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DPP-4 Inhibitors or Incretin Enhancers

A new diabetes medication, Januvia, is the first in a class of new drugs called DPP-4 inhibitors. It has been approved by the FDA for use in the U.S. by people with Type 2 diabetes.

Januvia, also called sitagliptin phosphate, works by blocking dipeptidyl peptidase IV (DPP-4), an enzyme that breaks down gut peptides, especially GLP-1. Blocking DPP-4 makes GLP-1 levels rise and increases insulin release after meals and when glucose levels are high. Slowing of DPP-4 allows levels of GLP-1, GLP-2, GIP, and other gut peptides to rise. GLP-1 referred to as an incretin-enhancer.

As a once-a-day tablet, this medication, coupled with diet and exercise, allows the body to produce the proper amount of insulin to handle high blood sugars without causing hypoglycemia. It has not been studied with other medicines known to cause low blood sugar, such as sulfonylureas or insulin. Before taking Januvia, be sure your doctor realizes it may not be appropriate if you are taking a sulfonylurea or other medicine that can cause low blood sugar.

During clinical trials, Januvia was examined in a few thousand patients with type 2 diabetes during studies lasting from 12 weeks to more than a year. These studies demonstrated improved blood sugar control when Januvia was used alone in patients not properly managed with metformin or a PPAR agonist.

DPP-4 inhibitors have a major advantage over other diabetes medications in that glucose control remains stable with little or no rise in A1c levels for long periods of use. With other drugs, a gradual and persistent rise in glucose levels over time is seen. This loss of drug effect has not been seen as yet with DPP-4 inhibitors or GLP-1 agonists which both work by raising GLP-1 levels in the blood. GLP-1 increases insulin levels by increasing beta cell mass and by decreasing apoptosis or destruction of cells, especially beta cells.

Safety Concerns

In clinical studies, the most common side effects of Januvia have been upper respiratory tract infection, sore throat and diarrhea. These side effects, so far, have appeared to be mild. Weight gain and low blood sugar are often seen with some diabetes medications but do not appear to be an issue with Januvia.

However, DPP-4 is a key enzyme that is involved in the breakdown of a variety of gut peptides that possess a variety of activities. Many breakdown products of these gut peptides also have their own biological activity, so shifts in biological activity occur not only because of the delay in breakdown and higher levels of some compounds, but also because this creates a delay in the appearance of biologically active breakdown products.

It is hoped that raising the levels of several biologically active gut peptides only produces positive results, though results of dosing so far have been encouraging. The overall consequences of interfering with gut peptide activity is not believed to be a major problem, but not all of the gut peptides that DPP-4 interacts with are known and some of the known ones, like GLP-2, have biological activities that are poorly understood.

Not all GLP-1 activities are positive. It can raise arterial blood pressure and heart rate through an increase in epinephrine levels, although the overall effect on peripheral blood pressure has been positive. Although the decrease in apoptosis or cell death would generally be considered positive, this effect might not be helpful if some cancer cells also lived longer.

Januvia is not for patients with Type 1 diabetes or for patients with diabetic ketoacidosis (increased ketones in the blood or urine). If you have kidney problems, your doctor may prescribe lower doses of Januvia.

Januvia can be taken alone or together with certain other diabetes medicines to help control blood sugar.Take Januvia exactly as your doctor has prescribed. For most people, the recommended dose is:

• one 100-mg pill once a day (anytime)
• by mouth, with or without food

Learn more about Januvia at www.januvia.com.

Two additional DPP-4 inhibitors are in the last phase of clinical trials for the FDA. These are vildaglipton by Novartis and MK431 by Merck.

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