 |
 |
 |
 |
 |
 |
 |
|
|
|
|||||||||
|
|||||||||||
at the time of writing, Geriatric Pharmacotherapy Resident, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit, MI; now, Elder Care Practitioner,North York General Hospital, North York, Ontario, Canada
Associate Professor, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University
Diabetes Fellow, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University
Associate Professor, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University
Reprints: Dr. O'Connell, Wayne State University, Eugene Applebaum College of Pharmacy and Health Sciences, Department of Pharmacy Practice, 259 Mack Ave., Suite 2190, Detroit, MI 48201, fax 313/577-5369, mboconnell{at}wayne.edu
OBJECTIVE: To discuss the evolution of peroxisome proliferator-activated receptor (PPAR) agonists from single site to multiple subtype or partial agonists for the treatment of type 2 diabetes, dyslipidemia, obesity, and the metabolic syndrome.
DATA SOURCES: Information was obtained from MEDLINE
(1966–March 2007) using search terms peroxisome proliferator-activated
receptor agonist, PPAR dual agonist, PPAR 
/
agonist, PPAR pan
agonist, partial PPAR, and the specific compound names. Other sources included
pharmaceutical companies, the Internet, and the American Diabetes Association
64th–66th Scientific Sessions abstract books.
STUDY SELECTION AND DATA EXTRACTION: Animal data, abstracts, clinical trials, and review articles were reviewed and summarized.
DATA SYNTHESIS: PPAR , , and 
receptors play an
important role in lipid metabolism, regulation of adipocyte proliferation and
differentiation, and insulin sensitivity. The PPAR dual agonists were
developed to combine the triglyceride lowering and high-density lipoprotein
cholesterol elevation from the PPAR- agonists (fibrates) with the
insulin sensitivity improvement from the PPAR- agonists
(thiazolidinediones). Although the dual agonists reduced hemoglobin
A1C (A1C) and improved the lipid profile, adverse effects
led to discontinued development. Currently, PPAR- agonists (GW501516 in
Phase I trials), partial PPAR- agonists (metaglidasen in Phase II and
III trials), and pan agonists (, , ; netoglitazone in
Phase II and III trials) with improved cell and tissue selectivity are
undergoing investigation to address multiple aspects of the metabolic syndrome
with a single medication. By decreasing both A1C and triglycerides,
metaglidasen did improve multiple aspects of the metabolic syndrome with fewer
adverse effects than compared with placebo. Metaglidasen is now being compared
with pioglitazone.
CONCLUSIONS: Influencing the various PPARs results in improved glucose, lipid, and weight management, with effects dependent on full or partial agonist activity at single or multiple receptors. Although the dual PPAR compounds have been associated with unacceptable toxicities, new PPAR agonist medications continue to be developed and investigated to discover a safe drug with benefits in multiple disease states.
Key Words: metaglidasen, muraglitazar, naveglitazar, peroxisome proliferator-activated receptor agonists, ragaglitazar, tesaglitazar
Published Online, May 22, 2007. www.theannals.com, DOI 10.1345/aph.1K013
This article has been cited by other articles:
|
|
 |
|
  B. Chopra, J. Hinley, M. B. Oleksiewicz, and J. Southgate Trans-Species Comparison of PPAR and RXR Expression by Rat and Human Urothelial Tissues Toxicol Pathol, April 1, 2008; 36(3): 485 - 495. [Abstract] [Full Text] [PDF]
|
|
 |
 |
 |
 |
 |
 |
 |
