dipeptidyl peptidase-4

**Physiology/Pathophysiology** - DPP-4 (also CD26, a T-cell activation antigen) is a membrane-bound and soluble serine exopeptidase expressed on endothelium, epithelium (gut, kidney), and lymphocytes. It cleaves N-terminal dipeptides from substrates with proline or alanine at position 2. - Key substrates: GLP-1 (from intestinal L cells) and GIP (from K cells). Native GLP-1 half-life is about 1-2 minutes because of DPP-4 degradation. - Incretin effect: oral glucose triggers a greater insulin response than IV glucose. GLP-1 and GIP act on pancreatic beta cells to increase glucose-dependent insulin secretion. GLP-1 also suppresses alpha-cell glucagon, slows gastric emptying, and promotes satiety. - In T2DM, the incretin effect is blunted (mainly reduced GIP responsiveness and relatively lower GLP-1 levels).

**DPP-4 inhibitors (gliptins)** - Drugs: sitagliptin, saxagliptin, linagliptin, alogliptin (vildagliptin is used outside the US). - Mechanism: inhibit DPP-4, raising active GLP-1 and GIP 2-3 fold. This increases insulin secretion and decreases glucagon only when glucose is elevated, so hypoglycemia risk is low as monotherapy. - Effects: modest HbA1c reduction (about 0.5-0.8%), weight neutral, and orally dosed. - Renal dosing: sitagliptin, saxagliptin, and alogliptin need dose adjustment in renal impairment. Linagliptin is eliminated mainly via bile/enterohepatic route and needs no renal adjustment. - Adverse effects: nasopharyngitis/upper respiratory infections, pancreatitis (rare; avoid if history of pancreatitis), severe joint pain (FDA warning), bullous pemphigoid, and heart failure hospitalization signal with saxagliptin (and possibly alogliptin). Hypoglycemia risk increases when combined with sulfonylureas or insulin. - Compared with GLP-1 receptor agonists (exenatide, liraglutide, semaglutide): GLP-1 RAs are injectable (except oral semaglutide) and cause weight loss, nausea/vomiting, and have proven cardiovascular benefit (liraglutide, semaglutide). DPP-4 inhibitors do not cause weight loss and show cardiovascular neutrality.

**Boards pearls** - "Gliptins" = DPP-4 inhibitors. Think "weight neutral, low hypoglycemia, pancreatitis risk." - Contraindicated or cautioned in patients with a history of pancreatitis. GLP-1 RAs also carry pancreatitis risk, and the GLP-1 RA class has a boxed warning for medullary thyroid carcinoma/MEN2 (not a DPP-4 inhibitor warning). - Other DPP-4 roles: CD26 on T cells, and a receptor for MERS-CoV (MERS-CoV uses DPP-4 for cell entry). - Mnemonic: DPP-4 chops up incretins. Inhibiting it keeps GLP-1 and GIP alive.