In the treatment of cardiovascular disease (CVD), national

Transcription

1 n report n Beyond LDL Cholesterol: The Role of Elevted Triglycerides nd Low HDL Cholesterol in Residul CVD Risk Remining After Sttin Therpy Peter Algon Jr, MD, FACC In the tretment of crdiovsculr disese (CVD), ntionl guidelines nd mny helthcre professionls focus on lowdensity lipoprotein (LDL) cholesterol. However, rther thn viewing LDL cholesterol level s therpeutic end point, helthcre professionls should consider modifiction of therothrombosis nd prevention of CVD events s the gol of ny lipid-ltering therpy or preventive strtegy. Tretments for mture CVD, including mechnicl revsculriztion, should be considered pllitive therpies tht help tret n episode in wht is chronic disese process. Mny ptients who undergo these interventions re going to hve dditionl or repet procedures relted to the progression of coronry rtery disese (CAD) or peripherl rteril disese. Consequently, it is importnt to recognize tht for these ptients to decrese their risk of recurrent events, they need to utilize every ggressive, preventive tretment strtegy vilble. This my include ddressing severl non-ldl cholesterol lipid prmeters. 1 Approximtely 28% of dults in the United Sttes hve high LDL cholesterol nd third or more hve high triglycerides (TGs) nd/ or low high-density lipoprotein (HDL) cholesterol. Almost 5% of dults hve t lest 1 lipid bnormlity. 2 One of the most effective clsses of medictions for preventing crdiovsculr events is hydroxymethylglutryl-coenzyme A reductse inhibitors, or sttins. However, exmintion of sttin clinicl tril dt revels tht significnt number of ptients being treted continue to experience crdiovsculr events. In the 4S (Scndinvin Simvsttin Survivl Study) tril, which studied ptients with very high LDL cholesterol levels nd known coronry hert disese (CHD), significnt risk reduction ws observed with sttin tretment. Although the reltive risk of mjor crdiovsculr event decresed by pproximtely one third, the results from 4S lso indicte tht over the study s durtion lmost 2% of sttin-treted ptients hd crdiovsculr event. 3 Indeed, dt collected from severl mjor sttin trils hve consistently reveled the existence of significnt residul crdiovsculr risk even fter lrge reductions of LDL cholesterol (Figure 1). 3-8 Additionl trils hve included high-risk ptients with CHD or dibetes mellitus who were treted with intensive LDLlowering sttin therpy. In the PROVE IT-TIMI 22 (Prvsttin or Atorvsttin Evlution nd Infection Therpy Thrombolysis in Mnged Cre & Helthcre Communictions, LLC Abstrct Mnged cre inititives to reduce crdiovsculr disese (CVD) risk hve, to dte, focused lmost exclusively on sttins, which re primrily low-density lipoprotein cholesterol lowering gents nd hve limited effects on triglycerides nd highdensity lipoprotein (HDL) cholesterol t commonly used doses. Significnt residul CVD risk (ie, risk of recurrent CVD events) remins fter tretment with sttins nd my stem, t lest prtilly, from low HDL cholesterol nd/or elevted triglycerides. Consequently, ntionl tretment guidelines suggest tht combintion therpy my be necessry to ddress multiple lipid trgets nd dding nicin or fibrte to sttin is strtegy to be considered. Recent clinicl tril evidence hs demonstrted the efficcy of nicin/sttin nd fenofibric cid/sttin combintion therpies in treting multiple lipid bnormlities. (Am J Mng Cre. 29;15:S65-S73) For uthor informtion nd disclosures, see end of text. VOL. 15, No. 3 n The Americn Journl of Mnged Cre n S65

