Report of the Conference on Low Blood

1046 Report of the Conference on Low Blood Cholesterol: Mortlity Associtions Dvid Jcobs, PhD; Henry Blckburn, MD; Millicent Higgins, MD; Dwyne Reed, MD, PhD; Hiroysu Iso, MD; Grdner McMilln, MD, PhD; Jmes Neton, PhD; Jmes Nelson, MD; John Potter, MD, PhD; Bsil Rifkind, MD; Jcques Rossouw, MD; Richrd Shekelle, PhD; nd Slim Yusuf, DPhil, for Prticipnts in the Conference on Low Cholesterol: Mortlity Associtions Bckground. A Ntionl Hert, Lung, nd Blood Institute (NHLBI) Conference ws held October 9-10, 1990, to review nd discuss existing dt on U-shped reltions found between mortlity rtes nd blood totl cholesterol levels (TC) in some but not other studies. Presenttions were given from 19 cohort studies from the United Sttes, Europe, Isrel, nd Jpn. A representtive of ech study presented its findings nd lso submitted tbles of proportionl hzrds regression coefficients for entry TC levels in regrd to deth, nd these were incorported into forml sttisticl overview djusted for ge, distolic blood pressure, cigrette smoking, body mss index, nd lcohol intke, s vilble. Methods nd Results. The U-shpe for totl mortlity in men nd the flt reltion in women resulted lrgely from positive reltion of TC with coronry hert disese deth nd n inverse reltion with deths cused by some cncers (e.g., lung but not colon), respirtory disese, digestive disese, trum, nd residul deths. Risk for combined noncrdiovsculr, noncncer cuses of deth decresed stedily cross the rnge of TC. The conference considered possible explntions for the sttisticl ssocitions found between low TC levels or ctive TC lowering nd certin cuses of deth. One is tht TC is lowered by some disese conditions themselves, such s wsting in chronic pulmonry disese or reduced production nd secretion of cholesterol-bering lipoproteins with liver disese. In this sort of sitution, the TC: mortlity ssocition found in observtionl studies my be due to preexisting disese. This ws ddressed by excluding erly deths from the nlysis, which did not chnge the results. The conference considered s well the biologicl function of cholesterol, which, if seriously dernged, might hypotheticlly cuse wide vriety of diseses nd dysfunction. The conference lso considered the biologicl functions tht might provide plusible mechnisms for the ssocitions found. Conclusions. Definitive interprettion of the ssocitions observed ws not possible, lthough most prticipnts considered it likely tht mny of the sttisticl ssocitions of low or lowered TC level re explinble by confounding in one form or nother. The conference focused on the pprent existence nd nture of these ssocitions nd on the need to understnd their source rther thn on ny pertinence of the findings for public helth policy. Further reserch is recommended to explin the observed ssocitions of low TC levels (nd TC lowering) with certin noncrdiovsculr diseses. This includes studies of the time course of TC chnge in disese, the reltion of TC to morbidity, further studies of possible epidemiologicl confounding, monitoring of popultion trends in TC nd mortlity, further studies of the reltions in women, uditing of noncrdiovsculr events in trils, studies of cell membrne, genetic nd moleculr links to cholesterol metbolism, TC level nd disese, studies of disese mnifesttions in specific lipid disorders, nd further study of the proposed cusl mechnisms linking low TC nd hemorrhgic stroke. (Circultion 1992;86:1046-1060) KEY WORDs * cholesterol * mortlity TNhis Ntionl Hert, Lung, nd Blood Institute (NHLBI) conference ws orgnized to exmine existing dt on the reltions of low blood totl cholesterol (TC) level to risk of deth nd morbidity nd to consider whether ny reltions found re cusl. The issue ws rised in 1971 by Jpnese investigtors Anlyses of the Yugoslvi Crdiovsculr Study were supported by Ntionl Institutes of Helth grnt NCI-CA23024. The NORA Address for correspondence: Dvid R. Jcobs Jr., PhD, Division project ws supported by grnt from the Joint Committee of the of Epidemiology, School of Public Helth, University of Minnesot, Nordic Medicl Reserch Councils. The Chicgo studies were 1300 South Second Street, Suite 300, Minnepolis, MN 55454. supported by grnts from the Ntionl Hert, Lung, nd Blood Supported by the Ntionl Hert, Lung, nd Blood Institute. Institute (NHLBI); from the Americn Hert Assocition nd its The Hiroshim/Ngski Study of the Rdition Effects Reserch Chicgo nd Illinois Affilites; from the Chicgo Helth Reserch Foundtion (RERF) is supported eqully by the Government of Foundtion; from the Illinois Regionl Medicl Progrm (for the Jpn through the Ministry of Helth nd Welfre nd the CHA study); nd from privte donors. The Honolulu Hert Government of the United Sttes through the Ntionl Acdemy Progrm is supported by NHLBI contrct NO1-HC-02901. of Sciences under contrct with the Deprtment of Energy. Received August 29, 1991; revision ccepted June 8, 1992.

Jcobs et l Conference on Low Blood Cholesterol nd Mortlity 1047 who observed the ecologicl ssocition of high rtes of cerebrl hemorrhge with low verge blood cholesterol levels in their popultions.' Lter, they noted decresing trend in stroke incidence rtes over the yers s men popultion TC levels rose nd blood pressure levels fell.2'3 Correltions were lso found in individuls between low TC level nd risk of cerebrl hemorrhge in Jpn,4-7 Honolulu,8'9 nd Multiple Risk Fctor Intervention Tril (MRFIT) screenee10 cohorts. The issue ws independently rised by observtions of greter colon cncer risk in individuls hving low TC levels within high-verge TC societies in some studies1l-13 but not in others.14-16 More recently, greter noncrdiovsculr disese (non-cvd) risk ws observed in those hving low TC levels.17 In ddition, the finding of excess non-cvd events nd deths mong treted cohorts in severl TC-lowering trils18-25 but not in other single or multifctor intervention trils26-30 hs contributed to renewed discussion bout the possible helth effects of low or of therpeutic lowering of TC levels. Finlly, ecologicl studies suggest tht popultions hving low verge TC vlues (notbly Jpn) usully do not hve excess cncer, non-cvd mortlity, or totl deth rtes, lthough they my hve excess rtes of hemorrhgic stroke.3' Public cmpigns re now under wy in industrilized countries to reduce elevted popultion men levels of TC nd low density lipoprotein (LDL) cholesterol, bsed on congruent evidence bout their determining influence on both popultion nd individul risk of therosclerosis nd epidemic coronry hert disese.32'33 If these progrms were to hve ny dverse effects, the nture nd mgnitude of such effects should be understood so tht they cn be voided or minimized. Moreover, the scientific questions rised by the pprent non-cvd disese ssocitions with low TC levels34 could led to new insights on generl issues of diet nd helth nd on the lrger role of cholesterol in humn biology. Issues relted to risks of elevted blood cholesterol nd the costs nd benefits of cholesterol lowering were ddressed in other recent NHLBI conferences, on "Cholesterol nd Hert Disese in Older Persons nd Women"35 nd "Cost nd Helth Implictions of Cholesterol Lowering".36 The question of possible ssocitions of low TC levels with cncer ws ddressed in 1981 conference37 sponsored by the NHLBI in which inconsistent evidence hd led to concern of possible increse in cncer risk t very low cholesterol levels (<180 mg/dl) in men.38 Becuse the mgnitude of this risk ws generlly modest when present, the pnelists concluded tht "the findings do not represent public helth chllenge; however, they do present scientific chllenge."37 In the 1990 NHLBI conference, the investigtors reported nlyses on ssocitions between low TC levels nd disese in individul cohorts nd in pooled dt. Popultion (ecologicl) correltions