STOCKHOLM — Tesaglitazar markedly reduces the prevalence of both metabolic syndrome and impaired fasting glucose in hypertriglyceridemic, insulin-resistant nondiabetic patients, Steen Stender, M.D., reported at the annual congress of the European Society of Cardiology.
Tesaglitazar (Galida) is a novel oral dual α and γ peroxisome proliferator-activated receptor (PPAR) agonist. Both animal and clinical studies indicate the investigational drug simultaneously improves both lipid profiles and glucose metabolism, said Dr. Stender of Gentofte University Hospital, Hellerup, Denmark.
He presented a post hoc analysis of data from the Study in Insulin Resistance (SIR), a seven-country randomized, double-blind, phase II, dose-finding study in which 397 nondiabetic patients with hypertriglyceridemia, increased waist-to-hip ratio, and insulin resistance were randomized to 12 weeks of placebo or tesaglitazar at 0.1, 0.25, 0.5, or 1.0 mg/day.
The trial's primary end point was a change in fasting triglyceride levels, which dropped in dose-dependent fashion by a maximum of 37% with the 1.0-mg dose of tesaglitazar.
The 1.0-mg regimen also boosted HDL cholesterol levels by 16%, reduced non-HDL cholesterol levels by 15%, lowered fasting insulin concentrations by 35%, and more than doubled the prevalence of the favorable LDL cholesterol pattern-A particle diameter.
Dr. Stender reported on tesaglitazar's effect on two key secondary end points—metabolic syndrome and impaired fasting glucose—that are recognized as major risk factors for the development of cardiovascular disease and diabetes, respectively.
In the trial, tesaglitazar reduced the prevalence of metabolic syndrome (as diagnosed under National Cholesterol Education Program criteria) and impaired fasting glucose in dose-dependent fashion. (See box below.)
“Simultaneous improvements in several risk factors have the potential to delay development of type 2 diabetes and reduce cardiovascular risk. This of course has to be shown in prospective studies, but the rationale for doing these [ongoing] phase III studies is present,” Dr. Stender said.
The drug was well tolerated. The most common side effect was dose-dependent weight gain, which averaged 0.8 kg in 12 weeks at 1.0 mg/day. Small reductions in hemoglobin and leukocyte count and a nonsignificant rise in creatinine were also seen. “Whether these small changes in laboratory parameters have clinical significance, we don't yet know,” Dr. Stender said.
Luc Van Gaal, M.D., voiced concern regarding the weight gain, which stems from tesaglitazar's PPAR-γ effect. If this weight gain comes mainly as abdominal fat, it will increase the waist-to-hip ratio, a known cardiovascular risk factor, noted Dr. Van Gaal, professor of diabetology, metabolism, and clinical nutrition at the University Hospital Antwerp, Belgium.
Dr. Stender replied that no change in waist-to-hip ratio was seen in SIR; however, that wouldn't be expected in a relatively short 12-week study. “That might take a couple of years.”
When asked how he envisions tesaglitazar's use in clinical practice if it eventually receives marketing approval, Dr. Stender said the drug's multiple effects make it very attractive at a time when patients are on so many medications for chronic conditions that compliance becomes a major consideration.
“Usually you have several drugs to treat one risk factor, as in hypertension. Here you have one drug treating several risk factors. So I expect it might be lifelong therapy, if it turns out tesaglitazar has an effect on the hard end points,” Dr. Stender said.
SIR was sponsored by AstraZeneca Pharmaceuticals LP.