2 Report n Figure 1. Residul CVD Risk After Sttin Therpy Ptients Experiencing Mjor CHD Events, % 35% % 28% 29% 26% 25% In mjor sttin trils, significnt reductions in CHD events occur with sttins compred with plcebo. However, substntil percentge of mjor CHD events still occurs in the sttin-treted groups. 3-8 AFCAPS/TexCAPS indictes Air Force/Texs Coronry Atherosclerosis Prevention Study; CARE, Cholesterol nd Recurrent Events; CHD, coronry hert disese; CVD, crdiovsculr disese; 4S, Scndinvin Simvsttin Survivl Study; HPS, Hert Protection Study; LDL, low-density lipoprotein; LIPID, Long-Term Intervention with Prvsttin in Ischemic Disese; WOSCOPS, West of Scotlnd Coronry Prevention Study. Myocrdil Infrction 22) study, 4162 ptients with cute coronry syndromes (ACS) were treted with either prvsttin 4 mg or torvsttin 8 mg. 9 Clinicl events were further reduced in the high-dose torvsttin group compred with the prvsttin group; however, during the 2-yer tril, 22.4% of the individuls treted with high-dose torvsttin still suffered mjor CVD event despite chieving men LDL cholesterol levels of 62 mg/dl. 9 Similr results were observed in the IDEAL (Incrementl Decrese in End Points Through Aggressive Lipid Lowering) nd TNT (Treting to New Trgets) studies, which further demonstrted tht significnt residul CVD risk remins in ptients even fter intensive sttin therpy tht chieves LDL cholesterol gols well below 1 mg/dl It is interesting to note tht evidence suggests only modest benefits re provided by lowering LDL cholesterol from 1 to 7 mg/dl, nd some investigtors believe cogent dt supporting the use of higher sttin drug dosges nd their greter costs nd possible toxicity re limited. 13 To continue to reduce the incidence of crdiovsculr events, it is pprent tht dditionl fctors need to be ddressed. 6 Beyond LDL Cholesterol: Low HDL Cholesterol nd Elevted TGs Increse CVD Risk Residul crdiovsculr risk is likely multifctoril. Recent evidence suggests the importnt contribution to CVD risk of lipid prmeters other thn LDL cholesterol, such s high TGs nd low HDL cholesterol. 1 In n nlysis of dt from the Coronry Primry Prevention Tril, the Multiple Risk Fctor Intervention Tril, the Lipid Reserch Clinics Prevlence Mortlity Follow-up Study, nd the Frminghm Hert Study, for every 1-mg/dL (.26 mmol/l) increse in plsm HDL cholesterol in the popultions studied, there ws decrese in CHD risk of pproximtely 2% in men nd 3% in women independent of other risk fctors, including plsm LDL cholesterol. 14 According to NHANES III (Third Ntionl Helth nd Nutrition Exmintion Survey), more thn one third of the overll US dult popultion hs low HDL cholesterol. 15 Thirty-five percent of dult men nd 39% of dult women were reported to hve HDL cholesterol below 4 mg/ dl nd 5 mg/dl, respectively. 15 The NCEP ATP III (Ntionl Cholesterol Eduction Progrm Adult Tretment Pnel III) guidelines report tht low HDL cholesterol is significnt, independent risk fctor for CHD. Often, low HDL cholesterol is correlted with elevtions of serum TG nd remnnt lipoproteins, nd is strongly nd inversely ssocited with CHD risk. 16 There re number of different mechnisms through which HDL cholesterol my exert its ntitherogenic effects. The penetrtion nd retention in the rteril wll of therogenic polipoprotein B contining lipoproteins, including LDL cholesterol nd very low-density lipoprotein (VLDL) cholesterol, my initite nd promote therosclerosis. 17 A vriety of studies show HDL cholesterol my promote the efflux of cholesterol from fom cells in therosclerotic lesions through reverse cholesterol trnsport. 18 In ddition, HDL cholesterol my inhibit therogenesis through ntioxidnt nd nti-inflmmtory properties 16,18,19 nd reduce crdiovsculr events vi ntithrombotic nd vsodiltory ctivities, nd endothelil repir. 19,2 Importntly, s shown by dt from the Frminghm Hert Study, even in the presence of very low LDL cholesterol, low HDL cholesterol is still potent risk fctor. As HDL cholesterol decreses, it contributes significntly to CHD risk t ll levels of LDL cholesterol nd, even when S66 n n march 29

