James V. Felicetta, MD Editor-in-Chief Raising High-Density Lipoprotein Levels: Out with the New, In with the Old?

ecent years have witnessed a HDL levels might not be all they were And the lipid benefits of don’t tremendous interest in phar- cracked up to be. But a closer examina- stop there. It turns out that niacin is Rmacologic strategies to increase tion of the situation reveals a few rays also fairly potent at lowering both LDL high-density lipoprotein (HDL) choles- of hope. For instance, data on several and triglyceride levels, either alone or terol levels. The hope has been that the other candidate CETP inhibitors under in combination with other well known antiatherosclerotic benefits development by rival drug companies (such as ). Additionally, it’s the associated with lowering low-density seem, thus far, to show comparable only agent other than estrogens that lipoprotein (LDL) levels elevations in HDL levels without any has been shown to lower lipoprotein(a) could be enhanced significantly by associated effects on blood pressure. levels. High lipoprotein(a) levels may medications designed to elevate levels These data, though preliminary, suggest be an independent risk factor for of HDL. that the blood pressure problem might coronary artery disease in certain This past fall, however, advocates be specific to torcetrapib.5 patients. of this strategy suffered a major set- Furthermore, in our quest for the Given these substantial benefits, back when (New York, NY) latest pharmaceutical blockbuster, we why aren’t we using niacin much more pulled its promising candidate drug, may have neglected a tried and true widely? The answer, of course, is that torcetrapib, from further develop- remedy that, since the 1950s, has been the drug has acquired a reputation for ment. This action was prompted by known to produce quite reliable and being difficult, a situation that isn’t results from the Investigation of Lipid robust HDL elevations. I am speak- helped by the reluctance of major drug Level Management to Understand ing, of course, of niacin, or nicotinic companies to speak on its behalf. But its Impact in Atherosclerotic Events acid. Niacin has long suffered from its is niacin really that problematic? I (ILLUMINATE) trial, which showed “lowly” status as a generic , would submit that the answer is no— an increased number of deaths in the with very limited appeal to the pharma- if both the patient and the provider group of patients randomly assigned ceutical industry as a source of revenue show a modest amount of patience to receive a combination of torcetrapib and profit. But despite the lack of pro- and persistence. and compared with those motion, it’s a highly effective medication The main concern with niacin is assigned to atorvastatin alone.1,2 with a good safety profile when pre- the adverse effect of flushing, which Data on torcetrapib from several scribed by a knowledgeable provider. occurs almost universally—though studies also has shown a consistent, Let’s review what niacin can do for the number of flushing episodes may though modest, increase in blood pres- lipids. First and foremost, its ability be fewer with a newer, proprietary, sure with this drug.3 Even slight blood to cause robust elevations in HDL extended-release formulation, Niaspan pressure elevations can translate— levels—up to 40%—renders it in a (Kos Pharmaceuticals, Cranbury, across large patient populations—into class by itself in terms of efficacy. By NJ).6 Flushing usually abates after significant associated increases in car- contrast, statins typically raise HDL lev- several days in all but the most fairly diovascular morbidity and mortality.4 els in the range of 5% to 10%. complexioned individuals. Although Could it be that torcetrapib’s potential (including and gemfibro- flushing does no serious or lasting effects on HDL levels, which occur zil) may do a little better, sometimes damage to the body, it’s amazing how through inhibition of the enzyme in the range of 10% to 15%. It’s true dismayed patients and providers can cholesteryl ester transfer protein that thiazolidinediones (also known as become over this phenomenon. It may (CETP), were “swamped out” by this glitazones) may raise HDL levels by as help to provide patients with some compound’s unfortunate proclivity to much as 20%, but their use is strictly tips for managing flushing (such as increase blood pressure? The connec- confined to patients with diabetes. avoiding ingestion of alcohol or hot tion does not seem implausible. Diabetic patients certainly are at high drinks around the time they take the Given this disappointment, a pes- risk for atherosclerotic events, but they drug)—and to suggest to them that simist hardly could be blamed for represent a relatively modest fraction of this nuisance can be a reminder that concluding that strategies for raising all patients with low HDL levels. the medication is hard at work increas-