were lso presented long with met-nlysis of clinicl trils of TC lowering. Discussions were directed to the evidence bout risk of specific diseses ssocited with low TC vlues including hemorrhgic stroke, cncers, nd other diseses nd with high TC vlues including coronry hert disese (CHD) nd brin infrction. Potentil mechnisms for the effects on disese or function of low blood or cell membrne cholesterol content were discussed, bsed on the metbolic nd physiologicl roles of cholesterol. Effects of disese on blood cholesterol levels were lso discussed, nd the lck of informtion on lipoprotein subfrctions ws cknowledged. Finlly, pnel recommended needs nd opportunities for further reserch. Methods A summry nlysis ws crried out under the direction of Dr. Jcobs on dt from 19 of 20 cohort studies invited to prticipte in the conference. A mnuscript from the 20th study ws shred with the study orgnizers.39 Tble 1 enumertes the studies nd includes 11 from the United Sttes,8-'0"6'40-57 one from southern Europe,58 one from Isrel,59-6' two from Gret Britin,17,62-65 one from Scndinvi, nd three from Jpn."2,5-7,6667 The Scndinvin study (NORA) represents pooled dt from five studies. Length of follow-up rnged from 9 to 30 yers. Dt were nlyzed t ech study center following stndrd protocol developed t the University of Minnesot, where the pooled estimtes were subsequently computed; dt for individul prticipnts were not vilble t the University of Minnesot. Dt presented s prt of the overview hd not been published before conference presenttion. The sttisticl overview itself hd strengths nd limittions tht re reviewed in lter section herein. Tble 2 gives for ech study, seprtely for men nd women, the numbers t risk nd numbers of totl deths, s well s deths mong those with TC level <160 mg/dl. Of totl of 68,406 deths in ll the studies, pproximtely 45% were coded to totl crdiovsculr cuses (ICD 9, 390-459), 33% to totl cncer cuses (ICD 9, 140-239) nd 22% to non-cvd, noncncer cuses. The ltter ctegory included respirtory (ICD 9, 460-519), digestive (ICD 9, 520-579), trumtic (ICD 9, 800-999), nd other cuses (ICD 9, 1-139, 240-389, nd 580-799), comprising 5%, 4%, 6%, nd 7% of totl mortlity, respectively. The distribution of cuses of deth is not presented by sex becuse numbers of deths were not seprted for ech cuse for ll studies in mterils submitted for the overview. The proportionl hzrds regression model ws used to study the reltion of TC level to totl mortlity, totl crdiovsculr disese (CVD) mortlity, totl cncer mortlity, nd combined noncrdiovsculr, noncncer mortlity for men nd women seprtely, both unstrtified nd strtified by smoking or lcohol intke. Subctegories of cuse of deth-chd, brest cncer, colon cncer, lung cncer, other cncers, respirtory disese, digestive disese, trumtic deth, nd ll other cuses-were studied seprtely for men nd women. Seprte regression coefficients for three TC clsses (<160, 200-239, nd.240 mg/dl) were computed for mortlity risk reltive to the clss hving TC levels 160-199 mg/dl. The ctegory 'TC< 160 mg/dl" ws studied becuse there ws some evidence tht such low levels, even though rrely found in middle-ged persons in U.S. nd Europen studies, might be ssocited with excess mortlity risk. The other ctegories were selected to study chnges in the TC: mortlity reltion s cholesterol incresed. It ws convenient to study people with TC>200 mg/dl nd those with TC>240 mg/dl becuse of the role these levels ply in the Ntionl Cholesterol Eduction Progrm. Hzrd rte rtios were computed s the exponentil of ech regression coefficient. Differences mong these hzrd rte rtios

1048 Circultion Vol 86, No 3 September 1992 TABLE 1. Description of Prticipting Studies Age Covribles rnge Mle Blck Yers of vilble Study nme (yers) (%) (%) follow-up t bseline 1. MRFIT screening* 35-57 100 6.4 12 ACD 2. NORA (five studies) 35-64 55.6 0 :9 ABCD 3. Kiser Permnente Northern Cliforni 35-69 47.1 22.2 18.5 ABCDE 4. Honolulu 45-68 100 0 18.6 ABCDE 5. Puerto Rico 35-69 100 16 12 ABCDE 6. Tecumseh 35-69 49.8 0 21.3 ABCDE 7. Frminghm 35-69 43.6 <0.1 30 ABCDE 8. NHEFS, NCHS 35-69 41.4 15.4 14.1 ABCDE 9. Yugoslvi 35-62 100 0 15 ABCDE 10. Pisley/Renfrew 45-64 45.8 <0.1 14.4 ABCD 11. Whitehll 40-64 100 '0 21 ABCD 12. Akit 40-69 44.7 0 19.6 ABD 13. Osk 40-69 33.8 0 8.9 ABCDE 14. Hiroshim/Ngski 35-69 36.5 0 14.7 ABCDE 15. Lipid Reserch Clinics 35-69 58.9 6.6 12.1 ABCDE 16. Chicgo Peoples Gs 42-60 100 0 16.8 ABCDEt 17. Chicgo Western Electric 41-57 100 0 20.8 ABCDE 18. Chicgo Hert Associtiont 35-69 53 0 14.3 ABCD 19. Isrel 40-65 100 ='0 23 ABCD A, ge; B, body mss index; C, cigrette smoking; D, distolic blood pressure; E, ethnol intke. *Studies re referred to by their number in ccompnying grphs. tthe Chicgo Peoples' Gs study hd informtion on lcohol only on problem drinkers. j:blck prticipnts in the Chicgo Hert Assocition study were not included. indicte curvture in the ssocited TC: mortlity reltions. A U shpe would be indicted, for exmple, by the sequence of hzrd rte rtios (for scending TC level grouping) 1.2, 1.0, 1.0, 1.2, nd liner trend would be suggested by the sequence 1.1, 1.0, 0.9, 0.8. In seprte nlyses, reltions of TC to mortlity were nlyzed with TC s continuous vrible. The resulting liner regression coefficients ignore curvture but indicte generlly lower risk of deth (for negtive coefficient) the higher the TC level, or generlly higher risk of deth (for positive coefficient) the higher the TC level. To ttempt to ccount for the potentil effects of preexisting illness on the entry TC level nd on subsequent disese reltions, deths occurring within 5 yers of bseline were excluded except where noted. The regressions contined covrites of ge, distolic blood pressure, cigrette smoking (18 studies), body mss index (18 studies), nd lcohol intke (12 studies). Dt were excluded from individuls younger thn 35 or older thn 69 yers t bseline or who hd definite CHD t bseline ccording to ech study's usul definition. The MRFIT lso excluded men tking mediction for dibetes. Regression coefficients were pooled inversely to their vrinces, including component of vrince for heterogeneity between studies, following the method of DerSimonin nd Lird.68 The MRFIT Screening Follow-up Study constitutes 67% of ll men reported here nd 38% of ll deths in men, nd its dt re therefore presented seprtely from the pooled regression coefficients. Not ll studies submitted strtified nd subctegory nlyses, nd some studies hd insufficient numbers for nlysis in specific TC cells. Results Tbles 3-7 give pooled hzrd rte rtios ( mesure of reltive risk) nd their ssocited t vlues, compring ech of the TC ctegories, <160 mg/dl, 200-239 mg/dl, nd.240 mg/dl, to the reference ctegory, 160-199 mg/dl. The t vlues re the number of stndrd devitions tht the estimted hzrd rte rtio deprts from 1. The pooled hzrd rte rtios for grouped mjor cuses of deth re summrized grphiclly in Figure 1 nd for the subctegories of noncrdiovsculr, noncncer cuses in Figure 2. Also given in Tbles 3-7 (with the lbel n>l1n) is the number of studies showing incresed risk compred with those with TC 160-199 mg/dl for ech TC ctegory nd end point event, providing mesure of consistency cross studies. All-Cuses Deth In men, risk for ll-cuses deth occurring t lest 5 yers fter bseline in reltion to TC level ws U-shped in the pooled estimtes nd in the MRFIT, with risk 14-22% greter for those with TC< 160 mg/dl or.240 mg/dl compred with those with TC 160-199 mg/dl (Tble 3 nd Figure 1). In women, the pooled estimte of risk for ll cuses-deth ws essentilly flt cross TC levels (Tble 3 nd Figure 1). Totl Crdiovsculr Deth In men whose entry TC levels were greter thn the reference TC clss 160-199 mg/dl, the estimted risk for totl CVD deth incresed systemticlly nd consistently (deths in the 5 yers fter bseline excluded: Tble 3 nd Figure 1). Risk for men with TC level < 160 mg/dl, compred with those in the reference clss, ws