3 Beyond LDL Cholesterol: Low HDL Cholesterol nd Elevted TGs Increse CVD Risk LDL cholesterol levels re optiml (<1 mg/dl), the lower the HDL cholesterol level, the higher the risk of CHD. 21 Even when LDL cholesterol levels re controlled with intensive sttin therpy, the heightened risk of CHD conferred by low HDL cholesterol remins. In the TNT investigtion of high-dose sttin therpy, individuls with cceptble LDL cholesterol levels (<7 mg/dl) hd significnt, incresed 5-yer risk of CHD events tht ws directly relted to HDL cholesterol levels (Figure 2). 22 Ptients in the highest HDL cholesterol quintile (Q5 55 mg/dl) hd lower risk for mjor crdiovsculr events thn did ptients in the lowest HDL cholesterol quintile (Q1 <37 mg/ dl; hzrd rtio [HR] vs Q5,.61; 95% confidence intervl [CI], ; P =.3). 22 Although LDL cholesterol is recognized s the most importnt therogenic lipoprotein, elevtions in TG levels cn be considered mrker for therogenic VLDL remnnt lipoproteins. Becuse VLDL cholesterol is the most redily vilble mesure of therogenic remnnt lipoproteins, it my be combined with LDL cholesterol to improve CVD risk prediction s mjor components of non-hdl cholesterol. When serum TG levels re elevted, the non-hdl cholesterol mesure better represents the concentrtion of ll therogenic lipoproteins thn does LDL cholesterol. 16 Non-HDL cholesterol incorportes ll therogenic lipoproteins, including LDL cholesterol, VLDL cholesterol, lipoprotein() (Lp[]), nd intermedite-density lipoprotein (IDL) cholesterol. Non-HDL cholesterol, ccording to the NCEP ATP III guidelines, is secondry trget of therpy fter LDL cholesterol gols hve been reched nd when TG levels re 2 mg/dl. 16 A recently published met-nlysis by Srwr et l included 29 Western prospective studies (262,525 prticipnts; 1,158 CHD cses) to investigte the ssocition between TGs nd CHD risk. 23 The met-nlysis reveled n djusted odds rtio of 1.72 (95% CI, ) in ptients in the highest third of TG vlues compred with those ptients in the lowest third of TG vlues. 23 An erlier study by Genest et l reported tht in both men nd women with premture CAD, the most significnt risk fctor is low HDL cholesterol, lthough these individuls often exhibit high TG levels s well. 24 Although this study hd smll numbers of ptients with premture CAD (n = 87 men; n = 15 women), TGs were significntly higher nd HDL cholesterol ws significntly lower compred with ptients from the Frminghm Offspring Study who were free of CHD t bseline. 24 Furthermore, in the 8-yer follow-up of 4639 middle-ged men with no history of myocrdil infrction or stroke in the PROCAM (Prospective Crdiovsculr Münster) study, elevted levels of TGs emerged s significnt, independent predictor for CHD events. There ws 6-fold incresed CHD risk in ptients with TGs >2 mg/dl nd LDL cholesterol to HDL cholesterol rtio >5.. According to the PROCAM dt, high TGs put middle-ged men t incresed risk for CHD regrdless of their HDL cholesterol or LDL cholesterol levels. 25 A recent nlysis of dt from the PROVE IT-TIMI 22 tril exmined combintion of LDL cholesterol nd TG levels on CVD risk in ACS ptients. 12 During the 2-yer follow-up, significntly fewer CHD events occurred in ptients who hd LDL cholesterol <7 mg/dl thn in ptients who hd LDL cholesterol 7 mg/dl (HR,.81; P =.15). Similrly, significntly fewer events occurred n Figure 2. Low HDL-C Is Associted With High CVD Risk Even If LDL-C Levels Are Well-Controlled (TNT Study) 5-Yer Risk of Mjor CVD Events, % Q1 Q2 Q3 Q4 Q5 HDL-C Quintiles, mg/dl <37 37 to <42 42 to <47 47 to <55 >55 Hzrd Rtio vs Q In the TNT study, ptients in the highest HDL-C quintile ( 55 mg/dl) hd lower risk for mjor CVD events thn did ptients in the lowest quintile (<37 mg/dl). The men LDL-C level in this group of ptients (n = 2661, receiving sttin therpy for 3 months) ws 56 mg/dl; men TG level ws 126 mg/dl. 22 CVD indictes crdiovsculr disese; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; TG, triglyceride; TNT, Treting to New Trgets. P =.3 for differences mong HDL-C quintiles. This informtion ws originlly published in Brter P, et l. N Engl J Med. 27;357(13): Copyright 27 Msschusetts Medicl Society. All rights reserved. VOL. 15, No. 3 n The Americn Journl of Mnged Cre n S67

