CURRENT THERAPEUTIC RESEARCH. VOLUME 65, No. 6, NOVEMBER/DECEMBER 2004

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1 CURRENT THERAPEUTC RESEARCH VOLUME 65, No. 6, NOVEMBER/DECEMBER 2004 An Open-Label Comparson of the Effects of Smvastatn and Nacn Alone and Combned on the Lpd Profle and Lpoproten (a) Level n an ndan Populaton wth Dyslpdema Krandeep Kaur, MD, Jaswant Ra, MD, Geeta Sharma, DA, MD, and Baljnder Sngh Bal, MD, FCCP, FCA, FACM Departments of Pharmacology and Medcne, Government Medcal College, Amrtsar (Punjab), nda ABSTRACT Background: Patents wth dyslpdema often requre the use of >1 lpdalterng agent to acheve the target levels recommended by the Natonal Cholesterol Educaton Program Adult Treatment Panel 111. Objectve: The am of ths study was to compare the effects of smvastatn and nacn alone and combned on the lpd profle and lpoproten (a) (Lp[a]) level n an ndan populaton wth dyslpdema. Methods: Ths 12-week, open-label, nonrandomzed study was conducted at the Departments of Pharmacology and Medcne, Government Medcal College, Amrtsar (Punjab), nda. Patents aged 30 to 70 years wth dyslpdema were elgble. Patents were assgned to 1 of 3 treatment groups. Group 1 receved smvastatn 20 mg/d for 12 weeks. Group 2 receved nacn at doses of 375 mg/d for 1 week, 500 mg/d for 1 week, and 500 mg BD for 10 weeks. Group 3 receved smvastatn 10 mg/d plus nacn (375 mg for 1 week and 500 mg for 11 weeks). The lpd profle (low-densty lpoproten cholesterol [LDL-C], hgh-densty lpoproten cholesterol [HDL-C], total cholesterol [TC], and trglycerdes [TG]) and Lp(a) were measured before the start of therapy and at 6 and 12 weeks of treatment. Percentage changes from baselne were calculated. Adverse effects (AEs) were recorded at weeks 6 and 12 and through spontaneous reportng. Results: Nnety patents were enrolled (50 men, 40 women; 30 patents per treatment group). n group 1, the mean (SD) percentage decrease n LDL-C level at 12 weeks was 42.79% (16.29%) (P< 0.05), but no sgnfcant change was seen n group 2 or 3. The mean (SD) percentage ncreases n HDL-C level were 18.43% (13.28%) and 20.82% (17.57%) n groups 2 and 3, respectvely (both, P < 0.05), but no sgnfcant change was seen n group 1. TC levels decreased by a mean (SD) of 32.97% (13.66%) n group 1 (P < 0.05), but no sgnfcant change was seen n group 2 or 3. TG and Lp(a) levels dd not change sgnfcantly n any of the 3 treatment groups. Flushng, myalga, and dyspepsa were the most common AEs n patents recevng nacn. Accepted fol publcaton December 8, Reproducton n whole or part s not permtted. do:l j.cu rtheres X/04/$19.00 Copyrght 2004 Excerpta Medca, nc. 455

