2002 medical director colloquycolloquy

TransformingDyslipidemia

Management

This program is supported by an unrestricted educational grant from

Colloquy2002 Medical DirectorColloquy2002 Medical Director

M A N A G E DSPECIAL SUPPLEMENT TO

CareCare Vol. 11, No. 9September 2002

Continuing education credit for physicians and pharmacistssponsored by the University ofArizona Colleges of Medicineand Pharmacy at the Arizona

Health Sciences Center, Tucson

Based on presentations at the 2002Medical Director Colloquy, Tucson,Ariz., May 16–18.

The program at the 2002 Medical Director Colloquy, in Tucson onMay 16–18, was developed to address, comprehensively, the under-diagnosis and undertreatment of the patient with dyslipidemia.

This publication, with adaptations of five of the presentations from thatmeeting, offers a fresh look at dyslipidemia management by illuminatingthe dynamic issues that shape the balance of outcomes and costs of ther-apy. Other presentations from the program will be presented in an October 2002 special supplement to MANAGED CARE.

Decision makers in managed care who focus on lipid managementhave many critical issues before them. Efficacy, cost, and treatmentchoices are primary determinants of a therapeutic model’s usefulness.Moreover, successful management of lipids brings a particular economicchallenge, because it involves a long-term approach to improving care,with results that may not be immediately apparent. The patient alsoneeds heightened education on cholesterol-related diseases and rapid ad-vances in treatment options. Finally, as the health system changes, theNational Committee for Quality Assurance (NCQA) seeks to shift ac-countability for clinical care from health plans to the actual providersof care. The NCQA’s cardiovascular panel will meet later this year to dis-cuss modifying existing measures or even developing new measures inthe Health Plan Employer Data and Information Set (HEDIS) to reflectthe changes in lipid management suggested by the third Adult TreatmentPanel of the National Cholesterol Education Program. All of these issuesare explored in these pages.

On July 23, 2002, Nicholas D. Kristof wrote in the New York Times,“Biotechnology is transforming the world around us far more quicklythan we can build a regulatory structure to accommodate it.” The latestclinical approaches to managing dyslipidemia are described by Neil J.Stone, MD, on page 4. He delineates the physiology of the atheroscleroticpatient and the mechanism of action of lipid-lowering drugs. Then, onpage 10, W. Virgil Brown, MD, looks at the clinical implications of newlyevolving therapies for dyslipidemia. On page 15, Juan Enriquez presentsa fascinating look at the far-reaching effects that genomics will have onour lives in the future. He describes how this new language will shapethe delivery of health care. On page 19, Philip M. Renner, MBA, explainsthe evolving performance measures that NCQA uses to evaluate choles-terol management and the clinical considerations involved in the reviewof NCQA’s HEDIS cholesterol measures. Next, on page 23, Paul E. Terry,PhD, identifies process-improvement priorities for management of lipidsin medical practice by examining behavior changes in providers, as wellas organizational improvements that enhance management of dys-lipidemia.

I encourage you to take advantage of the continuing education oppor-tunity that the University of Arizona offers to pharmacists and physiciansthrough this publication. I know that you will find the material withinthese pages to be extremely useful in your daily responsibilities.

EditorJOHN A. MARCILLE

Managing EditorMICHAEL D. DALZELL

Senior EditorFRANK DIAMOND

Senior Science EditorPAULA SIROIS

Senior Contributing EditorPATRICK MULLEN

Contributing EditorsBOB CARLSON

JOHN CARROLL

DAVID COLEMAN, JDJEFFREY J. DENNING

MIKE FOLIO, JDMICHAEL LEVIN-EPSTEIN

JACK MCCAIN

KAREN TRESPACZ, JD

Design DirectorPHILIP DENLINGER

Editorial Advisory Board ChairmanALAN L. HILLMAN, MD, MBASenior FellowCenter for Health PolicyLeonard Davis Institute

of Health EconomicsUniversity of Pennsylvania, Philadelphia

Group PublisherTIMOTHY J. STEZZI

PublisherTIMOTHY P. SEARCH, RPH

Eastern Sales ManagerSCOTT MACDONALD

Senior Account ManagerBLAKE REBISZ

Midwest Sales ManagerTERRY HICKS

Director of Production ServicesWANETA PEART

MANAGED CARE (ISSN 1062-3388) is published monthly by MediMedia USA Inc. at 780 Township Line Road, Yardley,PA 19067. This is Volume 11, Issue 9. Periodicals postagepaid at Morrisville, Pa., and at additional mailing offices.POSTMASTER: Send address changes to MANAGED CARE,MediMedia USA, 780 Township Line Road, Yardley, PA 19067.Prices: $10 per copy, $93 per year in the USA; $120 per yearelsewhere. Send letters to the editor c/o Frank Diamond,MANAGED CARE, 780 Township Line Road, Yardley, PA19067. Letters may be edited for length and clarity. E-mail:[email protected]. Phone: (267) 685-2788; fax (267) 685-2966; circulation inquiries (267) 685-2782. Copyright ©2002 MediMedia USA Inc.

CareM A N A G E D

CareI N T R O D U C T I O N

MICHAEL I . RUXIN, MDChairman and CEO

PeopleMed.com, Inc. andGlobal Med Technologies, Inc.

PHOTOGRAPHS BY DENNY COLLINS

CareM A N A G E D

CareTransforming Dyslipidemia Management

A CONTINUING EDUCATION ACTIVITY

Based on presentations at the 2002 Medical Director Colloquy

Continuing education objectives and accreditation statements............................2

Current Drug Treatments for Lipid Management .......................................4NEIL J. STONE, MD, Professor of Clinical Medicine (Cardiology)Feinberg School of Medicine, Northwestern University

Promising Therapies for Cholesterol Reduction .......................................10W. VIRGIL BROWN, MD, Chief of Medicine and Primary CareAtlanta Veterans Affairs Medical CenterCharles Howard Candler Professor of Internal Medicine and Director, Division of Arteriosclerosis and Lipid MetabolismEmory University School of Medicine

The Life Science Revolution................................................................................15JUAN ENRIQUEZ, DirectorLife Sciences Project, Harvard Business School

NCQA’s Evolving Clinical Performance Measures ........................................19PHILIP M. RENNER, MBA, Director, Measures DevelopmentNational Committee for Quality Assurance

Innovation in Disease Management .................................................................23PAUL E. TERRY, PHD, PresidentPark Nicollet Institute

CONTINUING EDUCATIONCME answer sheet/certificate request ....................................................................27CE answer sheet/request for statement of credit ...................................................28

Test questions ...........................................................................................................29

S P E C I A L S U P P L E M E N T

About this publication

This MANAGED CARE supplement is derived from presentations at the Medical Director Colloquy, “Transform-ing Dyslipidemia Management,” in Tucson, Ariz., May 16–18, 2002, and is supported by an unrestricted educa-tional grant from AstraZeneca.

Continuing education is offered to physicians and phar-macists who read this publication, answer the self-teston page 29, and fill out the appropriate evaluation formon either page 27 or 28.The genomics article on pages15–18 is presented due to its high interest value, but it isnot part of the CE/CME program.

MEDICAL ACCREDITATIONThis activity has been planned and implemented inaccordance with the Essential Areas and Policies of theAccreditation Council for Continuing Medical Education(ACCME) through the joint sponsorship of the Universityof Arizona College of Medicine at the Arizona Health Sci-ences Center and of MediMedia USA.The University ofArizona College of Medicine at the Arizona Health Sci-ences Center is accredited by ACCME to provide contin-uing medical education for physicians.

The University of Arizona College of Medicine at the Arizona Health Sciences Center designates this educa-tional activity for 2 hours in category 1 credit towardAMA Physician’s Recognition Award. Each physicianshould claim only those hours of credit that he/she actually spent in the educational activity.

Approval for category 1 credit by the University of Arizona College of Medicine should not be construed as endorsement of any product.

Release date: Sept. 25, 2002For a period of one (1) year.

PHARMACY ACCREDITATIONThe University of Arizona College of Pharmacyis approved by the American Council on Phar-

maceutical Education as a provider of continuing phar-maceutical education.This program is approved for 2contact hours (0.2 CEU). Credit will be awarded uponcompletion of registration form, successful completionof assessment questions (70 percent or better), andcompletion of program evaluation. If a score of 70 per-cent or better is not achieved, no credit will be awardedand the registrant will be notified.

ACPE program number: 003-999-02-031-H01

Release date: Sept. 25, 2002Expiration date: Sept. 25, 2003

Course descriptionThis activity is designed to educate physicians and phar-macists about effective medical treatment options forpatients with dyslipidemia, as well as to provide anoverview of the changes that biotechnological advanceswill bring to this area.The data and narratives in thispublication are derived from information presented at“Transforming Dyslipidemia Management,”a colloquyfor managed care professionals that took place May16–18, 2002 in Tucson, Ariz.

Educational needs assessmentMedical directors, pharmacists, pharmacy directors,practicing primary care physicians, and cardiologistsseek knowledge of the most effective treatmentapproaches for dyslipidemia. In a rapidly changinghealth care marketplace, these medical professionalswant to be kept informed of the most current medicaltreatments so as to use this knowledge to meet patients’needs.The information presented in this publication hasbeen compiled on the basis of faculty perceptions ofsignificant trends and issues related to medical thera-pies for treatment of dyslipidemia and optimal manage-ment of this disease.

Target audiencesMedical directors, chief medical officers, pharmacy direc-tors, and other senior managers in managed health careorganizations; primary care physicians; pharmacists; car-diologists.

Educational objectivesAfter reading this publication, the participant should beable to:

• Describe the therapeutic challenges for dyslipidemia.• Outline the current treatment options for dyslipidemia.• Explain the utility of behavior-change interventions.• Evaluate the clinical considerations involved in the

review of the HEDIS cholesterol measures.

Planning committee membersLynne Mascarella,director of continuing education,College of Pharmacy,University of Arizona,Tucson; KayO’Neill,CME coordinator,College of Medicine,University ofArizona,Tucson;Timothy Search,RPh,publisher,MANAGED CARE,a division of MediMedia USA Inc.,Yardley,Pa.

®

2 MANAGED CARE / SUPPLEMENT

SELF-STUDY CONTINUING EDUCATION ACTIVITYTransforming Dyslipidemia Management

Publisher’s statementThe opinions expressed herein are those of the sympo-sium faculty and do not necessarily reflect the views ofthe University of Arizona Colleges of Medicine andPharmacy, AstraZeneca, MediMedia USA Inc., or thepublisher, editor, or editorial board of MANAGED CARE.

Clinical judgment must guide each clinician in weigh-ing the benefits of treatment against the risk of toxicity.Dosages, indications, and methods of use for productsreferred to in this special supplement may reflect theclinical experience of the authors or may reflect theprofessional literature or other clinical sources, and maynot necessarily be the same as indicated on theapproved package insert. Please consult the completeprescribing information on any products mentioned inthis special supplement before administering.

PRIMARY FACULTY

W.Virgil Brown, MDChief of Medicine and Primary CareAtlanta Veterans Affairs Medical CenterCharles Howard Candler Professor of Internal MedicineDirector, Div. of Arteriosclerosis and Lipid MetabolismEmory University School of MedicineAtlanta

Juan EnriquezDirector, Life Sciences ProjectHarvard Business School Boston

Philip M. Renner, MBADirector of Measures DevelopmentNational Committee for Quality AssuranceWashington

Michael I. Ruxin, MD (moderator)Chairman and CEOPeopleMed.com, Inc.

and Global Med Technologies, Inc.Lakewood, Colo.

Neil J. Stone, MDProfessor of Clinical Medicine (Cardiology)Feinberg School of MedicineNorthwestern UniversityChicago

Paul E.Terry, PhDPresidentPark Nicollet InstituteMinneapolis

CONTENT REVIEWERS

Gordon A. Ewy, MDProfessor and Chief, CardiologyDirector, Sarver Heart CenterUniversity of Arizona

College of MedicineTucson

Amy Grizzle, PharmDAssistant DirectorCenter for Health Outcomes

and PharmacoEconomic ResearchUniversity of Arizona

College of PharmacyTucson

Conflict of interest policy in continuing medical educationIn compliance with this policy, the faculty for this activ-ity have disclosed financial interests, arrangements,and/or affiliations with corporate organizations offeringfinancial support or educational grants for continuingmedical education activities, as well as those organiza-tions with a direct interest in the subject matter of thisactivity.

Disclosures of significant relationshipsW.Virgil Brown, MD, acknowledges grant and researchsupport from, is a member of a speakers bureau for,and/or has consulting relationships with the followingcompanies: Abbott, AstraZeneca, Bayer, Beecham,Bristol-Myers Squibb, Kos, Merck, Merck/ScheringPlough, Novartis, Pfizer, Sankyo, and SmithKline. Heacknowledges ownership of stock in Vasocor, for whichhe serves on the board of directors. He also owns stockin and serves on the Scientific Advisory Board ofAtherogenics.

Philip M. Renner, MBA, acknowledges grant andresearch support from NCQA and is a member of theAstraZeneca speakers bureau.

Neil J. Stone, MD, acknowledges that he is a member ofa speakers bureau for AstraZeneca, Bristol-MyersSquibb, Reliant, Sankyo, and Wyeth-Ayerst.

The following faculty members have declared theyhave no financial interest, arrangement, or affiliationthat would constitute a conflict of interest concerningthis CME/CE activity: Juan Enriquez; Michael I. Ruxin,MD; Paul E.Terry, PhD.

SUPPLEMENT / MANAGED CARE 3


Like the predecessors of the current guidelines es-tablished by the third Adult Treatment Panel (ATPIII) of the National Cholesterol Education Project

(NCEP, 2001), the most recent version has been criticizedfor being too complex. In many ways, however, the treat-ment of dyslipidemia is no differentfrom the treatment of chronic ane-mia. Just as iron is not warrantedfor every anemic patient withoutcareful diagnostic assessment, nei-ther is there a single therapeutic ap-proach to dyslipidemia, the multiplecauses and manifestations of whichnecessitate varying therapeutic stra-tegies after careful evaluation hasbeen performed.

