76 Cardiovascular Medicine I NTERNAL M EDICINE N EWS • October 1, 2005 With Statin, Fenofibrate Safer Than Gemfibrozil

Risk for rhabdomyolysis increased significantly cases of rhabdomyolysis. Inclusion of pa- have a relationship with the companies that tients who were treated with cerivastatin market the two other brand formulations when gemfibrozil was combined with most statins. did not affect the safety disparity between of fenofibrate (Antava and Lofibra). fenofibrate and gemfibrozil. Based on the results of several studies, ARTICLES BY er than for fenofibrate plus a statin, said The study found that the FDA received the combination of a statin and a fibrate (ei- MITCHEL L. ZOLER Dr. Jones, codirector of the lipid metabo- two reports of rhabdomyolysis in patients ther gemfibrozil or fenofibrate) appears to Philadelphia Bureau lism and atherosclerosis clinic at Baylor treated with fenofibrate plus a statin oth- be very effective for normalizing serum College of Medicine, Houston. er than cerivastatin out of more than 3.4 lipid levels in patients who have diabetes, N EW Y ORK — The combination of Treatment with gemfibrozil appears to million prescriptions for the drug combi- metabolic syndrome, or atherogenic dys- fenofibrate and a statin appears to be safer boost the maximum concentration and the nation written dur- lipidemia, which than gemfibrozil and a statin, according to area under the curve for any concurrently ing the 4-year study features a high level an analysis of adverse event reports to the administered statin, an effect that is not period. In compari- Fenofibrate is of serum triglyc- Food and Drug Administration. seen with fenofibrate, Dr. Jones said. son, 57 reports of metabolized by erides and a low lev- In January 1998 through March 2002, Statins and gemfibrozil are metabolized rhabdomyolysis different liver el of HDL choles- the FDA received 0.6 reports of rhab- by the same liver enzymes, which means were submitted to enzymes and has terol. However, domyolysis for the combination of fenofi- that gemfibrozil competes with statins for the FDA regarding little impact on there are not yet brate plus any statin except cerivastatin per these enzymes and thus acts as a compet- patients treated statin metabolism. any study results to every million prescriptions written for this itive inhibitor of statin metabolism. Fenofi- with gemfibrozil prove that treat- drug combination, Peter H. Jones, M.D., brate is metabolized by a different set of plus any statin but DR. JONES ment with a statin- said at an international symposium on liver enzymes and hence has little impact cerivastatin out of fibrate combination triglycerides and HDL. on statin metabolism, said Dr. Jones at the more than 6.6 million prescriptions writ- leads to fewer clinical events than treatment During the same period, the FDA re- symposium, sponsored by the Giovanni ten for this combination. with a statin alone. A study designed to ad- ceived 8.6 reports of rhabdomyolysis for Lorenzini Medical Foundation. Dr. Jones receives research support from dress this question is currently in progress. the combination of gemfibrozil plus any The adverse report analysis by Dr. Jones Pfizer Inc., which markets gemfibrozil The usual starting and maintenance statin except cerivastatin per every million and his collaborator excluded cerivastatin (Lopid), and from Abbott Laboratories, dosage of fenofibrate when used in com- prescriptions written for this combina- because treatment with that statin was as- which markets fenofibrate (Tricor). He is bination with a statin is 160 mg/day, Dr. tion, a rate that is more than 14 times high- sociated with an unusually high number of also a consultant to Abbott. He does not Jones said. ■ New Treatments in Pipeline The Need for HDL Treatment Raise HDL in Short, Long Term Target Remains Debatable Topic N EW Y ORK — It’s time to set a Another option is to set a mini- N EW Y ORK — Drug treatments that raise of atherosclerosis was possible and that acute target for high-density lipoprotein mum goal of more than 40 mg/dL serum HDL cholesterol are already available, apo A1 infusions could be given to patients cholesterol in the U.S. lipid guide- or more than 45 mg/dL for every- but several potentially better, more targeted with ACS, Dr. Brewer said. Clinical testing is lines, Ernst J. Schaefer, M.D., said at one. The existing lipid goals of the treatments are moving through the develop- ongoing. an international symposium on National Cholesterol Education Pro- ment pipeline, H. Bryan Brewer Jr., M.D., said Ǡ HDL delipidation. In this process, a patient triglycerides and HDL. gram, the Adult Treatment Panel III, at an international symposium on triglycerides undergoes plasmapheresis to remove choles- “We should try to target patients do not set a treatment strategy for and HDL. terol from existing HDL particles using an or- to raise their HDL cholesterol, es- patients based on their serum HDL The new treatments are in a range of de- ganic solvent. The delipidated HDL is then re- pecially if they have established cholesterol level. velopment stages, from preclinical