2 CURRENT THERAPEUTC RESEARCH Conclusons: n ths study n ndan patents wth dyslpdema, smvastatnnacn combnaton therapy was assocated wth greater changes n lpd profle compared wth ether agent used alone. Nacn was also assocated wth greater changes n Lp(a) levels. AEs were less prevalent wth combnaton therapy than wth nacn alone. (Curr Ther Res Clm Exp. 2004;65: ) Copyrght 2004 Excerpta Medca, nc. Key words: dyslpdema, smvastatn, nacn, combnaton therapy. NTRODUCTON A major new feature of the gudelnes ssued by the Natonal Cholesterol Educaton Program (NCEP) Adult Treatment Panel 111 (ATP 111) 1 s a focus on prmary preventon of coronary artery dsease (CAD) n persons wth multple rsk factors. Most patents at hgh rsk for CAD are lkely to beneft from ntensve management. The ATP 111 report ncludes a modfed lst of rsk factors and ther management. 1 Now, a low-densty lpoproten cholesterol (LDL-C) level 100 mg/dl s consdered optmal. The desred level of hgh-densty lpoproten cholesterol (HDL-C) has been rased from <35 mg/dl to <40 mg/dl. The trglycerde (TG) cutoff pont has been lowered to 150 mg/dl. The ATP 111 report recognzes that the rsk for CAD s also nfluenced by factors that are not ncluded among the major ndependent rsk factors. These nclude lfestyle (eg, lack of exercse, poor det, smokng), elevated lpoproten (a) (Lp[a]) level, elevated homocystene level, and mpared glucose tolerance. ATP 111 also mentons management of the metabolc syndrome as a secondary goal of rskreducton therapy, after the prmary goal of decreasng LDL-C. Because the NCEP has revsed the taeget lpd levels, there s a need to reconsder the current treatment strategy for dyslpdema. Of the varous lpd-alterng agents avalable, statns are the most commonly prescrbed because of ther benefcal effects on LDL-C and total cholesterol (TC) levels. 2 Nacn, another lpdalterng agent, mproves HDL42, TG, 3"~ and Lp(a) 6 levels. The use of nacn has decreased over the years because of the severe adverse effects (AEs) assocated wth t (eg, myalgas, hepatotoxcty, flushng). Now, however, a lower dose (1-2 g/d) of nacn s beng consdered for ts effect on the lpd profle. n addton to monotherapy wth a lpd-alterng drug, the use of combnaton therapy s becomng ncreasngly mportant for effectve management of dyslpdema. Another factor to consder when prescrbng rsk-reducton therapy s that lpd profles n persons wth dyslpdema vary by race/ethnc group. For example, ndan patents wth dyslpdema typcally have hgh TG and Lp(a) levels and a low HDL-C level, 7 wth moderately elevated LDL-C and TC levels. One study showed that a serum cholesterol level normal n the whte populaton may be hgh for the Asan ndans. 8 A study n Sngapore showed that mean Lp(a) levels n ndans were hgher among all of the ethnc groups except blacks. 9 The present study was conducted to compare the effects of smvastatn and nacn alone and combned on dyslpdema n an ndan populaton. Smvastatn 456

3 K. Kaur et al. was chosen from the group of statns because, accordng to a MEDLNE search (key terms: lpd-alterng agents, dyslpdema, and statms; years: ), most studes of rsk reducton to date have focused on smvastatn. PATENTS AND METHODS Ths 12-week, open-label, nonrandomzed tral was conducted at the Departments of Pharmacology and Medcne, Government Medcal College, Amrtsar (Punjab), nda. The study and the consent procedure were approved by the ethcs commttee at the Government Medcal College. ncluson and Excluson Crtera Patents aged 30 to 70 years wth dyslpdema (defned as LDL-C >110 mg/dl, HDL-C <40 mg/dl, and/or TC >200 mg/dl) were elgble. Patents were recruted from an outpatent clnc at Guru Nanak Dev Hosptal, adjacent to the Government Medcal College. Patents wth the followng condtons were excluded from the study: hypersenstvty to smvastatn or nacn; sgnfcant metabolc, renal, hepatc, or gastrontestnal dsease; nfecton, gangrene, or surgery wthn the pror 3 months; hstory of myocardal nfarcton, unstable angna, or congestve heart falure; hstory of alcoholsm; hstory of a convulsve dsorder; hyperurcema; dabetes melltus; hstory of acute peptc ulcer dsease; hstory of muscle pan (fbromyalga) and an assocated ncrease n creatne phosphoknase level; hypothyrodsm; or hstory of hormone use. Pregnant and breastfeedng women were also excluded. The use of drugs such as verapaml, dltazem, erythromycn, clarthromycn, ketoconazole, and traconazole was not allowed durng the study. Elgble patents provded verbal nformed consent after recevng a full explanaton of the study procedures. Study Drug Admnstraton and Effcacy and Tolerahlty Assessments After enrolhnent, patents provded a medcal hstory; underwent a physcal examnaton (ncludng vtal sgn measurements and hemoglobn levels); and were assgned, based on physcan dscreton, to 1 of 3 treatment groups. Group 1 receved smvastatn monotherapy (20-mg tablet OD wth meals) for 12 weeks. Group 2 receved nacn (sustaned release [SR]) monotherapy (one 375-mg tablet taken wth the evenng meal for 1 week, followed by 500 mg OD wth the evenng meal for 1 week, and 500 mg BD wth meals for 10 weeks). Group 3 receved smvastatn 10 mg and nacn (SR) tablets. The doses of nacn were 375 mg/d for 1 week and 500 mg/d for 11 weeks. Durng treatment, patents were advsed to contnue ther earler lpd-lowerng det and physcal actvty f they had already been dong so (although they were not nstructed to begn these lfestyle changes for the purposes of the study). Lpd levels and lver enzymes (to montor for adverse effects) were measured before the start of therapy (week 0) and at weeks 6 and 12 of treatment (study 457

