Newer drugs like Pargluva aim to create a benefit by hitting more than one PPAR.
But PPAR gamma drugs come with an annoying side effect: They make patients fatter.
Moreover, weak drugs targeting a PPAR receptor associated with heart disease have been around for decades.
These PPAR alpha drugs include Lopid, which is available in generic form but developed by Pfizer.
Avandia works by hitting a drug target called the peroxisome proliferator-activated receptor (PPAR) gamma.
Among those PPAR drugs in development, Merck's MK-767 was believed to be farthest along.
Amgen and Pfizer also have some PPAR entrants, but haven't said much publicly about making them a priority.
Eli Lilly and GlaxoSmithKline are testing new drugs that bind to PPAR alpha perhaps 1, 000 times more strongly.
AstraZeneca is developing a PPAR drug called Galida, but concerns about kidney side effects may be worry some investors.
Some existing diabetes drugs work by affecting one PPAR (there are several switches).
The first PPAR drug, Rezulin from Pfizer, was pulled from the market in 2000 because of liver side effects.
Both Lopid and Tricor are thought to work by targeting a molecular signal called the peroxisome proliferators activator receptor (PPAR) alpha.
Still, two researchers closely associated with PPAR research are questioning whether the rat cancer can be extrapolated to humans in this case.
But a drug that trips a PPAR switch fires up dozens of genes, and side effects for these medicines have proved unpredictable.
Another set of potential winners: a class of diabetes medicines that may also eliminate the risk of heart attacks, known as PPAR drugs.
Drugs that hit one, two, or all three of the PPAR switches are some of the hottest experimental medicines in the drug industry right now.
GlaxoSmithKline, which makes Avandia, the main competitor to Actos, is working on one pill that would hit all three PPARs and another that focuses on PPAR delta.
Patients with a mutant version of the PPAR gamma gene have a 25% higher risk of developing adult-onset diabetes, in which cells stop responding to insulin's orders.
Steven Nissen , a cardiologist at the Cleveland Clinic who is working with some PPAR drugs, points out that hitting the PPAR receptors turns on dozens of genes.
The first PPAR drug, Rezulin from Pfizer (nyse: PFE - news - people ), was pulled from the market in 2000 because of liver side effects.
The first of these PPAR receptors was discovered 17 years ago, and for a long time many researchers, including Steve Nissen, thought drugs designed to hit them might prevent heart attacks.
Some of the experimental PPAR medicines are extremely promising.
GlaxoSmithKline (nyse: GSK - news - people ), which makes Avandia, the main competitor to Actos, is working on one pill that would hit all three PPARs and another that focuses on PPAR delta.
As described in the journal The Public Library of Science, Evans and his colleagues created the "marathon mice" by modifying the PPAR delta gene and these furry runners provide powerful clues as to how the PPAR delta gene actually works.
Eli Lilly (nyse: LLY - news - people ) and GlaxoSmithKline (nyse: GSK - news - people ) have a whole slate of PPAR drugs in development, all of which seem to work at least a little differently.
Existing diabetes drugs, such as Actos from Eli Lilly (nyse: LLY - news - people ) and Avandia from GlaxoSmithkline (nyse: GSX - news - people ), resensitize the body to insulin by turning on the PPAR gamma receptor.
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