This article will discuss the ap-proaches taken by ATP III to fourspecific dyslipidemias — very highlevels of low-density lipoproteincholesterol (LDL-c), elevated trigly-cerides, low levels of high-densitylipoprotein cholesterol (HDL-c),and diabetic dyslipidemia — and the four classes ofdrugs available to treat them. These classes are the HMG-CoA reductase inhibitors, or statins; bile acid seques-trants; nicotinic acid (niacin, or vitamin B3); and fibricacid derivatives.

Therapeutic lifestyle changes leading to improvementsin diet, physical activity, and body weight are the foun-dations of treatment for dyslipidemia, but most high-riskpatients require additional drug therapy to meet theirgoals. Under the ATP II guidelines, about 18 millionAmericans qualified for drug therapy to alter their lipidprofiles. The more expansive ATP III criteria defining pa-tients at risk from dyslipidemia suggest that 36 millionAmericans would benefit from drug therapy.

Under ATP III, LDL-c remains the primary target oftherapy. Carrying two thirds of plasma cholesterol, LDL-cinitiates atherosclerosis, and when high levels of LDL-care present, it aggravates atherosclerosis at every stage.

Reduction of LDL-c has been shown by multiple clini-cal trials including diverse patient populations to reducemorbidity and, most importantly, in two large trials ofsubjects with high levels of LDL-c, mortality. For exam-ple, the Helsinki Heart Study showed that gemfibrozil re-

duced the incidence of coronaryheart disease (CHD) in asympto-matic middle-aged men with dys-lipidemia (Frick, 1987); the West ofScotland Coronary PreventionStudy (WOSCOPS) showed thebenefit of lowering LDL-c, withpravastatin, in men with high levelsof LDL-c but no history of heartdisease (Shepherd, 1995); Choles-terol and Recurrent Events (CARE)showed the benefits of cholesterolreduction, again with pravastatin,in men and women with a history ofheart disease but with an averageLDL-c of only 139 mg/dL (Sacks,1996); and the Air Force/TexasCoronary Prevention Project (AF-

CAPS/TexCAPS) showed the benefit of cholesterol re-duction, with lovastatin, in generally healthy men andwomen without clinical evidence of cardiovascular dis-ease and with average cholesterol levels but lower-than-average HDL cholesterol (Downs, 1998). Reduction inmortality was shown in the Scandinavian SimvastatinSurvival Study (4S) in subjects with established coronaryartery disease (SSSS, 1994) and the Long-Term Inter-vention with Pravastatin in Ischemic Disease (LIPID)trial, which looked at subjects with both unstable anginaand myocardial infarction (LIPID, 1998).

These clinical trials demonstrated the value of statintherapy over a wide range of LDL-c. In more difficultcases, where it is hard to reach goal levels of LDL-c,statins can be augmented by drugs that work in the in-testine, such as the bile acid sequestrants. For patientspresenting with hypertriglyceridemia, fibrates or fish oilsmay be a better option. For patients with low HDL-c,

FACULTY PRESENTATION

Current Drug Treatments For Lipid ManagementNEIL J. STONE, MD

Professor of Clinical Medicine (Cardiology), Feinberg School of Medicine,Northwestern University, Chicago

N E I L J . S T O N E , M D


niacin deserves consideration. Combination therapy,however, can increase risks of side effects and must be ap-proached in a systematic and careful fashion.

Very high LDL-c. The pioneering Seven CountriesStudy (Kromhout, 1995), a longitudinal study that in-vestigated the links between diet and cardiovascular dis-eases, demonstrated that an atherogenic diet (such as theEast Finnish diet that was extremely high in saturated fatand dietary cholesterol) could lead to average total cho-lesterol levels exceeding 260 mg/dL and correspondinglyhigh levels of LDL-c. Because the focus on just diet canbe misleading, clinicians should suspect a genetic com-ponent whenever a patient with a reasonable diet presentswith LDL-c concentrations exceeding 190 mg/dL (Table1). Genetic causes of high LDL-c include monogenic familial hypercholesterolemia, familial defective apolipo-protein B-100, autosomal recessive hypercholesterolemia,and polygenic hypercholesterolemia. When a patientwith extremely high LDL-c is encountered, screening ofother family members is warranted.

Regimens for reducing extremely high LDL-c includestatin monotherapy (using higher doses of the more po-tent statins); statins plus bile acid sequestrants; and tripletherapy with statins, bile acid sequestrants, and niacin.

Elevated triglycerides. Patients who present with hightriglycerides represent a second population requiringtreatment, because there are atherogenic triglyceride-rich particles that clearly increase the risk of atheroscle-rotic progression and CHD events. Patients whosetriglyceride levels are borderline high (150–199 mg/dL)respond well to therapeutic lifestyle changes — more ex-ercise, weight loss, and improved diet. Patients with hightriglyceride levels (200–499 mg/dL) are likely to havetriglyceride-remnant particles that promote progressionof atherosclerosis. Triglycerides at these concentrationsmay also be a marker for underlying metabolic problems.

Elevated triglycerides often result from a lifestyle thatinvolves excessive smoking and drinking, physical inac-tivity, and excessive weight. About 65 percent of Ameri-cans are overweight or obese, and only 25 percent arephysically active in a meaningful sense. Many people fer-vently embrace low-fat diets only to end up with high-carbohydrate diets. High-carbohydrate diets (carbohy-drates accounting for 60 percent or more of caloricintake) are a cause of elevated triglycerides. In addition,high triglyceride levels may stem from several diseases(type 2 diabetes, chronic renal failure, nephrotic syn-drome), certain drugs (corticosteroids, estrogens, retin-oids for acne therapy, beta blockers — taken orally or aseye drops) (Stone, 2002), and excess alcohol ingestion.

Truly cost-effective care for most patients withhypertriglyceridemia begins with therapeutic lifestylechange. When triglyceride levels are extremely high (500mg/dL or greater), the patient is at risk not only for heartdisease but also for pancreatitis. These patients are not

frequently seen, but when they are, they require more in-tensive therapy, with a very-low-fat diet (fats providingno more than 15 percent of caloric intake) and usuallydrug therapy such as a fibrate or nicotinic acid. The pri-mary goal of treatment is to prevent pancreatitis by re-ducing triglycerides below 500 mg/dL minimally andbelow 150 mg/dL optimally. In all other cases of dys-lipidemia, reduction of LDL-c is the primary goal oftherapy.

Many patients present with high levels of LDL-c andtriglycerides and still have triglyceride levels of 200 mg/dLor higher after their LDL-c goal has been met. Becausethey are still at risk for CHD events, they require moreintensive treatment. ATP III specified that a secondarygoal in such patients should be non-HDL-c levels. Non-HDL cholesterol is calculated by subtracting HDL-c fromtotal cholesterol. The non-HDL lipoproteins are athero-genic, and the goal for non-HDL cholesterol is set 30mg/dL higher than the LDL goal (Table 1). Thus, thesehigh-risk patients require therapy that brings both theLDL-c and the non-HDL-c levels below goal. In many ofthese patients, treatment will include some form of com-bination therapy.

Low HDL-c. Low HDL-c previously was defined as aconcentration of less than 35 mg/dL, but the new guide-lines define it as a concentration below 40 mg/dL. Causesof low HDL-c include elevated triglycerides, excessiveweight, physical inactivity, type 2 diabetes, cigarettesmoking, a diet in which carbohydrates contribute morethan 60 percent of caloric intake, and drugs such as betablockers, anabolic steroids, and progestational agents.Patients with low HDL-c and abdominal obesity oftenhave the metabolic syndrome, making weight loss and in-creased physical activity an important part of therapy.

In ATP III, low HDL-c levels serve as a major risk fac-tor and as an important component of the metabolic syn-drome. Low HDL-c also serves as a marker for thosehigh-risk patients who derive great angiographic andclinical benefit from statin therapy (Ballantyne, 1999).ATP III, however, specifies that LDL is the primary tar-get; yet once LDL-c levels are at goal, if triglycerides re-main at 200 mg/dL or greater, a secondary target is non-HDL-c. Also, metabolic syndrome is a secondary target.

TABLE 1 LDL-c and non-HDL-c goals

LDL goal Non-HDL goal Risk category (mg/dL) (mg/dL)

CHD and CHD risk equivalent, 10-year risk for CHD >20% <100 <130

Multiple (2+) risk factors,10-year risk ≤ 20% <130 <160

0–1 Risk factor <160 <190


Thus, patients with low HDL-c should have improve-ments in their HDL-c levels, although not always in a pre-dictable manner, through the treatment efforts directedat LDL-c, non-HDL-c, and the metabolic syndrome.

Experienced clinicians realize that all the componentsof therapeutic lifestyle change may raise HDL-c (weightloss, regular physical activity, avoiding excess carbohy-drates in the diet, cessation of cigarette smoking). In ad-dition, drug therapy that lowers LDL-c also raises HDL-c by variable amounts. For example, all statins raiseHDL-c, in the range of 5 percent to 15 percent. Niacinis the best agent for increasing HDL-c, achieving in-creases of up to 35 percent. Fibrates also are effective forlow HDL-c, raising it by 10 percent to 20 percent. Niacinor fibrates may be particularly useful for patients whopresent with low HDL-c and CHD but essentially nor-mal LDL-c.

In the Veterans Affairs Cooperative Studies ProgramHigh-Density Lipoprotein Cholesterol Intervention Trial(VA-HIT), gemfibrozil reduced the risk of nonfatal myo-cardial infarction, stroke, and fatal CHD in patientswhose baseline levels of LDL-c and HDL-c were a meanof 111 mg/dL and 32 mg/dL, respectively (Rubins, 1999).Gemfibrozil increased HDL-c by a mean of 6 percent andlowered triglycerides by 31 percent, while LDL-c levelsremained unchanged. Thus, fibrates may be appropriatefor patients who present with low levels of LDL-c as wellas HDL-c, yet they are at high risk or have coronary dis-ease. Most often, these patients have features of the meta-bolic syndrome.

Diabetic dyslipidemia. Low HDL-c also is a feature ofa lipoprotein pattern known as diabetic dyslipidemia,whose other defining characteristics are high trigly-cerides and a preponderance of small, dense LDL. Thispattern is highly atherogenic. The LDL-c goal for suchpatients is below 100 mg/dL. Because of their high levelof triglycerides, their non-HDL goal is less than 130mg/dL. Most patients will require LDL-lowering drugsto reach these goals.

ATP III states that drug therapy is optional for high-risk patients whose LDL-c is in the range of 100 mg/dLto 129 mg/dL. The results of the recently published HeartProtection Study (HPS) are likely to encourage clini-cians to take a more aggressive approach to treatingthose at high risk of CHD. HPS enrolled 20,536 subjects

(including nearly 6,000 with diabetes) and showed theoverall benefit of statin therapy in subjects at all levels ofLDL-c (Heart Protection Study, 2002). It should be notedthat in ATP III, high-risk individuals with lower levels ofLDL-c are still treated with statins if their triglycerides are200 mg/dL or more and their non-HDL-c levels remainelevated.

Drug therapiesStatins. The first statin was introduced in 1987 (Table

2), so these drugs did not figure prominently in the de-liberations of the first Adult Treatment Panel, whoseguidelines were released in 1988. Since then, statins havebecome the drug of choice because they are the agentswith the most data from clinical trials, the outcomes ofwhich have been striking. Statins reduce LDL-c in therange of 18 percent to 55 percent, along with a parallelreduction of triglycerides, in the range of 7 percent to 30percent, and, as previously noted, produce a modest in-crease in HDL-c. Statins that reduce LDL-c levels with thegreatest potency, also have a strong effect on triglyc-erides. On the other hand, the statins vary in their effectson HDL-c levels.

As a class, the statins are remarkably safe, despite theexperience with cerivastatin, which was withdrawn fromthe market in August 2001 due to an unacceptable num-ber of cases of death from rhabdomyolysis. In half thesecases, cerivastatin was taken in conjunction with gemfi-brozil. The rest of the statins have been well tolerated,with a very low incidence of myositis in clinical trials.

The major side effects reported in clinical trials ofstatins are myopathy (creatine kinase [CPK] elevated 10times the upper limit of normal or higher) and elevatedliver enzymes (above three times the upper limit of nor-mal).A concern that was not often seen in the clinical tri-als of statins but has been noted in practice is a complaintof myalgias not associated with a rise in CPK or muscleweakness. These myalgias can be so troublesome that thepatient and physician feel the need to try another statin.Rarely, patients find it difficult to tolerate any statin.

Statins are contraindicated in patients with active liverdisease. Although usually well tolerated, elevated livertransaminase levels can be seen with statin therapy andare often mild. Transaminase elevations less than 1.5times the upper limit of normal should not trigger alarm.

TABLE 2 HMG-CoA reductase inhibitors (statins)

Generic name Brand name Launch date Daily dose range

Lovastatin Mevacor 1987 (Sept.) 20–80 mgPravastatin Pravachol 1991 (Nov.) 20–80 mgSimvastatin Zocor 1992 (Jan.) 20–80 mgFluvastatin Lescol 1994 (April) 20–80 mgAtorvastatin Lipitor 1997 (Feb.) 10–80 mgRosuvastatin Crestor FDA approval pending FDA approval pendingPitavastatin (NK 104) Pending In Phase III trials In Phase III trials

Many times, the liver-enzyme profile returns towardnormal as the patient is followed. Often, if the livertransaminase tests are borderline elevated, having pa-tients either reduce alcohol intake and/or increase physi-cal activity and reduce calories to lose weight and elim-inate any tendency toward fatty liver can help pinpointthe problem.

The clinician must be alert for drug interactions withstatins. For example, I saw a patient treated with lova-statin — and to the best of his recollection, nothing else— uncharacteristically present with liver enzymes ele-vated 10 times the upper limit of normal. The mysterywas explained when his wife reminded him that his der-matologist had given him an antibiotic the day before hebecame ill. Physicians should always be concerned aboutdrug-drug interactions with statins and particularly withmacrolides, certain antifungal medications, cyclosporine,niacin, and fibrates.

Similarly, large amounts of grapefruit juice, which in-hibit cytochrome P450 3A4, should be avoided by pa-tients taking atorvastatin, simvastatin, or lovastatin, be-cause those statins are metabolized by that enzymesystem. On the other hand, a patient taking pravastatincould drink grapefruit juice without concern, becausepravastatin is not metabolized to a significant extent byCYP 3A4.

