DPP-4 inhibitor

**Mechanism** - After a meal, intestinal L cells release GLP-1 and K cells release GIP. Together these are the "incretins". - Incretins act on pancreatic beta cells to increase glucose-dependent insulin secretion. GLP-1 also suppresses alpha-cell glucagon release, slows gastric emptying, and promotes satiety. - DPP-4 is a serine protease that rapidly inactivates GLP-1 and GIP, giving GLP-1 a half-life of only a few minutes. - DPP-4 inhibitors prolong the activity of endogenous incretins. The effects are glucose-dependent, so hypoglycemia is uncommon unless the drug is combined with a sulfonylurea or insulin.

**Drugs (-gliptins)** - Sitagliptin, saxagliptin, linagliptin, alogliptin, and vildagliptin (not available in the US). - Sitagliptin, saxagliptin, alogliptin, and vildagliptin are renally cleared, so they need dose adjustment in renal impairment. Linagliptin is excreted mainly via the biliary/enterohepatic route and needs no renal adjustment. - Saxagliptin is metabolized by CYP3A4/5, so strong inhibitors raise its levels.

**Clinical effects** - They lower HbA1c modestly, by about 0.5–0.8%. - They are weight neutral, unlike GLP-1 agonists (weight loss) and sulfonylureas, TZDs, or insulin (weight gain). - They are oral, once daily (except for vildagliptin, which is twice daily), and generally well tolerated. - They are used as add-on therapy to metformin or as monotherapy in patients who cannot take metformin.

**Adverse effects and warnings** - Pancreatitis: avoid in patients with a history of it. This is a labeled warning, though the causal link is debated. - Heart failure: increased hospitalization with saxagliptin (SAVOR-TIMI 53) and possibly alogliptin (EXAMINE). Sitagliptin (TECOS) and linagliptin (CARMELINA) were neutral. - Severe, disabling arthralgia. - Bullous pemphigoid, which is a classic association with gliptins. - Nasopharyngitis, URI, and headache. Hypersensitivity reactions such as angioedema and Stevens-Johnson syndrome are rare. - Hypoglycemia occurs mainly when combined with sulfonylureas or insulin.

**Comparison with other incretin-based therapy** - GLP-1 receptor agonists (exenatide, liraglutide, semaglutide, dulaglutide) are injectable (except oral semaglutide). They give supraphysiologic GLP-1 receptor activation, cause greater weight loss, and have CV and renal benefit (liraglutide, semaglutide, dulaglutide). Their adverse effects are nausea and vomiting, pancreatitis, and the thyroid C-cell tumor boxed warning (MTC, MEN2). - DPP-4 inhibitors are weaker, with no significant weight loss and no proven CV benefit, and they should not be combined with GLP-1 agonists because they are redundant.

**Boards pearls** - Think "gliptin = oral incretin enhancer, weight neutral, low hypoglycemia risk." - Pancreatitis, heart failure (saxagliptin/alogliptin), and bullous pemphigoid are the classic adverse effects. - Compared with SGLT2 inhibitors (genital mycotic infections, euglycemic DKA, benefits in HF and CKD), gliptins have no major CV or renal benefit.