25.15: Dipeptidyl Peptidase 4 Inhibitors

Dipeptidyl peptidase 4 (DPP-4) is a serine protease widely distributed in the body. It's involved in the inactivation of GLP-1 and GIP hormones, which are crucial for insulin regulation. DPP-4 inhibitors, such as sitagliptin (Januvia), saxagliptin (Onglyza), linagliptin (Tradjenta), alogliptin (Nesina), and vildagliptin (Galvus), help increase the proportion of active GLP-1, enhancing insulin secretion. These inhibitors work by competitively binding to DPP-4. This binding causes a significant increase in active GIP and GLP-1 hormones, leading to improved insulin secretion and lower glucagon levels. The result is improved fasting and postprandial hyperglycemia without affecting insulin sensitivity, gastric motility, or satiety.

Used alone, DPP-4 inhibitors reduce A1c levels by 0.8% on average. They're also effective when added to other diabetes treatments, reducing A1c by about 0.5%.

The recommended doses for DPP-4 inhibitors vary: alogliptin (25mg), linagliptin (5mg), saxagliptin (5mg), sitagliptin (100mg), and vildagliptin (50mg once or twice daily). DPP-4 inhibitors are effectively absorbed from the small intestine. Most circulate primarily in unbound form and are excreted unchanged in the urine; lower doses should be given to patients with reduced renal function. Linagliptin binds extensively to plasma proteins and is cleared primarily by the hepatobiliary system. Saxagliptin, metabolized by hepatic microsomal enzymes, requires dosage adjustment when coadministered with strong CYP3A4 inhibitors.

No consistent adverse effects are noted with DPP-4 inhibitors.However, large cardiovascular safety studies indicate no significant impact on the incidence of cardiovascular events for most DPP-4 inhibitors. An exception is saxagliptin, which has been associated with an increased risk of hospitalizations for heart failure. This suggests that saxagliptin requires careful patient selection and monitoring, particularly in individuals with a history of heart failure or those at high cardiovascular risk. The FDA warns of rare, severe joint pain with this class of drugs. DPP-4 is expressed in lymphocytes, so its effects on immune function need scrutiny as more patients are treated with these compounds.

Dipeptidyl peptidase 4, or DPP-4 inhibitors, called gliptins inhibit incretin hormone inactivation.

These drugs bind to DPP-4,  increasing the levels of active GIP and GLP-1 hormones.

This improves insulin secretion and reduces glucagon levels, remedying fasting and postprandial hyperglycemia without directly affecting insulin sensitivity, gastric motility, or satiety.

Some examples of this class include sitagliptin, saxagliptin, linagliptin, and vildagliptin.

When used alone, DPP-4 inhibitors decrease A1c levels by an average of 0.8%. However, when combined with other hypoglycemics, they cause a total decrease in A1c levels by 1.3%

Linagliptin undergoes extensive plasma protein binding and hepatobiliary clearance. Saxagliptin is metabolized by hepatic microsomal enzymes and requires dosage adjustment when coadministered with strong CYP3A4 inhibitors.

Although these agents are well tolerated, they rarely show adverse effects, such as heart failure risks, severe joint pain, and pancreatitis.