4 CURRENT THERAPEUTC RESEARCH end). Patents were advsed to mmedately report unexplaned muscle pan or fatgue, low urne output, rrtable bowel, and any other AE, whether thought to be caused by the study drug or by cardovascular problems. At the end of therapy, patents were montored for AEs for 4 to 6 addtonal weeks at the Departments of Pharmacology and Medcne. Laboratory Procedures Laboratory analyses were performed at weeks 0, 6, and 12. Blood samples were drawn after 12 hours of fastng and allowed to clot at room temperature. Serum was assayed by centrfugaton at 2000 rpm for 10 mnutes at 37 C and used to determne TC level, followed by HDL-C level after precptaton of very low-densty lpoproten (VLDL) and LDL-C wth dextran sulfate magnesum chlorde wth use of the enzymatc cholesterol oxdase, para-amnophenazone peroxdase method l,n (Bosystems kt, Bosystems Dagnostcs, Span). The serum TG level was determned by measurement of glycerol after enzymatc hydrolyss wth lpase 12 (Bosystems kt). The LDL-C level was calculated usng the followng formula13: LDL-C TC - HDL-C - VLDL Serum Lp(a) was measured usng the turbdmetry method. 14 Blood samples were analyzed usng a spectrophotometer (Spectronc 20, Spectronc Analytcal nstruments, Garforth, Leeds, Unted Kngdom). The lpd tetrad ndex (a comprehensve lpd ndex proposed to ascertan the total burden of dyslpdema n ndans 15) was calculated at weeks 0, 6, and 12 usng the followng formula: Tetrad ndex TC x TG x (Lp[a]/HDL-C) Statstcal Analyss The data were analyzed usng the t test. P < 0.05 was consdered statstcally sgnfcant. RESULTS Nnety patents were enrolled (50 men, 40 women; 30 patents per treatment group) (Table ). All patents lved n the state of Punjab, nda, wth 60 (67%) from urban areas and 30 (33%) from rural areas. CAD rsk factors present at baselne are shown n Table. Effcacy Table presents the mean lpd levels and percentage changes from weeks 0to 12. Fgure 1 shows the mean serum LDL42 levels throughout the study. Group 1 had a sgnfcant decrease over 12 weeks (from [55.62] mg/dl at baselne 458

5 K. Kaur et al. Table. Dstrbuton of ndan patents (no. [%]) wth dyslpdema by baselne lpd levels.* Group t Group 2 ~ Group 3 Lpd/Level, mg/dl (n 30) (n 30) (n 30) LDL C ~1 O0 0 (0) 10 (33) 0 (0) >1oo 15o 7 (23) 13 (43) 6 (20) >16o (30) 7 (23) lo (33) > (47) 0 (0) 14 (47) HDL C ~40 10 (33) 21 (70) 16 (S3) >40 20 (67) 9 (30) 14 (47) TC ~200 0 (0) 14 (47) 0 (0) > (37) 11 (37) 8 (27) > (33) S (17) 8 (27) >300 9 (30) 0 (0) 14 (47) TG ~1 S0 9 (30) 4 (13) 3 (1 O) > (33) 6 (20) 7 (23) > S (17) 12 (40) 11 (37) >250 6 (20) 8 (27) 9 (30) Lp(a) ~3o 19 (63) 7 (23) 19 (63) >30 11 (37) 23 (77) 11 (37) LDL C low densty lpoproten cholesterol; HDL C hgh densty lpoproten cholesterol; TC total cholesterol; TG trglycerdes; Lp(a) lpoproten (a). *Percentages may not total 100 due to roundng. tgroup 1 receved smvastatn monotherapy (20 mg tablet OD wth meals) for 12 weeks. tgroup 2 receved nacn (sustaned released [SR]) monotherapy (one 375 mg tablet taken wth the evenng meal for 1 week, followed by 500 mg OD wth the evenng meal for 1 week, and 500 mg BD wth meals for 10 weeks). ~Group 3 receved smvastatn 10 mg and nacn (SR) tablets. The doses of nacn were 375 mg/d for 1 week and 500 mg/d for 11 weeks. to [36.49] mg/dl at week 6 [P < 0.002] to [24.06] mg/dl at week 12 [P < 0.001]; mean [SD] percentage decrease, 42.79% [16.29%]). n group 2, no sgnfcant change was seen. n group 3, the decrease from baselne was sgnfcant at week 6 (from [65.71] mg/dl to [48.06] mg/dl; P < 0.001) but no sgnfcant change was seen at 12 weeks. Mean serum HDL-C levels throughout the study are shown n Fgure 2. n group 1, the ncrease from baselne to week 6 was sgnfcant (from [2.90] mg/dl to [2.93] mg/dl; P < 0.014), but no sgnfcant change was seen at week 12. Group 2 showed a nonsgnfcant ncrease from baselne to week 6 and 459

