Inflammation in diabetes mellitus: role of peroxisome proliferator-activated receptor-alpha and peroxisome proliferator-activated receptor-gamma agonists.
Patients with type 2 diabetes mellitus and/or the metabolic syndrome have considerable cardiovascular risk. Treatment with 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) and with antihypertensive and some antihyperglycemic agents reduces this risk, but residual macrovascular morbidity and mortality persist, even in patients assigned to intensive multifactorial intervention programs. Therapeutic strategies that target inflammation and lipid abnormalities not well addressed by statins may offer additional opportunities for improving the prognosis of these patients. Inflammation, a key mechanism of atherogenesis, appears to have particular relevance to diabetic vascular complications, as well as in the development of diabetes itself. Oxidative stress and hyperglycemia also figure among the pathogenic factors that promote cardiovascular complications in patients with the metabolic syndrome and/or diabetes and may augment the ongoing inflammation. Peroxisome proliferator-activated receptor (PPAR)-alpha and PPAR-gamma, members of the nuclear receptor family, form ligand-activated transcription factors that regulate key important metabolic pathways. PPARs have become therapeutic targets through the use of the fibrate class of antidyslipidemic drugs (PPAR-alpha) and the insulin-sensitizing thiazolidinediones (PPAR-gamma). The activation of these PPARs may also suppress inflammation and atherosclerosis. Recent clinical trials (Fenofibrate Intervention and Event Lowering in Diabetes [FIELD], Prospective Pioglitazone Clinical Trial in Macrovascular Events [PROactive]) have considered the impact of these PPAR agonists on cardiovascular disease, with mixed effects that require careful analysis, especially given ongoing trials and additional PPAR agonists in development.
Libby
Peter
P
Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA. plibby@rics.bwh.harvard.edu
Plutzky
Jorge
J
D003324:Coronary Artery Disease / Q000378:metabolism* / Q000517:prevention & control*; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism*; D050171:Dyslipidemias / Q000188:drug therapy / Q000378:metabolism; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use; D006943:Hyperglycemia / Q000378:metabolism; D000960:Hypolipidemic Agents / Q000627:therapeutic use; D047493:PPAR alpha / Q000378:metabolism; D047495:PPAR gamma / Q000819:agonists; D012307:Risk Factors
D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D000960:Hypolipidemic Agents; D047493:PPAR alpha; D047495:PPAR gamma