Jcobs et l Conference on Low Blood Cholesterol nd Mortlity 1049 TABLE 2. Smple Size nd Numbers of Deths for the Entire Popultion nd for Cses With Blood Cholesterol <160 mg/dl Men 1. MRFIT screening 2. NORA (five studies) 3. Kiser Permnente Northern Cliforni 4. Honolulu 5. Puerto Rico 6. Tecumseh 7. Frminghm 8. NHEFS, NCHS 9. Yugoslvi 10. Pisley/Renfrew 11. Whitehll 12. Akit 13. Osk 14. Hiroshim/Ngski 15. Lipid Reserch Clinics 16. Chicgo Peoples Gs 17. Chicgo Western Electric 18. Chicgo Hert Assocition 19. Isrel Totl Women 2. NORA (five studies) 3. Kiser Permnente Northern Cliforni 6. Tecumseh 7. Frminghm 8. NHEFS, NCHS 10. Pisley/Renfrew 12. Akit 13. Osk 14. Hiroshim/Ngski 15. Lipid Reserch Clinics 18. Chicgo Hert Assocition Totl Totl Totl Crude deth <160 mg/dl <160 mg/dl <160 mg/dl smple number rte per Smple Totl non-cvd size of deths 105 pers*yr size deths deths 350,977 21,499 42,156 2,404 41,109 8,259 7,642 2,055 9,061 1,394 1,901 714 2,046 1,211 3,293 920 6,351 1,167 6,707 1,902 17,597 4,022 1,012 309 4,589 195 2,986 794 3,486 346 1,210 469 1,903 691 12,292 1,753 9,358 3,032 523,737 55,525 33,677 46,081 1,917 2,647 4,664 8,044 1,250 8,966 5,552 2,937 9,179 124,814 755 6,051 475 1,180 705 1,396 254 159 882 241 783 12,881 1.04 in the pooled dt (rtio greter thn 1 in 11 of 18 contributing studies) nd ws 0.89 in the MRFIT. In women, findings between studies were inconsistent; for exmple, totl CVD deth rte for those women hving TC level.240 mg/dl ws greter thn for those hving TC level 160-199 mg/dl in five of 11 studies (Tble 3). The pooled estimted risk for totl CVD deth in women showed no trend cross TC levels (Tble 3 nd Figure 1). In men, liner regression coefficients for TC nd totl CVD deth were positive in the MRFIT nd for 16 of 18 other studies (only Osk nd Hiroshim/Ngski hd negtive coefficients). In women, liner regression coefficients were positive in nine of 11 studies (only Tecumseh nd Hiroshim/Ngski hd negtive coefficients). Totl Cncer Deth In men with TC level <160 mg/dl compred with 160-199 mg/dl, the risk rtio for totl cncer deths ws greter thn 1 in 15 of 18 studies; reltive risk ws 1.18 in the pooled studies nd 1.23 in the MRFIT. The 613 570 2,009 2,689 1,538 3,756 5,919 2,639 1,838 2,836 2,286 3,053 425 2,659 993 3,876 3,631 1,426 3,240 224 1,313 2,614 4,458 1,512 1,735 2,032 177 1,589 821 853 21,185 639 1,151 364 1,235 85 56 172 1,997 188 2,189 604 796 977 174 44 40 721 898 33,515 592 1,359 117 50 282 77 666 1,103 1,308 157 453 6,164 1,136 36 175 139 232 24 34 58 417 78 489 180 43 286 15 15 14 87 234 3,692 11 107 21 13 29 15 109 25 172 6 27 535 850 27 109 105 151 17 24 41 287 48 271 106 38 206 3 7 8 51 139 2,488 9 88 11 7 19 8 55 18 112 3 23 353 cncer risk rtio ws close to 1 for clsses of TC level >200 mg/dl (deths in the 5 yers fter bseline excluded: Tble 3 nd Figure 1). In women, findings between studies were inconsistent; for exmple, totl cncer deth rte for those women hving TC level < 160 mg/dl ws greter thn for those hving TC level 160-199 mg/dl in six of 11 studies (Tble 3). In pooled dt, there ws little vrition in women's risk for totl cncer deths cross the four TC ctegories (Tble 3 nd Figure 1). In men, liner regression coefficients were negtive in the MRFIT nd in 14 of 18 other studies (only NORA, Tecumseh, Chicgo Western Electric, nd Whitehll hd positive coefficients). In women, liner regression coefficients were negtive in seven of 11 studies (only Tecumseh, NHEFS/NCHS, Akit, nd Hiroshim/Ngski hd positive coefficients). Combined Non-CVD, Noncncer Deth Risk estimtes for combined non-cvd, noncncer deths in reltion to TC level were similr from the

1050 Circultion Vol 86, No 3 September 1992 TABLE 3. Risk Rtios for Deths Occurring.5 Yers After Study Bseline Blood Noncrdiovsculr, cholesterol All cuses Totl crdiovsculr Totl cncer noncncer (mg/dl) Rte rtio t n>l/n Rte rtio t n<l/n Rte rtio t n>l/n Rte rtio t n>l/n Pooled except MRFIT, men <160 1.17 3.6 14/18 1.04 0.8 11/18 1.18 2.3 15/18 1.32 5.3 16/17 200-239 1.02 0.8 9/18 1.16 3.6 14/18 0.95-1.8 8/18 0.89-2.5 5/18.240 1.14 5.1 14/18 1.48 9.5 16/18 0.95-1.2 8/18 0.87-3.6 3/17 MRFIT men <160 1.17 4.0 0.89-1.7 1.23 3.5 1.48 5.6 200-239 1.05 2.5 1.31 9.0 0.95-1.7 0.87-3.5.240 1.22 10.0 1.86 20.7 0.91-2.3 0.84-3.4 Pooled women <160 1.10 1.1 8/11 0.96-0.3 6/11 1.05 0.5 6/11 1.41 2.0 7/11 200-239 0.94-1.4 3/11 0.95-0.7 4/11 1.01 0.2 7/11 0.92-1.2 5/11 >240 0.97-0.6 4/11 1.09 1.2 5/11 0.97-0.6 5/10 0.82-2.0 3/11 Adjusted proportionl hzrds model hzrd rte rtios, reltive to 1.0 for blood totl cholesterol 160-199 mg/dl. Ages 35-69 t bseline, excluding people with coronry hert disese. Adjusted for ge, distolic blood pressure, cigrette smoking, body mss index nd lcohol intke, where vilble. The hzrd rte rtio is computed s eo, t is the regression coefficient divided by its stndrd error, n>l /n is the number of studies with hzrd rte rtio > 1, of ll contributing studies. n my vry from one comprison to nother becuse some studies did not hve enough observtions t the totl cholesterol level to mke proportionl hzrds estimte. t is the number of stndrd devitions tht the estimted hzrd rte rtio deprts from 0. Iti.1.645 corresponds top<0.10, 1.96 top<0.05, 2.56 top<0.01, nd 3.3 to p<0.001. MRFIT men, from ll other men pooled, nd from ll women pooled. In both men nd women, risk ws consistently greter, by bout 40%, for those hving low TC levels (<160 mg/dl) compred with the reference clss (TC level, 160-199 mg/dl). Figure 3 summrizes the hzrd rte rtios mong those with TC levels <160 mg/dl compred with those with TC level 160-199 mg/dl for combined non-cvd, noncncer deth for individul studies, with ech study indicted by its identifying number given in Tble 1. Consistency of excess risk in those with TC level <160 mg/dl is seen cross studies, lthough most of the individul study estimtes re not sttisticlly significnt. In both sexes, estimted risk ws bout 10% less thn the reference clss mong those in TC clss 200-239 mg/dl nd ws consistently less, by bout 15%, in those men nd women in the higher TC clss.240 mg/dl (deths in the 5 yers fter bseline excluded: Tble 3 nd Figure 1). In men, liner regression coefficients were negtive in the MRFIT nd in 15 of 18 other studies (only NORA, Frminghm, nd Chicgo People's Gs hd positive coefficients). In women, liner regression coefficients were negtive in nine of 11 studies (only Akit nd Osk hd positive coefficients). Effect on Reltive Risk of Including Deths in the First 5 Yers Pooled estimted hzrd rte rtios were clculted to include erly deths (those occurring in the 5 yers fter bseline). Grdients of pooled estimted risk between TC ctegories re generlly few percent steeper thn those in Tble 3. Anlyses Strtified by Alcohol Intke nd Smoking Pooled estimtes of hzrd rte rtios (deths in the 5 yers fter bseline excluded) re presented for those with TC < 160 nd for those with TC.240 (ech versus the reference clss of 160-199 mg/dl), strtified on lcohol drinking sttus (Tble 4) nd smoking hbit (Tble 5). Not ll studies provided these nlyses. Puerto Rico nd Yugoslvi estimtes of hzrd rte rtios for ll drinkers combined were used in pooling dt for both lighter nd hevier drinkers. Strtifiction reduced the numbers t risk nd rendered some estimtes meningless. All cuses, totl CVD, totl cncer nd combined non-cvd, noncncer cuses of deth were studied. Reltive risk for these four deth outcomes were similr to the unstrtified nlysis of Tble 3 for ech strtum of drinking sttus (Tble 4) nd smoking sttus (Tble 5) for both men nd women. Note tht there ws very little informtion vilble concerning women who drnk.30 ml/dy of lcohol, prticulrly for TC< 160 mg/dl. Subctegory Cuses of Deth Pooled estimtes of rte rtios for men nd for women nd estimtes for the MRFIT men seprtely re presented for nine subctegory cuses of deth in Tbles 6 nd 7 nd Figure 2. Numbers of studies contributing informtion to the pooled estimtes re indicted for ech TC rnge. Some studies re omitted either becuse they did not provide these nlyses or becuse subctegory cuse of deth ws rre. Coronry nd Other Crdiovsculr Deth CHD mortlity rtes incresed consistently with incresing TC level in most studies (Tble 6). The grdient of risk ws steeper for the MRFIT thn for the pooled estimtes. Pooled estimtes were slightly steeper for men thn for women. Hemorrhgic stroke ws not