Recent evidence from a retrospective analysis suggeststhat discontinuation of statin therapy may negate itsbenefits in certain patient populations (Heeschen,2002).The data were from the Platelet Receptor Inhibi-tion in Ischemic Syndrome (PRISM) study, in which3,232 subjects with coronary artery disease had varyingexposure to statins before and after hospitalizations dueto chest pain. The study results indicated that cessationof statins after hospitalization for chest pain resulted ina worse short-term outcome than in those who contin-uesd statins.

This study was hypothesis-generating, not hypothesis-proving. It is the only study of its kind so far, and its pop-ulation comprised extremely sick patients (i.e., coronarypatients with unstable angina pectoris). Research isneeded to confirm this finding and to determine, if true,the mechanism(s) underlying the putative worseningwith statin discontinuance.

Bile acid sequestrants. During the 1970s and 1980s,bile acid sequestrants were the mainstay of therapy.Although these agents could lower LDL-c by 15 percentor 20 percent, and up to 30 percent if very large doseswere employed, they were difficult to use. Levels of trigly-cerides could increase, and patients frequently experi-enced gastrointestinal distress and constipation. Today,these agents are used much differently. They are usuallygiven in small doses to augment the statin therapy. Theyalso are useful when the clinician wants to avoid givinga systemic drug to younger patients.


The resins have been shown to reduce the risk of majorcoronary events and CHD mortality (Lipid Research,1984), adding further validity to the idea that lipid-low-ering is beneficial.

Niacin. Niacin, or vitamin B3, lowers all the athero-genic lipoproteins: LDL-c, by 5 percent to 25 percent;triglycerides, by 20 percent to 50 percent; and remnantparticles. It also increases HDL-c by 15 percent to 35 per-cent. It reduces Lp(a).* Niacin has been shown to reducethe rate of atherosclerotic progression (Brown, 1990;Blankenhorn, 1987) and to reduce the risk of recurrentmyocardial infarction (Coronary Drug Project ResearchGroup, 1975) and total mortality (Canner, 1986).

Niacin therapy must be monitored carefully as niacincan trigger gout, cause upper gastrointestinal distress,symptomatic liver dysfunction, and increased glucoselevels. Niacin must be used with care in patients with im-paired fasting glucose because of the danger of raisingblood sugars above the diabetic threshold. On the otherhand, niacin can be used safely and to good effect as alipid-modifying agent in patients with stable, controlled,type 2 diabetes, as was shown in the Arterial DiseaseMultiple Intervention Trial (ADMIT) (Elam, 2000).

Crystalline niacin is inexpensive, and it is very cost ef-fective. Recent studies have highlighted the usefulness ofniacin when added to a statin (Brown, 2001). For best re-sults with niacin, however, niacin side effects should bereviewed by the physician with the patient. Niacin is a va-sodilator, resulting in flushing. The flushing isprostaglandin-mediated, so a daily aspirin can reduceflushing, but not completely.With time, tachyphylaxis oc-curs.

Many prefer extended-release niacin (Niaspan) thathas a more favorable side-effect profile, with less flush-ing and hepatotoxicity (Grundy,2002). One importantcaution — when switched from crystalline niacin to asustained-release formulation of niacin, the patientshould be started on a low initial dose. If this precautionis not followed, hepatotoxicity may be seen, as the highdose of crystalline niacin may be too high for the patientwhen given as a sustained-release dose.

Fibric acids. The fibric acid derivatives, such as fenofi-brate and gemfibrozil, have been shown to reduce theprogression of coronary lesions and the rate of majorcoronary events in clinical trials (Staels, 1998). The pri-mary action of these agents is indeed complex, with ef-fects on both the production and catabolism of triglyc-eride-rich particles. The result is a marked drop intriglycerides and an associated rise in HDL-c. Clofibratefell into general disfavor following a study by the WorldHealth Organization in which excess noncoronary mor-tality was seen in the treatment group (Committee, 1978;

*Lp(a) is a protein made from the apo(a) gene. High levels ofLp(a) increase the risk of developing coronary disease.

Blankenhorn DH, Johnson RL, Nessim SA, et al. The CholesterolLowering Atherosclerosis Study (CLAS): Design, methods,and baseline results. Control Clin Trials. 1987;8:356–387.

Brown G, Albers JJ, Fisher LD, et al. Regression of coronaryartery disease as a result of intensive lipid-lowering therapyin men with high levels of apolipoprotein B. N Engl J Med.1990;323:1289–1298.

Brown BG, Zhao XQ, Chait A, et al. Simvastatin and niacin,antioxidant vitamins, or the combination for the preven-tion of coronary disease. N Engl J Med. 2001;29:345(22):1583–1592.

Canner PL, Berge KG, Wenger NK, et al. Fifteen-year mortalityin Coronary Drug Project patients: Long-term benefit withniacin. J Am Coll Cardiol. 1986;8:1245–1255.

Committee of Principal Investigators. WHO cooperative trial onprimary prevention of ischaemic heart disease with clofi-brate to lower serum cholesterol: final mortality follow-up.Report of the Committee of Principal Investigators. Lancet.1984;2(8403):600–604.

Committee of Principal Investigators. A cooperative trial in theprimary prevention of ischaemic heart disease using clofi-brate. Report from the Committee of Principal Investiga-tors. Br Heart J. 1978;40:1069–1118.

Coronary Drug Project Research Group. Clofibrate and niacin incoronary heart disease. JAMA. 1975;231:360–381.

Diabetes Atherosclerosis Intervention Study. Effect of fenofibrateon progression of coronary-artery disease in type 2 dia-betes: The Diabetes Atherosclerosis Intervention Study, arandomised study. Lancet. 2001;357:905–910.

Downs JR, Clearfield M, Weis S, et al. Primary prevention ofacute coronary events with lovastatin in men and womenwith average cholesterol levels: Results of AFCAPS/Tex-CAPS. Air Force/Texas Coronary Atherosclerosis Preven-tion Study. JAMA. 1998;279:1615–1622.

Elam MB, Hunninghake DB, Davis KB, et al. Effect of niacin onlipid and lipoprotein levels and glycemic control in patientswith diabetes and peripheral arterial disease. The ADMITstudy: A randomized trial. Arterial Disease Multiple Inter-vention Trial. JAMA. 2000;284:1263–1270.

Frick MH, Elo O, Haapa K, et al. Helsinki Heart Study: Primary-prevention trial with gemfibrozil in middle-aged men withdyslipidemia. Safety of treatment, changes in risk factors,and incidence of coronary heart disease. N Engl J Med.1987;317:1237–1245.

Grundy SM, Vega GL, McGovern ME, et al.Efficacy, safety, andtolerability of once-daily niacin for the treatment of dys-


Committee, 1984). Fenofibrate and gemfibrozil thus arethe two agents in this class that are used today.

In the Diabetes Atherosclerosis Intervention Study(DAIS), treatment with fenofibrate was shown to re-duce the angiographic progression of coronary arterydisease in patients with type 2 diabetes (Diabetes, 2001).As previously noted, gemfibrozil was shown in VA-HITto reduce the rate of fatal and nonfatal coronary arterydisease events and stroke in a significant fashion.

Figure 1 shows the general strategy for initiation andprogression of drug therapy recommended by ATP III.For most patients, ATP III recommends a dietary trial ofat least 3 months prior to drug therapy, but for patientswith the metabolic syndrome, a program of therapeuticlifestyle change and drug therapy can begin simultane-ously.

Successful drug therapy necessitates that the clinicianmonitor the patient’s response and adherence to therapy,as guided by the “four Cs”— characteristics of the patient,cost of drugs, complexity of the patient’s medical situa-tion, and the chronicity of the illness. It may be helpful tointroduce a fifth “C” — a card. Patients can be instructedby their physician to carry, at all times, a card listing allmedications they are taking, and to present it immediatelyon reporting to an emergency department. The possessionof such a card makes a simple but powerful point aboutthe importance of the patient’s medications.

In summary, ATP III recommends a regimen ofevidence-based drug treatments that are built on a foun-dation of therapeutic lifestyle changes to manage specificdyslipidemias. Because of their high efficacy and toler-ability, the statins will be the first-line agents for manypatients.

ReferencesBallantyne CM, Herd JA, Felic LL, et al. Influence of low HDL

on progression of coronary artery disease and response tofluvastatin therapy. Circulation. 1999;99:736–743.

FIGURE 1 Progression of drug therapy in primary prevention

Initiate LDL-loweringdrug therapy

• Start statin or bile acidsequestrant or nicotinic acid

6 weeks ➡

6 weeks ➡

Q 4–6 mo➡

• Consider higherdose of statin or bile acidsequestrant or nicotinic acid

• If LDL goal achieved, treatother lipid riskfactors

If LDL goal not achieved,intensify LDL-loweringtherapy

If LDL goal not achieved,intensify drugtherapy or refer to a lipid specialist

Monitor response andadherence totherapy


lipidemia associated with type 2 diabetes: Results of the as-sessment of diabetes control and evaluation of the efficacyof niaspan trial. Arch Intern Med. 2002;162(14):1568–1576.

Heart Protection Study Collaborative Group. MRC/BHF HeartProtection Study of cholesterol lowering with simvastatinin 20,536 high-risk individuals: a randomised placebo-con-trolled trial. Lancet. 2002;360:7–22.

Heeschen C, Hamm CW, Laufs U, Snapinn S, Bohm M, WhiteHD. Withdrawal of statins increases event rates in patientswith acute coronary syndromes. Circulation. 2002;105:1446–1452.

Kromhout D, Menotti A, Bloemberg B, et al. Dietary saturatedand trans fatty acids and cholesterol and 25-year mortalityfrom coronary heart disease: the Seven Countries Study.Prev Med. 1995;24:308–315.

The Lipid Research Clinics Coronary Primary Prevention Trialresults. Reduction in incidence of coronary heart disease.JAMA. 1984;251:351–364.

LIPID Study Group. Prevention of cardiovascular events anddeath with pravastatin in patients with coronary heart dis-ease and a broad range of initial cholesterol levels. TheLong-Term Intervention with Pravastatin in Ischaemic Dis-ease (LIPID) Study Group. N Engl J Med. 1998;339:1349–1357.

National Cholesterol Education Program (NCEP). Third Reportof the Expert Panel on Detection, Evaluation, and Treat-ment of High Blood Cholesterol in Adults (Adult Treat-

ment Panel III). Bethesda, Md.: National Heart, Lung andBlood Institute, 2001. Available at:«www.nhlbi.nih.gov/guidelines/cholesterol/index.htm»

Rubins HB, Robins SJ, Collins D, et al. Gemfibrozil for the sec-ondary prevention of coronary heart disease in men withlow levels of high-density lipoprotein cholesterol. VeteransAffairs High-Density Lipoprotein Cholesterol InterventionTrial Study Group. N Engl J Med. 1999;341:410–418.

Sacks FM, Pfeffer MA, Moye LA, et al. The effect of pravastatinon coronary events after myocardial infarction in patientswith average cholesterol levels. Cholesterol and RecurrentEvents Trial investigators. N Engl J Med. 1996;335:1001–1009.

Shepherd J, Cobbe SM, Ford I, et al. Prevention of coronaryheart disease with pravastatin in men with hypercholes-terolemia. West of Scotland Coronary Prevention StudyGroup. N Engl J Med. 1995;333:1301–1307.

SSSS Group. Randomised trial of cholesterol lowering in 4444patients with coronary heart disease: The ScandinavianSimvastatin Survival Study (4S). Lancet. 1994:344:1383–1389.

Staels B, Dallongeville J, Auwerx J, et al. Mechanism of action offibrates on lipid and lipprotein metabolism. Circulation.1998:2088–2093.

Stone NJ, Blum CB. Management of Lipids in Clinical Practice, 4th

ed., chap. 4, Causes of secondary hyperlipoproteinemia.Professional Communications Inc., 2002.


For nearly 40 years, the prevalence of coronary dis-ease in the United States has declined. We may beat the end of this era of decline — barring the dis-

covery of some means to induce overweight Americansto suddenly start burning an additional 500 to 1,000 calo-ries daily, to persuade the 25 percent of Americans whostill smoke to abandon the habit, andto motivate patients to take theirmedications exactly as prescribed.Without those unlikely events, coro-nary disease will increase. Largelydue to weight gain and reduction ininfectious disease, coronary disease isalready the leading cause of deathworldwide. This is documented insouthern China, in the middle-classpopulation of the Indian subconti-nent, and among the Pima Indians inthe southwestern United States. Theaddition of animal fat to the diet andhigher blood cholesterol levels arefound in such populations. Majorpublic health measures are neededto turn this tide. However, with the growing affluence inmany societies, effective and safe medications may be partof the answer.This article will discuss some promising newtherapies for cholesterol reduction, which range frommore efficacious statins to agents that may prevent accu-mulation of cholesterol in the arterial wall (Table 1).

To date, the statins clearly have been the most benefi-cial treatment for coronary disease. When all the clinicaltrials are taken into consideration, it can be seen that anoverall reduction of about 30 percent in the rate of coro-nary events has been achieved. Nothing in medicine hasbeen more clearly demonstrated than the fact that a ratereduction of this magnitude stems from a 30-percent re-duction in low-density lipoprotein cholesterol (LDL-c)during the course of five years (LaRosa, 1999). Most ofthe benefit accrues in the third, fourth, and fifth years.

Of the statin drugs, only pravastatin (Pravachol), lo-vastatin (Mevacor), and simvastatin (Zocor) currentlyhave an evidence base stemming from long-term clini-cal trials to support the claim that they reduce morbid-ity and mortality. On the basis of a presumed class effect,atorvastatin (Lipitor) has become the U.S. market leader,

commanding about 55 percent. Twoextremely large trials in progress aredesigned to determine the benefitsof lowering LDL-c to even lowerlevels than previously achieved.

In the meantime, atorvastatin isregarded as one of the most potentstatins. Even when patients aretitrated with this statin from 10 mgto 80 mg per day, however, morethan 20 percent of patients whosebaseline total cholesterol (TC) is inthe range of 291 to 330 mg/dL fail toachieve their LDL-c goal (Leiters-dorf, 2001). About one third of pa-tients with TC values between 330and 369 mg/dL did not achieve their

LDL-c goals with atorvastatin therapy, along with al-most three quarters of patients whose baseline TC wasgreater than 369 mg/dL.

