In Controlling Lipid and Glucose Levels. The novel compound tesaglitazar (Galida) appears to be effective in reducing fasting glucose while decreasing triglyceride levels and increasing high-density lipoprotein (HDL) cholesterol levels. One of the new class of compounds called peroxisome proliferator-activated receptor (PPAR) alpha/gamma agonists being developed to address, simultaneously, the insulin resistance and lipid disorders that coexist in patients with type 2 diabetes, tesaglitazar appears to achieve the intended "double effect" at doses as low as 1 mg.
"I have to admit that I was skeptical about these PPARs way back when, because as far as I know there is no precedent for developing a drug in this way with multiple targets on one chemical. But this study and other PPAR studies are giving us some insight into this approach," said the study’s lead author Barry Goldstein, MD, PhD, director of the Division of Endocrinology, Diabetes and Metabolic Diseases at Jefferson Medical College in Philadelphia, Pennsylvania. "The question, for the future, is can you develop a drug that has a good efficacy profile and is at least as safe as the drugs we have now but may be better at managing lipid problems?"
The tesaglitazar Glucose and Lipid Assessment in Diabetes (GLAD) trial was a placebo-controlled dosing study involving 500 patients with type 2 diabetes, with an open-label group of 75 patients who received pioglitazone. Patients receiving tesaglitazar, which was given in doses ranging from 0.1 to 3.0 mg, experienced reductions in fasting plasma glucose levels of up to 61 mg/dL at high doses and a reduction of 41 mg/dL at the better tolerated dose of 1.0 mg. Similarly, there was a dose-dependent decrease in fasting triglyceride level of 33% at the 1.0-mg dose and up to 41% at the 3.0-mg dose. High-density lipoprotein (HDL) cholesterol levels increased up to 15% with the 1.0-mg dose and appeared "to plateau at that point," Dr. Goldstein noted. Patients who took the 45 mg of pioglitazone experienced a mean fasting glucose level reduction of 38 mg/dL and a 6% increase in HDL level.
As with other PPARs under development and being investigated, tesaglitazar was associated with the adverse effects of edema and slight weight gain. About three to five cases of edema occurred in each dosing group but was also seen in the placebo group. Weight gain was approximately 2 kg in the 0.5- and 1.0-mg groups. "I think the fluid retention and weight gain are manageable adverse effects, and in this particular study we did not see any episodes of CHF (congestive heart failure) at 12 weeks, even at the higher doses," Dr. Goldstein said. "I think what we are learning is that the PPAR-gamma drugs appear to help heart metabolism." Dr. Goldstein noted that this new class of drugs are not appropriate for patients with diagnosed preexisting cardiovascular disease.
Dr. Goldstein acknowledged that the combination-pill approach is one that is being used in other areas of medicine, and it may also be a good approach for patients with diabetes, who often take other medications for comorbidities. But Dr. Goldstein cautions that the PPARs, if their safety and efficacy are confirmed in additional trials, are not likely to become a single-pill solution for type 2 diabetes. "It does not solve every problem because patients are still most likely going to have to take a statin to get to low-density lipoprotein cholesterol goals," Dr. Goldstein said. "Still, there is a large group of patients with type 2 diabetes who are generally overweight and have dyslipidemia — it is certainly a majority — so they might become candidates for this type of more aggressive management of their lipid problems, which generally are not well addressed."
While the current trials of PPARs appear promising, clinicians must remember that the numbers are still small, a few thousand patients to date, and that safety has not been confirmed, said session moderator David Kendall, MD, medical director of the International Diabetes Center and associate professor of medicine at the University of Minnesota Medical School in Minneapolis. "These [the PPAR drugs] appear to be effective, but at this point it is important to remember that there is really limited experience with these compounds. But the tesaglitazar [study] is intriguing, especially because of the comparator group with pioglitazone."
The study was sponsored by AstraZeneca, the maker of tesaglitazar.
ADA 65th Annual Scientific Sessions: Abstract 83-OR. Presented June 11, 2005.
Gottlieb, S. (2005). Heart rate is a good predictor of sudden cardiac death, study shows. BMJ 330: 1105