|
||||||
|
|
|
|
|||||||||||
|
|||||||||||||
| ||||||||||||||||||||||||||||||||||||
A growing body of evidence suggests that the insulin-sensitizing thiazolidinedione (TZD) drugs have benefits beyond glucose control and improved insulin resistance, according to studies presented at the 65th Scientific Sessions of the American Diabetes Association (ADA), held June 10–14 in San Diego.
Research indicates that pioglitazone (Actos, Takeda/Eli Lilly) and rosiglitazone (Avandia, GlaxoSmithKline)—both peroxisome proliferator–activated receptor (PPAR)-gamma agonists—also can improve the cardiovascular risk profile of people with type 2 diabetes.
Meanwhile, the next generation of dual-action PPARs, muraglitazar (Pargluva, Bristol-Myers Squibb/Merck) and tesaglitazar (Galida, AstraZeneca), are on deck in late-stage clinical trials and may be even more effective in reducing cardiovascular risk. Glitazone drugs target PPAR-gamma, which is associated with insulin sensitivity and glycemic control. The glitazars target PPAR-gamma and PPAR-alpha, which is associated with regulation of lipids.
Comorbidities of type 2 diabetes and cardiovascular disease, including hyperglycemia, dyslipidemia, insulin resistance, and hypertension, "provide a rationale for new therapies that provide both glycemic control and lipid control," says muraglitazar researcher David Kendall, MD, medical director of the International Diabetes Center and associate professor of medicine at the University of Minnesota Medical School in Minneapolis.
"The current glitazones, particularly pioglitazone, have had a nice effect on the lipid profile," says Anne Peters, MD, director of diabetes programs at the University of Southern California. "The glitazars may have an additional lipid benefit, but the big question is, what's the effect on outcomes?"
WINNING PRESCRIBERS
Since their introduction in 1997, the TZD drugs have earned a place as frontline oral agents in the treatment of type 2 diabetes. Targeting PPAR-gamma, the TZD drugs have been shown to reduce insulin resistance. The first drug to reach the market, troglitazone (Rezulin, Parke-Davis/Warner-Lambert), was withdrawn in 2000 due to reports of liver toxicity.
Drugmakers continue to vie for the hearts and minds of prescribing physicians by sponsoring research highlighting advantages of the two TZDs still on the market.
At the ADA Scientific Sessions, Takeda and Eli Lilly presented data indicating that pioglitazone appears to have an anti-inflammatory effect and to help lower cholesterol even more in people with type 2 diabetes who take statins. One study looked at adults age 40–80 years who had good glycemic control with insulin and were given pioglitazone as an add-on. During an 8- to 10-week follow-up period, those who took the drug had significantly reduced levels of C-reactive protein and interleukin-6, both markers of inflammation.
In the COMPLEMENT study, a 17-week multicenter open-label study of 305 people with type 2 diabetes taking statins, a substantially greater effect was seen in participants who took pioglitazone. Patients who took the TZD in addition to a statin had 21% lower triglycerides and 10.5% lower cholesterol. Side effects reported with pioglitazone include weight gain and fluid retention.
Therapeutic benefits were observed in clinical trials of rosiglitazone as well. One study of 668 people by Philip D. Home, DM, of the University of Newcastle, U.K., found that those who took rosiglitazone in combination with metformin or a sulfonylurea had clinically and statistically greater reductions in blood pressure than those who did not. A separate study of 389 patients who had rosiglitazone added to metformin therapy showed reduced microalbuminuria, a marker of cardiovascular disease.
NEXT GENERATION
New drugs in the pipeline may give rosiglitazone and pioglitazone a run for their money. Muraglitazar and tesaglitazar, both non-TZD drugs that inhibit the PPAR-gamma and -alpha receptors, appear in clinical trials to have greater effect in reducing cardiovascular risk factors.
At the ADA meeting, data from the initial 24 weeks of a double-blind phase III clinical trial of 985 patients showed that muraglitazar therapy was linked to significantly lower triglycerides, non-HDL cholesterol, and apolipoprotein B, as well as higher HDL cholesterol. The patients, all of whom were in their mid-50s, were generally obese, and had diabetes 5–6 years, were randomized to receive pioglitazone (15 mg/day) or one of five once-daily doses of muraglitazar (0.5–20 mg).
Eighty-eight of 157 participants in the 5-mg muraglitazar arm continued on 5 mg for the entire 2-year durability trial, and all achieved tight blood glucose control.
In another trial, investigators enrolled 1,159 subjects with type 2 diabetes who had inadequate glycemic control on metformin monotherapy. While continuing on metformin, patients were randomized to receive either 5 mg muraglitazar or 30 mg pioglitazone.
Muraglitazar significantly outperformed pioglitazone in reducing levels of glycated hemoglobin (A1C) and fasting plasma glucose while also improving lipid measures, according to Kendall, who presented the findings. Patients on muraglitazar went from an average A1C of 8% to 6.5% by week 20.
"Muraglitazar can lower A1C 0.25%–1.76% and improves the dyslipidemia of diabetes," Kendall says. "Both effects are sustainable for 2 years."
Bristol-Myers Squibb and Merck filed a new drug application for muraglitazar with the Food and Drug Administration in December 2004. The drug is still under review by the agency, and as of mid-2005 had not been scheduled for an advisory committee meeting. The most common side effects were edema in 5–8% of the durability study participants and weight gain of 2–10 lb.
Tesaglitazar showed promise in two phase II clinical trials reported at the ADA Scientific Sessions. The Glucose and Lipid Assessment in Diabetes (GLADD) trial was a 12-week, randomized, double-blind, dose-ranging study of 500 patients with type 2 diabetes that supported moving the 0.5-mg and 1-mg doses of tesaglitazar into phase III development.
GLADD also showed that tesaglitazar appeared effective in reducing fasting glucose while decreasing triglyceride levels and increasing HDL cholesterol.
The Study in Insulin Resistance (SIR) trial was a 12-week, randomized,
phase II study of 390 nondiabetic subjects with insulin resistance. The
double-blind, placebo-controlled study examined the effect of tesaglitazar at
0.1–1 mg, compared with placebo. Analysis revealed a dose-dependent
reduction in triglycerides, with a reduction of 37% in fasting triglycerides
and 41% in postprandial triglycerides at the 1-mg dose. Researchers also noted
significant improvements in HDL cholesterol and fatty acids. "There is
potentially enhanced cardiovascular protection from [glitazars], but they're a
new class of drug, so we need to prove it," Peters says. "We need
to know what the side-effect profile is, too." 
CiteULike 
Del.icio.us 
Digg 
Reddit 
Technorati What's this?
| ||||||||||||||||||||||||||||||||||||
|
||||||
|
| DOC News | Diabetes | Diabetes Care | Clinical Diabetes | Diabetes Spectrum |