It may be tempting to dismiss such patients with ex-tremely high TC as a minor presence in general practice,but it should be remembered that the prevalence of fa-milial hypercholesterolemia, a genetic disorder of theLDL receptor, is 1 in 500. It thus affects about 600,000Americans — more than the 466,000 known patientswith AIDS and/or HIV (Centers for Disease Control andPrevention, 2001). Moreover, the death rate from famil-ial hypercholesterolemia is comparable to the AIDS deathrate in middle life. Even so, familial hypercholesterolemiareceives minimal attention in comparison to the atten-tion given to AIDS, and even the most effective of the cur-rently available statins are often inadequate treatments


Promising Therapies For Cholesterol ReductionW. VIRGIL BROWN, MD

Chief of Medicine and Primary Care, Atlanta Veterans Affairs Medical CenterCharles Howard Candler Professor of Internal Medicine and Director, Division of Arteriosclerosisand Lipid Metabolism, Emory University School of Medicine, Atlanta

W. V I R G I L B R O W N , M D


rosuvastatin and pitavastatin have similar dose-responsecurves and follow the old rule of all statins: that once thefirst dose has been given, doubling the dose results in afurther LDL-c reduction of only about 6 percent.

Statins reduce serum levels of LDL-c by inhibiting anenzyme, HMGR, involved in the synthesis of cholesterol;other agents achieve this through activity in the intestine,either by disrupting bile acid transport of cholesterol orby inhibiting absorption of cholesterol by the intestine.

Inhibitors of bile acid transportThe average person has about 1,500 mg of cholesterol

delivered to the gut each day. The body synthesizes about900 to 1200 mg of this amount, and another 300 to 500mg is provided by the diet. Some of the cholesterol in theliver is converted to a series of detergent moleculesknown as bile acids. These are also delivered to the in-testine in bile, helping to solubilize the cholesterol.About50 percent of the intestinal cholesterol and over 95 per-cent of the bile acids are absorbed returning to the liver.The remainder appears in the stool. When an agent thatbinds bile acids in the intestine (e.g., colesevelam) isadded, the bile acid pool is depleted. Hepatic cholesterol

for it. This provides a strong justification for findingeven more effective drugs for cholesterol reduction. Someselected examples of drug development in this area arediscussed next.

More efficacious statins on the wayMore efficacious statins are in development, notably

rosuvastatin (Crestor) and pitavastatin (NK-104). In ahead-to-head trial against atorvastatin in a population ofpatients with hypercholesterolemia, rosuvastatin, 5 mg or10 mg, was associated with statistically significantlygreater reductions in LDL-c than atorvastatin — 40 and43 percent, respectively, versus 35 percent; p<.01 andp<.001, respectively — and with statistically significantincreases in high-density-lipoprotein cholesterol (HDL-c)— 13 percent and 12 percent, respectively, versus 8 per-cent; p<.01 and p<.05, respectively (Davidson, 2002).Similarly, 8 weeks of pitavastatin, 2 mg, resulted in a 41-percent reduction in LDL-c in patients with heterozygousfamilial hypercholesterolemia; when the dosage was in-creased to 4 mg, the LDL-c reduction reached 49 percentafter 4 more weeks (Noji, 2002).

Although they are more potent than the other statins,

TABLE 1 Drugs under development

Comment

More efficacious statins

• Rosuvastatin “Approvable” letter from FDA received June 2002• Pitavastatin In Phase III trials

Inhibitors of bile acid transport Additive to statinsPotential for diarrhea owing to colonic irritation

• Colesevelam (WelChol) Low risk of systemic toxicity because agent is not absorbed• GT 102-279• IBATs

Inhibitors of cholesterol absorption Additive to statins

• Phytosterol esters (Take Control) Available in U.S. as nutraceutical• Phytostanol esters (Benecol) Available in U.S. as nutraceutical• Ezetimibe Acts on or in enterocyte

Inhibitors of cholesterol esterification Development hindered by lack of means to assess lesions in human arterial wall

• ACAT inhibitors (avasimibe) In Phase II clinical trials

Triglyceride reducers

• MTP inhibitors New mechanism of action that may act additively or synergistically with other drugs

Inhibition of fat transport may lead to excessive fat storage in liver• PPAR agonists• Dual PPAR agonists • LPL activator • CETP inhibitor May prevent HDL from transfering cholesterol to VLDL in exchange

for triglycerides

ACAT = acyl-CoA:cholesterol acyltransferase, CETP = cholesteryl ester transfer protein, IBAT = inhibitor of bile acid transport,LPL = lipoprotein lipase, MTP = microsomal triglyceride transfer protein, PPAR = peroxisome proliferator-activated receptor


is converted to more bile acid, reducing the cholesterolcontent of the liver cells.

To sustain the cholesterol content, the liver increases itssynthesis of cholesterol. However, the blocking of bile acidreabsorption also triggers the expression of an increasednumber of LDL-c receptors on the surface of liver cells,which bind LDL-c and take it in, thus reducing the massof LDL-c circulating in the plasma.

A new class of agents, known as inhibitors of bile acidtransport (IBATs), has been developed to block the re-absorption of bile acids at the intestinal epithelial cell. Intheory, a truly effective inhibitor of reabsorption cancause the loss of up to three grams of bile acids daily andtherefore may deplete the liver of an equivalent amountof cholesterol. This could lead to a profound reductionof plasma LDL. However, there are some potential prob-lems that may develop with such drugs, based on our ex-perience with bypass procedures for the distal smallbowel. These procedures also lower blood cholesterol byincreasing bile acid delivery into the colon for excretion.Bile acids can be very irritating to the colon and, when de-livered in large quantities, can cause diarrhea. Increasedbile acids also cause colonic absorption of oxalates, re-sulting in the formation of renal and urinary tract stonesover the long term (Binder, 1974; Dobbins, 1976). Diar-rhea has been seen in clinical trials of some IBATs. To date,the development of oxalate stones has not been observedin short-term clinical trials.Additional research is neededto take advantage of the potential of IBATs while evalu-ating and avoiding the theoretical adverse effects.

Large doses of phytosterols — a plant’s equivalent ofcholesterol — have been used for many years to blockcholesterol absorption. By attaching a fatty acid to aphytosterol or a phytostanol (a chemically treated phy-tosterol), the molecule becomes even more effective asan inhibitor of cholesterol absorption. These phytosterolesters (Take Control) and phytostanol esters (Benecol)are available in the United States as nutraceuticals.As ad-junctive therapy, they may result in further reductions inLDL-c, in the range of 6 percent to 10 percent.

Inhibitors of cholesterol absorptionEzetimibe (Zetia) would be the first in a new class of

drugs that inhibit the intestinal absorption of cholesterol.After ezetimibe enters the gut, a molecule of glucuronicacid is added as the drug is taken up by mucosal cells. Theglucuronidated product blocks cholesterol absorption toan even greater extent than does the native drug. Eze-timibe localizes in the brush border of enterocytes, whereit acts by a mechanism that is not fully understood. Pre-sumably, it interacts with a specific protein on or in theenterocyte that transports cholesterol into the epithelialcells of the gut. Ezetimibe undergoes rapid enterohep-

atic recycling, which provides for a prolonged residencetime and once-daily dosing (Kosoglou, 2000).

In clinical trials, ezetimibe, 10 mg, reduces mean LDL-c levels by 18 percent to 20 percent (Bays, 2000; Ezzet,2001; Lipka, 2000), or about two thirds of the reductionthat is seen with the earlier statins, such as lovastatin andpravastatin. The near maximal effects of ezetimibe areseen at this dose; increasing the dose to 40 mg achievesa further reduction of about only 5 percent. To date therehave been no adverse effects clearly linked to ezetimibetreatment.

Statins in combination with ezetimibe or niacinAdditive effect of ezetimibe. Used in combination

with statins, ezetimibe, 10 mg, has an additive effect inLDL-c reduction; its addition is comparable to triplingthe starting dose of the statin (Kosoglou, 2000). Ezetim-ibe also causes a modest reduction in triglycerides, alongwith an increase in HDL-c roughly comparable to thatseen with the currently marketed statins. The effect onHDL-c elevation also is additive to that achieved withstatin therapy.

Physicians will be challenged to identify the most re-sponsive patients whenever ezetimibe is prescribed andwill have to monitor to judge its efficacy in each patient.Patients exhibit wide variations in the amount of cho-lesterol that is absorbed by the intestines. Some individ-uals can absorb as much as 90 percent of the cholesterolthat passes through the intestines, whereas others absorbonly 10 percent; absorption in the great majority of peo-ple is in the range of 40 percent to 65 percent. The highabsorbers may respond more dramatically to ezetimibe,but the low absorbers may have a weak response. Stud-ies to prove this relationship have not been reported,however. The most obvious use in the current setting willbe as an add-on to statin therapy in those patients whoare unable to reach LDL target goals.

Another combination strategy for achieving large in-creases in HDL-c, along with dramatic reductions inLDL-c, is to combine a statin and niacin in a single pill.The combination of extended-release niacin (Niaspan)and lovastatin was released in January 2002 as Advicor.This product has been tested in combinations rangingfrom Niaspan/lovastatin 500 mg/10 mg up to 2,000mg/40 mg; it is available in combinations of 500, 750, or1,000 mg of extended-release niacin with 20 mg of lo-vastatin. Niacin also lowers triglycerides and raises HDLcholesterol, both actions which are thought to further re-duce risk of cardiovascular disease. The most commonadverse event associated with this product is flushing,which caused 10 percent of patients to withdraw fromone clinical trial (Kashyap, 2002). For carefully chosen pa-tients, this new product may prove quite useful.


Inhibitors of cholesterol esterificationACAT inhibitors.Thus far, this article has examined at-

tempts to reduce the risk of cardiovascular disease bymodifying the lipid profile through a focus on a reductionof LDL-c and triglycerides and an increase in HDL-c. Acompletely different approach is to attack cholesterol at thesite where it presents the greatest danger — in the arter-ial wall. This may be accomplished with drugs known asacyl-CoA:cholesterol acyltransferase (ACAT) inhibitors.

ACAT inhibitors initially were conceived of as agentsthat would prevent cholesterol esterification in the gutand thereby reduce the amount of cholesteryl ester inchylomicrons, with a net effect that might be similar tothat achieved with ezetimibe. Unfortunately, this ap-proach yielded only a modest effect. Nevertheless, ACATinhibitors may have utility for reaching the ultimate goal,that of preventing the accumulation of cholesterol inthe arterial wall. By acting on the end point of the cellu-lar mechanism leading to atherogenesis,ACAT inhibitorsmay make the amount of LDL-c in a patient’s plasma lesscritical.

The enzyme ACAT is involved in the accumulation ofcholesteryl ester in macrophages. The macrophage foamcell is of particular interest, because much of the se-quence of pathophysiologic events in arteriosclerosis isattributable to the accumulation of cholesteryl ester bythis cell. Foam cells develop from macrophages when therate of cholesterol influx exceeds the rate of efflux. Toomuch free cholesterol in a cell is toxic. When there is anexcess of cholesterol, an enzyme known as ACAT1 at-taches a fatty acid to cholesterol, forming a cholesterolester. This allows the storage of cholesterol in macro-phages in the inert form of cholesterol oleate, thus pro-tecting the cell. However, the accumulation of cholesterololeate results in the activation of the macrophage thatdoes all the damage in the arterial wall — secreting cyto-kines and oxidative and lipolytic enzymes and breakingdown the surrounding protein through the action ofproteases (e.g., collagenase) in the process that leads toatherosclerotic disease. Another enzyme, ACAT2, loadslipoproteins in the gut (chylomicrons) and in the liver(very-low-density lipoproteins, or VLDL). Thus far, everyagent that inhibits one form of ACAT also inhibits theother.

Poor absorption has been a problem with ACAT in-hibitors. They may enter the intestinal epithelial cell butdo not enter the systemic circulation; almost none reachthe arterial wall. Avasimibe, however, has been shown toprevent atherosclerosis in animal models in a fashion thatis independent of its effects on plasma cholesterol (Del-sing, 2001). In terms of pharmacodynamics, the problemwith an agent that may affect the arterial wall but pro-duces few other interesting signals is that the agent is dif-

ficult to evaluate in humans. There is no mechanism forassessing the number of fat-filled cells in human arter-ies, which are the objects of interest. Yet that number iscritical as an end point for dose-ranging studies and isvirtually inaccessible at the moment. This has proved tobe a major hindrance to the development of this promis-ing new drug class.

Novel agents for reducing triglyceridesMTP inhibitors. A growing body of evidence sug-

gests that the triglyceride particle is a major instigator ofarterial disease. One way to reduce the level of triglyc-erides is to prevent them from being loaded in the liveronto VLDL. A protein essential to this loading process ismicrosomal triglyceride transfer protein (MTP), whichloads neutral lipids onto apolipoprotein B. The auto-somal recessive disorder called abetalipoproteinemia isdue to the dysfunction or the absence of MTP. In theory,inhibitors of MTP may reduce VLDL synthesis and re-duce the load of triglyceride carried into the body; thusfar, however, no trials involving large numbers of patientshave demonstrated that these agents are efficacious.

A potential drawback to MTP inhibition is that itmight lead to fatty liver. The liver is a major energy-processing center. On a continuous basis, it receives en-ergy from adipose tissue and the diet. One of the ways itmaintains an energy balance is to synthesize triglyceridemolecules, package them in VLDL, and ship them intothe plasma for use by muscle and adipose tissue andother organs. Interference with that process could havenegative consequences for the liver. In fact, the incidenceof fatty liver already has derailed the development ofone otherwise promising MTP inhibitor.