Jcobs et l Conference on Low Blood Cholesterol nd Mortlity 1051 TABLE 4. Risk Rtios for Deths Occurring.5 Yers After Study Bseline by Alcohol Strtum Alcohol Noncrdiovsculr, intke All cuses Totl crdiovsculr Totl cncer noncncer strtum (ml/dy) Rte rtio t n>lin Rte rtio t n>ln Rte rtio t n>lin Rte rtio t n>lin Pooled except MRFIT, men <160 vs. 160-199 mg/dl 0 1.20 2.8 6/8 1.02 0.2 4/8 1.23 1.6 3/8 1.42 3.1 7/8 <30 1.22 2.6 7/9 1.20 1.5 5/9 1.14 0.8 7/9 1.45 3.8 9/9.30 1.32 3.2 8/9 1.27 2.1 5/8 1.40 1.9 7/9 1.49 3.8 9/9 >240 vs. 160-199 mg/dl 0 1.04 0.4 4/9 1.30 2.4 5/9 1.03 0.3 3/9 0.85-1.7 2/8 <30 1.10 2.5 7/9 1.49 5.5 7/8 0.85-1.9 3/8 0.96-0.5 5/9.30 1.02 0.5 4/9 1.20 1.9 5/9 0.94-0.5 3/8 0.99-0.1 3.8 MRFIT men (lcohol use not queried) Pooled women <160 vs. 160-199 mg/dl 0 1.23 2.0 6/6 1.11 0.5 3/6 1.31 1.0 5/6 1.80 3.6 4/5 <30 1.36 2.6 6/6 1.23 0.6 4/5 1.38 1.8 4/5 1.92 2.8 4/5.30 1.14 0.9 2/3 1.87 1.3 3/3 1.03 0.0 1/1 1.36 0.3 1/2.240 vs. 160-199 mg/dl 0 1.03 0.6 3/6 1.13 1.2 3/6 1.00 0.0 2/6 0.90-1.0 3/6 <30 1.05 0.4 4/6 1.23 1.7 4/6 1.04 0.4 3/5 0.84-0.7 2/5 c30 0.88-1.0 1/5 1.12 0.4 2/3 0.87-0.7 1/5 0.77-1.2 1/4 Adjusted proportionl hzrds model hzrd rte rtios. Adjusted for ge, distolic blood pressure, cigrette smoking, nd body mss index, where vilble (see Tble 1). See notes Tble 3. Iti.1.645 corresponds top<0.10, 1.96 top<0.05, 2.56 top<0.01, nd 3.3 top<0.001. considered in the overview nlysis becuse it is rre outcome in studies from the United Sttes nd northern Europe. In the MRFIT Screening Study, hemorrhgic stroke risk ws inversely relted to TC, nd nonhemorrhgic stroke risk ws positively relted to TC.10,69 The risk grdient for CHD in men nd women cross TC clsses in Tble 6 ws steeper thn tht for totl crdiovsculr disese in Tble 3. Therefore, the risk grdient cross TC ctegories for non-chd crdiovsculr deth ws less steep thn tht for CHD deth. Cncer Deth Subctegory cncer deths re considered in Tble 6. There is little indiction of risk grdient cross TC clsses for brest (not shown) or colon cncer. The low reltive risk estimte of 0.58 for colon cncer for women in the low TC clss (<160 mg/dl) is bsed on only two studies. Pooled estimted risk of lung cncer deth nd of deth from ll other cncers combined ws less with greter level of TC, suggesting continuous downwrd grdient for cncer risk cross TC levels. Dt from the MRFIT suggest tht some other subctegory cncers my lso be elevted with low TC levels, notbly liver, lymphtic, nd hemtopoietic cncers.69 Subctegories of Noncrdiovsculr, Noncncer Deth Deth rtes in subctegories of noncrdiovsculr, noncncer cuses of deth tended to be higher the lower the TC level, excluding deths within 5 yers (Tble 7 nd Figure 2). Pooled nd MRFIT estimtes of hzrd rte rtios for respirtory disese deth were > 1 for those with TC< 160 mg/dl nd were progressively higher with lower TC level mong the four ctegories considered here, suggesting continuously negtive grded risk. Digestive disese deth rtes showed pttern of elevtion t low TC levels nd reduction t high TC levels, lso suggesting continuously grded risk. Deth from trum nd from ll residul cuses showed excess estimted hzrd rte rtios for men (pooled nd MRFIT) nd women with low TC (<160 mg/dl) but were little different from 1 t higher TC levels. The pooled estimted hzrd rte rtio for trumtic deth for women with TC<160 mg/dl ws similr to tht for men but hd higher vrince nd therefore lower t vlue. Consistency of Findings Across Studies The extent of consistency of findings cross the rnge of TC levels found in these studies is noteworthy in the similrity of findings for such disprte popultions s Jpn, the United Sttes, nd Europe, covering wide rnge of verge popultion TC levels nd cultures. For exmple, noncrdiovsculr, noncncer mortlity rtes in men were elevted for those with TC< 160 mg/dl compred with those with TC 160-199 mg/dl in 13 of 14 U.S. nd Europen studies (ll except the Lipid Reserch Clinics study) s well s in the Osk, Akit, nd Hiroshim/Ngski studies in men (studies 12, 13, nd 14 in Figure 3). In U.S. nd Europen women, the Frminghm nd Pisley/Renfrew studies were the only two to show lower noncrdiovsculr, noncncer mortlity rtes t TC levels

1052 Circultion Vol 86, No 3 September 1992 TABLE 5. Risk Rtios for Deths Occurring.5 Yers After Study Bseline by Smoking Strtum Noncrdiovsculr, Smoking All cuses Totl crdiovsculr Totl cncer noncncer strtum Rte rtio t n>lin Rte rtio t n>1ln Rte rtio t n>1/n Rte rtio t n>lin Pooled except MRFIT, men <160 vs. 160-199 mg/dl Nonsmoker 1.14 2.6 11/13 1.06 0.8 8/13 1.12 1.2 9/13 1.33 3.1 9113 Smoker 1.14 2.3 10/13 1.04 0.5 6/13 1.14 1.7 11/13 1.30 3.8 10/13.240 vs. 160-199 mg/dl Nonsmoker 1.09 1.7 8/13 1.39 4.9 9/12 0.92-1.0 6/12 0.88-2.1 1/12 Smoker 1.13 4.6 11/13 1.47 8.4 13/13 0.98-0.3 7/13 0.88-2.3 4/13 MRFIT men < 160 vs. 160-199 mg/dl Nonsmoker 1.25 4.0 0.96-0.4 1.29 3.0 1.59 4.4 Smoker 1.11 2.0 0.82-1.9 1.17 2.0 1.37 3.2.240 vs. 160-199 mg/dl Nonsmoker 1.32 8.7 1.87 12.7 0.98-0.3 1.03 0.4 Smoker 1.18 5.7 1.86 13.7 0.89-2.4 0.73-4.7 Pooled women < 160 vs. 160-199 mg/dl Nonsmoker 1.22 1.7 6/8 1.18 0.8 6/8 1.05 0.3 4/7 1.70 3.4 6/8 Smoker 1.24 2.0 6/8 1.30 1.2 5/6 1.14 0.7 4/7 1.82 3.0 5/6.240 vs. 160-199 mg/dl Nonsmoker 0.94-0.8 3/8 1.03 0.4 3/8 0.98-0.3 5/8 0.81-1.5 3/8 Smoker 1.02 0.3 4/8 1.24 2.3 5/8 1.00 0.0 3/7 0.82-1.7 2/8 Adjusted proportionl hzrds model hzrd rte rtios. Adjusted for ge, distolic blood pressure, body mss index, nd lcohol intke, where vilble (see Tble 1). See notes Tble 3. Iti.1.645 corresponds top<0.10, 1.96 top<0.05, 2.56 top<0.01, nd 3.3 top<0.001. <160 mg/dl, wheres the NORA nd NHEFS/NCHS studies showed no difference in noncrdiovsculr, noncncer mortlity rtes in women t TC levels < 160 versus 160-199 mg/dl. Elevted noncrdiovsculr, noncncer mortlity rtes were seen in the low TC clss of two of three studies of Jpnese women (Figure 3). This pttern ws repeted in seprte nlyses of respirtory, digestive, trumtic, nd ll other deths nd ws found more consistently in men thn in women. Mortlity rtes were elevted for these TABLE 6. Risk Rtios for Deths Occurring 25 Yers After Study Bseline: Coronry Hert Disese nd Subctegories of Cncer Blood Coronry hert disese Colon cncer Lung cncer Other cncer cholesterol (mg/dl) Rte rtio t n>1/n Rte rtio t n>1ln Rte rtio t n>1/n Rte rtio t n>1ln Pooled except MRFIT, men <160 0.92-1.2 3/12 1.00 0.0 5/9 1.20 1.2 6/12 1.19 1.8 10/12 200-239 1.23 5.7 10/13 0.82-1.7 3/11 0.93-1.1 4/11 0.92-2.1 6/12.240 1.69 10.6 11/12 0.92-0.7 3/9 0.90-1.2 6/11 0.91-1.6 5/11 MRFIT men <160 0.78-2.6 1.07 0.4 1.27 2.5 Anlysis 160-199 1.00 1.00 1.00 not done 200-239 1.48 9.7 1.21 2.0 0.86-2.6.240 2.20 19.7 1.13 1.1 0.83-2.9 Pooled women <160 1.02 0.1 4/8 0.58-0.9 0/2 2.79 1.4 4/5 1.36 2.1 5/8 200-239 1.12 1.3 6/8 1.16 0.6 5/8 1.15 1.0 5/7 1.04 0.4 4/8.240 1.56 3.5 8/9 1.13 0.6 3/6 0.99-0.1 4/6 0.98-0.2 3/7 Adjusted proportionl hzrds model hzrd rte rtios. Adjusted for ge, distolic blood pressure, cigrette smoking, nd body mss index, where vilble (see Tble 1). See notes Tble 3. Itli1.645 corresponds top<0.10, 1.96 top<0.05, 2.56 top<0.01, nd 3.3 top<0.001.

