PPAR Agonists: Definition and Overview

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What Is a PPAR Agonist

What is a PPAR agonist?

PPAR agonists are a family of drugs that activate certain proteins in the body called peroxisome proliferator-activated receptors (PPARs). The PPAR agonists can help to improve blood glucose levels and levels of blood lipids (fats and cholesterol) and may also reduce risks of atherosclerosis because PPARs regulate the expression of genes that affect blood lipid metabolism, the generation of adipocytes (fat cells), and blood glucose control.

Over the years, researchers have come to recognize that a number of risk factors for cardiovascular disease tend to occur together, including insulin resistance, elevated blood glucose levels, Type 2 diabetes, blood lipid abnormalities, and inflammation. Consequently, they are on the lookout for drugs that might address all of these risk factors at once.

Scientists have identified three different forms of PPARs, dubbing them PPAR-alpha, PPAR-gamma, and PPAR-delta (also called PPAR-beta). PPAR-alpha, the first form of PPAR to be identified, is produced primarily in the skeletal muscle and the liver, where it is involved in the body’s breakdown and transport of fatty acids. PPAR-alpha may also play a role in reducing inflammation. PPAR-gamma is made primarily in fat cells and affects the production of fat cells and the metabolism of lipids and reduces insulin resistance. PPAR-delta is produced in virtually all of the cells throughout the body and may have roles in energy metabolism and reducing inflammation. All three forms of PPAR are also made in the endothelial cells lining the blood vessels and in inflammatory cells, suggesting that they may play a role in the development of atherosclerosis. When activated, the PPARs stimulate metabolic pathways that may reduce the risk of atherosclerosis, but some research (mainly in mice) indicates that they may also activate pathways that can promote atherosclerosis.

The currently available PPAR agonists aimed at diabetes are known as thiazolidinediones or “glitazones.” These include pioglitazone (brand name Actos) and rosiglitazone (Avandia). These drugs are known to increase the sensitivity of the body’s tissues to the action of insulin. Researchers now recognize that the thiazolidinediones exert this effect by binding to and activating PPAR-gamma. Furthermore, these drugs may inhibit certain proteins in the blood vessel walls called chemokines, which attract inflammatory cells and thus promote atherosclerosis. Researchers have also come to realize that certain drugs called fibrates may work to lower levels of triglycerides (a blood fat) and raise levels of high-density lipoprotein (HDL, or “good”) cholesterol in part by activating PPAR-alpha.

Recognizing the predominantly beneficial effects of activating the PPARs, scientists have set about to design drugs that activate both PPAR-alpha and PPAR-gamma, which would not only help sensitize the body to insulin but would also have a beneficial effect on lipids. This novel class of Type 2 diabetes medicines, called dual PPAR activators (or PPAR-alpha/gamma agonists or “glitazars”), include the investigational drugs muraglitazar and tesaglitazar.

In preliminary clinical trials presented at the 2005 Annual Meeting of the American Diabetes Association, both drugs significantly improved blood glucose control and lipid profiles in people with Type 2 diabetes. However, in May 2006, the maker of muraglitazar abandoned its development because of concerns about heart safety, and the maker of tesaglitazar halted its development because it didn’t appear to be any more effective than existing diabetes drugs. Other dual PPAR agonists are in various stages of development at other drug companies.

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