PPAR activators. Fibrates have been used for manyyears to lower elevated plasma triglycerides, but theirmechanisms of action were not understood until re-cently. It now is believed that fibrates activate nuclearPPAR receptors, which in turn activate transcription fac-tors for a variety of genes. These transcription factors maybe activators or suppressors of the gene promoter for sev-eral proteins and enzymes involved in lipid metabolism.In rodents, the nuclear receptors that lead to this alter-ation of genetic expression cause a marked increase inpackets of oxidative enzymes called peroxisomes andtherefore have been given the name peroxisome prolif-erator-activated receptors (PPARs). So far, three differ-ent forms of PPAR have been identified: alpha, beta, andgamma. PPAR-alpha is found mainly in the liver. Fattyacids and their derivatives appear to be its natural ligands,and fibrates are synthetic ligands for PPAR-alpha.

PPAR-alpha activation suppresses synthesis of an im-portant apolipoprotein, apo C-III. One of the functionsof apo C-III is to allow triglyceride-rich lipoproteins,

tack and stroke. In the medical arena, reducing elevatedblood cholesterol has proved to be one of the most suc-cessful strategies to prevent these catastrophic clinicalevents. Several excellent drugs are currently in clinicaluse, but there remain patients for whom improved ther-apeutic options are needed. Fortunately, an extensivedevelopmental effort is under way to develop new drugsthat are even more efficacious. Among these are agentsthat offer new mechanisms of action that will be addi-tive to those currently used and that may be more effec-tive in some patients who have found it difficult so far toreach their target goal for LDL cholesterol.

ReferencesBays HE, et al. Atherosclerosis. 2000; 151;133 (abstract).Binder HJ. Intestinal oxalate absorption. Gastroenterology.

1974;67:441.Davidson M, Ma P, Stein EA, et al. Comparison of effects on

low-density lipoprotein cholesterol and high-densitylipoprotein cholesterol with rosuvastatin versus atorvas-tatin in patients with type IIa or IIb hypercholesterolemia.Am J Cardiol. 2002;89:268–275.

Delsing DJ, Offerman EH, van Duyvenvoorde W, et al. Acyl-CoA:cholesterol acyltransferase inhibitor avasimibe reducesatherosclerosis in addition to its cholesterol-lowering effectin ApoE*3-Leiden mice. Circulation. 2001;103:1778–1786.

Dobbins JW, Binder HJ. Effect of bile salts and fatty acids on thecolonic absorption of oxalate. Gatstroenterology.1976;70:1096.

Ezzet F, Wexler D, Statkevich P, et al. The plasma concentrationand LDL-C relationship in patients receiving ezetimibe. JClin Pharmacol. 2001;41:943–949.

Kashyap ML, McGovern ME, Berra K, et al. Long-term safetyand efficacy of a once-daily niacin/lovastatin formulationfor patients with dyslipidemia. Am J Cardiol.2002;89:672–678.

Kosoglou T, et al. Atherosclerosis. 2000 (abstract).Lipka HJ, et al. J Am Coll Cardiol. 2000;35(suppl A):275A (ab-

stract).LaRosa JC, He J, Vupputuri S. Effect of statins on risk of coro-

nary disease. A meta-analysis of randomized controlled tri-als. JAMA. 1999;282:2340–2346.

Leitersdorf E. Cholesterol absorption inhibition: filling anunmet need in lipid-lowering management. Eur Heart J.2001;3(suppl E):E17-E23.

Noji Y, Higashikata T, Inazu A, et al. Long-term treatment withpitavastatin (NK-104), a new HMG-CoA reductase in-hibitor, of patients with heterozygous familial hypercholes-terolemia. Atherosclerosis. 2002;163:157–164.

Staels B, Dallongeville J, Auwerx J, et al. Mechanism of action offibrates on lipid and lipoprotein metabolism. Circulation.1998;98:2088–2093.


namely, VLDL and chylomicrons, to circulate in theplasma long enough to interact with lipoprotein lipaseand to deliver the fat to the right tissue — adipose tis-sue and muscle. An excess of apo C-III allows VLDLand chylomicrons to remain in circulation for a longtime. When apo-CIII is decreased, the clearance oftriglycerides increases and the levels fall. In animal mod-els, apo C-III deficiency results in extremely high clear-ance of triglycerides, which also is seen in two geneticdisorders that result in C-III deficiency in humans. Con-versely, overexpression of apo C-III in mice can causetriglyceride concentrations of up to 4,000 mg/dL. PPAR-alpha agonists also mediate the induction of lipoproteinlipase (LPL) expression. This enzyme hydrolyzes bothVLDL and chylomicrons. Fibrates also reduce trigly-ceride synthesis and increase lipoprotein lipase action inhumans. All of these actions contribute to their abilityto lower elevated triglycerides.

When triglyceride-rich lipoproteins remain in theplasma over a long time, they alter other lipoproteins aswell. This is the result of an exchange process by whichtriglycerides form VLDL and chylomicrons are traded forcholesterol ester in HDL and LDL. This process is abet-ted by cholesteryl ester transfer protein (CETP). Thenet result is the creation of small, dense LDL as well assmall, dense HDL. Inhibition of the apo C-III gene en-ables the triglyceride-rich lipoproteins to be cleared morerapidly from the plasma and results in larger and morecholesterol-rich LDL and HDL.

CETP inhibitors. The involvement of CETP in re-ducing HDL and in generating the small dense LDL hasresulted in the hypothesis that CETP inhibition mightlead to a less atherogenic plasma lipoprotein profile. In-hibition of this function is now possible through thedevelopment of specific drugs that have entered phase IIand phase III clinical trials. CETP inhibition is an excit-ing topic, because it holds the promise of preventingHDL from transferring its cholesterol to VLDL in ex-change for triglycerides. Despite an increase in HDL val-ues in animal models, it is not clear whether CETP in-hibition leads to reduced atherosclerosis. The cholesteroladded to VLDL remnants is taken up by the liver, and insome people this may be an important pathway of cho-lesterol clearance from the blood. HDL metabolism iscomplicated and every HDL-raising drug will requirecareful clinical assessment with regard to atherogenesis.

ConclusionArteriosclerotic vascular disease results from a variety

of factors that have been addressed by public health ef-forts and improved medical care in recent decades. Somestrong negative trends are now at work that threaten toreduce the gains made in the effort to prevent heart at-


Great and dramatic changes often come unher-alded. In the fall of 1492, few people realizedthat as of October 12 their entire world view was

about to shift. Even on that day, not one person under-stood the enormity of what had occurred, nor did theyrecognize that Spain was about to become the dominantpower in the world.

Columbus himself died penniless, unaware of wherehe had landed. No contemporary portrait of Columbusexists, because in his day he was not important enoughto have a portrait done while he was alive.

Nevertheless, on that day when Columbus landed inthe New World, the balance of power began to change ir-reversibly, along with the map of the world.

Just over 500 years later, on Feb. 12, 2001, humankindproduced another map — the single most importantmap ever published — that of the human genome. Theimplications of this discovery far surpass the radicalchanges that were made to the map that Columbus onceused to navigate the world.

Once again, it is not yet evident where we have landed,and we don’t yet know howthings will change. We do notknow which powers willdominate and which will dis-appear. But the explosivegrowth of genetic data meansthat we are now standing atthe threshold of inevitablechange that will redefine thebasic structure of our lives.

If you go forward from1492 to about 1556, the firstmap of the Western hemi-sphere is still slightly dis-torted: Japan sits in the mid-dle of a Pacific Ocean that’ssmaller than the Atlantic, andIndia is in the Arctic Circle.

Although this map was partly wrong and quite dis-torted, an unprecedented process of change had begun.Today, this is where we are with the map of the genome.

Mice and menWe now know that there is about a 95-percent gene

overlap between miceand men. With about 3billion letters in each ofits cells, the only differ-ence between one hu-man and another is ap-proximately 1 in 1,000of those 3 billion letters.And because only 3 per-cent of your genome di-rectly controls biologi-cal activities — that is,provides instructions tobe carried out — youcan argue that the real difference between you, your bestfriend, and your worst enemy is about 1 in 1,000 times3 percent.

But small changes can make a huge difference. InCatherine Dulac’s Harvard lab, an investigator removedthe TRIP-2 gene from two male mice (Stowers, 2002).The effect was that these mice made love instead of war;

they lost interest in cannibal-izing and fighting. Unfortu-nately, we have not found agene overlap that looks likethis in human beings, so wecan’t apply it yet in Congress.

(And as this research goeson, in some states you can stillfind stickers on biology text-books that say, “Warning:Evolution is only a theory.”)

Data drive empiresGiven that our genes gen-

erally overlap with those ofmice, what is it that makes usmice or men?

When the human genomewas first revealed, many people were shocked that so fewof our genes differed from those of other species. Butthere is a significant difference between mice and men,monkeys and men, or whales and human beings: Onlyhumans can transmit abstract concepts across time.

Humans became the dominant species on the planet

PERSPECTIVE ON GENOMICS

The Life Science RevolutionJUAN ENRIQUEZ

Director, Life Sciences Project, Harvard Business School

FIGURE 1 Maps created after Columbus’s voyageswere imperfect but immensely influential.The map ofthe human genome will also be profoundly influential.

J U A N E N R I Q U E Z


by drawing on cave walls. The pictures describe the tribeitself, how, what, and where to hunt, how to make fire —and how to transmit information across time.And, to theextent that you can effectively transmit more data, youcan make a group smarter.

The Egyptians built an empire by using hieroglyphicsto standardize a set of cave-wall paintings. Suddenlyeveryone could use the same basic symbols to conveymeaning. And, because you could write on papyrus, thisdata system became portable. People in Upper Egyptcould communicate effectively with those in LowerEgypt.

When you standardize an alphabet, you can tax andbuild structures that take three generations to create.You can run a central government and coordinate a largearmy. You can build an empire.

As a species, we have gotten ever more capable of stan-dardizing and accelerating datatransmission. The Chinese ap-proached language by stan-dardizing a series of pictographsinto an extremely powerful sys-tem that evolved over 3,000years from images that lookedlike cave-wall paintings tohighly stylized pictographs. Thissystem generated the most pow-erful economy in the world forover a millennium, giving rise to14 dynasties. The Chinese in-vented paper, guns, gunpowder,the compass, a central civil ser-vice, and probably explored to the tip of Africa. Theycame to dominate about a third of the global economy.

Power shiftsYet how you generate wealth and power changes over

time. When China became the dominant country, thebasis for growth was “bigger is better.” The way to growwealthy was to grow a large family, and to have a lot offarmland and farm animals.

Before computers were invented, it was extremely dif-ficult to transmit the thousands of symbols that make upthe Chinese language. Imagine the size of a Chinese type-writer….

So what happened?The Chinese may have invented moveable type four

centuries before Gutenberg did, but the problem withmovable type in China was that if you want upper andlower case along with a few variations in calligraphicstyle, you have to contend with tens of thousands ofsymbols. Typesetting becomes an overwhelming task.

The next dominant group on the planet found a wayto transmit data with 26 to 29 symbols. Everything thecavemen depicted, everything the Egyptians wrote, every-

thing the Chinese stated with thousands of symbols,could now be conveyed with one alphabet (A,B,C …),and it could be typeset.

That’s partly how Western Europe came to dominatethe planet — by transmitting data with greater efficiencyand speed than anybody else. Language shifts are powershifts.

These days, we do not store data on papyrus; we oftenstore it on a DVD or a CD. We are using yet another al-phabet, a deceptively simple code comprising zeros andones.

A CD is recorded in a binary code (1,0). It is a methodof data transmission that surpasses all others. What wereonce three separate systems — a 26-letter alphabet toconvey words; musical symbols to convey music; andpainting, drawing, and photography to depict images— are now transmitted using a two-letter alphabet.

A digital system is so effi-cient that it allows an amountof data equivalent to the con-tents of the Library of Congressto be transmitted in 1.6 sec-onds across a single fiber-opticline.

Digital language was, untilvery recently, the most potentlanguage on the planet. It pow-ered nearly 20 percent of theU.S. economy at the end of the20th century.

Civilizations, groups, com-panies, and people that under-

stood this particular language shift toward the digitalthrived. Twenty years ago, not many people would haveassociated the three words, high tech and Ireland, butthe Irish have almost the same per-capita income todayas the British because they understood a shift in lan-guage, educated their kids, and attracted smart peoplefrom other countries.

Not long ago, few would have associated Finland withtechnology leadership. It would have been illogical tothink that a factory that made plastic boots would be-come the single most valuable company in Europe. Yettoday that company is well known — it is Nokia.

The folks at Nokia understood the language shift, andit makes a substantial difference when you understandthat the prevailing language has changed.

Changing the rulesDuring the first 1,830 years of the Christian era, global

economic growth occurred at a rate of 0.1 percent peryear. To generate greater economic growth in the yearsbetween 1000 and 1830, the rules of the game were quitesimple: Have more children, and acquire and cultivatemore land.

FIGURE 2 Cave painting of a horse, c.15,000 B.C.

GET

TY IM

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ES


So the dominant world powers used to be China andIndia, with 40 percent of the global economy.

The global economy suddenly started to grow whenan obscure little island, called Britain, began to build ma-chines. Now, having 12 kids did not hold up to having1,000 horsepower. The rules of the game changed. Soci-eties that didn’t understand this got into real trouble.

Then, from the 1950s onward, economic growth ex-ploded — mainly because of the rise of the knowledgeeconomy and the application of digital code. Now, thedifference in productivity between the richest and thepoorest countries in the world is no longer 5 to 1; it is 400to 1 — and climbing fast.

Speeding upAs late as the 1960s, a third of the global economy was

agriculture, a third was manufacturing, and anotherthird was knowledge. Agriculture is now 4 percent. Thisis where Argentina blows up. In 1800, Argentines wereabout as rich as Americans. But the United States edu-cated its population, built infrastructure, accumulatedcapital, adopted high-tech methods in agriculture andtextiles, and shifted towards a digital economy.

What the Argentines did is to say, “We’ll take one Ar-gentine peso, and we’ll make it equal to one U.S. dollar.That way, we cut inflation. We stabilize the currency. Wecut our interest rates.”But they remained an agriculturaleconomy competing against a knowledge economy.

Knowledge matters in a modern economy, because itpowers growth. And while it takes 3,000 Americans togenerate one U.S. patent, it takes 800,000 Argentines togenerate an equivalent patent. When there is a delta inproductivity of 260, one country’s currency and societyblow up if you tie the two currencies together.

