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New Study Finds Additional LDL-C Drops When WelChol (Colesevelam HCl) is Added to Fenofibrate in Patients with Mixed Hyperlipidemia

WelChol/fenofibrate combination produced non-significant changes in triglyceride lowering and HDL-C raising effects of fenofibrate monotherapy

PARSIPPANY, NJ -- October 5, 2005 -- A new study published in the September 2005 issue of Current Medical Research and Opinion demonstrated that the addition of WelChol(R) (colesevelam HCl) to a stable dose of fenofibrate (e.g. TriCor(R)(1)) in patients with mixed hyperlipidemia lowered LDL-C, or "bad" cholesterol, levels by an additional mean 12.4% (P <.0001).

The first study to evaluate WelChol's efficacy in treating patients with mixed hyperlipidemia, it demonstrated that WelChol, a non-systemic lipid-lowering agent that works to reduce LDL-C, did not statistically significantly affect the triglyceride-lowering or HDL-C-raising attributes of fenofibrate. The addition of WelChol to fenofibrate resulted in mean reductions in non-HDL-C of 9.6% (P <.0001), total cholesterol of 7.4% (P <.0001), and apolipoprotein B of 8.0% (p = 0.0002). The combination of WelChol and fenofibrate was also safe and well-tolerated over the six-week treatment period.

"Mixed hyperlipidemia is a significant cause of heart disease, and a challenge for physicians to treat, especially in those patients who cannot tolerate statin therapy," said study investigator James McKenney, PharmD. "Combining a bile acid sequestrant to provide additional LDL-cholesterol-lowering with a fenofibrate to lower triglyceride levels may provide an alternate therapy which can positively affect lipid levels. However, further studies may be necessary to show the long-term value of this combination."

A study released last year demonstrated that there was no significant effect of WelChol on the bioavailability of fenofibrate(2). The findings from the previous study were consistent across two different dosing options of each of the therapies -- when WelChol was given at the same time as TriCor, or when the fibrate was given four hours prior to WelChol.

Therapeutic targets in mixed hyperlipidemia include reducing LDL-C and triglyceride levels and increasing HDL-C levels. Statins are typically first-line therapy for treating mixed hyperlipidemia, but combination therapy is often required. Combining a statin with a fibrate has demonstrated efficacy, however, increased risk of myopathy and rhabdomyolysis can be associated with this combination. WelChol and fenofibrate combination may be a promising treatment for patients with mixed hyperlipidemia.

About the study
In a 14-week, multicenter, randomized, double-blind, placebo-controlled parallel group trial, patients with mixed hyperlipidemia were evaluated to determine the efficacy and safety of WelChol when added to a stable dose of fenofibrate.

The study involved 129 patients between the ages of 30 and 70 with a mean age of 55, and 56% of the patients were male. Following a 4-8 week washout period, participants received fenofibrate 160 mg/day for eight weeks. Patients were randomized to either WelChol 3.75 g/day (n=64) or placebo (n=65), in combination with fenofibrate 160 mg/day.

Study entry criteria included LDL-C greater than or equal to 115 mg/dL and triglyceride levels between 150-750 mg/dL after the washout period with mean LDL-C baseline levels of 158.2 mg/dL and median triglyceride levels of 223.5 mg/dL. Patients excluded from the study included those patients with a body mass index of greater than 40 kg/m2, HbA1C greater than 10%, type 1 diabetes, history of intolerance to fibrates or WelChol, or history of dysphagia, swallowing disorders or intestinal motility disorder.

The primary efficacy endpoint of the study was mean% change in LDL-C during the six weeks of treatment while taking either WelChol or placebo in addition to fenofibrate. Secondary endpoints included absolute and percentage changes in mean levels of LDL-C, triglycerides, HDL-C, non-HDL-C, total cholesterol and apolipoproteins A-I and B during randomized treatment and from washout to end of randomized treatment.

The combination of fenofibrate and WelChol had mean total LDL-C reductions of 17.0% and non-HDL-C reductions of 21.0% compared with reductions of 6.0% and 14.4%, respectively, with fenofibrate monotherapy. While fenofibrate monotherapy did cause reductions in several cholesterol indicators, the addition of WelChol produced further reductions beyond those triggered by the fibrate alone. WelChol reduced mean LDL-C by an additional 12.4% (P <.0001), non-HDL-C by an additional 9.6% (P <.0001), total cholesterol by an additional 7.4% (P <.0001) and apo B levels by an additional 8.0% (P =.0002) over fenofibrate monotherapy, with no statistically significant effects on the triglyceride lowering or HDL-C raising effects of fenofibrate. The combination was well-tolerated over the six-week combination treatment period.

About WelChol
WelChol, a non-absorbed specifically engineered BAS (SE-BAS) indicated for LDL-C lowering approved by the U.S. Food and Drug Administration (FDA) for marketing in May 2000, is the top-selling branded drug in the bile acid sequestrant (BAS) class. Because WelChol is engineered for affinity, specificity and high capacity bile acid binding, it may have a lower drug-drug interaction potential than conventional bile acid sequestrants.

WelChol is different from most other cholesterol-lowering drugs on the market because it is non-systemic, meaning that the body does not absorb it and it is eliminated without traveling to the liver or kidneys. Systemic medications, which include the statin and fibrate classes, are those that are absorbed from the intestine into the bloodstream and travel throughout the body.

WelChol is a prescription drug indicated alone or in combination with a statin, as an adjunct to diet and exercise for the reduction of elevated LDL cholesterol in patients with primary hypercholesterolemia (Fredrickson Type IIa) when the response to diet and exercise has been inadequate. Liver-function monitoring is not required with WelChol when used as monotherapy, and in combination with a statin, no additional liver-function monitoring is required beyond that for the prescribed statin alone.

In clinical trials, with patients with primary hypercholesterolemia, when WelChol was given alone in addition to a low-fat diet and exercise, it was shown to reduce LDL cholesterol by an average of 15 to 18%.

When WelChol is given in combination with a statin, the combination can lower cholesterol levels more effectively than using either therapy alone. In pivotal studies where WelChol was taken with a statin, WelChol 3.8 g provided up to an additional mean 16% (32 mg/dL) reduction in LDL cholesterol. WelChol is the only non-systemic cholesterol-lowering agent approved by the FDA for combination with a statin. WelChol can be used in combination with any dose of any statin. It has been studied with four commonly prescribed statins -- Lipitor(R) (atorvastatin calcium), Zocor(R) (simvastatin), Pravachol(R) (pravastatin sodium) and Mevacor(R) (lovastatin).

WelChol is not for everyone, especially those with bowel blockage. Caution should be exercised when treating patients who have trouble swallowing or severe stomach or intestinal problems. Side effects may include constipation, indigestion and gas.

Like most prescription drugs, WelChol has not been studied in combination with all medications or supplements. Patients should always tell their doctor about all medications and supplements they are taking before starting any new therapy, including WelChol. WelChol has not been shown to prevent heart disease or heart attacks.

Any trademarks not owned by Sankyo Pharma Inc. are the property of their respective owners.

(1) The study was conducted with a previously marketed formulation of fenofibrate (TriCor 160 mg/day) according to the standard package insert instructions provided at that time.

(2) The first study examining WelChol with TriCor was published in the September 2004 issue of Clinical Pharmacokinetics.


SOURCE: Sankyo Pharma Inc.

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