different trials that happen to agree with the favoured hypothesis. The results are actually important. They show that more attention should be paid to the adverse.
in the studies they chose to analyse and their objectives were specific; the important results are therefore the primary overall results. If the authors had wished to exclude data (such as the clofibrate trial data) they could have excluded them from the start. As this was the largest study, however, excluding it may have seriously reduced the significance of all the findings of the pooled analysis. One simply cannot select the bits from different trials that happen to agree with the favoured hypothesis. The results are actually important. They show that more attention should be paid to the adverse effects of attempts at reducing cholesterol concentrations in the general population. Epidemiological surveys of the relation between cholesterol concentrations and total mortality have generally shown a U or J shaped relation, with the lower concentrations of cholesterol repeatedly associated with a possible increased mortality from cancer.2" This study has now shown that far from being an inconsistent relation this is a consistent finding in trials designed to lower cholesterol concentrations. Though the authors excluded the clofibrate data because of the hypothesis that deaths from cancer may have been related to clofibrate treatment, the current data would equally well argue for a reappraisal of this hypothesis. It now seems equally likely that clofibrate treatment increased mortality from cancer because significant reduction in cholesterol concentration is always associated with an increased mortality from cancer. The results do not support the authors' claim that the increased mortality from cancer may be attributable to the carcinogenic properties of certain drugs. Their subgroup analysis shows that the relation between low cholesterol concentrations and mortality from cancer is stronger in the groups treated by dietary measures (p=004) than in those treated with drugs (p=0-11). Clearly no firm conclusions can be drawn either way. One conclusion that should be drawn from this study, however, is that screening whole populations, enabling treatment of the patients at highest risk, is the way forward, not treating whole populations. No study has ever shown the slightest benefit in lowering cholesterol concentrations in patients with low or satisfactory cholesterol concentrations but many have shown significant harm. M A JAMES
Bristol Royal Infirmary, Bristol BS2 8HW 1 Muldoon MF, Manuck SB, Matthews KA. Lowering cholesterol concentrations and mortality: a quantitative review of primary prevention trials. BrMed3' 1990;301:309-14. (11 August.) 2 Isles CG, Hole DJ, Gillis CR, Hawthorne VM, Lever AF. Plasma cholesterol, coronary heart disease, and cancer in the Renfrew and Paisley survey. BrMedJ 1989;298:920-4. 3 Schatzkin A, Hoover RN, Taylor PR, etal. Serum cholesterol and cancer in the NHANES I epidemiological follow up study. Lancet 1987;ii:298-301. 4 Kark GD, Smith AH, Hames CG. The relationship of serum cholesterol to the incidence of cancer in Evans County, Georgia. J ChronicDis 1980;33:311-22. 5 Williams RR, Sorlie PD, Feinleib M, et al. Cancer incidence by levels of cholesterol. 7AMA 1981;245:247-52. 6 Garcia-Palmieri MR, Sorlie PD, Costas R, et al. An apparent inverse relationship between serum cholesterol and cancer mortality in Puerto Rico. AmJ7 Epidemiol 1981;114:29-40.
SIR,-In terms of biological plausibility it seems highly unlikely that an average reduction of blood cholesterol concentrations of 10% will lead to changes in mood and behaviour and result in increased deaths not related to illness. Dr Matthew F Muldoon and colleagues give no indication that those experiencing such deaths had shown the greatest reduction in blood cholesterol values.' Though modifying the fat in the diet has both biochemical and behavioural consequences in infants, laboratory rats, and monkeys, there is little evidence to suggest that this happens in middle aged men. Further, there is no geographical evidence to suggest that communities with lower blood cholesterol concentrations have a BMJ
VOLUME 301
15 SEPTEMBER 1990
higher incidence of suicide, accidents, or violence. The authors comment on reports of low serum cholesterol concentrations among criminals, those with violent or aggressive conduct disorders, homicidal offenders with a history of violence and suicide attempts related to alcohol, and those with poorly internalised social norms and low self control. All of these conditions suggest a background of alcohol misuse and so does an increased incidence of suicide, accidents, and violence. Nowhere is the possibility raised that alcohol could be a confounding variable, leading both to lowered blood cholesterol concentrations and to the fatal end points. We need to know whether the deaths from suicide, accidents, and violence were related to alcohol misuse and whether those who were randomised to the diet and drug regimens were more likely to increase their alcohol intake than control subjects. There is also the possibility that those on a low fat diet or taking certain drugs respond differently to their usual amount of alcohol. To conclude that the association between cholesterol reduction and death not related to illness warrants further investigations seems reasonable. To conclude that this meta-analysis "justifies a more cautious appraisal of the probable benefits of reducing cholesterol concentrations in the community" is less reasonable. It implies that our public health action on coronary heart disease should depend on the outcome of limited trials in middle aged subjects over fairly short periods rather than on all our epidemiological, clinical, and experimental knowledge ofcoronary heart disease. A G SHAPER D G COOK
Royal Free Hospital School of Medicine, London NW3 2PF 1 Muldoon MF, Manuck SB, Matthews KA. Lowering cholesterol concentration and mortality: a quantitative review of primary prevention trials. BrMedJ 1990;301:309-14. (11 August.)