TABLE 7. Jcobs et l Conference on Low Blood Cholesterol nd Mortlity 1053 Risk Rtios for Deths Occurring 25 Yers After Study Bseline: Subctegories of Noncrdiovsculr, Noncncers Blood Respirtory Digestive Trum Residul cholesterol (mg/dl) Rte rtio t n>1/n Rte rtio t n>l/n Rte rtio t n>1/n Rte rtio t n>,/n Pooled except MRFIT, men < 160 1.11 1.0 8/12 1.41 2.6 10/12 1.40 3.0 12/14 1.43 3.2 10/13 200-239 0.89-1.3 7/13 0.74-3.1 2/13 0.98-0.2 6/13 1.02 0.2 5/13.240 0.75-2.9 2/10 0.72-2.0 3/11 0.91-1.1 5/12 1.03 0.5 8/12 MRFIT men <160 1.21 1.1 1.70 3.4 1.27 1.9 1.84 4.4 200-239 0.68-3.9 0.81-2.0 0.90-1.5 1.06 0.7.240 0.58-4.8 0.78-2.2 0.92-1.0 1.06 0.6 Pooled women <160 1.85 2.4 4/6 2.01 3.0 6/7 1.26 0.5 4/6 1.53 2.2 5/7 200-239 0.91-0.6 1/8 0.85-2.8 2/7 0.98-0.1 4/8 0.97-0.2 5/9.240 0.76-1.9 3/8 0.69-2.2 1/8 0.95-0.3 4/9 0.99-0.1 3/8 Adjusted proportionl hzrds model hzrd rte rtios. Adjusted for ge, distolic blood pressure, cigrette smoking, nd body mss index, where vilble (see Tble 1). See notes Tble 3. ItI.1.645 corresponds top<0.10, 1.96 top<0.05, 2.56 top<0.01, nd 3.3 top<0.001. four deth subctegories t low TC level for t lest two of the three Jpnese studies except for trum in women, where the Akit study hd insufficient informtion to contribute to the nlysis. A finding of elevted mortlity due to liver cncer, chronic heptitis, cirrhosis, nd nonmedicl deths t low TC levels hs H z r d R t e R t 1 0 2.1 Totl Mortlity 1.9 1.7 1.5 i.3 1.1 0.9. 0.7 0.5.. 1. <160 160-200- 2240 199 239 2'. 1.9. 1.7. 1.5. 1.3. 1.1. 0.9. 0.7. 1.1-0.5.- Totl Cncer Mortli1ty 33% of Totl MortlIty. *.... <160 160-200-.240 1-99 239 '.9 1.7. '.5 1.3. 1.1. 0.9. 0.7 0.5 21. I.9. 1.7 1.5. 1.39 1.1. 0.9 0.7. 0.51 Blood Totl Cholesterol (mg/dl) Totl Crdiovsculr Mortlity 45% of Totl Mortlity < 1 60 160-200- 2240 199 239 Combined Noncrdlovsculr, Noncncer Mortlity 22% of Totl Mortllty X I 60 160-200- >240.199 239 ---* Pooled Men M-- ĪRFIT Men ---- Pooled Women FIGURE 1. Grphs of pooled nd Multiple Risk Fctor Intervention Tril (MRFIT) estimtes ofdjusted hzrd rte rtios in deths occurring t lest 5 yers fter bseline in men nd women ged 35-69 yers without coronry hert disese t bseline. lso been reported in Chinese study of more thn 9,000 Shnghi residents followed for 8-13 yers,39 with men TC level %160 mg/dl, with nlyses of men nd women combined, with regression dilution bis removed, nd with djustment for ge, sex, distolic blood pressure, cigrette smoking, nd lcohol drinking sttus. H z r d R t e R t 1 0 21J 1.9.,.7~ 1.5. 1.3 0.7' 0.5. 21. 1.9, 1.7. 1.3. 1.1 0.9 0.7 0.5S Respirtory Mortlity 5% of Totl Mortllty < 1 60 160-200- 2240 199 239 Trumtic Mortllty 6% of Totl Mortlity l.7. I.5S 1.3. 0.9 0.7 ' o.si,.-,.. 1.9. 1.7. 1.5. 1.3. 1.11 0.9-21- 1.9-.l- 2.1-0.9. 0.7. 0.S5 Digestive Mortlity 4% of Totl Mortlity <160 160-200- 2240 199 239 Residul Mortllty 7% of Totl Mortlity 1 60 160-200- 2240 < 160 160-200-.240 199 239 199 239 Blood Totl Cholesterol (mg/dl) ----- Pooled men ---*- MRFIT Men Pooled Women FIGURE 2. Grphs of pooled nd Multiple Risk Fctor Intervention Tril (MRFIT) estimtes of djusted hzrd rte rtios in deths occurring t lest 5 yers fter bseline in men nd women ged 35-69yers without coronry hert disese t bseline.