4 Report in ptients with TGs <15 mg/dl thn in those ptients with TGs 15 mg/dl, s reveled through univrite nlysis (HR,.73; 95% CI, ; P <.1). A Cox proportionl hzrds model ws utilized to further exmine the reltionship between chieved LDL cholesterol nd TGs t the dy 3 time point nd risk of recurrent CHD events. Compred with ptients who hd LDL cholesterol 7 mg/dl nd TGs 15 mg/dl, lower CHD risk ws observed with low on-tretment TGs (<15 mg/dl) nd LDL cholesterol (<7 mg/dl) (HR,.72; 95% CI, ; P =.17). 12 Ptients with TGs <15 mg/dl, even if they hd LDL cholesterol >7 mg/dl, exhibited CHD event rtes 15% lower thn those ptients who hd low LDL cholesterol but high TGs. Among ptients receiving sttin therpy fter ACS, on-tretment TGs <15 mg/dl were ssocited with lower risk of recurrent CHD events independent of the level of LDL cholesterol. Therefore, chieving both lower LDL cholesterol nd TG levels my be n importnt therpeutic strtegy in ptients with ACS. 12 When considering lipid prmeters beyond LDL cholesterol, non-hdl cholesterol (ie, totl cholesterol HDL cholesterol) is better estimte of the totl therogenic burden nd is esily clculted from nonfsting lipid vlues. Non-HDL cholesterol represents therogenic VLDL remnnt lipoproteins, including LDL cholesterol, VLDL cholesterol, IDL cholesterol, nd Lp(). 16 Dt from the Frminghm Hert Study suggest tht non-hdl cholesterol is stronger predictor of CHD risk thn is LDL cholesterol. 26 Overll, the ssocition with CHD incidence ws stronger for non-hdl cholesterol thn for LDL cholesterol t ll levels of non-hdl cholesterol, regrdless of whether TG levels were <2 or 2 mg/dl. 26 Ntionl Guideline Recommendtions for Treting Beyond LDL Cholesterol Severl ntionl guidelines ddress the tretment of high TGs nd non-hdl cholesterol nd low HDL cholesterol. Therpeutic lifestyle chnges, s noted in the NCEP ATP III recommendtions, remin very importnt nd include diet, exercise, nd smoking cesstion. The NCEP ATP III guidelines trget elevted LDL cholesterol s the primry therpeutic intervention to decrese CVD risk. 16 Becuse elevted non-hdl cholesterol levels in ptients with hypertriglyceridemi (eg, TGs 2 mg/dl) imprt incresed risk for crdiovsculr events even fter the LDL cholesterol gol hs been reched, non-hdl cholesterol is considered to be secondry therpeutic trget tht my provide dditionl CHD risk reduction. 27,28 The 24 updte to the 21 NCEP ATP III guidelines emphsized the incresing evidence for the benefits of combintion therpy, s compred with monotherpy, by recommending the possibility of dding fibrte or nicin to LDL-lowering therpy in high-risk ptients with elevted TGs or low HDL cholesterol levels. 27 In 27 the Americn Dibetes Assocition (ADA) nd the Americn Hert Assocition (AHA) collborted on joint sttement recommending LDL cholesterol remin the primry trget of lipid-modifying therpy. The ADA/AHA guidelines further recommend n LDL cholesterol gol <1 mg/dl in ptients with dibetes mellitus. 29 The ADA nd the AHA hve lso individully relesed guidelines for CVD prevention tht include therpies trgeting multiple lipid frctions. According to the 28 ADA guidelines, the primry gol in ptients with dibetes mellitus is n LDL cholesterol level <1 mg/dl in individuls without overt CVD, lthough lower LDL cholesterol gol (<7 mg/dl) is n option in individuls with overt CVD. 3 In ddition, the ADA suggests TG gol <15 mg/dl nd HDL cholesterol gols >4 mg/dl in men nd >5 mg/dl in women. 3 For ptients with TGs between 2 nd 499 mg/dl, the AHA recommends non- HDL cholesterol gol <13 mg/dl. 29 Interestingly, the AHA dvoctes efforts to rise HDL cholesterol levels but does not specificlly designte therpeutic gols. The ADA/AHA joint sttement suggests tht combintion of sttins with fibrtes or nicin my be necessry to chieve multiple lipid trgets. 