6 CURRENT THERAPEUTC RESEARCH Table. Baselne rsk factors for coronary artery dsease (CAD) n ndan patents wth hyperlpdema (no. [%]). Group 1" Group 2 t Group 3* Rsk Factor (n 30) (n 30) (n 30) Hypertenson 22 (73) 24 (80) 25 (83) Lp(a) >30 mg/dl 12 (40) 20 (67) 13 (43) Famly hstory of CAD 10 (33) 8 (27) 10 (33) Lp(a) lpoproten (a). *Group 1 receved smvastatn monotherapy (20 mg tablet OD wth meals) for 12 weeks. fgroup 2 receved nacn (sustaned released [SR]) monotherapy (one 375 mg tablet taken wth the evenng meal for 1 week, followed by 500 mg OD wth the evenng meal for 1 week, and 500 mg BD wth meals for 10 weeks). tgroup 3 receved smvastatn 10 mg and nacn (SR) tablets. The doses of nacn were 375 mg/d for 1 week and 500 mg/d for 11 weeks. Table. Lpd levels (mg/dl) and percentage changes n ndan patents before and after 12 weeks of therapy for hyperlpdema. Data are mean (SD). Group 1" Group 2 t Group 3* Lpd/Tme Pont (n = 30) (n = 30) (n = 30) LDL C Week (55.62) (38.86) (65.71) Week (24.06) (27.88) (40.76) %A (16.29) 5.47 (27.47) 42.5o (16.01) HDL C Week (2.90) (6.67) (5.89) Week (2.72) (3.94) (2.78) %A 7.95 (6.39) (13.28) (17.57) TC Week (50.76) (38.22) (61.91) Week (24.60) (24.61) (38.51) %A 32.97(13.66) 8.56(12.97) (11.51) TG Week (74.08) (82.84) (76.85) Week (48.66) (50.57) (45.68) %A (15.04) (12.91) (15.67) Lp(a) Week (19.84) (31.44) (29.79) Week (10.39) 26.45(15.92) 18.52(14.11) %A (22.29) (21.56) (23.58) LDL C = low densty lpoproten cholesterol; HDL C = hgh densty lpoproten cholesterol; TC = total cholesterol; TG = trglycerdes; Lp(a) = lpoproten (a). *Group 1 receved smvastatn monotherapy (20 mg tablet OD wth meals) for 12 weeks. fgroup 2 receved nacn (sustaned released [SR]) monotherapy (one 375 mg tablet taken wth the evenng meal for 1 week, followed by 500 mg OD wth the evenng meal for 1 week, and 500 mg BD wth meals for 10 weeks). tgroup 3 receved smvastatn 10 mg and nacn (SR) tablets. The doses of nacn were 375 mg/d for 1 week and 500 mg/d for 11 weeks. ~P < 0.05 versus week

7 K. Kaur et al. 220 q 200 q Group 1" (n = 30) Group 2t (n = 30) ~, ~ Group 3~ (n -- 30) ~.~, E 180 l 160 q.j L2 -h 140 ~'~"~'~"~\ Study Week Fgure 1. Mean (SD) low-densty lpoproten cholesterol (LDL-C) levels n ndan patents recevng treatment for dyslpdema. *Group 1 receved smvastatn monotherapy (20-mg tablet OD wth meals) for 12 weeks, tgroup 2 receved nacn (sustaned released [SR]) monotherapy (one 375-mg tablet taken wth the evenng meal for 1 week, followed by 500 mg OD wth the evenng meal for 1 week, and 500 mg BD wth meals for 10 weeks). ~Group 3 receved smvastatn 10 mg and nacn (SR) tablets. The doses of nacn were 375 mg/d for 1 week and 500 mg/d for 11 weeks. P < 0.05 versus week 0. a sgnfcant ncrease at week 12 (from [4.95] mg/dl to [3.94] mg/dl [P 0.04]; mean [SD] percentage ncrease, 18.43% [13.28%]). n group 3, the ncreases from baselne to weeks 6 and 12 were sgnfcant (from [5.89] mg/dl at baselne to [3.15] mg/dl at week 6 [P < 0.015] to [2.78] mg/dl at week 12 [P< 0.001]; mean [SD] percentage ncrease, 20.82% [17.57%]). Fgure 3 shows the mean TC levels n the 3 treatment groups. Group 1 showed a sgnfcant decrease from baselne to weeks 6 and 12 (from [50.76] mg/dl at baselne to [34.85] mg/dl at week 6 [P < ] to [24.60] mg/dl at week 12 [P < 0.001]; mean [SD] percentage decrease, 32.97% [13.66%]). n group 2, no sgnfcant change from baselne was seen. n group 3, the decrease n TC level was sgnfcant at week 6 (P < 0.001), but no sgnfcant change was seen at week