1054 Circultion Vol 86, No 3 September 1992 E 1 6 S E *1 4. 3. 2-0.1..2.2 1 PL 2 3 4 5 6 7 8 9 101112131415171819 I WON i m l lh il l l II PL 2 3 6 7 8 10 12 13 14 15 18 FIGURE 3. Grphs of noncrdiovsculr, noncncer deths (djusted proportionl hzrds regression coefficients) in deths t lest 5 yers fter bseline for blood cholesterol comprison <160 vs. 160-199 mg/dl. PL, pooled studies. B±1.96 SE stnds for the regression coefficient ±1.96 times its stndrd error. Strengths nd Limittions of Overview Anlysis The brod perspective of the overview of observtionl studies presented here suggested sttisticl ssocitions of low TC level with vriety of noncrdiovsculr cuses nd subctegories of deth, prticulrly lung cncer, respirtory disese, digestive disese, trum (less relibly in women thn in men), nd residul of noncrdiovsculr, noncncer, nonrespirtory, nondigestive, nd nontrumtic cuses. The overview provided "first level investigtion" of confounding by djusting for ge, distolic blood pressure, cigrette smoking, body mss index, nd (where vilble) usul lcohol intke. It strtified on cigrette smoking nd lcohol with end points of mjor cuses of deth. Further reserch is needed on the possible confounding effects of lifestyle fctors such s socioeconomic sttus, lcohol, smoking, nd ge. Lw nd Thompson70 reported 15% greter estimted risk in men for totl cncer (mortlity nd incidence) t low levels of TC in 35 studies pooled but found no TC:cncer reltions within four study popultions from the highest socioeconomic strtum. Similrly, Smith et 165 pointed to fctors such s employment grde nd mritl sttus in suggesting tht inverse TC: deth rte ssocitions were generlly stronger in popultion smples tht contin sick individuls thn in smples in which the "helthy worker effect" would operte. Chen et 139 suggested tht endemic heptitis in Asin popultions is the true cuse of excess mortlity t low levels of TC ssocited with liver disese. Lifetime lcohol exposure is difficult II 1 to mesure with self-report mesures, nd hevy exposure is known to cuse liver disese, which my both lower TC nd ultimtely cuse deth. Smith et 165 suggested tht excess risk of cncer deth t low TC levels is restricted to smoking-relted cncers; the MRFIT Screening Study69 similrly found excess risk ssocited with low TC for deth cused by lung cncer or chronic obstructive lung disese to be concentrted in smokers. Whether the excess mortlity risk t low TC levels is seen in younger s well s in older people ws not resolved t the conference. The overview of observtionl studies eliminted the first 5 yers of deths, which would most likely be the ones in which TC ws low s result of preexisting disese. There is, in fct, little informtion bout the time course of TC level in mny diseses. Smith et 165 reported cross-sectionl inverse ssocition between respirtory cpcity nd symptoms nd TC t bseline in prticipnts of the Whitehll study. A clssic exmple of low TC: deth ssocition is found in cncer deths within severl yers of TC mesurement, where low TC vlue is lmost certinly consequence of disese.14,71-74 It is documented tht people with cute nd chronic inflmmtory diseses hve low totl nd highdensity lipoprotein (HDL) cholesterol. Cytokines such s tumor necrosis fctor nd IL-6 hve been found to lower TC levels when injected into nimls.75,76 Furthermore, cytokines re elevted in ptients with chronic diseses including congestive hert filure.76'77 Chronic inflmmtion leds to the relese of cytokines, which my subsequently decrese heptic secretion of lipoproteins.76 Cytokines my be relesed due to inflmmtion in chronic obstructive pulmonry disese. Low TC is ssocited with wide vriety of nemis.78,79 Leukemic cells (especilly in cute nonlymphocytic leukemi) show exceptionl elevtions of high-ffinity, LDL receptor-medited cholesterol degrdtion, nd the rte of degrdtion is inversely relted to plsm TC levels.71 There is lso evidence tht mong leukemi ptients in remission fter therpy, TC levels rise significntly.80 Dietry sources of ft nd cholesterol strongly influence serum TC levels, nd mlbsorption syndromes re ccompnied by low TC levels. Alcohol secreted in the lung my lter membrne integrity nd cell function by inducing lipid chnges nd impiring surfctnt secretion.81 Nevertheless, some studies69,82 found tht elevted mortlity t low levels of TC persisted even fter the first 10 or more yers of deths were removed from nlysis. Becuse TC is mesured with uncertinty due to both lbortory vrition nd true dy-to-dy biologicl vrition, observed ssocitions found between TC nd deths my be fltter thn the true ssocitions.83 Correction for regression dilution bis cused by withinperson error would be expected to result in steeper positive slope estimtes, such s tht for TC versus therosclerotic disese deths,84 nd steeper negtive slope estimtes, such s tht found in the overview for TC versus some other cuses of deth. The influence on the observtion of TC: mortlity reltions of withinperson error in TC nd in covrites should be studied further. There ws considerble conference discussion of the mening of the overview nlysis. An sset of the overview ws considered to be the identifiction of

Jcobs et l Conference on Low Blood Cholesterol nd Mortlity 1055 consistencies nd inconsistencies between studies in low TC: mortlity reltions, including Jpnese s well s U.S. nd Europen studies. Identifiction of consistencies through exmintion of quntittive estimtes of the mgnitude of the sttisticl reltions ws thought to be prticulrly importnt in the study of low TC: mortlity reltions, where typicl individul studies hve low power. Despite these contributions, the overview ws hmpered in severl respects. For logistic resons, nmely tht only two nlysis requests could be filled (the second not by ll the studies) before the conference, ll desirble nlyses could not be done, nd, specificlly, the underlying ssumptions of the proportionl hzrds model could not be checked thoroughly. The mjor potentil devition from these ssumptions would be filure of the proportionlity ssumption, for exmple, if the excess risk t low TC levels disppered fter sufficiently long period fter bseline. A second importnt potentil devition from underlying ssumptions of the proportionl hzrds model would be interction of low TC level nd mortlity with third fctor, such s lcohol buse, dietry intke, ge, or genetic fctors. A vrition of this problem is the possibility tht the sttisticl ssocitions re bsed on different mechnisms in different popultions. A third possibility for bis in the overview nlysis is the lck of dt from ll studies hving pertinent dt. An idel, if logisticlly difficult, method would hve been to crete list of ll extnt studies hving minimum number of observtions of the reltion of low TC level nd deth, nd to then nlyze ll such studies. However, mny conference prticipnts thought it unlikely tht such results would differ from those reported here becuse of the extensive nture of the 19 studies included here. It would hve been preferble to nlyze more specific cuses of deth, prticulrly in the nlyses strtified by smoking nd lcohol intke, which were restricted to mjor cuses of deth. A hypothesis tht could not be ddressed in nlyses generted for this conference ws tht it my not be the bsolute level of TC tht mtters but the position in the TC distribution. For exmple, genetic bnormlities of cell membrnes (linked with their cholesterol content) might predominte in those who hve low cholesterol for their culture independent of bsolute level of TC. Another interpretive difficulty, which follows from the fct tht the observtionl studies were designed with hypotheses bout CVD in mind, is the generl bsence of cohort dt on morbidity nd of dt on fctors tht might confound the reltions of low TC nd noncrdiovsculr disese. Another possible problem is lck of comprbility of TC mesurements mong studies. The pooled nlysis gives estimtes of TC-end point event reltions within ech study, before pooling, so tht, for exmple, those with mesured TC <160 mg/dl re compred with people in the sme study with mesured TC level between 160 nd 199 mg/dl. If comprbility of TC between studies were poor, the comprison of ctul TC levels might be offset, for exmple, to <150 to 150-189 mg/dl in one study, nd < 180 to 180-219 mg/dl in nother. For these resons, there ws generl greement mong conference prticipnts tht the overview nl- yses were insufficient to indicte tht the reltions found of low TC nd excess mortlity were cusl but were nevertheless importnt s guides for reserch. Reltion of Low TC to Deth in Women Mny findings for women were discrepnt from those for men. Of prticulr importnce in women ws considered to be the essentilly flt reltion of TC to totl mortlity, totl CVD, nd totl cncer. Despite the lck of reltion of TC to totl CVD in women, it ws noted tht the reltion of TC to CHD deth ws strong nd positive in both sexes, in greement with the findings of previous met-nlysis.35 However, women re less studied thn men, nd when findings for women were concordnt with findings for men, they were t times more likely due to chnce (e.g., for