SIR,-Dr Matthew F Muldoon and colleagues examined six primary prevention trials of cholesterol reduction. I The trials were dissimilar in that two of them selected people irrespective of their initial cholesterol concentrations whereas the remaining four chose people who had high cholesterol concentrations. Interestingly, the observed increase in deaths from accidents, violence, and suicide is seen in all six trials. This suggests that the effect might operate for all cholesterol concentrations, further supporting the authors' call for a more cautious appraisal of the effects of reducing cholesterol concentrations in the general population. When dealing with diseases with multiple aetiological factors, however, it could be misleading to isolate the effects of one factor on mortality without taking into account the others. It is also not clear how much time elapsed between the actual lowering of cholesterol concentrations and deaths occurring. This information may provide clues to the induction and latent periods of the effect. Examining the effects of varying degrees and varying rates of reduction of cholesterol concentrations would also provide interesting information. Studies to look at international and regional differences in both cholesterol concentration and mortality from accidents, violence, and suicide may shed further light on the issue. In the Grampian region of Scotland, for example, death rates from accidents and violence are higher in Banff and Buchan district than in Aberdeen district (average annual age-sex standardised death rate per 100 000 for accident and violence, 1982-7: Banff and Buchan district 79, Aberdeen district 63). Banff and Buchan district has lower population serum cholesterol concentrations than Aberdeen (table),2 again suggesting an inverse relation between serum
Cholesterol concentrations in men and women aged 40-59 living in two health districts, 1984-6 Banff and
Aberdeen
Buchan district
district
Men Women Men Women Mean serum cholesterol
(mmolIA) % With cholesterol >6 S mmol/l % With cholesterol >80 mmol/l
6-3
6-4
6-4
6-5
41
48
43
46
10
11
12
9
cholesterol concentration and mortality from accidents and violence. Finally, the objectives of health promotion and research into disease prevention should not be restricted to reducing mortality but in developed societies should aim at improving quality of life, reducing morbidity, and extending active life expectancy.3 Appraisal of the probable benefits of reducing cholesterol concentrations in the general population should attempt to address these issues. K M V NARAYAN
Grampian Health Board, Aberdeen AB9 8QP I Muldoon MF, Manuck SB, Matthews KA. Lowering cholesterol concentrations and mortality: a quantitative review of primary prevention trials. BrMedJ 1990;301:309-14. (11 August.) 2 Smith WCS, Tunstall-Pedoe H, Crombie IK, Tavendale R. Concomitants of excess coronary deaths: major risk factor and lifestyle findings from 10 359 men and women in the Scottish heart health study. ScoutMedJ 1989;34:550-5, 3 Fries JF, Green LW, Levine S. Health promotion and the compression of morbidity. Lancet 1989;i:481-3.
SIR,-Dr Matthew F Muldoon and colleagues do not seem to have considered the possible influence of social class on their findings.' Although they make reference to unnatural deaths aggregating in various populations, this is not followed up. Could it be that unnatural deaths are increased in, for example, classes IV and V, thus masking a drop in rate of death from cardiac disease in other classes? Or could people in classes IV and V, who have more likelihood of vulnerable personalities, have died from causes unrelated to illness because of mood disorders, once again masking a genuine drop in coronary deaths in other groups? J A G WAlT
Gartnavel Royal Hospital, Glasgow G12 OXH I Muldoon MF, Manuck SB, Matthews KA. Lowering cholesterol concentrations and mortality: a quantitative review of primary prevention trials. BrMedJ 1990;301:309-14. (11 August.)
SIR,-The report of Dr Matthew F Muldoon and colleagues' re-emphasises the most serious concern that the investigators in the World Health Organisation trial have had for many years2: that reducing cholesterol concentration does not reduce total mortality.' Three comments are appropriate. Firstly, five of the six trials analysed did show a significant reduction in the rate of non-fatal infarction in the intervention groups. Lowering high cholesterol concentrations postpones infarction and is therefore important to public health. Secondly, the statement that the investigators in the WHO trial hypothesised that the unexpected excess mortality in the intervention group might have resulted from hepatobiliary disease due to clofibrate needs to be qualified. This was only one of three proposals.4 The line of reasoning was that enhanced excretion of cholesterol and neutral biliary sterols, which results from clofibrate treatment, might have contributed not only to an excess of biliary disease but to more intestinal disease. Another more general suggestion was that in some people loss of cholesterol from cell membranes might have a deleterious effect on biological function.45 A third hypothesis was that the result 553
