DPP-4 Inhibitors

The incretins GLP-1 (from intestinal L cells) and GIP (from K cells of the stomach and proximal small intestine) are released within minutes of a meal and act on the β cell to increase insulin secretion; GLP-1 also lowers glucagon secretion from α cells, reducing hepatic glucose output. DPP-4 inactivates them almost at once — GLP-1 has a half-life of under 2 minutes and GIP of about 5–7 minutes. In type 2 diabetes GLP-1 concentrations are reduced, but the insulin response to it is preserved.

DPP-4 inhibitors slow that inactivation, so the concentrations of the active hormones rise (2- to 3-fold after a meal with sitagliptin) and their action is prolonged. Insulin release increases and glucagon falls in a glucose-dependent manner — the incretins act when glucose is normal or high — so fasting and postprandial glucose fall, yet in healthy people sitagliptin did not lower glucose or cause hypoglycemia. That explains the class profile: a low risk of hypoglycemia unless combined with a sulfonylurea or insulin, and no weight effect. Sitagliptin, linagliptin and alogliptin are selective for DPP-4 over DPP-8 and DPP-9. (The physiology of the incretin receptors, and the drugs that stimulate them directly, are on the GLP-1 Agonists page.)

The class acts the same way, but clearance differs — and clearance decides renal dosing and drug interactions. Sitagliptin is about 87% bioavailable and mostly (about 79%) excreted unchanged in the urine by active tubular secretion, so exposure roughly doubles in moderate and quadruples in severe renal impairment; the dose is adjusted for kidney function. Alogliptin is nearly completely absorbed and 60–71% excreted unchanged in the urine, so it too is dose-adjusted for renal function. Saxagliptin is metabolized by CYP3A4/5 to an active metabolite (5-hydroxy saxagliptin, half as potent), and both are cleared partly by the kidney — so strong CYP3A4/5 inhibitors raise its levels and renal impairment lowers its dose.

Linagliptin is the outlier: it binds DPP-4 reversibly but saturably (a terminal half-life of more than 100 hours from saturable binding, with an accumulation half-life of about 11 hours), and about 80% leaves through the enterohepatic system, with only about 5% in the urine. It therefore needs no renal dose adjustment, but strong P-gp or CYP3A4 inducers such as rifampin cut its exposure to likely ineffective levels.

The labels share postmarketing warnings: acute pancreatitis, including fatal hemorrhagic or necrotizing cases (the drug is stopped if it is suspected); severe and disabling arthralgia, starting from a day to years into therapy, relieved by stopping and sometimes recurring with the same or another DPP-4 inhibitor; bullous pemphigoid requiring hospitalization (report blisters or erosions); and serious hypersensitivity — anaphylaxis, angioedema and exfoliative skin conditions, including Stevens-Johnson syndrome — with caution in a patient who had angioedema with another DPP-4 inhibitor. Alogliptin also has postmarketing reports of fatal and nonfatal hepatic failure.

In cardiovascular outcome trials, more patients were hospitalized for heart failure on saxagliptin (SAVOR) and alogliptin (EXAMINE) than on placebo, and patients with prior heart failure or renal impairment were at higher risk; the sitagliptin and linagliptin labels carry the warning as "observed with two other members" of the class. Otherwise the gliptins did not raise the risk of cardiovascular death, myocardial infarction or stroke versus placebo.