29 Similr recommendtions for lipid vlues nd tretments were published in the 26 AHA/ Americn College of Crdiology Secondry Prevention Guidelines for ptients with coronry nd other therosclerotic vsculr disese. 31 This updte provides trget levels for TGs nd non-hdl cholesterol. The guidelines recommend tht if TGs re between 2 nd 499 mg/dl, the non-hdl cholesterol gol should be <13 mg/dl. Moreover, it is resonble to consider reducing non-hdl cholesterol <1 mg/dl when ptient is t sufficiently high risk for crdiovsculr events. The therpeutic S68 n n march 29

5 Beyond LDL Cholesterol: Low HDL Cholesterol nd Elevted TGs Increse CVD Risk options to reduce non-hdl cholesterol re more intensive LDL cholesterol lowering or the ddition of nicin or fibrte to reduce TGs nd increse HDL cholesterol fter LDL-lowering therpy hs been initited. 31 Combintion Therpies for Residul CVD Risk Reduction Recently, severl clinicl end point nd rteriogrphic investigtions were compred for efficcy in reducing crdiovsculr events (Figure 3). 32 Across vriety of trils, combintion therpies produced n verge clinicl event reltive risk reduction of 71.6%, n verge number needed to tret (NNT) of 9.6, nd n verge NNT per yer of These dt revel significntly enhnced efficcy for reducing clinicl events with the combintion of LDL cholesterol lowering plus HDL cholesterol rising phrmcologic therpy compred with LDL cholesterol lowering therpy lone. The SEACOAST (Sfety nd Efficcy of Fixed Dose Nicin ER nd Simvsttin Combintion Therpy) tril, 24-week rndomized clinicl tril, compred simvsttin monotherpy with combintion of extended-relese nicin (nicin ER)/ simvsttin in ptients with mixed dyslipidemi. 33,34 Following simvsttin run-in phse, during which ptients received simvsttin 2 or 4 mg for t lest 2 weeks, ptients were ssigned to either simvsttin low-dose (SEACOAST I) or simvsttin high-dose (SEACOAST II) groups. In SEACOAST I, the tretment groups were simvsttin 2 mg, nicin ER/simvsttin 1 mg/2 mg, nd nicin ER/ simvsttin 2 mg/2 mg. 34 In SEACOAST II, which included more intensive lipid-modifying therpy during both the run-in phse nd the 24-week tril phse, the tretment groups were simvsttin 8 mg, nicin ER/simvsttin 1 mg/4 mg, nd nicin ER/simvsttin 2 mg/4 mg. The primry end point in SEACOAST ws the medin percent chnge in non-hdl cholesterol during the period from bseline to week ,34 In SEACOAST I, the nicin ER/simvsttin 1 mg/2 mg nd 2 mg/2 mg combintion therpies produced significnt, dose-relted improvements in non-hdl cholesterol, HDL cholesterol, TGs, nd Lp() compred with simvsttin 2-mg monotherpy. 34 As shown in Figure 4A, 22.5% reduction in non-hdl cholesterol ws n Figure 3. Strtegies for Reducing CHD Risk Averge Clinicl Event Reltive Risk Reduction, % Clinicl Point LDL-C Trils 4S LIPID CARE WOSCOPS AFCAPS/ TexCAPS CARDS 27.2 Intensive Therpy LDL-C Trils IDEAL TNT PROVE-IT 16. Arteriogrphic LDL-C Trils MARS MAAS REGRESS PLAC-1 CCAIT 29.6 observed with high-dose nicin ER/simvsttin s compred with the 7.4% reduction seen with simvsttin 2-mg monotherpy. Although there ws dose-relted response in LDL cholesterol levels, there were no significnt differences in LDL cholesterol between these groups; simvsttin lone resulted in 7.1% decrese in LDL cholesterol, wheres high-dose nicin ER/simvsttin produced 14.2% reduction. The results of SEACOAST I lso showed 24.9% increse in HDL cholesterol ssocited with high-dose nicin ER/simvsttin nd substntil reduction in TGs tht reched 38% in the high-dose group. Finlly, significnt 25% reduction in Lp() ws observed with the high-dose nicin ER/simvsttin tretment, Arteriogrphic LDL-C Trils + HDL-C Trils FATS FATS 8-yer CLAS CLAS 2-yer HATS SCRIP 71.6 Averge NNT NNT/y In comprison of different types of trils, the LDL-C lowering plus HDL-C rising drug trils showed the gretest beneficil effects, chieving n