23 Role of Dual PPAR γ and α Agonists in Diabetes Mellitus—Have They Met a Road Block or They Are Dead?

Abstract: There are three peroxisome proliferator-activated receptors (PPARs) subtypes which are commonly designated PPAR alpha, PPAR gamma and PPAR beta/delta. PPAR alpha activation increases high density lipoprotein (HDL) cholesterol synthesis, stimulates “reverse” cholesterol transport and reduces triglycerides. PPAR gamma activation results in insulin sensitization and antidiabetic action. Combined treatments with PPAR gamma and alpha agonists may potentially improve insulin resistance and alleviate atherogenic dyslipidemia, whereas PPAR delta properties may prevent the development of overweight which typically accompanies “pure ” PPAR gamma ligands. The new generation of dual-action PPARs—the glitazars, which target PPAR-gamma and PPAR-alpha (like muraglitazar and tesaglitazar) were on deck in late-stage clinical trials for sometime and were considered effective in reducing cardiovascular risk, but their long-term clinical effects were unknown. Thus glitazars offered a hope of a new approach to diabetes care addressing not just glycemia, but dyslipidemia and other components of the metabolic syndrome, though the side effect profile remains unknown. No human data is available, and so it remains highly speculative. The glitazars and on the newly published results for muraglitazar and tesaglitazar. “The PPAR-alpha is a good target and is being developed to yield more potent drugs that work through PPAR-alpha, and at the same time, improve on the PPAR-gamma. Efforts is on to get the glucose lowering with few of the adverse effects. This thinking has met with problems as many clinical trials have been terminated due to dominant side effects. Beyond these and other novel agents being developed to meet the challenge of the worldwide epidemic of diabetes, the central place of insulin in diabetes care cannot be forgotten. In view of this the continued efforts of improvement in insulin delivery, kinetics and action have spurred such innovations as the various inhaled insulins and new insulin analogues. There is cause for guarded optimism and excitement about the years ahead as we expect a plethora of new avenues of management