8 CURRENT THERAPEUTC Hgure 4 shows the mean TG levels by treatment group. n groups 1 and 2, the mean TG levels were smlar to baselne at week 12. n group 3, the decrease was sgnfcant at week 6 (P < 0.011), but no change was seen at week 12. The mean (SD) percentage decrease over 12 weeks n group 3 was 34.11% (15.67%). Serum Lp(a) levels are shown n Fgure 5. At week 12, the mean Lp(a) levels were smlar to baselne n all 3 groups. The mean (SD) lpd tetrad ndex decreased n the followng manner. n group 1, a statstcally sgnfcant decrease n the lpd tetrad ndex was seen at week 6 (from 32, [29,316.5] to 16,952 [ 14,527.92]; P 0.04), but no sgnfcant change was seen at week 12. n group 2, a statstcally sgnfcant decrease was seen n 12 weeks (from 59,210.5 [34,309.2] to 30,070.3 [16,309.1] n the frst 6 weeks 5O l 48 Group ]*(n = 30) Group 2t (n = 30) Group 3~ (n = 30) /~48.53 ~ ~" ~ / 46,56 "~ 44, d4,.,,.l W z 42 ~ ~ 4o~ ' 38 k 41,05 A/ // 39, 64m~// [ 1 Fgure Study Week Mean (SD) hgh-densty lpoproten cholesterol (HDL-C) levels n ndan patents recevng treatment for dyslpdema. *Group 1 receved smvastatn monotherapy (20-mg tablet OD wth meals) for 12 weeks, tgroup 2 receved nacn (sustaned released [SR]) monotherapy (one 375-mg tablet taken wth the evenng meal for 1 week, followed by 500 mg OD wth the evenng meal for 1 week, and 500 mg BD wth meals for 10 weeks). ~;Group 3 receved smvastatn 10 mg and nacn (SR) tablets. The doses of nacn were 375 mg/d for 1 week and 500 mg/d for 11 weeks. P < 0.05 versus week 0.

9 K. Kaur et al. E ~2 Fgure q 290 [ 270 l 250 l 230 l l 210 4, 190 [ "97aN,X\ ~.\~ ~ \, \\ ~'\x ~ + Groupl*(n=30) 4 Group 2t(n = 30) Group 3*(n = 30) ~ ",,.~ Study Week Mean (SD) total cholesterol (TC) levels n ndan patents recevng treatment for dyslpdema. *Group 1 receved smvastatn monotherapy (20-mg tablet OD wth meals) for 12 weeks, tgroup 2 receved nacn (sustaned released [SR]) monotherapy (one 375-mg tablet taken wth the evenng meal for 1 week, followed by 500 mg OD wth the evenng meal for 1 week, and 500 mg BD wth meals for 10 weeks). *Group 3 receved smvastatn 10 mg and nacn (SR) tablets. The doses of nacn were 375 mg/d for 1 week and 500 mg/d for 11 weeks. P < 0.05 versus week 0. [P < 0.002] to 16,329.5 [8946.2] n the next 6 weeks [P < 0.003]). n group 3, the decrease was sgnfcant at weeks 6 and 12 (from 46,521.1 [36,115.0] at baselne to 19,851.0 [15,185] at 6 weeks [P< 0.005] to 10,463 [4987] at 12 weeks [P< 0.015]). Tolerablty Muscle pan (myalga) developed n 5 (17%), 9 (30%), and 6 (20%) patents n groups 1, 2, and 3, respectvely. Flushng was seen n 15 patents (50%) n group 2; ths AE subsded wthn 3 weeks n all affected patents. All patents n group 3 tolerated the ncrease n nacn dose (e, no flushng was seen). Dyspepsa was observed n 8 (27%) and 5 (17%) patents n groups 2 and 3, respectvely. Elevated alanne amnotransferase levels were found at 12 weeks ('out not at 6 weeks) n 2 (7%), 3 (10%), and 2 (7%) patents n groups 1, 2, and 3, respectvely. These 463