MARCH 2007 • FEDERAL PRACTITIONER • 15 EDITORIAL

ing their good cholesterol and lowering this outcome if one sticks to the crystal- adverse effects—before administering their bad cholesterol. line or extended-release formulations. pharmacologic therapy to patients. Another persistent hindrance to the It is disappointing to have lost widespread use of niacin is the idea the promise of torcetrapib from the References 1. In interests of patient safety, Pfizer stops all torcetra- that it shouldn’t be used in diabetic therapeutic armamentarium. But the pib clinical trials; company has notified FDA and is patients due to a detrimental effect silver lining in this dark cloud is in in the process of notifying all clinical investigators and other regulatory authorities [press release]. New on blood glucose control. Two large the opportunity to rediscover an old York, NY: Pfizer Inc; December 2, 2006. studies, the Arterial Disease Multiple friend—niacin. Niacin has been highly 2. Pfizer stops all torcetrapib clinical trials in interest of patient safety [FDA statement]. Rockville, MD: U.S. Intervention Trial (ADMIT) on crys- effective at improving lipids for half a Food and Drug Administration; December 3, 2006. talline niacin and the Assessment of century and undoubtedly will remain 3. O’Riordan M. Larger-than-anticipated increases in systolic blood pressure with torcetrapib. New York, Diabetes Control and Evaluation of the an important lipid lowering medication NY: Medscape; November 3, 2006. Available at: Efficacy of Niaspan Trial (ADVENT), 50 years from now. ● www.medscape.com/viewarticle/518571. Accessed February 13, 2007. showed that the effects on blood glu- 4. Lewington S, Clarke R, Qizilbash N, Peto R, Collins cose levels are generally very small and Author disclosures R, and the Prospective Studies Collaboration. Age- specific relevance of usual blood pressure to vascu- easily managed with a minor tweaking Dr. Felicetta reports no actual or potential lar mortality: A meta-analysis of individual data for of the antiglycemic regimen.7,8 Indeed, conflicts of interest with regard to this one million adults in 61 prospective studies. Lancet. 2002;360:1903–1913. diabetic patients are high risk individu- editorial. 5. Cortez MF, Zimm A. Pfizer’s cholesterol setback als who typically have subpar levels of may help Roche, Merck. New York, NY: Bloomberg; November 13, 2006. Available at: www.bloomberg. HDL and, therefore, are strong candi- Disclaimer com/apps/news?pid=newsarchive&sid=aIXFovccQ dates for niacin therapy. The opinions expressed herein are those of HBM. Accessed February 16, 2007. 6. Niaspan [prescribing information]. Cranbury, NJ: The other adverse effects of niacin the author and do not necessarily reflect Kos Pharmaceuticals Inc; 2005. are relatively infrequent. Mild gastroin- those of Federal Practitioner, Quadrant 7. Elam MB, Hunninghake, DB, Davis KB, et al, for the ADMIT Investigators. Effect of niacin on lipid and testinal distress is seen occasionally, and HealthCom Inc., the U.S. government, lipoprotein levels and glycemic control in patients an acute episode of gout can sometimes or any of its agencies. This article may with diabetes and peripheral arterial disease. JAMA. 2000;284:1263–1270. be precipitated by niacin therapy. The discuss unlabeled or investigational use 8. Grundy SM, Vega GL, McGovern ME, et al, for disastrous complication of fulminant of certain drugs. Please review complete the Diabetes Multicenter Research Group. Efficacy, safety, and tolerability of once-daily niacin for the hepatic necrosis essentially is seen only prescribing information for specific drugs treatment of dyslipidemia associated with type 2 with the long-acting, timed-release or drug combinations—including indica- diabetes. Arch Intern Med. 2002;162:1568–1576. preparations. There is little need to fear tions, contraindications, warnings, and

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