verge clinicl event reltive risk reduction of 71.6%, n verge NNT of 9.6, nd n verge NNT/yer of AFCAPS/TexCAPS indictes Air Force/Texs Coronry Atherosclerosis Prevention Study; CARDS, Collbortive Atorvsttin Dibetes Study; CARE, Cholesterol nd Recurrent Events; CCAIT, Cndin Coronry Atherosclerosis Intervention Tril; CHD, coronry hert disese; CLAS, Cholesterol-Lowering Atherosclerosis Study; FATS, Fmilil Atherosclerosis Tretment Study; 4S, Scndinvin Simvsttin Survivl Study; HATS, HDL-Atherosclerosis Tretment Study; HDL-C, high-density lipoprotein cholesterol; IDEAL, Incrementl Decrese in Clinicl Endpoints Through Aggressive Lipid Lowering; LDL-C, low-density lipoprotein cholesterol; LIPID, Long-Term Intervention with Prvsttin in Ischemic Disese; MAAS, Multicenter Anti-Atherom Study; MARS, Monitored Atherosclerosis Regression Study; NNT, number needed to tret to prevent 1 clinicl event; PLAC-I, Prvsttin Limittion of Atherosclerosis in the Coronry Arteries; PROVE-IT, Prvsttin or Atorvsttin Evlution nd Infection Therpy; REGRESS, Regression Growth Evlution Sttin Study; SCRIP, Study of Crdiovsculr Risk Intervention by Phrmcists; TNT, Treting to New Trgets; WOSCOPS, West of Scotlnd Coronry Prevention Study. Ftl nd nonftl myocrdil infrction. VOL. 15, No. 3 n The Americn Journl of Mnged Cre n S69

6 Report n Figure 4. SEACOAST Tril of Nicin ER/Simvsttin Combintion Therpy Medin Chnge From Bseline, % b 22.5 c c Simvsttin 2 mg (n = 9) 18.3 c Nicin ER/simvsttin 1/2 mg (n = 78) Nicin ER/simvsttin 2/2 mg (n = 4) b 26.5 b 25. c 38. c Medin Bseline, mg/dl Non HDL-C LDL-C HDL-C TG Lp() A. Efficcy of nicin ER/simvsttin combintion therpy: SEACOAST I. Nicin ER/simvsttin 1-mg/2-mg nd 2-mg/2- mg combintion therpies demonstrted significnt, dose-relted improvements in non HDL-C, HDL-C, TG, nd Lp() compred with simvsttin 2-mg monotherpy. 34 ER indictes extended relese; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; Lp(), lipoprotein (); SEACOAST, Sfety nd Efficcy of Fixed Dose Nicin ER nd Simvsttin Combintion Therpy; TG, triglyceride. Simvsttin 2 mg t bseline. b P <.1 vs simvsttin 2 mg. c P <.1 vs simvsttin 2 mg. Medin Chnge From Bseline, % b 17.1 b c 21.9 c Simvsttin 8 mg (n = 9) Nicin ER/simvsttin 1/4 mg (n = 82) Nicin ER/simvsttin 2/4 mg (n = 8) d 22.8 c 21. c 31.8 c Medin Bseline, mg/dl Non HDL-C LDL-C HDL-C TG Lp() B. Efficcy of nicin ER/simvsttin combintion therpy: SEACOAST II. Nicin ER/simvsttin 1-mg/4-mg nd 2-mg/4-mg combintion therpies were comprble to simvsttin 8-mg monotherpy in reduction of non HDL-C. Both nicin ER/simv sttin 1-mg/4-mg nd 2-mg/4-mg combintion therpies resulted in significnt, dose-relted improvements in HDL-C, Lp(), nd TG compred with simvsttin 8-mg therpy. 33 ER indictes extended relese; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; Lp(), lipoprotein (); SEACOAST, Sfety nd Efficcy of Fixed Dose Nicin ER nd Simvsttin Combintion Therpy; TG, triglyceride. Simvsttin 4 mg t bseline. b Comprble to simvsttin 8 mg. c P <.1 vs simvsttin 8 mg. d P <.1 vs simvsttin 8 mg. S7 n n march 29

7 Beyond LDL Cholesterol: Low HDL Cholesterol nd Elevted TGs Increse CVD Risk wheres little chnge in Lp() ws observed with simvsttin monotherpy. A similr pttern of results ws observed in SEACOAST II, s shown in Figure 4B. A 17.1% reduction in the primry end point of non-hdl cholesterol ws seen with the high-dose nicin ER/simvsttin 2-mg/4-mg combintion therpy s compred with 1.1% reduction with simvsttin 8-mg monotherpy, lthough this difference ws not sttisticlly significnt. Decreses in LDL cholesterol were observed to be comprble ( 11.6% high-dose nicin ER/ simvsttin 2 mg/4 mg vs 12.7% simvsttin 8 mg) cross ll tretment groups. Both nicin ER/ simvsttin 1 mg/4 mg nd 2-mg/4-mg combintion therpies resulted in significnt, doserelted improvements in HDL cholesterol, Lp(), nd TGs, compred with simvsttin 8-mg therpy. 