10 CURRENT THERAPEUTC RESEARCH patents were asked to dscontnue treatment and mantan an optmal lpd profle by makng lfestyle changes. None of the patents wthdrew from the study. DSCUSSON CAD s a major health problem among people n nda. Studes have shown that the prevalence of trple-vessel CAD s 45% n young ndans (age at onset, <40 years) compared wth 8% to 15% n young people n Western countres Genetc factors (eg, hgh Lp[a] levels) appear to play an mportant role n CAD, together wth the conventonal rsk factors (eg, smokng, hypertenson, hypercholesterolema) and newly defned rsk factors (eg, hypertrglycerdema, hgh G" E L~ 250 ~ + Group 1" (n = 30) ~ Group 2t(n = 30) [ ~ -~-Group 3*(n = 30) 81 q~ 1 235, )\ [ 190~ \~] \\~\\\\\\\~ 166, M2"~-..~ "'~ ~ r tudyWeek Fgure 4. Mean (SD) trglycerde (TG) levels n ndan patents recevng treatment for dyslpdema. *Group 1 receved smvastatn monotherapy (20-mg tablet OD wth meals) for 12 weeks, tgroup 2 receved nacn (sustaned released [SR]) monotherapy (one 375-mg tablet taken wth the evenng meal for 1 week, followed by 500 mg OD wth the evenng meal for 1 week, and 500 mg BD wth meals for 10 weeks). *Group 3 receved smvastatn 10 mg and nacn (SR) tablets. The doses of nacn were 375 mg/d for 1 week and 500 mg/d for 11 weeks. P < 0.05 versus week O. 464

11 K. Kaur et al. 55 q,o_ ~t~-group 1*(n = 30) ~Group 2t(n = 30) ~, Group3*(n=30) -~ 4oq g -~ 35.J ~".-2 \ \ \ A. "X\ ~.. "~'~'~'~.~.~ ~'~ 26, " [ 15~ r... ~ O 6 1'2 Study Week Fgure 5. Mean (SD) lpoproten (a) (Lp[a]) levels n ndan patents recevng treatment for dyslpdema. *Group 1 receved smvastatn monotherapy (20-mg tablet OD wth meals) for 12 weeks. *Group 2 receved nacn (sustaned released [SR]) monotherapy (one 375-mg tablet taken wth the evenng meal for 1 week, followed by 500 mg OD wth the evenng meal for 1 week, and 500 mg BD wth meals for 10 weeks). *Group 3 receved smvastatn 10 mg and nacn (SR) tablets. The doses of nacn were 375 mg/d for 1 week and 500 mg/d for 11 weeks. homocystene levels, low HDL-C levels, nsuln resstance). The conventonal rsk factors fal to explan the hgh ncdence of CAD n ndans. n Asan ndans, CAD s often premature (age at onset, <40 years), severe, and extensve, and follows a malgnant course. 7 Asan ndans have also shown a sgnfcantly hgher prevalence of dabetes melltus, hypertrglycerdema, a low HDL-C level, and lower prevalences of cgarette smokng, systolc hypertenson, and famly hstory of CAD. 7 The ndan patents n the present study had hgh TG and Lp(a) levels and low HDL-C levels. The mean baselne Lp(a) level was (29.04) mg/dl. Many observatonal studes have reported that ndans have hgher levels of Lp(a) compared wth all other races except blacks The Coronary Artery Dsease 465