animal stud- turned to the patient. This 4-hour treatment heart disease. We have as much data Dr. Schaefer reviewed the evi- ies to phase III clinical trials, said Dr. Brewer, can increase cholesterol efflux about 20-fold, today for HDL as we had in 1988 dence that documents the prognos- director of lipoprotein and atherosclerosis re- said Dr. Brewer. It is scheduled to start clinical when we were asked to set guide- tic importance of a low level of search at the Washington Hospital Center. testing in late 2005. Dr. Brewer is also chief sci- lines for LDL,” said Dr. Schaefer, HDL cholesterol and the risk re- Short-term treatments to raise HDL are entific director for Lipid Sciences Inc., the professor of medicine at Tufts Uni- duction that occurs when the level geared to treating patients with acute coronary company that is developing this treatment. versity in Boston. of HDL cholesterol is raised. For ex- Ǡ syndrome (ACS) who need rapid plaque stabi- Synthetic apo A1 mimetic peptide. Re- But another lipid expert who ample, in the Framingham study lization. This approach includes infusion of ex- searchers have produced an 18-amino-acid pep- spoke at the symposium disagreed. the strongest predictor of a per- ogenous apolipoprotein A1, the main protein tide that mimics the structure of a portion of “The time is not yet right for firm son’s cardiovascular risk was total component of HDL cholesterol, delipidation the amphipathic, helical peptide that forms apo HDL guidelines,” said Antonio M. cholesterol divided by HDL choles- of HDL, or infusion of an apo A1 mimetic pep- A1. In vitro and animal studies indicate that the Gotto Jr., M.D., dean of the Weill terol. tide. 18-amino-acid peptide can remove cholesterol Medical College of Cornell Univer- Existing guidelines in both Cana- Long-term treatments designed to lower from cells without cytotoxicity. Animal studies sity in New York. “Results from clin- da and Europe say that patients cardiovascular risk are also in the works. The are continuing with this intravenous agent. ical trials must confirm the benefit with existing coronary disease strategies include oral treatment with an apo Ǡ CETP inhibitors. The most advanced of of treating patients with agents that should be treated until this ratio A1 mimetic peptide or treatment with an agent these agents is torcetrapib. In a pilot, uncon- primarily target HDL cholesterol,” drops below 4.0. that inhibits the cholesterol ester transfer pro- trolled study with 19 patients, 120 mg torce- he said. Treatment data have document- tein (CETP), which is involved in regulating the trapib daily for 4 weeks boosted serum HDL “It’s important to treat beyond ed the efficacy of several drugs to size of cholesterol particles. Reduced CETP ac- by about 50% (N. Engl. J. Med. 2004;350:1505- LDL cholesterol,” said Dr. Schaefer, raise serum levels of HDL choles- tivity is antiatherogenic. 15). Torcetrapib’s clinical efficacy is being test- who is also director of the lipid and terol and reduce the risk of car- Speaking at the symposium, sponsored by ed in a study that will follow atherosclerosis re- heart disease prevention clinic and diovascular disease events. These the Giovanni Lorenzini Medical Foundation, gression using intravascular ultrasound. But, in laboratory at Tufts-New England have included studies using Dr. Brewer summarized the progress to date a controversial move, Pfizer, which is devel- Medical Center. “A substantial frac- cholestyramine, gemfibrozil, sim- on these treatments: oping torcetrapib, is now studying it clinically tion of patients don’t get treated to vastatin, and niacin, Dr. Schaefer Ǡ Apo A1 infusion. The first of the new wave only in combination with atorvastatin. An- increase their HDL. But for every said at the symposium, which was of HDL cholesterol treatments used a recom- other CETP inhibitor, JTT-705, is being devel- 1% increase in HDL, there is about sponsored by the Giovanni Loren- binant, variant apo A1 protein, apo A1 Milano. oped by Roche and is also in clinical studies. a 1%-3% reduction in coronary zini Medical Foundation. Ǡ Five weekly infusions of apo A1 Milano given Oral synthetic apo A1 mimetic peptide. heart disease risk.” “There is a consistent pattern to 36 patients with ACS led to an average drop The D-4F peptide is similar in concept to the Dr. Schaefer said that he was un- that’s much stronger statistically [for in atheroma volume of about 1%, a signifi- other synthetic apo A1 mimetic peptide under sure of the best target level for HDL raising HDL cholesterol] than for cantly better reversal of atherosclerosis than study, except it is made exclusively from D- cholesterol. One option is to rec- [lowering] LDL cholesterol. In- was seen in a control group of 11 patients amino acids, is not digested, and is orally ac- ommend raising levels to at least 40 creasing HDL cholesterol by even a (JAMA 2003;290:2292-300). The results of this tive. The D-4F peptide is in early-phase human mg/dL for men and 50 mg/dL for small amount may benefit patients,” “landmark” study showed that rapid regression testing. ■ women. Dr. Schaefer said. ■