A lot of people don’t understand this change in howto generate wealth. The average price of a commodity isabout one fifth of what it was 150 years ago, which meansthat China and India have gone from being 40 percentof the global economy to being under 4 percent at the endof the 20th century. So a third of the global population,over 2 billion people, produces less than 4 percent of theoutput — because they didn’t grasp the language shift.

The next dominant languageForty-nine years ago, Watson and Crick came up with

a model that explained a different alphabet, a doublehelix, which essentially is two intertwined spiral stair-cases. The backbones of this helix are sugar and phos-phates, and its rungs are composed of four substances —adenine, thiamine, cytosine, and guanine — or ATCG.

Recently, using an automated football-field sized laband one of the world’s most powerful computer sys-tems, a private company sequenced the human genomein about 9 months (Venter, 2001).

The world’s most powerful and compact informa-

tion–processing system is a cell; it reads, interprets, andapplies genomic and proteomic data. We’re starting toread and understand this language on a very primitivelevel — for instance, what single-point mutations do. Ob-viously, not all single-point mutations have the same ef-fect, nor do all of them matter. In fact, most of them don’tmatter. A few of them, however, are critical.

We have a very rough map. Do we know where we’velanded? No. Do we have the full map? No. Do we haveeven the outline of the continents? No. Will this changeeverything? Yes.Will the ability to understand and recodelife forms really make a difference? Yes.

We read the full code of a plant last year (Arabidopsisthaliana, 2000). Next time you hold a fruit in your hand,imagine that it sits on a tree, absorbing energy, mindingits business, and then one fine day it goes “plunk”— andit starts to execute code. And that code is a long string ofletters: AAATCAAGGACCC… That might be code for“Make a root.” Next line of code: TACAAGG…,“Make astem.” Next line: TACAGG…, “Make green leaves, whiteflowers, bloom in spring.”

We’re beginning to understand how to read and recodelife forms. In clinical trials, you can now be vaccinatedagainst cholera by eating a banana.You can now grow anear of corn that produces polyester that feels like silk.

The societies and companies that understand this par-ticular change are going to be the dominant ones on theplanet.

Personalized medicineAffymetrix, a company in California, takes over an

old National Semiconductor manufacturing facility, pol-ishes the silicon used in the chips and, instead of insert-ing transistors in them, inserts hybrid bits of deoxyri-bonucleic acid (DNA). Take a biological sample, overlayit on a gene chip the size of a credit card, and out comesa determination as to whether you have one of 40,000 ge-netic conditions.

Within the next three years, you could have most of therelevant parts of the human genome on a single chip. Theimplications of this are vast. This is the start of person-alized medicine. In some cases, you should be able to testwhether one drug or another works best for you beforeyou take it, rather than waiting to see if you suffer sideeffects. Medicine then starts to become prospective as op-posed to prescriptive.

Ever wonder why, when you give the same treatmentto people who have ostensibly the same symptoms anddisease, the outcomes are sometimes so different? TheWhitehead Institute for Biomedical Research is typingdifferent forms of leukemia: ALL, MLL, and AML. Andif you run a sick person’s samples through a gene chip,some genes will overexpress. This lights up certain wellson the chip and leads to different treatments for differ-ent patients.


Scientific understanding shifts business activities.Some pharmaceuticals could become niche productmakers, targeting individual genotypes. The language ofmedicine will shift from binary answers (you are sick/notsick) to probability curves. Medication could become achronic indication starting at the beginning of life.

Because people don’t like to ingest pills or receive in-jections, food companies are very interested in all this. Ifan individual has to take a medication every day, maybeit will make sense to get it from food, drink, shampoo,soap or a transdermal patch.

That means that the competition that pharmaceuticalcompanies will face will not come onlyfrom biotech companies; it will come fromplaces such as Procter & Gamble thatmight suddenly consider the prospect ofbuying a pharmaceutical company.

Then there’s the growing area called nu-traceuticals. It turns out that in some hos-pitals, Campbell’s is giving specificallytyped soups to people who have certainforms of disease.

We are generating databases and struc-tures of knowledge and language that gofar beyond anything done before. And weare not changing just the pharmaceutical,biotech, and food sectors. The computerindustry is changing. The largest project atIBM today is Blue Gene. The largest pro-ject at Compaq was deciphering thehuman genome; the largest project at SunMicrosystems is also related to the life sci-ences.

It’s about to get a lot more complex,because gene code comprises 3 billion let-ters in a two-dimensional four-letter code.Protein is 20 building blocks in three dimensions — andthe folding matters. This increases the size of these data-bases exponentially. It is estimated that it takes a petaflopyear — a computer that can run 1,000 trillion operationsper second running for one year — to simulate the fold-ing of one protein.

Spawning life formsBecause almost all of your cells contain your entire ge-

netic code, and because we are beginning to learn howto reprogram them, we can start to think about repro-gramming cells. Eventually we may grow our own skin,bone, eye, or pancreatic tissue. That again changes therules of the game.

We are beginning to find ways to save species from ex-tinction. There are a few hundred gaurs left in the world;it’s a rare breed of Asian ox. ACT, a company in westernMassachusetts, got together with a conservation group

and took the code from cells in an adult gaur’s mouth.Then it inserted that code into a fertilized cow’s egg thathad had the gene code removed. A few months later agaur was born; unfortunately, it died soon after.

The cloning debate pales by comparison with what’sahead.

The accelerating revolutionThese days, smart people are concentrating in a very

few geographic locations. These genomics companiesare extremely volatile. Entire economic sectors can bebuilt, as well as destroyed, quite rapidly. The general

sense that things are moving too quicklyis terrifying, even to many giant multina-tional companies. Those that are not mar-ket-savvy and technology-literate willhave an even tougher time staying in thegame.

Pharmaceutical companies are facingchoices with increasingly high stakes: Cre-ating a new drug may cost $500 millionand take more than a decade. With betsthis size, you can lose half the value ofyour company overnight if you make amistake late in the game.

The genomics revolution could lead tothousands of new medications, whichcould, if we do not become more efficient,require that the pharmaceutical industryspend trillions on research and develop-ment.

The rules are changing.We are sitting right where Columbus

was when that first little map was drawn.We know very little. We don’t know wherewe’re going; we don’t know where we’ve

landed; we don’t know what’s going to happen, but it isalready happening … fast. There is no language morepowerful than a language that allows us to directly anddeliberately reprogram all life forms on this planet. Andwe’re just beginning to figure out what we’re going to dowith that information.

AcknowledgementI would like to thank Rodrigo Martinez and Ray Gold-

berg for their input for this article.

References Analysis of the genome sequence of the flowering plant Ara-

bidopsis thaliana. Nature. 2000 Dec 14;408:796–815.Stowers L, Holy TE, Meister M, Dulac C, Koentges G. Loss of sex

discrimination and male-male aggression in mice deficientfor TRP2. Science. 2002 Feb 22;295:1493–1500.

Venter JC, Adams MD, Myers EW, et al. The sequence of thehuman genome. Science. 2001 Feb 16;291:1304–1351.

For further reading:ENRIQUEZ J. As the Future

Catches You: How Genomics &Other Forces Are Changing Your

Life,Work, Health & Wealth.New York: Crown Business;

2001.


The National Committee for Quality Assurance(NCQA) is a not-for-profit national health careoversight organization whose mission is to im-

prove the quality of health care delivered to people every-where. NCQA evaluates health care three ways: througha comprehensive member satisfaction survey; accredita-tion (a rigorous onsite review of keyclinical and administrative pro-cesses); and the Health Plan Em-ployer Data and Information Set, orHEDIS, a tool used to measure per-formance in such key areas as im-munization and mammography-screening rates.

HEDIS is the most widely usedhealth care performance measure-ment set in the United States. Main-tained by NCQA, HEDIS providesstandardized information on thequality of care delivered by managedcare organizations and includesmore than 50 performance mea-sures in domains including effec-tiveness of care, access and avail-ability of care, utilization of services, and satisfactionwith the experience of care (Roski, 2001).

HEDIS data for the commercial population are col-lected and reported to NCQA by 65 percent of managedcare organizations, which cover 80 percent of the nearly79.5 million people enrolled in managed care plans(NCQA, State of Managed Care Quality 2001; Inter-Study). The HEDIS data set was designed to give publicand private purchasers comparative cost and quality in-formation and to encourage quality improvementthrough public dissemination of MCO performance re-ports. NCQA publishes performance data throughInternet-based report cards (NCQA Health Plan ReportCard) and NCQA’s Quality Compass data base (QualityCompass, 2001).

NCQA has also developed programs to evaluateproviders. An example of a program reflecting the shiftof quality measurement to the provider level is NCQA’sDiabetes Provider Recognition Program (DPRP). The

DPRP is a voluntary program aimed at improving thequality of diabetes care.

The program was developed cooperatively by the Amer-ican Diabetes Association, NCQA, the Health Care Fi-nancing Administration (HCFA, now the Centers forMedicare and Medicaid Services),and the American Med-

ical Association. Elements of therecognition program are similar tothose in the measure for diabetes inNCQA’s HEDIS. A difference is thatthe diabetic foot exam is part of therecognition program, but it is ex-cluded from the HEDIS measure be-cause of difficulties in confirming ac-cess to foot examination in the chart.

In the recognition program, phy-sicians abstract data from theircharts. Recognition is granted if cer-tain thresholds are achieved, in con-trast to HEDIS measures, in whichplans are compared with each other.Only those achieving recognitionare named. Names of applicants notachieving recognition are not re-

leased. They often reapply after improving their perfor-mance.

Cholesterol measures in HEDIS Based on ATP II, the HEDIS cholesterol measures as-

sess screening and control in patients with diabetes andin those who have had an acute cardiovascular eventwithin the prior year (Lee, 2000; NCQA, Diabetes Qual-ity) (Table 1). The measure of cholesterol screening re-ports the percentage of patients with diabetes or coronaryheart disease (CHD) who have had an LDL-c screening.The measure of cholesterol control reports the percent-age of members with diabetes or CHD who have a doc-umented LDL-c level below 130 mg/dL (HEDIS, 2002)Both measures report rates separately for members withdiabetes and members with CHD.

Measures for comparative purposes are most usefulwhen the scores show significant variation. Thereshould be enough room to improve performance so as


NCQA’s EvolvingClinical Performance MeasuresPHILIP M. RENNER, MBA

Director, Measures Development, National Committee for Quality Assurance

P H I L I P M . R E N N E R , M B A


to minimize a ceiling effect and enough high-perform-ing entities to set performance benchmarks. In calen-dar year 2000 (2001 results will be available in fall 2002),median HEDIS cholesterol screening performance in-creased to 75.0 percent of patients with CHD, up from69.5 percent in 1999. The median MCO cholesterolcontrol rate increased to 55.8 percent of patients withCHD, up from 47.0 percent in 1999. Median screeningrates in patients with diabetes increased from 71.2 per-cent in 1999 to 77.8 percent in 2000. Median cholesterolcontrol rates in patients with diabetes increased from38.7 percent in 1999 to 45.7 percent in 2000 (NCQA,State of Managed Care Quality 2001). These medianrates imply that there is still room for improvementusing the existing measure.

Variance often decreases with improvement in per-formance. There has been some reduction in the amountof variance in the screening measure for patients withCHD. The interquartile range was reduced almost byhalf between 1998 (21.9) and 2000 (11.0). Most of thisreduction has occurred in the lower levels of perfor-mance, suggesting that health plans are converging onhigher performance. Nevertheless, the amount of varia-tion has not changed for the measure of control in CHDpatients and has shown only a slight reduction in bothof the measures in patients with diabetes.

Implications of ATP IIIThe release of the ATP III guidelines will have impli-

cations for the HEDIS cholesterol screening and controlmeasures (Tables 2 and 3). Performance measures arelinked to, but conceptually different from, guidelines.Guidelines describe best practice, helping clinicians tomake decisions when they are providing care for indi-vidual patients. Although performance measures arebased on guidelines, measures assess how well the systemis caring for the health of a population. When perfor-mance measures are crafted, care therefore must be takennot to penalize physicians for making the right decisionsin the gray areas.

All HEDIS measures are reviewed by an expert panelat least every three years, more frequently if new infor-mation becomes available. As a result of the publicationof the ATP III guidelines for cholesterol management, theNCQA’s cardiovascular measurement advisory panel willreview the relevant measures later in 2002. Two issues willbe before the panel: First, should the threshold definingLDL-c control be lowered, setting a more aggressive stan-dard than 130 mg/dL? Second, given that ATP III placesthe main emphasis on risk factors instead of lipid levels,should a new measure be developed for primary pre-vention of heart disease, based on patients with multi-ple risk factors?

There are a number of measurement and clinical con-siderations involved in the review of the HEDIS choles-terol measures. When designing a performance mea-sure, the threshold for performance should be set at alevel that discriminates between the effects due to the pa-tient and effects due to the actions of the physician orhealth plan. If physicians and health plans are to be heldaccountable for patients’ achievement of a given lipidlevel, it is important that the threshold be set at a level

TABLE 1 HEDIS cardiovascular measures

Existing measures Cholesterol management elements within measure

Beta-blocker treatment after a heart attack

Cholesterol management after acute cardiovascular events • LDL-c screening performed• LDL-c controlled

Comprehensive diabetes care • LDL-c screening performed• LDL-c controlled

Controlling high blood pressure

Frequency of selected procedures: angioplasty,CABG, and cardiac catheterization

TABLE 2 New features of ATP III

Focus on multiple risk factors• Raises persons with diabetes without CHD to the

risk level of CHD risk equivalent• Uses Framingham projections of 10-year absolute

CHD risk to identify certain patients with multiple(2+) risk factors for more intensive treatment

• Identifies persons with multiple metabolic risk fac-tors (metabolic syndrome) as candidates for inten-sified therapeutic lifestyle changes

Modifications of lipid and lipoprotein classification• Identifies LDL cholesterol <100 mg/dL as optimal• Raises categorical low HDL cholesterol from <35

mg/dL to <40 mg/dL• Lowers the triglyceride classification cutpoints to

give more attention to moderate elevations

SOURCE: NCEP 2001


within the physician’s control. Achievement of LDL-clevels below 130 mg/dL or 100 mg/dL depends on morethan a physician’s actions to identify appropriate pa-tients, prescribe medications, and recommend lifestylemodifications to the patients. Much depends on pa-tients’ adherence to therapy and their innate response tothe medication. Unpublished data indicate that anLDL-c threshold of 130 mg/dL will capture more of thephysician’s influence, as opposed to patient influence.