the reltion of low TC to trumtic deth). The conferees considered tht biologicl differences between men nd women might ccount for some of the sex differences in the ssocitions. However, some of the mbiguities might be ttributed to lck of power cused by the bsence of lrge cohort study in women nlogous to the MRFIT Screening Study in men. It ws suggested tht studies should include women up to ge 79 yers to chieve comprble ge-specific deth rtes to those in men, where studies used n ge cutoff of 69 yers. Further, the study of ssocitions of disese with lipoprotein subfrctions, not possible in this conference, is prticulrly pertinent in women becuse their HDL subfrction tends to be reltively greter proportion of totl lipoprotein thn is the cse in men. Findings From Clinicl Trils Three studies85-87 with ngiogrphic end points nd severl met-nlysesl81 2324 of rndomized clinicl trils show tht TC lowering reduces the incidence of CHD. On the other hnd, non-cvd deth ppers to be incresed in those treted to lower TC, lrgely in single-fctor primry prevention trils tht used drug tretments. In contrst to these single-fctor primry cholesterol-lowering trils, n excess in non-chd deths hs been seen in only one of four multifctor intervention trils,25,27-30 nd no excess ws seen in severl trils of secondry prevention.88'89 At the conference, Yusuf presented n extension of n erlier met-nlysis of clinicl trils of TC lowering.90 This extension involved 32 rndomized clinicl trils of TC lowering in over 42,000 individuls in which TC lowering reduced CHD incidence nd mortlity (p<o.ool). The reduction in CHD ws relted to the "strength of the intervention" defined s degree of cholesterol lowering times durtion of the study, with benefit seen in both dietry nd drug trils nd in primry nd secondry prevention studies. On the other hnd, in this met-nlysis of clinicl trils, there ws n excess of noncrdic deths in treted compred with control groups. Yusuf noted tht this excess ws of borderline sttisticl significnce, ws spred over number of cuses, nd ws not relted to the strength of the intervention. Yusuf interpreted these findings s biologiclly implusible nd probbly due to chnce; specific methodology nd detils of this met-nlysis were not vilble for this report. Whether the excess in noncrdic deths in some clinicl trils is rel or due to chnce remins to be determined. 91,92

1056 Circultion Vol 86, No 3 September 1992 TABLE 8. Ecologicl Correltions Between Ftty Acids in the Diet in 1979-81 nd Mortlity in 1987, Ages 35-74, 31 Countries Ftty cids (1979-1981) Sturted Monounsturted Polyunsturted Men Women Men Women Men Women -0.02-0.14-0.26-0.36-0.15-0.18-0.31-0.42-0.53-0.31-0.28-0.02-0.22-0.24-0.49-0.27-0.62-0.54-0.51-0.15-0.14 0.51 0.34 0.18-0.10-0.17 0.56 0.32 0.30 0.10-0.03 0.49 0.22 0.07 0.00-0.20 0.48 0.40 0.16-0.10-0.15 0.66 0.50. 0.12-0.58-0.54-0.51-0.19-0.06 Cuse of deth (1987) Totl mortlity Totl crdiovsculr -0.02 Coronry hert 0.25 Stroke -0.63 Totl cncer 0.29 Colon cncer 0.48 Colorectl cncer 0.48 Lung cncer 0.29 Brest cncer Stomch cncer -0.55 Combined noncrdiovsculr, noncncer -0.35 Digestive -0.55 Respirtory -0.10 Trum -0.14 Ftty cids expressed s grms of intke per dy. -0.12-0.46-0.03-0.00-0.26-0.15-0.19-0.14-0.14-0.19-0.29-0.10 0.02 0.21-0.12-0.11 0.02 0.17-0.14-0.07 The conference prticipnts noted importnt differences in mening between the findings in clinicl trils of TC lowering nd those of observtionl studies. The TC lowering of clinicl trils occurred over reltively short period during midlife nd rrely reched vlues of interest in the nlyses of observtionl studies (i.e., TC< 160 mg/dl), wheres the low TC vlues in observtionl studies probbly represent long-stnding low levels. Clinicl tril prticipnts lso tend to hve higher CVD risk nd higher verge entry TC levels thn the popultions from which they derive nd tend to be more select volunteers thn re prticipnts in observtionl studies. Therefore, the mechnisms by which ctive TC lowering might influence end point events re likely to be different from those by which customrily low TC level might influence risk. Findings From Interntionl Studies nd Ecologicl Associtions Averge popultion TC versus deths rtes. Averge TC levels obtined systemticlly for whole popultions were only vilble from 15 centers of the World Helth Orgniztion-sponsored MONICA Project,93'94 wheres vilble totl nd cuse-specific deth rtes were for whole countries. Ecologicl correltions computed from these dt for TC levels nd vrious cuses of deth re therefore not presented here. Nutrients versus deth rtes. Averge popultion nutrient intke ws exmined becuse of other evidence tht diet determines the verge TC level of popultions (Tble 8). Associtions of dietry components with subctegory cuses of deth mong countries were bsed on per cpit food disppernce dt supplied by the United Ntions Food nd Agriculture Orgniztion.3195-100 Ecologicl correltions with CHD deth were positive for sturted ftty cids in men only nd negtive for monounsturted ftty cids in both sexes. Ecologicl correltions between sturted or monounsturted ftty cid intke nd cncer deth rtes were positive in men nd women except for stomch cncer, which ws negtive in both sexes. Stmler's nlysis of dt on nutrient intke from 20 countries is in greement with findings in Tble 8 for brest, colon, nd stomch cncer.101,102 Both sturted nd monounsturted ftty cids were strongly inversely correlted with totl stroke deth nd less strongly inversely correlted with noncrdiovsculr, noncncer cuses of deth. Ecologicl correltions with polyunsturted ftty cid intke were generlly smll except for negtive correltions with CHD deth in both men nd women. Biologicl Plusibility of Low TC s Cuse of Deth The conferees considered possible biologicl mechnisms whereby the low TC stte might be cuslly relted to disese. It ws postulted tht either n excess or deficiency in functions relted to cholesterol metbolism could led to disese risk. There is wide evidence tht cholesterol is essentil to nd intimtely involved with mny spects of cellulr structure nd function.103104 For exmple, it ffects the fluidity of cell membrnes, membrne permebility, trnsmembrne exchnge, signl trnsmission, nd other cell properties. Cholesterol is precursor for five mjor clsses of steroid hormones. It ffects gluconeogenesis nd immune function; its trnsport forms, the lipoproteins, lso serve s vehicles for ft-soluble vitmins, ntioxidnts, drugs, nd toxins. Thus, cholesterol plys generl, fundmentl, nd highly specific roles in the economy of the body. Little evidence ws presented t the conference, however, tht the low serum cholesterol levels exmined in the overview studies (<160 mg/dl) would be sufficient to cuse cellulr dysfunction. The conference considered the exceedingly rre condition of homozygous betlipoproteinemi in which there re low circulting levels of TC (<50 mg/dl).105 Intestinl mlbsorption of ft, progressive degenertion of the centrl nervous system, retinl pigmentry degenertion, bnorml red

Jcobs et l Conference on Low Blood Cholesterol nd Mortlity 1057 blood cells, nd crdiomyopthy probbly involve functionl disturbnce of delivery of cholesterol to peripherl tissues nd is prtly correctble by dministrtion of lrge doses of vitmin E nd wter-soluble vitmin A nd vitmin K.105 Becuse the defects would not be corrected simply by rising TC, hypocholesterolism is not nlogous to hypothyroidism. It ws considered difficult to relte directly these multiple mnifesttions of genetic disorder to the multiple noncrdiovsculr, noncncer cuses of deth mong older dults hving low TC levels. Considerble work hs been done on the possible biologicl role of low TC in hemorrhgic stroke ptients. The inverse reltion between TC level nd the risk of hemorrhgic stroke suggests tht low TC, possibly excerbted by hypertension, my predispose with these conditions over those with either hypertension or low TC level lone.8'10,69 Cerebrl hemorrhge occurs mostly from intrprenchyml smll rterioles in the bsl gngli of the brin. Angionecrosis, the bsic pthologicl finding, is not prolifertive disorder of the intim like therosclerosis but rther involves the disppernce of medil smooth muscle cells, which my ultimtely led to burst microneurysms. The presence or bsence of dietry fctors tht exert deleterious or protective effects on endothelil nd medil elements of the vessels is seen s importnt. Low cholesterol content of endothelil cell membrnes my ply role in intrcerebrl hemorrhge,'06-1"' lthough one study found no reltion of cell membrne microviscosity to TC.112 Brown et l113 nd Goldstein et l1"4 emphsize the powerful homeosttic mechnisms controlling cellulr content of unesterified cholesterol. This frgmentry evidence of possible cusl reltion between low TC level nd hemorrhgic stroke ws considered inconclusive becuse the chin of events ssociting low TC to loss of medil smooth muscle cells is unknown. It ws suggested tht the chin of events could relte to nutritionl fctors tht contribute both to high blood pressure nd low TC, wheres low TC per se might ply no role in loss of smooth muscle