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Introduction: Utilization of SurrogateMarkers of Atherosclerosis forthe Clinical Development of
Pharmaceutical AgentsMichael H. Davidson, MD
Low-density lipoprotein cholesterol (LDL-C) is cur-rently the primary established therapeutic targetfor cardiovascular disease (Table 1).1 However, re-search indicates that other lipoproteins (high-densitylipoprotein [HDL], apolipoprotein-B, and lipopro-tein[a]) may also be useful for stratifying patients atrisk for cardiovascular disease for drug therapy. Overthe past 5 years, advances in the understanding oflipoprotein metabolism and the pathogenesis of ath-erosclerosis have led to a significant increase in thepotential for therapeutic targets. This has further led toa large number of new drugs and genetic targets in thedevelopment pipeline (Figure 1, Table 2). To advancethese drugs through the US Food and Drug Adminis-tration (FDA) approval process for clinical use willmost likely require surrogate markers.
During a satellite meeting at the International Sym-posium on Atherosclerosis in Stockholm, Sweden, onJune 27, 2000, leading researchers discussed the useof surrogate markers of atherosclerosis for clinicaldevelopment of pharmaceutical agents. The session,which I organized and introduced entitled The Utili-zation of Surrogate Markers of Atherosclerosis for theClinical Development of Pharmaceutical Agents.
What is a surrogate marker? Surrogate markershave to predict risk of coronary disease, and improve-ment in the marker must correlate with improvementin the atherosclerotic process. However, we have toask, ideally, whether it is required that the markercorrelate with a reduction in cardiovascular events.
What is the rationale for using surrogate markers?Primarily it is a result of increasing ethical concernsabout long-term morbidity/mortality trials that includea placebo group. Surrogate markers can reduce thetime and cost of evaluating certain therapies that maybenefit populations at risk. Surrogate markers are alsouseful in evaluating the impact of other lipoproteinson the atherosclerotic process (e.g., triglycerides,HDL, lipoprotein[a]) or novel mechanisms to lowerLDL low-density lipoprotein (LDL) (e.g., microsomaltriglyceride transfer protein [MTP] inhibitors, squalenesynthase, or cyclase inhibitors). They are also usefulfor identifying antiatherosclerotic drugs that do not
significantly affect lipoproteins (e.g., cholesterol acyl-transferase inhibitors, matrix metalloprotease inhibi-tors).
Table 3 outlines under what circumstances surro-gate endpoints are required for FDA approval of var-ious drugs. The FDA presently requires a minimum15% decrease in LDL, non-HDL, or apolipoprotein Bfor systemic drugs.
Use of surrogate risk predictors of improvement inatherosclerosis will enhance the ability to do clinicaltrials by enabling researchers to accumulate a higher-risk population and conduct trials in a shorter timeframe with fewer patients. One of the best models forpredicting risk is the adapted Framingham Global
From the Chicago Center for Clinical Research, Chicago, Illinois,USA; and Department of Preventive Cardiology, Rush-PresbyterianSt.Lukes Medical Center, Chicago, Illinois, USA.
Address for reprints: Michael H. Davidson, MD, Chicago Centerfor Clinical Research, 515 North State Street, Suite 2700, Chicago,Illinois 60610-4324.
TABLE 1 National Cholesterol Education Program TreatmentRecommendations and Goals According to Risk Status*
Treatment/Risk StatusLDL-C Goal
Dietary therapyWithout CAD and ,2 risk factors ,160Without CAD and $2 risk factors ,130With known CAD #100
Drug treatmentWithout CAD and ,2 risk factors ,160Without CAD and $2 risk factors ,130With known CAD #100
CAD 5 coronary artery disease; LDL-C 5 low-density lipoprotein cholesterol.*Adapted from JAMA.1
Michael H. Davidson, MD
1A2001 by Excerpta Medica, Inc. 0002-9149/01/$ see front matterAll rights reserved. PII S0002-9149(01)01418-7
FIGURE 1. Lipoprotein metabolism. ABC 5 adenosine triphosphate binding cassette protein; ABCG 5 adenosine triphosphate bindingcassette protein G1 transport; Apo A1 5 apolipoprotein A1; CE 5 cholesteryl ester; CETP 5 cholesterol ester transfer protein; FC 5free cholesterol; HDL 5 high-density lipoprotein; HL 5 Hepatic lipase; HMG-CoA 5 3-hydroxy-3-methylglutaryl coenzyme A; IBAT 5illeal bile acid transport; LCAT 5 lecithin cholesterol acyl transferase; LDL 5 low-density lipoprotein; MTP 5 microsomal transfer pro-tein; SR-A 5 scavenger receptor A; SR-B1 5 scavenger receptor B1; VLDL 5 very-low-density lipoprotein.