33 Across these lipid prmeters, simvsttin 8-mg monotherpy hd essentilly no effect beyond tht conferred by the simvsttin 4-mg dose dministered during the run-in phse. In SEACOAST, tretment with nicin ER/simvsttin for 24 weeks ws well-tolerted with no unnticipted dverse effects. Only flushing ws significntly more frequent with nicin ER/simvsttin combintion therpy s compred with simvsttin monotherpy, nd there ws no evidence of incresed risk of heptoxicity or myopthy with nicin ER/ simvsttin therpy. Overll, these dt support the use of nicin ER/simvsttin combintion therpy in brod popultion of dyslipidemic ptients to help them rech nd mintin multiple lipid gols. 33,34 Fibrtes, similr to nicin, hve been dded to sttin therpy to ddress multiple lipid bnormlities. Recently, new formultion of fenofibrte (fenofibric cid) hs been investigted in combintion with rosuvsttin in ptients with mixed dyslipidemi. This 12-week, rndomized, double-blind, ctive-controlled tril compred the efficcy of fenofibric cid 135-mg monotherpy, rosuvsttin 1-mg monotherpy, nd fenofibric cid/rosuvsttin 135-mg/1-mg combintion therpy in ptients with mixed dyslipidemi. Combintion therpy with fenofibric cid/rosuvsttin (Figure 5) resulted in significntly greter reduction in LDL cholesterol compred with fenofibric cid monotherpy n Figure 5. Fenofibric Acid nd Rosuvsttin Combintion Therpy in Ptients With Mixed Dyslipidemi Men % Chnge From Bseline Fenofibric cid 135 mg 2.3 c Rosuvsttin 1 mg 15. Fenofibric cid/rosuvsttin 135/1 mg 8.5 n = 223 n = 243 n = 231 n = 242 n = 252 n = 252 n = 22 n = 239 n = b 47.1 c Medin Bseline, mg/dl LDL-C HDL-C TG Combintion therpy with fenofibric cid nd rosuvsttin resulted in significntly greter reduction in LDL-C compred with fenofibric cid monotherpy. Combintion therpy with fenofibric cid nd rosuvsttin lso resulted in significntly greter increses in HDL-C nd reductions in TGs compred with rosuvsttin monotherpy. 35 HDL-C indictes high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; TG, triglyceride. Mixed dyslipidemi: LDL-C 13 mg/dl, TG 15 mg/dl, nd HDL-C <4 mg/dl in men nd <5 mg/dl in women. b P <.1 vs fenofibric cid. c P <.1 vs rosuvsttin 1 mg. VOL. 15, No. 3 n The Americn Journl of Mnged Cre n S71

8 Report (P <.1). Combintion therpy with fenofibric cid/rosuvsttin resulted in significntly greter increses in HDL cholesterol nd reductions in TGs compred with rosuvsttin 1-mg monotherpy (P <.1). 35 In ddition to its beneficil effects on vrious lipid prmeters, fenofibric cid/rosuvsttin combintion therpy resulted in substntil shift in the percentge of ptients with lrge, less therogenic LDL prticles from 13.3% t bseline to 51.8% following 12 weeks of therpy. Conversely, rosuvsttin monotherpy produced more modest shift, with only 18.2% of ptients expressing lrge, less therogenic LDL prticles s compred with 6.8% t bseline. 36 Fenofibric cid/rosuvsttin combintion therpy lso resulted in significntly greter improvements in the rtios of totl cholesterol to HDL cholesterol, non-hdl cholesterol to HDL cholesterol, polipoprotein B to polipoprotein A-I, nd TG to HDL cholesterol compred with fenofibric cid monotherpy or rosuvsttin monotherpy. 37 Importntly, fenofibric cid/rosuvsttin combintion therpy ws well-tolerted; no heptic, renl, or muscle sfety signls were identified. 35 Summry Severl lipid prmeters, such s LDL cholesterol, TGs, HDL cholesterol, nd therogenic remnnt lipoproteins, re strongly ssocited with therosclerosis nd heightened CVD risk. The primry therpeutic trget is LDL cholesterol, nd lipid-lowering therpy with sttins hs proved to be highly beneficil for reducing crdiovsculr event rtes. However, significnt crdiovsculr risk remins in ptients treted even with intensive sttin therpy to reduce LDL cholesterol. As result, there hs been n incresed focus on elevted TGs nd low HDL cholesterol nd their significnt contributions to crdiovsculr risk even when LDL cholesterol