12 CURRENT THERAPEUTC Among ndans study reported Lp(a) levels >30 mg/dl (the threshold at whch the rsk for CAD s beleved to ncrease) n 25% of Asan ndans, 17% of whtes, and 8% of Hspancs. 2 Among the 90 patents n the present study, 45 (50%) had Lp(a) levels >30 mg/dl. The mean TG level at the begnnng of the tral was (81.16) mg/dl. The mean baselne HDL-C level was (5.52) mg/dl. Enas et al 7 reported that HDL-C levels n ndan Amercan men were 5 mg/dl lower than n European Amercans and 15 mg/dl lower than n Japanese Amercans. The mean LDL-C and TC levels n the present study were (68.03) mg/dl and (64.98) mg/dl, respectvely. Ths TC level was hgher than that reported n another populaton of ndan patents (199 mg/dl). 23 The hgher values found here mght have been due to the urban lfestyle of these patents (e, many urban dwellers consume hgh-calore dets and have sedentary lfestyles). The mean lpd tetrad ndex at the start of the study was 46, (34,600.39). Apart from provdng evdence concernng the typcal pattern of dyslpdema n ndans, ths study also showed sgnfcant results for the effcacy of smvastatn and nacn alone or combned. We observed that smvastatn alone and n combnaton wth nacn was assocated wth sgnfcant decreases n LDL-C and TC levels. Although the dose of smvastatn was lower (10 mg/dl) n combnaton therapy, the percentage decreases n LDL-C and TC levels were smlar n monotherapy and combnaton therapy. Nacn monotherapy (1 g/d) was not assocated wth a change n LDL4~ or TC level. A decrease of 20% to 30% n LDL-C levels has been reported wth very hgh doses of nacn ( g/d). 2 n the present study, the effect may have been smaller because of the low baselne levels of LDL-C and TC n group 2. Another explanaton for the lower decrease n LDL-C n ths group s beta-shft: 11 patents had ncreases n LDL-C. The effects on other lpd levels vared accordng to treatment. Combnaton therapy was assocated wth a sgnfcant decrease n TG level at 6 weeks, whereas monotherapy wth ether drug was not assocated wth any change n TG level. n a study by Guyton et al, 24 a decrease of 16% to 29% was reported wth nacn 1.5 to 2.0 g/d. The mean (SD) decrease of 20.44% (15.04%) wth smvastatn was hgher than that seen n other trals. 25,26 One study, however, reported a dose-dependent reducton n TG level of 22% to 45% wth all of the statns when the baselne levels were >250 mg/dl. 27 At 12 weeks, the mean ncrease n HDL-C level was sgnfcant wth nacn monotherapy and wth combnaton therapy. Few data are avalable concernng the effect of smvastatn on HDL-C. More studes are needed to ascertan the effect of statns on HDL-C. 2 Nacn monotherapy was most effcacous n lowerng the Lp(a) levels, whereas smvastatn monotherapy and combnaton therapy were not assocated wth any changes n Lp(a) levels. At 12 weeks, nacn alone and n combnaton wth smvastatn was assocated wth a sgnfcant decrease n the lpd tetrad ndex. Nacn monotherapy was assocated wth more AEs (eg, flushng, myalga, dyspepsa, elevated alanne amnotransferase level) compared wth the other 2 treatments. Contrary to the typcal assumpton that the AEs ncrease when 466

13 K. Kaur et al. lpd-alterng agents are gven n combnaton, ths combnaton therapy was not assocated wth an ncreased prevalence of myalga or elevated lver enzyme levels compared wth ether drug alone. The lower number of AEs found wth combnaton therapy may have been due to the lower dose of both drugs n combnaton treatment. Although ths study showed the effects of smvastatn and nacn on the lpd profle, some mportant results could not be derved because of lmtatons of the study. Because the study was not randomzed, the results n the 3 treatment groups cannot be compared. Because the patents n group 2 had lower levels of LDL-C and TC at baselne compared wth the other 2 groups, the effect of nacn on hgh levels of these 2 parameters could not be observed. Better conclusons could be drawn from a study such as ths f randomzaton were performed at the begnnng. CONCLUSONS n ths populaton of ndan patents wth dyslpdema, smvastatn and nacn had benefcal effects on dfferent parameters of the lpd profle. The smvastatnnacn combnaton was assocated wth mprovement n almost all of the parameters of the lpd profle. n ths study populaton, the prevalence of AEs dd not ncrease when low doses of smvastatn and nacn were combned. REFERENCES 1. Expert Panel on Detecton, Evaluaton, and Treatment of Hgh Blood Cholesterol n Adults. Executve summary of the Thrd Report of the Natonal Cholesterol Educaton Program (NCEP) Expert Panel on Detecton, Evaluaton, and Treatment of Hgh Blood Cholesterol n Adults (Adult Treatment Panel ll). JAMA. 2001;285: Mahley RW, Bersot TE Drug therapy for hyperoholesterolema and dyslpdema. n: Hardman JG, Lmbrd LE, eds. Goodman & Glman's the Pharmacologcal Bass of Therapeutcs. 10th ed. New York: McGraw-Hll; 2001: ~lopp RH, Gnsberg J, Albers J J, et al. Contrastng effects of unmodfed and tmerelease forms of nacn on lpoprotens n hyperlpdemc subjects: Clues to mechansm of acton of nacn. Metabolsm. 1985;34: Vega GL, Grundy SM. Lpoproten responses to treatment wth lovastatn, gemfbrozl, and ncotnc acd n normolpdemc patents wth hypoalphalpoprotenema. Arch ntern Med. 1994;154: Martn-Jadraque R, Tato F, Mostazo JM, et al. Effectveness of low-dose crystallne ncotnc acd n men wth low hgh-densty lpoproten cholesterol levels. Arch ntern Med. 1996;156: Carlson LA, Hamsten A, Asplund A. Pronounced lowerng of serum levels of lpoproten Lp(a) n hyperlpdaemc subjects treated wth ncotnc acd. J ntern Med. 1989;226:

14 CURRENT THERAPEUTC RESEARCH 7. Enas EA, Yusuf S, Mehta JL. Prevalence of coronary artery dsease n Asan ndans. Am J Cardol, 1992;70: Enas EA, Mehta JL. Malgnant atheroscleross n young ndans. Thought on pathogeness. Preventon and treatment. Cln Cardol, 1995;18: Sandholzer C, Halman DM, Sahe N, et al. Effect of apolpoproten (a) polymorphsm on the lpoproten (a) concentraton n seven ethnc groups. Hum Genet. 1991;86: Allan CC, Poon LS, Chan CS, et al. Enzymatc determnaton of total serum cholesterol. Cln Chem. 1974;29: Bursten M, Scholnck HR, Morfn R. Rapd method for the solaton of lpoprotens from human serum by precptaton wth polyanons. JLpd Res, 1970;11: Bucolo G, Davd H. Quanttatve determnaton of serum trglycerdes by use of enzymes. Cln Chem. 1973;19: Fredewald WT, Levy R, Fredrckson DS. Estmaton of the concentraton of lowdensty lpoproten cholesterol n plasma, wthout use of the preparatve ultracentrfuge. Cln Chem. 1972;18: Metzmann E. Proten quanttaton on both branches of the Hedelberger curve by montorng the knetc of mmunoprecptaton. Behrng lnstmtt. 1985;78: Enas EA, Garg A, Davdson MA, et al. Coronary heart dsease and ts rsk factors n the frst-generaton mmgrant Asan ndans to the Unted States of Amerca. ndan Heart ~ 1996;48: lb. Jalowec DA, Hll JA. Myocardal nfarcton n the young and n women. Cardovasc Cln, 1989;20: Sharma SN, Kaul U, Sharma S, et al. Coronary arterographc profle n young and old ndan patents wth schaemc heart dsease: A comparatve study. ndan Heart 1990;42: Dave TH, Wasr HS, Prabhakaran D, et al. Profle of coronary artery dsease n ndan women: Correlaton of clncal, non nvasve and coronary angographc fndngs. ndan Heart ~ 1991;43: Negus BH, Wllard JE, Glamann DB, et al. Coronary anatomy and prognoss of young, asymptomatc survvors of myocardal nfarcton. Am JMed, 1994;96: Enas EA, Yusuf S, Garg A, et al. Lpoproten (a) levels n ndan physcans. Comparson wth black and whte physcans n the U.S.A. ndan Heart ~ 1994;46 (Suppl): Enas EA, Yusuf S. Thrd meetng of the nternatonal Workng Group on Coronary Artery Dsease n South Asans. 29 March 1998, Atlanta, USA. ndan Heart ~ 1999; 51: Low PS, Heng CK, Saha N,'Fay JS. Racal varaton of cord plasma lpoproten(a) levels n relaton to coronary rsk level: A study n three ethnc groups n Sngapore. Pedatr Res, 1996;40: G pnath N' Chadha SL' Sehgal A' et al' What s 'desrable' lpd pr fle' lndan Heart J 1994;46: Guyton JR, Blazng MA, Hagar J, et al. Extended-release nacn vs gemfbrozl for the treatment of low levels of hgh-densty lpoproten cholesterol. Arch ntern Med. 2000;160: Randomsed tral of cholesterol lowerng n 4444 patents wth coronary heart dsease: The Scandnavan Smvastatn Survval Study (4S). Lancet. 1994;344:

15 K. Kaur et al. 26. Sweany AE, Shapro DR, Tate AC, et al, for the NDDM Study Group. Effects of smvastatn versus gemfhrozl on lpds and glucose control n patents wth non-nsulndependent dabetes melltus. Cln The~ 1995;17: Sten EA, Lane M, Laskarzewsk R Comparson of statns n hypertrglycerdema. Am J Cardol. 1998;81:66B-69B. Address correspondence to: Dr. Krandeep Kaur, Z15-A, Sewak Colony, Patala , Punjab, nda. E-mal: kransonh@redffmal.com, kransondh@hotmal.com 469