TABLE 2 Current Status of Potential Therapeutic Targets
Potential Therapeutic Targets Status
Upregulate ABC-1 Animal testingInfuse nascent HDL or Apo A-I/Apo A-I Milano Early human testingUpregulate LCAT Animal testingInhibit hepatic lipase Animal testingInhibit CETP Phase 2
c Oral CETP inhibitorc Anti-CETP immunization
Upregulate SR-B1 Animal testingInhibit MTP and VLDL assembly Early human testingUpregulate ABCG1 Animal testingInhibit bile acid reabsorption FDA approved: cholestyramine, colestipol, colesevelamInhibit cholesterol absorption or reabsorption Phase 3
c EzetimibeInhibit IBAT Phase 3Upregulate LDL receptors
c Inhibit HMG-CoA reductase (statins) FDA approved: lovastatin, pravastatin, simvastatin, cerivastatin, fluvastatin, atorvastatinPhase 3: rosuvastatinPhase 2: NK104
c Inhibit squalene synthase Early human testingc Inhibit squalene cyclase Early human testing
Inhibit VLDL secretion FDA approved: Niaspan, gemfibrozil, fenofibrateActivate LPL FDA approved: gemfibrozil, fenofibrate
Phase 2: NO-1896Inhibit ACAT Phase 2: avisimbeIncrease HDL synthesis FDA approved: Niaspan
Phase 2: CI-1027PPAR -a, -g, -d (multiple potential effects) Phase 2
ABC-1 5 adenosine triphosphate binding cassette protein; ABCG1 5 adenosine triphosphate binding cassette G1 transport; ACAT 5 acyl coenzyme A: cholesterolacyltransferase; Apo 5 apolipoprotein; CETP 5 cholesterol ester transfer protein; FDA 5 US Food and Drug Administration; HDL 5 high-density lipoprotein;HMG-CoA 5 3-hydroxy-3-methylglutaryl coenzyme A; IBAT 5 ileal bile acid transport; LCAT 5 lecithin cholesterol acyltransferase; LDL 5 low-density lipoprotein;LPL 5 lipoprotein lipase; MTP 5 microsomal triglyceride transfer protein; PPAR 5 peroxisome proliferator-activated receptor; SR-B1 5 scavenger receptor B1; VLDL 5very-low-density lipoprotein.
2A THE AMERICAN JOURNAL OF CARDIOLOGYT VOL. 87 (4A) FEBRUARY 16, 2001
Risk Score (Tables 4 and 5).2 The question is, Willother surrogates, such as electron beam computedtomography, anklebrachial index, carotid ultrasound,magnetic resonance imaging, and brachial artery re-activity, improve on the predictability of the Framing-ham Global Risk Score? For example, anklebrachialindex appears to enhance our predictability for pa-tients at risk for both coronary artery disease andstroke (Figure 2).3
We also have to consider what are the best surro-gates. Is LDL the best predictor of risk, or is apoli-poprotein B preferred for assessing the effects of drugtherapy? Because non-HDL correlates very closelywith apolipoprotein B, perhaps non-HDL is more pre-dictive than LDL for patients at risk for cardiovascularevents. Figure 3 compares major coronary events ontreatment non-HDL versus LDL in the ScandinavianSimvastatin Survival Study (4S) trial.4 As demon-strated in Figure 3, non-HDL appears at least as ef-fective, and perhaps more linear, than LDL as a pre-dictor of cardiovascular events.4 As further demon-strated in Figure 4, apolipoprotein B appears quitelinear in its relation to cardiovascular mortality in the4S trial.4 Figure 5 demonstrated in overlap analysisthat lovastatin-treated patients in the Air Force/TexasCoronary Atherosclerosis Prevention Study (AF-CAPS/TexCAPS) had a lower event rate than patientsin the placebo group with the same LDL-C value atyear 1.5 In Figure 6, using apolipoprotein B versusLDL as the variable, the overlapping difference be-
tween lovastatin and placebo was significantly nar-rowed, and the estimated percentage of patients withendpoints was related to apolipoprotein B in a morelinear fashion than LDL-C. Apolipoprotein B/apoli-poprotein A-I was the most predictive variable in theAFCAPS/TexCAPS trial (Figure 7).5 Further, to sup-port the hypothesis that apolipoprotein B rather thanLDL-C should be the primary endpoint for FDA ap-proval, the Heart Estrogen Progesterone ReplacementStudy (HERS) failed to demonstrate a decrease inclinical events in women with coronary artery diseasedespite reductions in LDL-C (Figure 8).6 Althoughapolipoprotein B has yet to be measured in the HERScohort, other studies have indicated that apolipopro-tein B is only slightly decreased with hormone re-placement therapy and in patients with hypertriglyc-eridemia (pattern B), estradiol may increase apoli-poprotein B levels (Figure 9).69 In a post-hoc analysisof the HERS cohort, patients with increased lipopro-tein(a) and decreased triglyceride values appeared tobenefit from hormone replacement therapy, but pa-tients with increased triglycerides and decreased li-poprotein(a) appeared at increased cardiovascular riskwith hormone replacement therapy.7 Therefore, thefailure of hormone replacement therapy to decreaseapolipoprotein B may partially explain the lack ofclinical benefit in cardiovascular event reduction inpostmenopausal women with coronary artery disease.
The articles in this supplement to The AmericanJournal of Cardiology address the following issues:
FIGURE 2. Percentage of elderly men with coronary artery disease (CAD) and stroke bypresence or absence of abnormal anklebrachial index. (Adapted from Arterioscler ThrombVasc Biol.3)
TABLE 3 Surrogate Endpoints Required for US Food and Drug Administration D