QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Résumé Extracto Full Text PDF Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Articles Ahead of Print [Order Reprint] Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Chang, F. Articles by O'Connell, M. B. Search for Related Content PubMed PubMed Citation Articles by Chang, F. Articles by O'Connell, M. B.

GENERAL MEDICINE

Evolution of Peroxisome Proliferator-Activated Receptor Agonists

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

Linda A Jaber, PharmD

Associate Professor, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University

Helen D Berlie, PharmD

Diabetes Fellow, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University

Mary Beth O'Connell, PharmD BCPS

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 A_1C (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:

				F. M. Gregoire, F. Zhang, H. J. Clarke, T. A. Gustafson, D. D. Sears, S. Favelyukis, J. Lenhard, D. Rentzeperis, L. E. Clemens, Y. Mu, et al. MBX-102/JNJ39659100, a Novel Peroxisome Proliferator-Activated Receptor-Ligand with Weak Transactivation Activity Retains Antidiabetic Properties in the Absence of Weight Gain and Edema Mol. Endocrinol., July 1, 2009; 23(7): 975 - 988. [Abstract] [Full Text] [PDF]

				T. L. Levien and D. E. Baker New Drugs in Development for the Treatment of Diabetes Diabetes Spectr, April 1, 2009; 22(2): 92 - 106. [Abstract] [Full Text] [PDF]

				N. R Pinelli, R. Cha, M. B Brown, and L. A Jaber Addition of Thiazolidinedione or Exenatide to Oral Agents in Type 2 Diabetes: A Meta-Analysis Ann. Pharmacother., November 1, 2008; 42(11): 1541 - 1551. [Abstract] [Full Text] [PDF]

				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]