With the recent development of such drugs as insulin analogues, insulin glargine (Lantus), insulin detemir (Levemir), exenatide (Byetta), and pramlintide acetate (Symlin), this is truly a new era for treating diabetes. The development of another new class of drugs, the peroxisome proliferator-activated receptor (PPAR) alpha/ gamma agonists, confirms that this new era is not about to end anytime soon. This class, if approved, will target not only glycemic control, but also one of the comorbidities that often plagues persons with type 2 diabetesdyslipidemia. With more than 20 million patients with diabetes in the United States alone, new treatment modalities are a welcome addition to the current strategies for managing this disease.
Two PPAR agonists that are currently available, rosiglitazone and pioglitazone (glitazones), are PPAR gamma agonists that primarily affect glucose levels. PPAR gamma is known to be important in the regulation of glucose. The glitazones lead to insulin sensitization through the binding to and activation of PPAR gamma. Whereas the main effect of the glitazones is glucose lowering, some recent small studies demonstrate that pioglitazone also may have a favorable effect in reducing small, dense low-density lipoprotein (LDL) particles and raising high-density lipoprotein (HDL) levels. A second PPAR isotype, PPAR alpha, has been recognized as one that regulates different target genes, most of which are involved in lipid metabolism. PPAR alpha is expressed primarily in the liver and skeletal muscle.
The new class of medications, PPAR dual agonists, activates both PPAR alpha and PPAR gamma and may lead to a combination effect on insulin sensitization plus lipid lowering by increasing fatty acid oxidation. Muraglitazar is the first dual PPAR agonist to be considered for approval by the FDA. Early results from a 2-year phase 3 study look very promising.1-3
The initial trial included 985 patients randomized to 1 of 4 different doses of muraglitazar (0.5-20 mg) or to pioglitazone 15 mg daily. An extension study included 88 type 2 diabetes patients who continued on muraglitazar 5 mg daily. These patients achieved an average hemoglobin A1C level of 6.5% within 4 months after beginning the drug and maintained that level of control throughout the 2 years. Lipid results in that group included an average triglyceride reduction of 28.4% and an average HDL increase of 19.2%. No significant effects on LDL concentrations were seen.
The most common forms of dyslipidemia present in patients with type 2 diabetes are elevated triglycerides and decreased HDL. Although these levels are just markers, it is well understood from multiple studies that dyslipidemia must be managed in patients with diabetes in order to reduce the risk of cardiovascular disease.
On other secondary end points, muraglitazar was associated with significant reductions from baseline in fasting plasma glucose, fasting plasma insulin, apolipoprotein B, free fatty acid, and non- HDL cholesterol levels. Muraglitazar treatment also was associated with increased insulin sensitivity, as measured by a decrease in homeostasis model assessment of insulin resistance.
Adverse effects with muraglitazar are similar to those with PPAR gamma agonists. They include weight gain (2-4 kg), peripheral edema (10% incidence), and chronic heart failure exacerbation. A major concern is that an increased incidence of adverse cardiovascular events (myocardial infarction, stroke, transient ischemic attack) has been observed, and more safety studies need to be conducted to analyze the potential cardiovascular risks of this drug. No cases of hypoglycemia have been observed. Hepatotoxicity, a concern with the PPAR gamma agonists, thus far has not been observed.
Many patients with diabetes will require lipid-lowering therapy along with their medications for blood glucose control. The current drug therapies available for the treatment of dyslipidemia include 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins), fibrates, niacin, bile acid resins, and cholesterol absorption inhibitors. Although, if approved, the PPAR dual agonists are not likely to replace current therapies available, they certainly will provide a new treatment option for the multiple facets of diabetes management.
Dr. Brian is a clinical specialist with Cornerstone Health Care, High Point, NC.
For a list of references, send a stamped, self-addressed envelope to: References Department, Attn. A. Stahl, Pharmacy Times, 241 Forsgate Drive, Jamesburg, NJ 08831; or send an e-mail request to: email@example.com.
In Seniors: Consider CMV Serostatus
When Recommending Flu Vaccine
Older people who have cytomegalovirus seem to have less robust responses to the trivalent influenza vaccine than those who do not have CMV.
News from the year's biggest meetings
Clinical features with downloadable PDFs