Rather than measure achievement of a single thresh-old, one could sort performance into bands. Cardiovas-cular risk is a continuous function that does not stoponce LDL-c concentrations drop below 130 mg/dL or100 mg/dL. Achievement of lower levels could receivemore “points” than higher levels, and a weighted scorecould be calculated. Such a system would reflect more ofan aggregate performance, but would be difficult to in-terpret as there could be many different distributions thatwould yield the same weighted score. In addition, anysuch method would need a clearly defined risk curve toyield an evidence-based scoring design.

Some argue that the benefit is in relative reductionfrom baseline values, rather than the final level achieved(Fazio, 2001). Currently, no credit is given for moving apatient’s LDL-c from 129 mg/dL to below 100 mg/dL, andnone is given for reducing LDL-c from 200 mg/dL to140 mg/dL. Because reducing a patient from 160 mg/dLto 130 mg/dL generally provides more clinical benefitsthan does taking a patient from a baseline of 130 mg/dLto 100 mg/dL, it may be more appropriate to measurechange from baseline, rather than whether a patient is onone side or the other of an arbitrary line. Measuringchange from baseline would require two measurements,of course, along with the establishment of a time frame.

A measure based on change from baseline would givecredit for moving patients down the risk curve, but notfor maintenance of low LDL-c levels. Maintenance canbe a more significant challenge, given treatment discon-tinuation rates predicted at 50 percent after one yearand 85 percent after two years (LaRosa, 2000). Feasibil-ity issues — such as setting time periods for remeasure-ment, the need to locate two values in the chart, a smallersample size — also challenge a reduction-from-baselineapproach.

Finally, NCQA will need to consider whether newmeasures for cholesterol control should be developedfor cholesterol management in patients in the new cate-gories of “risk equivalent” CHD other than diabetes.While there are some technical issues that may need tobe addressed in creating a new measure, the major bar-rier is likely to be the slow adaptation of the new guide-lines in practice (Mottur-Pilson, 2001), and especially theuse of the rather complicated scoring system in identi-fying patients who should be considered for treatment.

In summary, the changing structure of the delivery sys-tem and the publication of the report of the Third AdultTreatment Panel present a number of important chal-lenges for performance measurement. NCQA staff, theCardiovascular Measurement Advisory Panel, and theCommittee on Performance Measurement will need toconsider carefully how the factors above affect the rele-vance, scientific soundness, and feasibility of any per-formance measures deployed.

ReferencesFazio S, Linton MF. Debate: “How low should LDL cholesterol be

lowered?” Viewpoint: “It doesn’t need to be very low.” CurrControl Trials Cardiovasc Med. 2001;2:8–11.

TABLE 3 HEDIS LDL-c goals and cutpoints for therapy in different risk categories

LDL-c level at which to initiate therapeutic LDL-c level at which

Risk category LDL-c goal lifestyle changes (TLC) to consider drug therapy

CHD or CHD risk equivalents <100 mg/dL ≥100 mg/dL ≥130 mg/dL (10-year risk >20%) (100–129 mg/dL: drug optional)*

2+ Risk factors <130 mg/dL ≥130 mg/dL ≥130 mg/dL(10-year risk 10%–20%)

2+ Risk factors <130 mg/dL ≥130 mg/dL ≥160 mg/dL(10-year risk <10%)

0–1 Risk factor † <160 mg/dL ≥160 mg/dL ≥190 mg/dL(160-189 mg/dL:LDL-c-lowering drug optional)

*Some authorities recommend use of LDL-c-lowering drugs in this category if an LDL c <100 mg/dL cannot be achieved by therapeu-tic lifestyle changes. Others prefer use of drugs that primarily modify triglycerides and HDL, e.g., nicotinic acid or fibrate. Clinical judg-ment also may call for deferring drug therapy in this subcategory.

†Almost all people with 0–1 risk factor have a 10-year risk <10%, thus 10-year risk assessment in such people is not necessary.

SOURCE: NCEP 2001


HEDIS 2002, Vol. 2: Technical Specifications. 2001. Washington: Na-tional Committee for Quality Assurance.

InterStudy Competitive Edge: HMO Industry Report 11.2. Availableat: «http://www.mcareol.com/factshts/factnati.htm». Accessed Aug. 30, 2002.

LaRosa JH, LaRosa JC. Enhancing drug compliance in lipid-loweringtreatment. Arch Fam Med. 2000;9:1169–1175.

Lee TH, Cleeman JI, Grundy SM. Clinical goals and performancemeasures for cholesterol management in secondary preventionof coronary heart disease. JAMA. 2000;283:94–98.

Mottur-Pilson C, Snow V, Bartlett K. Physician explanations for fail-ing to comply with “best practices.” Eff Clin Pract.2001;4:207–213.

NCEP (National Cholesterol Education Program). Executive sum-mary of the third report of the National Cholesterol EducationProgram expert panel on detection, evaluation, and treatment

of high blood cholesterol in adults (Adult Treatment Panel III).JAMA. 2001;285(19):2486–2497.

National Committee for Quality Assurance. Diabetes quality improve-ment project initial measure set (final version). Available at:«http://www.ncqa.org/dprp/dqip2.htm». Accessed Aug. 30, 2002.

National Committee for Quality Assurance. Health plan report card.Available at: «http://hprc.ncqa.org/index.asp». Accessed Aug.30, 2002.

National Committee for Quality Assurance. The State of ManagedCare Quality 2001. Available at:«http://www.ncqa.org/somc2001/». Accessed Aug. 30, 2002.

Quality Compass 2001. Washington: National Committee for Qual-ity Assurance.

Roski J, Gregory R. Performance measurement for ambulatory care:moving towards a new agenda. Int J Qual Health Care.2001;13:447–453.


Effective leadership distinguishes organizations thatwill produce breakthroughs in disease manage-ment (DM) from those that settle for marginal

gains. Improving patient behaviors is directly related toimproving the processes physicians use to identify at-riskpopulations and to motivate patients. Behavior-changetheories suggest that physicians become effective catalystsfor changes in patient behavior when they have tools toshow patients their susceptibility to health problems andto demonstrate to patients that without some behaviorchange, the outcomes of their present practices could besevere. Moreover, the degree towhich a DM program modifies thebehavior of clinical providers isoften the most telling predictor ofan organization’s ability to modifypatients’ health practices. Whetheran organization is developing inter-nal DM initiatives or contractingsuch services with vendors, it is thecapabilities relative to process im-provement and support for patientbehavior change that ultimately de-termine a program’s effectiveness.

To serve as change agents, physi-cians need to understand the pro-cesses that affect their ability toidentify and monitor patient prac-tices, and to adapt their practice en-vironment continually to maximize their ability to sup-port changes in patient behavior that promote goodhealth. Two common examples of systems for change: re-minder systems for identifying when patients are due forpreventive exams and flagging the charts of smokers.

Additionally, patients need support in gaining an un-derstanding about the risks and benefits of their lifestyleand self-care choices, as well as assistance in finding psy-chological and environmental support for improvement.Stages of change theory, also known as the transtheoreti-cal model, is a popular concept for understanding a pa-tient’s readiness to make lifestyle changes and to complywith a new therapeutic regimen (Prochaska, 1997).

Principles of process management in organizationssuggest that we can change physicians’ practices, im-proving work processes that are flawed, inefficient, or re-dundant (Eckes, 2001). Too often, however, DM initia-

tives focus on either organizational processes or indi-vidual behavior, whereas effective leaders recognize thecontributions of both in achieving the goals of DM.

Formal methodologiesFormal methodologies to improve work processes,

such as Six Sigma, often are used by manufacturing com-panies and, increasingly, by the health care industry. Justas behavior change theories imply that individuals varyin their readiness for change, process-management prin-ciples assume that an organization has work processes in

place, whether good or bad.To clarify the use of the term

“work processes,” consider that onan individual level, a person’s daymay be perceived as a set of coreprocesses — getting up, going towork, working, coming home, wind-surfing, etc. Further, each core pro-cess then can be divided into sub-processes that may be targeted forquantifiable improvement. In ahealth plan, for example, improv-ing the health of a population wouldbe a core process, whereas dyslipi-demia management would be a sub-process.

George Eckes, a consultant whoadvises Park Nicollet Health Services

(an integrated health system in Minnesota) on processmanagement, recommends that within a given coreprocess, no more than five or six subprocesses should beselected for improvement. This sharpens the leadershipfocus, helping to move an organization forward more ef-fectively. The most important criteria for determining anorganization’s high-priority subprocesses are (1) whichsubprocess provides the greatest return on investmentand (2) which subprocess is in the greatest need of im-provement. Similarly, transtheoretical-model researchsuggests that “decisional balance,” the gains and lossesfrom an individual choice, is operational when a personmoves from one stage of readiness for change to the nextstage. Conceptually, then, the most powerful change ini-tiative would be one in which a subprocess is selected anddesigned to match the stage of readiness of the targetpopulation.


Innovation in Disease ManagementPAUL E. TERRY, PHD

President, Park Nicollet Institute

PA U L E . T E R R Y, P H D

Six SigmaSix Sigma, when used in the context of process man-

agement, is a term credited to a Motorola statisticiannamed Mikel Harry. Six Sigma is a method for studyingprocess variation. Such variation, when measured sta-tistically, can be expressed as standard deviations from amean — hence, the use of the Greek expression for sigma.When statistical measurement is used to indicate how fara given process deviates from a specification desired bythe patient, Six Sigma essentially becomes a device formeasuring how far an organization is from perfection.

For example, a patient’s expectations as to how manyerrors per million transactions are acceptable for read-ing a throat culture correctly will differ from the error ratethat patient would be willing to accept relative totargeting the proper limb for surgery.

In many respects, this processimprovement approach mir-rors the behavior-change con-cept of stages of change and thevariability of individuals’ readi-ness to change habitual behaviors.In practice, Six Sigma is a quanti-tative methodology that enables anorganization to achieve various im-provements in quality by using theDMAIC method — Define, Measure,Analyze, Improve, and Control.

The stages of change methodology sug-gests that in caring for patients with chronicdisease, practitioners use the following stagesto identify a patient’s level of readiness forchange: precontemplation, contemplation, prepa-ration, action, and maintenance. Stages of changetheory thus enables the process change engineer,whether a physician or systems improvementadministrator, to improve patient behavior byaligning clinical processes with the appropri-ate level of readiness. For example, the addi-tion of a reminder system to trigger preventiveexams may be useful for moving patients froma contemplation to an action stage of readi-ness, while a patient-surveillance system isneeded for patients who have made changes in healthpractices and are in the maintenance stage.

In theory, Six Sigma can be applied to the work pro-cesses of any organization. So far, it has been appliedchiefly by large corporations, typically publicly heldmanufacturers. For Six Sigma to be helpful in the chal-lenging health care environment, most health plans willneed to upgrade their organizational structures (Wessner,2002). In manufacturing, marketers, product developers,and systems engineers team up to change processes. Inhealth care, the involvement of senior leaders, physi-cians, pharmacists, patients, nurses, marketers, recep-


tionists, and others may be needed to determine both thedesired specifications and the best process for achievingperfection. The impact of what may appear to be a sim-ple change can be strongly felt by those on a team devotedto service but accustomed to time-honored routines.

DM necessitates dependable support people and ex-perts in population health. Currently, these experts tendto be unavailable in the average health care organization.Because it is costly and complicated, Six Sigma needs oneor more champions who can marshal financial resourcesand internal support. Six Sigma will not succeed unlessmanagement subscribes to the concept that improve-ment of clinical work processes, as well as patient-behavioral assessment and intervention, are critical to aDM program’s success.

Health systems that incorporateDM programs that rely oneither process change or pa-

tient behavior change, insteadof coordinating both of these

strategies, will be ineffective.AtPark Nicollet, which is commit-

ted to both process managementand patient-behavior change, we

initiated a dyslipidemia manage-ment project in 1998. The results

have been encouraging. As of thefirst quarter of 1999, only 50 percent

of eligible patients had their lipidlevels measured, but by the fourth

quarter of 2001, 80 percent of eligiblepatients were being screened. Im-

provements in the rate of lipid testingwere accompanied by improvements in

the percentage of tested patients whosucceeded in reducing their low-densitylipoprotein cholesterol (LDL-c) to a con-centration below 130 mg/dL (Jarvis,2001).

There were three keys to the improve-ment of our work processes and patienteducation related to dyslipidemia man-agement. First, we employed a team ap-

proach in which physicians worked closely with nursingstaff. Nancy Jarvis, MD, a medical director at Park Nicol-let, designed data surveillance process changes and ledcontinual educational sessions that taught physicianshow to use data about their patient population to iden-tify patients in need of preventive services. Patient in-formation about preventive services guidelines that werespecific to their patients’ age and gender was made avail-able. Stages of change theory shows that the provision ofinformation is needed most when moving peoplethrough the early stages of readiness.Accordingly, we gavepatients specific information about their individual sus-

FIGURE 1 Park Nicolletpatients receive dyslipi-demia information specifi-cally when they are in earlystages of readiness for it.


ceptibility to dyslipidemia and about preventive measuresthat can be taken (Figure 1).

Second, we put population-based measurement sys-tems and improved work processes into place. Givingphysicians data that demonstrate that their performancewas only average or below average proved to be especiallymotivational, because every physician wants to be aboveaverage.

Finally, additional patient-education materials wereused to reinforce those patients taking action to managetheir cholesterol levels. During office visits last year, wegave an educational brochure to 20,000 patients whowere candidates for lipid measurement. From relatedprojects, we’ve learned that patient satisfaction improveswhen the patient gets the educational materials from thephysician at the office rather than in a mailed envelopeat a different time (Terry and Healey, 2000). In turn, thelikelihood that physicians will be seen as a resource forhelping patients maintain their therapeutic regimen in-creases.