cells. Recommended Reserch for Study of Reltions Between Low Blood Cholesterol Level nd Disese Time course of TC chnge in disese. Little is known bout the time course of TC chnge in disese, prt from some cncers. Is TC lredy low in those who will develop disese (consistent with cuslity)? Does TC drop grdully throughout stges of developing disese or rther precipitously t given stge? These questions should be exmined in cohorts hving repet TC mesurements, long with concomitntly collected lifestyle nd diet dt, to scertin the chin of events leding to low TC nd to disese. Epidemiologicl confounding. Centrl to issues of confounding is further reserch bout the role of lcoholism, nutritionl sttus, socioeconomic fctors, evidence of preexisting disese including liver dysfunction, nd other potentil confounders of ssocitions found between low TC level nd deth. Further study is wrrnted of fctors considered in the overview, including ge, sex, lcohol intke, cigrette smoking, body ftness, nd blood pressure level. Study should lso focus on chrcteristics of popultion subgroups with low TC levels compred with other TC strt. Popultion monitoring. Studies of time trends in TC levels, in prllel with other risk fctor levels, lifestyle trends, tretment trends, nd disese nd deth rtes, re recommended to evlute ecologicl reltions. Are trends of popultion TC levels (down or up) relted to trends of disese rtes? TC :mortlity reltions in women. To obtin more precise informtion bout TC: mortlity ssocitions in women, screening nd mortlity follow-up study should be undertken, comprble in size to the MRFIT Screening Study. Such study should mesure HDL cholesterol s well s TC nd should include older women, for exmple, up to ge 79 yers. Active TC lowering. Further explortion is needed on whether the ctive lowering of TC by vrious mens hs deleterious effects in some persons or situtions, nd, if so, wht is the "trde-off' with the well-demonstrted beneficil effects from lowering the risk nd severity of therosclerotic diseses. Studies re needed from existing rndomized clinicl trils of the internl consistency nd vlidity of reltions found between non-cvd events nd TC lowering in treted groups, including cse udits."15 There should be further study whether ny observed ssocition of disese risk with low TC level, or of experimentl lowering of TC level, is grded one.1'6 Long-term follow-up studies mong cohorts of the experimentl nd control subjects of cholesterol-lowering trils re recommended to exmine brod set of CVD nd non-cvd disese end points ccording to 1) type of intervention on cholesterol lowering (diet, clsses of drugs, primry or secondry surgery, single or multifctoril intervention), 2) durtion nd mgnitude of TC chnge, nd 3) toxic or beneficil effects of drugs (by compring plcebo nd drug groups for the ssocition between TC chnge nd risk). Mechnisms Questions should be pursued bout biologicl mechnisms tht might help explin low TC: disese ssocitions. Studies of cell mechnisms. Cell mechnisms of low cholesterol effects require studies long severl lines. 1) Is chnge in membrne lipid composition nd function of nucleted cells (such s endothelil cells, pulmonry cells, or intestinl cells) ssocited with chnge in serum TC level in the physiologicl rnge of interest? 2) How much vrition in membrne lipid regultion is there between individuls nd between cellulr beds, nd does this vrition relte to TC level? 3) Vessel endothelium nd smll intrcrnil vessels should be studied by electron microscopy in subjects hving low TC level (e.g., in spontneously hypertensive rts). 3) Is lipoprotein trnsport to site of ction of substnces such s ntioxidnts or toxins ffected by chnges in serum TC level in the rnge of interest? 4) Wht is the effect of nutrition nd TC level on smll rtery integrity, on ngiogenesis, nd on mintennce of norml structure nd function of the fully differentited rtery? 5) How re blood nd cell cholesterol relted to immune response in neoplsi nd inflmmtion nd to the roles of cytokines in inflmmtion nd cell-cell communiction? Diseses possibly relted to specific lipid disorders. Studies re recommended of the long-term risk nd nture of CVD nd of non-cvd, ccording to lipoprotein

1058 Circultion Vol 86, No 3 September 1992 levels nd chnge in lipoprotein levels, in individuls hving specific lipid disorders including both genetic hypocholesterolemis nd those cused by gstrointestinl surgery such s ileojejunl bypss or gstrectomy. Systemtic investigtion is recommended of possible links between cholesterol metbolism nd specific cncers or other disese processes tht my be ssocited with low TC level. This includes, for exmple, potentil pthwys by which intermedite products in cholesterol biosynthesis influence the ctivtion of oncogenes, processes under genetic control, mrkers for which my soon be vilble. Acknowledgments The uthors re grteful for extensive comments on the mnuscript from Dr. Jeremih Stmler. Appendix Prticipnts in the Conference on Low Cholesterol: Mortlity Associtions MRFIT screenee Follow-up: Jmes Neton, Deborh Wentworth, Dvid Jcobs, Lewis Kuller, Jeremih Stmler, Roger Sherwin, Duck-Joo Lee, Jonn Shih, Henry Blckburn. Nordic Risk Assessment Project (NORA): Hns Wedel, Lrs Wilhelmsen, Dg Thelle, Kjell Bjrtveit, Jkko Tuomilehto, Leif Hgerup. Kiser Permnente/Northern Cliforni: Stephen Sidney, Irene Tekw, Robert Wtt. Honolulu: Dwyne Reed, John Frnk, John Grove, Richrd Benfnte. Puerto Rico: Pul Sorlie, Mrio Grci-Plmieri. Tecumseh: Millicent Higgins, Jke Keller. Frminghm: Albert Belnger, Willim Knnel, Rlph D'Agostino. Ntionl Helth Exmintion Follow-up Study/Ntionl Center for Helth Sttistics: Tmr Hrris, Jcob Feldmn, Joel Kleinmn, Dine Mkuc, Wlter Ettinger, Richrd Gillum, Jennifer Mdns. Yugoslvi: Dn McGee, Tvi Gordon, Dj. Kozrevic. Pisley/Renfrew: Dvid Hole, Christopher Isles, Chrles Gillis, Victor Hwthorne. Whitehll: George Dvey Smith, Mrtin Shipley, Michel Mrmot. Osk nd Akit: Hiroysu Iso, Yoshio Komchi, Msmitsu Konishi, Tkshi Shimmoto, Minoru Iid. Hiroshim/Ngski: Hideo Sski, Kzunori Kodm, Fumiyoshi Ksgi. Lipid Reserch Clinics Prevlence Study Follow-up: Jcques Rossouw, Bsil Rifkind, Shriknt Bngdiwl. Chicgo: Aln Dyer, Jeremih Stmler, Richrd Shekelle. Isrel: Jck Medlie, Uri Goldbourt, Stephen Zyznski, Shlomit Yri. Other conference presenters: Frederick Epstein, John Frquhr, Dvid Gordon, Antonio Gotto, Peter Greenwld, Willim Hrln, A.S. Hoffimn, Mlcolm Lw, Grdner Mc- Milln, Henry McGill, Pul Meier, Jmes Nelson, Thoms Person, John Potter, Ross Prentice, Thoms Price, Ernst Schefer, Thoms Thom, Hermn Tyroler, Knut Westlund, Philip Wolf, Slim Yusuf. References 1. Komchi Y, lid M, Shimmoto T, Chikym Y, Tkhshi H, Konishi M, Toming S: Geogrphic nd occuptionl comprisons of risk fctors in crdiovsculr diseses in Jpn. Jpn Circ J 1971;35:189-207 2. Shimmoto T, Komchi Y, Ind H: Trends for coronry hert disese nd stroke risk fctors in Jpn. Circultion 1989;79: 503-515 3. Blckburn H, Jcobs DR: The ongoing nturl experiment of crdiovsculr diseses in Jpn. Circultion 1989;79:718-720 4. Komchi Y, lid M, Ozw H, Shimmoto T, Ueshim, Tnigki M, Tsujiok K: Risk fctors of stroke (in Jpnese). Sishin Igku 1977;32:2264-2269 5. Ueshim H, lid M, Shimmoto T, Konishi M, Tsujiok K, Tnigki M, Nknishi N, Ozw H, Kojim S, Komchi Y: Multivrite nlysis of risk fctors for stroke: Eight-yer followup study of frming villges in Akit, Jpn. Prev Med 1980;9: 722-740 6. Tnk H, Ued Y, Hyshi M, Dte C, Bb T, Ymshit H, Shoji H, Tnk Y, Owd K, Detels R: Risk fctors for cerebrl hemorrhge nd cerebrl infrction in Jpnese rurl community. Stroke 1982;13:62-73 7. Konishi M, Komchi Y, Iso H, lid M, Nito Y, Sto S, Kiym M, Shimmoto T, Kitmur A, Doi M, Ito M: Seculr trends in therosclerosis of the coronry rteries nd bsl cerebrl rteries in Jpn: The Akit Pthology Study. Arteriosclerosis 1990;10: 535-540 8. Yno K, Reed DM, Mclen CJ: Serum cholesterol nd hemorrhgic stroke in the Honolulu Hert Progrm. Stroke 1989;20: 1460-1465 9. Kgn A, Popper JS, Rhods GG, Yno K: Fctors relted to stroke incidence in Hwii Jpnese men: The Honolulu Hert Study. Stroke 1980;11:14-21 10. Iso H, Jcobs DR, Wentworth D, Neton JD, Cohen J: Serum cholesterol levels nd six-yer mortlity from stroke in 350,977 men screened for the Multiple Risk Fctor Intervention Tril. N Engl J Med 1989;320:904-910 11. Miller SR, Trlter PI, Pptests AE, Slter G, Aufses AH: Serum cholesterol nd colon cncer. J Nil Cncer Inst 1981;67: 297-300 12. Rose G, Blckburn H, Keys A, Tylor HL, Knnel WB, Pul 0, Reid DD, Stmler J: Colon cncer nd blood cholesterol. Lncet 1974;1:181-183 13. Stemmermn GN, Nomur AMY, Heibrun LK, Pollck ES, Kgn A: Serum cholesterol nd colon cncer incidence in Hwiin Jpnese men. JNCI 1981;67:1179-1182 14. Interntionl Collbortive Group: Circulting cholesterol level nd risk of deth from cncer in men ged 40 to 69 yers. JAMA 1982;248:2853-2859 15. Tornberg SA, Holm LE, Crtensen JM, Eklund GA, Odont D: Risks of cncer of the colon nd rectum in reltion to serum cholesterol nd bet-lipoprotein. N Engl J Med 1986;315: 1629-1633 16. 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