Drug Review: Dipeptidyl-Peptidase-4 Inhibitors (sitagliptin, saxagliptin, linagliptin)

The three dipeptidyl-peptidase-4 inhibitors available in the U.S. are sitagliptin (sold as Januvia), saxagliptin (sold as Onglyza), and linagliptin (Tradjenta). Vildagliptin is available in other countries. 

Remember that drug names vary by country and manufacturer.  This is a brief drug review; consult your physician or pharmacist for details. 

How do they work?

DPP-4 inhibitors decrease both fasting and after-meal blood sugar levels primarily by increasing insulin release from pancreas beta cells.  How they do it is complicated.

First off, you need to know that two gastrointestinal hormones levels—glucagon-like peptide-1 (GLP-1) and gastric inhibitory polypeptide—increase in response to a meal.  These hormones increase insulin secretion by pancreas beta cells, suppress glucagon secretion from pancreas alpha cells after meals, help suppress glucose production by the liver, and improve glucose uptake by tissues outside the liver.  GLP-1 also slows emptying by the stomach and reduces food intake.  All this tends to lower glucose levels after meals. 

Did I mention it was complicated?

If we could make these gut hormones hang around longer, their glucose-lowering action would be enhanced.  How can we make them hang around and work longer?  Easy: suppress the enzyme that degrades them: dipeptidyl-peptidase-4.  That’s what DPP-4 inhibitors do. 

The small intestine hormone GLP-1 is a major player in normal carbohydrate metabolism.  GLP-1 levels, by the way, are decreased in type 2 diabetes. 

For the DPP-4 inhibitors, we have no data on long-term safety, mortality, or diabetic complications.

Uses

Sitagliptin is FDA-approved as initial drug therapy for the treatment of type 2 diabetes, and as a second agent in those who do not respond to a single agent, such as metformin, a sulfonylurea, or a thiazolidinedione.  It can also be used as a third agent when dual therapy with a sulfonylurea and metformin does not provide adequate blood sugar control.

Saxagliptin and linagliptin are FDA-approved as initial drug therapy for the treatment of type 2 diabetes (in adults) or as add-on drugs for those who do not respond to a single drug, such as metformin, a sulfonylurea, or a thiazolidinedione.  In case you’re wondering, you wouldn’t use several of the DPP-4 inhibitors at the same time.  Linagliptin has not been studied in patients taking insulin, nor in pregnant or nursing women; I’m not sure about sitagliptin and saxagliptin in those settings. 

Dosing

The DPP-4 inhibitors are given by mouth.   The usual dose of sitagliptin is 100 mg once daily, with reduction to 50 mg for moderate to severe kidney impairment and 25 mg for severe kidney impairment.  The usual dose of saxagliptin is 2.5 or 5 mg once daily, with the 2.5 mg dose recommended for patients with moderate to severe kidney impairment.  Linagliptin’s dose is 5 mg daily, regardless of liver or kidney funtion.

Side Effects

Generally well-tolerated.  No risk of hypoglycemia when used as the sole diabetes drug.  They do not cause weight gain.  Sitagliptin and linagliptin might cause pancreatitis.   

Don’t use if you have . . .

. . . moderate or severe kidney impairment (sitagliptin) or severe kidney impairment (saxagliptin).
Use sitagliptin with caution and careful monitoring if you have a history of pancreatitis. 

Steve Parker, M.D.

Updated May 6, 2011