levels re well-controlled. Tretment guidelines recommend tht combintion therpy my be necessry to chieve multiple lipid gols, including non-hdl cholesterol, HDL cholesterol, nd TGs. When considering ll of the evidence ddressing vrious lipid frctions nd CVD risk, lipid mngement in specific ptients should not be limited to sttin monotherpy. Rther, chieving multiple lipid gols nd reducing CVD risk should utilize sttins nd dditionl therpeutic gents to trget lipid prmeters other thn LDL cholesterol when necessry. The benefits conferred by rising HDL cholesterol with nicin pper dditive to LDL cholesterol lowering with sttins. This combintion ddresses severl therogenic lipid bnormlities, slows the progression of therosclerosis, nd reduces residul CVD risk. Nicin/sttin combintion therpy hs n excellent sfety profile nd my be needed to optimlly reduce CVD risk in high-risk ptients. Similrly, recent reports indicte tht combintion therpy of fenofibric cid with rosuvsttin lso ppers to sfely nd effectively correct severl therogenic lipid bnormlities. Consequently, severl options exist for combintion lipid therpy tht my be necessry to optimlly ddress multiple lipid bnormlities nd improve ptient outcomes. Author Affilition: From Pennsylvni Stte College of Medicine, Penn Stte Hert nd Vsculr Institute, Hershey, PA. Funding Source: This work ws supported by n eductionl grnt from Solvy Phrmceuticls nd Abbott. Author Disclosure: Honorri: Abbott, Merck Schering- Plough, Pfizer. Authorship Informtion: Concept nd design; drfting of the mnuscript; criticl revision of the mnuscript for importnt intellectul content; supervision. Address correspondence to: Peter Algon Jr, MD, FACC, The Milton S. Hershey Medicl Center, Pennsylvni Stte Hert nd Vsculr Institute, H47, 5 University Dr, Hershey, PA E-mil: plgon@hmc.psu.edu. References 1. Fruchrt JC, Scks FM, Hermns MP, et l. The Residul Risk Reduction Inititive: cll to ction to reduce residul vsculr risk in ptients with dyslipidemi. Am J Crdiol. 28;12(suppl):1K-34K. 2. Ghndehri H, Kml-Bhl S, Wong ND. Prevlence nd extent of dyslipidemi nd recommended lipid levels in US dults with nd without crdiovsculr comorbidities: the Ntionl Helth nd Nutrition Exmintion Survey Am Hert J. 28;156(1): Rndomised tril of cholesterol lowering in 4444 ptients with coronry hert disese: the Scndinvin Simvsttin Survivl Study (4S). Lncet. 1994;344(8934): Prevention of crdiovsculr events nd deth with prvsttin in ptients with coronry hert disese nd brod rnge of initil cholesterol levels. The Long-Term Intervention with Prvsttin in Ischemic Disese (LIPID) Study Group. N Engl J Med. 1998;339(19): Hert Protection Study Collbortive Group. MRC/ BHF Hert Protection Study of cholesterol lowering with simvsttin in 2,536 high-risk individuls: rndomised plcebo-controlled tril. Lncet. 22;36(9326):7-22. S72 n n march 29

9 Beyond LDL Cholesterol: Low HDL Cholesterol nd Elevted TGs Increse CVD Risk 6. Downs JR, Clerfield M, Weis S, et l. Primry prevention of cute coronry events with lovsttin in men nd women with verge cholesterol levels: results of AFCAPS/TexCAPS. Air Force/Texs Coronry Atherosclerosis Prevention Study. JAMA. 1998;279(2): Scks FM, Pfeffer MA, Moye LA, et l. The effect of prvsttin on coronry events fter myocrdil infrction in ptients with verge cholesterol levels. Cholesterol nd Recurrent Events Tril investigtors. N Engl J Med. 1996;335(14): Shepherd J, Cobbe SM, Ford I, et l. Prevention of coronry hert disese with prvsttin in men with hypercholesterolemi. West of Scotlnd Coronry Prevention Study Group. N Engl J Med. 1995;333(2): Cnnon CP, Brunwld E, McCbe CH, et l. Intensive versus moderte lipid lowering with sttins fter cute coronry syndromes. N Engl J Med. 24;35(15): LRos JC, Grundy SM, Wters DD, et l. Intensive lipid lowering with torvsttin in ptients with stble coronry disese. 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