A4 (main), CYP2C8 Saxagliptin Renal and hepatic Saxagliptin: 2.5 hours Major metabolite: 3.1 hours 2-4 hours CYP3A4/5 Major metabolite is also a DPP4 inhibitor but 50% potency Linagliptin Faeces (80%), urine (5%) >100 hours (saturable tight binding of linagliptin to DPP-4) 1.5 hours Weak CYP3A4 substrate Alogliptin Urine (76%), faeces (13%) 21 hours 1-2 hours Negligible Vildagliptin Urine (85%), faeces (15%) 3 hours 1.7 hours Negligible Cautions and contraindications Cautions and contraindications for the use of DPP-4 inhibitors are listed below: Cautions Contraindications Saxagliptin: Severe renal impairment/ moderate hepatic impairment/ Moderate-severe heart failure/elderly Viladagliptin: end stage renal impairment on haemodialysis History of pancreatitis Ketoacidosis Type 1 diabetes Hepatic impairment (saxagliptin/alogliptin/vildagliptin) Heart failure (vildagliptin/alogliptin) Adverse effects Created in BioRender. Jones, O. (2025) https://BioRender.com/6sjf2q1 Fig 2: Adverse effects of DPP-4 inhibitors Other adverse effects include: Increased risk of infection with saxagliptin, alogliptin and vildagliptin Hypersensitivity reactions (including anaphylaxis, angioedema, stevens-johnson syndrome) Sitagliptin: interstitial lung disease, impaired renal function, thrombocytopenia, and acute renal failure. Saxagliptin: erectile dysfunction, dyslipidaemia, and hypertriglyceridaemia. Linagliptin: cough, increased amylase and lipase levels. Vildagliptin: peripheral oedema and nasopharyngitis Interactions Clinically significant drug interactions are described as follows: Interacting Drug/Class Effect Beta-blockers May mask symptoms of hypoglycaemia (e.g., tremor). ACE inhibitors Increased risk of angioedema (especially with vildagliptin). Digoxin Sitagliptin increases plasma levels — monitor for toxicity. Rifampicin May reduce plasma concentrations of linagliptin and saxagliptin. Ketoconazole (and strong CYP3A4 inhibitors) May increase sitagliptin* and saxagliptin levels, especially in renal impairment. *Sitagliptin is metabolised primarily by CYP3A4, in severe renal impairment metabolism plays a more significant role in sitagliptin elimination, therefore potent CYP3A4 inhibitors (ketoconazole, itraconazole, ritonavir, clarithromycin) may increase sitagliptin plasma levels in severe renal impairment The blood glucose-lowering effects of DPP-4 inhibitors may also be enhanced or inhibited by other substances: Created in BioRender. Boucher, M. (2025) https://BioRender.com/7rsskv1 Fig 3: drugs that affect the glucose lowering effects of DPP-4 inhibitors References DPP-4 inhibitors | Prescribing information | Diabetes – type 2 | CKS | NICE Sitagliptin 100 mg Film-coated Tablets – Summary of Product Characteristics (SmPC) – (emc) Onglyza 2.5mg film-coated tablets – Summary of Product Characteristics (SmPC) – (emc) Trajenta 5 mg film-coated tablets – Summary of Product Characteristics (SmPC) – (emc) Alogliptin 12.5 mg film-coated tablets – Summary of Product Characteristics (SmPC) – (emc) Do you think you’re ready? Take the quiz below Pro Feature - Quiz DPP-4 Inhibitors Question 1 of 3 Submitting... Skip Next Rate question: You scored 0% Skipped: 0/3 More Questions Available Upgrade to TeachMePharmacy Pro Challenge yourself with over 2100 multiple-choice questions to reinforce learning Learn More Rate This Article