Management modelsThe precise details of what was done at Park Nicollet

are of little consequence, however, because a successfulstrategy for improving work processes and patient be-havior at one organization may fail at another. Organi-zations have different cultures and organizations, andtheir leaders have different styles and practices.

Leadersource, a leadership-development company inMinneapolis, describes one model involving the inter-action of three variables affecting interpersonal rela-tionships — personal power (“I”), relational power(“we”), and contribution to the organization (“it”). Lead-ers use all three types of power, rather than rely too heav-ily on one dimension, in the effort to reach their goals(Leadersource, 2002).

The degree to which these three components are in-tegrated in a person, team, or organization gives rise tocertain sets of values. More often, core values in leader-ship predict success in making systems changes than thesystems-change process or methodology that is used.

Identifying the prevailing leadership dynamic in an or-ganization is a good first step in determining an organi-zation’s readiness for designing or improving DMprocesses. Three models from Leadersource are brieflydescribed below, along with suggestions about how theshortcomings inherent in each model might explain whyorganizations so often miss the need for improving sys-tems as well as personal behavior.

“Heroic” model. In a heroic leader, team, or organi-zation, the “we” component of the dynamic is subordi-nated to the “I”and “it”components. Such leaders believethat they must drive themselves because they are incharge. It is their responsibility. Further, they perceivethemselves as being able to outperform all others —

other people just slow down the process and get in theway. This is a focus on individual behavior change at theexpense of systems changes.

Too often, well-intentioned leaders impose paternal-istic programs or policies aimed at getting patients tomake better choices. Economic penalties for smokers ormandatory participation in health education sessionswould be an example of the encouragement — or per-haps it is coercion — that comes from a heroic leader. ForDM initiatives to succeed, heroic leaders need to focusmore on engaging the competing views of others andchanging the environment of the organization. Behaviorchange rarely occurs, even in the most ready of popula-tions, if systems and support processes are not aligned tosupport healthier practices.

“Organizational” model. In organizational leaders,the “it” component overshadows the personal and rela-tional components. Whatever the organization wants istheir purpose. These leaders are characterized by the be-lief that results are everything — and that without orga-nizational achievement, the individual does not exist.Inherent in this leadership style is a strong tendency forsystems thinking to dominate at the expense of an ap-preciation for the role of individual. While it is true thatchanging the environment can go a long way towardshaping individual choices, it remains that humans arefar more complex than mice in a maze. Organizationalleaders need to focus on behavior change models like thestages of change theory that address purpose and valuesat the level of the individual as well as the team.

“Good time” model. In a culture that values cooper-ation, the good time model prevails, in which the “we”component dwarfs “I” and “it.” Having fun and workingharmoniously are the top priorities within this leadershipmodel, because it is characterized by the view that every-one must be happy. While valuing cooperation may leadto attempts to integrate both systems thinking and per-sonal-health management approaches, the preferencefor harmony diminishes the drive it takes to move physi-cians and patients toward improvement. People withthis leadership dynamic need to focus more on their in-dividual and collective leadership and to pay more at-tention to producing tangible and sustainable outcomes.

Obviously, some of these models are incompatiblewith a rigorous system for improving quality in an or-ganization. There would be little point in attempting toinstitute Six Sigma in a culture with a strong good timeleadership dynamic, for example. Such a culture must bemodified first, or at least be amenable to modification.

The heroic model — strong physicians acting inde-pendently and looking out for the welfare of their ownpatients — still prevails in health care. Modern medicineis too complex, however, for a single physician, no mat-ter how strong and well-intentioned, to develop andmanage work processes or to change patient behavior


through persuasion alone. A team approach is neededthat includes both process and behavior change sensi-tivity. The heroic model calls for a different kind of lead-ership.

“Authentic” leadershipA leadership style that appreciates the need

for concurrent work in systems changeand health promotion is characteris-tic of the authentic leader modelespoused by Robert Terry (no re-lation to this author). Terry(1993) writes: “Leadership in-volves knowing what is reallygoing on inside ourselves andoutside in the world, making wisedecisions based on diagnosis, hav-ing the courage to act with follow-through and the humility to serve coreethical principles and deep abiding andemerging truth.”

This view of leadership fits well withhealth-promotion professionals, whosework is grounded in improving thelives of others and in improvingthe systems that allow that to hap-pen. It is also a view that confrontstoday’s preoccupation with single-source solutions or approaches that try to engineer theperson out of the improvement equation. To bring aboutimprovements in DM, it is necessary to acknowledgehuman failings and frailties along with a conviction rel-ative to the pursuit of perfection. It also will necessitateequal measures of investment to enable individual changeand enact systems change. Leadership that addressesthese polarities, embracing both the humanistic andpragmatic aspects of health improvement, is character-istic of the authentic leader (Figure 2).

Supporting changeIn a culture that supports change, the start-up phase

of a lipid management program requires the presence ofa clinical department amenable to change; a committed,passionate physician leader; and funding sources. In ad-dition to the department’s ability to absorb some finan-cial losses during the start-up phase, funding could beprovided by a combination of government and privategrants as well as support from the pharmaceutical in-dustry. To sustain the program, a talented support staff isneeded along with an understanding of the technicaltools used for process improvement and diverse revenuesources, such as earned revenue and additional grants andgifts. By calling public attention to the program’s successesthrough peer-reviewed publications and presentationsat national professional meetings (in addition to internal

presentations), further support can be garnered. Thoughthere is some evidence that DM programs can savemoney, most efforts in this regard have not been subjectedto rigorous analysis (Wagner, 1998). Ideally, federal andinsurance reimbursement policies will change to accom-modate DM programs, once such programs can regularly

demonstrate cost effectiveness.In implementing the program, oneimproved work process will be

characterized by a reliance onhealth education experts whouse the latest tools to facilitatebehavior change in patients.Our studies have shown thatwell-designed patient education

programs improve satisfactionwith the physician visit, reduce the

number of unnecessary visits, in-crease utilization, and heighten knowl-edge about the need for preventive ser-vices (Terry, 2002). With process-management systems like Six Sigma inplace, as much as 30 percent of an orga-

nization’s cost can be reduced byeliminating repetitive work anddefective output (Wessner, 2002).

In turn, the more that patientsknow about their health, the more

involved they can be in their care and the better the over-all result of their health care experience will be.

ReferencesEckes G. The Six Sigma Revolution. Danvers, Mass.: John Wiley

and Sons Inc.; 2001.

Jarvis N, Spurr C, Abelson D, Bissen J. Innovations in caring forhigh-risk patients. Compendium 2001. American MedicalGroup Association, 2001.

Leadersource Ltd., Minneapolis. Executive to Leader Institute,2002.

Prochaska JO, Velicer WF. The transtheoretical model of behav-ior change. Am J Health Promot. 1997:12;38–48.

Terry PE. Medical self-care. In: O’Donnell MP, ed. Health Promo-tion in the Workplace. 3rd ed. Albany, N.Y.: Delmar Press;2002:363–388.

Terry PE, Fowler EJ, Fowles JB. Are health risks related to medi-cal care charges in the short-term? Challenging traditionalassumptions. Am J Health Promot. 1998;12:340–347.

Terry PE, Healey ML. The physician’s role in educating patients:a comparison of mailed versus physician-delivered patienteducation. J Fam Pract. 2000;49:314–318.

Terry R. Authentic Leadership: Courage in Action. San Francisco:Jossey-Bass Publishers; 1993.

Wagner EH. Chronic disease management: What will it take toimprove care for chronic illness? Effective Clinical Pract.1998;1:2–4.

Wessner DK. Six sigma. A tool for leadership in health care.MetroDoctors. 2002;4:4–6.

Authenticleadership

Process management

Innovation in disease manage-

ment

Patient behavior change

FIGURE 2 Authentic leadership achievespositive outcomes in DM by aligning systemchange with behavior-change incentives.


CONTINUING EDUCATION ANSWER SHEET/CERTIFICATE REQUESTTransforming Dyslipidemia Management

Sponsored by the University of Arizona College of Medicine at the Arizona Health Sciences Center

Name _________________________________________FIRST MI LAST

Title __________________________________________

Specialty_______________________________________

Address _______________________________________

City ___________________________________________

State ___________________________ ZIP ___________

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Physician — Maximum of 2 hours in category 1credit.This learning module may be used for category 1 credit through Sept. 25, 2003.

Complete answer sheet/evaluation form and mail to:

Continuing Medical EducationUniversity of Arizona College of MedicinePO Box 245121Tucson, AZ 85724-5121

Alternately, you may fax this completed sheet to:(520) 626-2427.

Credit will be awarded upon successful completionof assessment questions (80 percent or better) andcompletion of program evaluation. If a score of 80percent or better is not achieved, no credit will beawarded and the registrant will be notified.

Please allow up to six weeks for processing.

The cost of this activity is provided at no charge to the participant through an unrestricted educa-tional grant by AstraZeneca.

EXAMINATION: Place an X through the box of the let-ter that represents the best answer to each question onpage 29. There is only ONE answer per question. Placeall answers on this answer form:

A. B. C. D.1. �� 2. �� 3. �� 4. �� 5. �� 6. �� 7. �� 8. �� 9. ��

10. �� 11. �� 12. ��

PROGRAM EVALUATIONSo that we may assess the value of this self-study program,we ask that you please fill out this evaluation form.

Overall activity ratingExcellent Very good Good Fair Poor

5 4 3 2 1

Were the educational objectives met?A great deal Not at all

5 4 3 2 1

Will this activity benefit you and improve patient care?Very much Very little

5 4 3 2 1

What other topics would you like to see addressed?________________________________________________________________________________________________

Give an example of what you will do differently in yourpractice as a result of participating in this activity:________________________________________________________________________________________________

Did you detect any bias in this presentation?Yes ___ No ___

If yes, explain: _____________________________________________________________________________________

Comments:________________________________________________________________________________________________________________________________________________

CME Credit for PHYSICIANS See page 28 for answer sheet for pharmacists


CONTINUING EDUCATION ANSWER SHEET/ REQUEST FOR STATEMENT OF CREDITTransforming Dyslipidemia Management

Sponsored by the University of Arizona College of Pharmacyat the Arizona Health Sciences Center

Name _________________________________________FIRST MI LAST

Specialty_______________________________________

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______________________________________________

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State ___________________________ ZIP ___________

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Pharmacist — This program is approved for 2 contact hours (0.2 CEU).

ACPE program number: 003-999-02-031-H01.Expiration date: Sept. 25, 2003.

Complete answer sheet/evaluation form and mail to:

Office of Continuing EducationUniversity of Arizona College of PharmacyPO Box 210207Tucson, AZ 85721-0207

Alternately, you may fax this completed sheet to(520) 626-2023.

Credit will be awarded upon successful completionof assessment questions (70 percent or better) andcompletion of program evaluation. If a score of 70percent or better is not achieved, no credit will beawarded and the registrant will be notified.

Please allow up to six weeks for processing.

The cost of this activity is provided at no charge to the participant through an unrestricted educa-tional grant by AstraZeneca.

CE Credit for PHARMACISTSEXAMINATION: Place an X through the box of the let-ter that represents the best answer to each question onpage 29. There is only ONE answer per question. Placeall answers on this answer form:

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PROGRAM EVALUATIONTo receive pharmacy credit, please provide all informationrequested below.This will assure prompt and accurateissuance of your continuing education credit.

Please rate this program as follows:

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CONTINUING EDUCATION QUESTIONSTransforming Dyslipidemia ManagementDirections: Please tear out the combined answer sheet/assessment form on page 27 (physicians) or 28 (pharma-cists). On the answer sheet, place an X through the box of the letter corresponding with the correct response foreach question.

5. The enzyme acyl-CoA: choles-terol acyltransferase is re-sponsible for:a. Synthesis of mevalonate in

the cholesterol pathwayb. Storage of cholesteryl ester in

foam cellsc. Loading neutral lipoproteins

onto apolipoprotein Bd. Transfer of cholesterol from

HDL to VLDL in exchange fortriglycerides

6. A side effect associated withinhibitors of bile acid trans-port is:a. Tachycardiab. Bradycardiac. Diarrhead. Flushing

7. In determining an organiza-tion’s high-priority sub-processes, it is advisable tolook at which subprocess provides the greatest returnon investment and which subprocess is in the greatestneed of improvement.a. Trueb. False

8. Transtheoretical model research suggests that “decisional balance” is operational when a personmoves from one __________ to the next.a. organizational levelb. stage of readiness for changec. career pathd. health plan

9. The ______________ changeinitiative would be one inwhich a subprocess is selectedand designed to match thestage of readiness of the target population.a. most unusualb. most controversialc. most powerfuld. most ineffective

10. In ATP III, modification of lipidand lipoprotein classification:a. Identifies LDL cholesterol

<100 mg/dL as optimalb. Raises categorical low HDL

cholesterol to <40 mg/dLc. Lowers the triglyceride

classification cutpointsd. All of the above

11. Which of the following statements is true?a. Cardiovascular risk ceases

once LDL-c concentrationsdrop below 130 mg/dL.

b. Cardiovascular risk ceasesonce LDL-c concentrationsdrop below 100 mg/dL.

c. Cardiovascular risk is acontinuous function thatdoes not stop once LDL-cconcentrations drop below130 mg/dL or 100 mg/dL.

d. None of the above.

12. ATP III emphasizes:a. Absolute lipid levelsb. Relative lipid levelsc. Risk factorsd. Family history

1. Which of the following is not a strategy for reducing veryhigh LDL-c?a. Niacinb. High-dose statin

monotherapyc. Statins plus bile acid

sequestrantsd. Statins, bile acid sequestrants,

and niacin

2. Diabetic dyslipidemia is worrisome, because it is:a. Very difficult to diagnoseb. Very difficult to treatc. More atherogenic than other

dyslipidemiasd. A direct cause of diabetic

retinopathy

3. The primary goal of therapyunder the ATP III guidelines is:a. Reducing levels of LDL-cb. Reducing levels of

triglyceridesc. Reducing levels of HDL-cd. Increasing levels of HDL-c

4. Ezetimibe lowers LDL-c by:a. Binding bile acids in the

intestineb. Inhibiting HMG-CoA

reductasec. Inhibiting uptake of

cholesterol by enterocytesd. Inhibiting lipoprotein lipase

2002 medical director colloquycolloquy

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