Lipid lowering, statins and cancer

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Lipid lowering, statins and cancer

Why the interest in lipid-lowering

drugs and cancer? This is an old story

and dates back to jeremiads issued in

the early days of lipid-lowering drug

therapy. Analyses of epidemiological

studies showed that low levels of cho-

lesterol were associated with excess

cancer (1,2). The first intervention

studies with lipid-lowering drugs

showed significant benefits on cardio-

vascular events but the first large-scale

endpoint study – the World Health

Organization Clofibrate Study scared

everyone (3). This study showed a

20% reduction in cardiovascular

events at 5 years at the expense of a

20% increase in total mortality (4).

Later re-analysis of the data after fol-

low up for 8 years reduced the excess

mortality to 11% and identified many

of the excess events as due to the con-

sequences of cholecystectomy but

there was still a suggestion of excess

cancers (5). Similarly later fibrate

studies including the Helsinki Heart

Study also showed reductions in car-

diovascular events but no reduction in

total mortality and a non-significant

increase in cancers at 8.5 years (30 vs.

18; p ¼ 0.08) but this resolved by

10 years (6). In addition, fibrate ther-

apy in rats resulted in an increase in

colon carcinomas (7). Hence, the story

that lipid lowering causes cancer,

which has bedevilled the field of

atherosclerosis, arose over the last dec-

ade (8,9). Everyone forgot that associ-

ation and causality are not identical

(1,2). In actual fact, reverse causality

operates in this area – cancers cause

low cholesterol through induction of

cytokines (10). Despite this mechan-

ism, the sceptics have demanded fur-

ther evidence with each new class of

lipid lowering drug and each individ-

ual compound and lately each dose

(9).

Statins reduce cardiovascular events

and have been proven to reduce car-

diovascular mortality in secondary pre-

vention. Yet despite the publication of

the Scandinavian Simvastatin Survival

Study (4S) in 1995 that showed no

difference in cancers at 5 years (11) or

later 10 years (12), doubts persisted.

When the results of the Cholesterol

and Recurrent Events (CARE) Study

were presented in 1996 the story reap-

peared (13). There was a 12-fold

increase in breast cancer. Actually 12

cases vs. 1 case, many in patients with

pre-existing disease who had been

recruited into the trial in a study of

middle aged individuals (80% men)

totalling 20,000 patient years. In con-

trast, colorectal cancers were reduced

(12 cases vs. 21 cases) and overall

there was little difference in cancer

incidence (172 cases vs. 161 cases).

Emergency analyses were conducted of

the concurrent 9014 patient 5-year

Long-term Intervention with Pravasta-

tin in Ischaemic Heart Disease

(LIPID) study prior to its completion

and reassurance was gained from the

fact that combining the studies

pravastatin therapy was associated with

non-significant numbers of cancers

(22 cases vs. 11 cases) in a study

where pravastatin therapy was associ-

ated with reduced cancer incidence

(379 cases vs. 403 cases) (14). In the

PROspective Study of Pravastatin in

the Elderly at Risk (PROSPER) study

pravastatin therapy in 5804 individu-

als aged 170 years was associated

with an increase in cancer [115 cases

vs. 91 cases; RR ¼ 1.28 (0.97–1.68);

p ¼ 0.08] with the excess due to

gastrointestinal [65 cases vs. 43 cases;

RR ¼ 1.46 (1.0–2.13); p ¼ 0.05]

and breast cancers [18 cases vs. 11

cases; RR ¼ 1.65 (0.78–3.49);

p ¼ 0.15] with a 25% increase in

frequency of new cancers (15). Yet in

the meta-analysis conducted for this

trial for cancer-related endpoints (15)

and in the prespecified pravastatin

pooling program cancer incidence at

5 years in 21,000 patients and

112,000 patient years was unchanged

(16). Similarly long-term data from

the LIPID study at 8 years (17) and

4S (12) at 10 years showed no excess

cancers. While pooled data from the

atorvastatin studies is still awaited each

individual trial shows no excess of

cancers. There is no evidence for

excess cancer with lovastatin although

the trial database is limited. In this

issue, Stein et al. (18) present a

pooled analysis of all the major flu-

vastatin trials. In a group of 7801

patients with average exposure of

48 months to fluvastatin 20–80 mg is

associated with a 19% reduction in

total cancers (6.3% vs. 8%;

p ¼ 0.03). The only tumour that

may show an adverse effect in this

analysis is non-melanoma skin cancers

(3.6% vs. 4.6%; p ¼ 0.05) but the

numbers of events are small. There is

no association of LDL-C reduction

1022 EDITORIAL

ª 2006 The AuthorsJournal compilation ª 2006 Blackwell Publishing Ltd Int J Clin Pract, September 2006, 60, 9, 1021–1027

with incidence of cancer. This is sim-

ilar to the data combining trials of

simvastatin, pravastatin and atorvasta-

tin in the Cholesterol Treatment Tri-

allists’ collaboration pooling 100,000

patients where there is no excess can-

cer with statins (RR 1.00; 0.95–1.06;

p ¼ 0.9) (19).

The more interesting question is not

whether statins cause cancer but whe-

ther they prevent it. Many of the

tumours that are associated with west-

ern lifestyle, e.g. adenocarcinomas of

the breast, colon and prostate are asso-

ciated with high-saturated fat intake

and in parallel with that high choles-

terol (20). These tumours are known to

involve activation of oncogenes that are

sensitive to isoprenoids (21,22). Statins

have a number of other actions besides

induction of the LDL-receptor(23).

They reduce levels of isoprenoid inter-

mediates of cholesterol synthesis and

both geranylation and farnesylation are

known mechanism of regulating pro-

tein function and inhibitors have been

investigated in cancer drug develop-

ment (24,25). Statins can cause apopto-

sis of tumour cell lines through effects

on farnesylation of the c-ras oncogene

amongst other effects (26–28).

Therefore do statins reduce cancer?

This is a difficult question to answer.

None of the cardiovascular trials was

designed with cancers as a primary end-

point or recruitment criterion so the

evidence from these trials has to be con-

sidered post hoc. Prospective epidemio-

logical large long-term studies of

patients on statin therapy are few

although they are beginning to appear.

One intriguing hint comes from the

Simon Broome Register Study, an on-

going prospective cohort study of 2500

patients with familial hypercholesterol-

aemia which has follow up of up to

20 years in patients who have always

received the maximum possible dose of

any LDL-C lowering compound (lately

statins). Here long-term lipid-lowering

therapy is associated with a 40 (20–

60)% reduction in cancers (29). The

caveat applicable to this study is that

this cohort is regularly followed up in

secondary care and the life table com-

parator data is derived from primary

care and thus this difference may repre-

sent differences in efficiency of cancer

screening rather than an effect of the

drugs themselves.

Most of the data is therefore based

on retrospective analysis of cancer regis-

try data (30). In the Jutland study, sta-

tin therapy was associated with a

relative risk of 0.85 (0.78–0.95) (31)

while in the Womens Health Initiative

study, though statin therapy had little

effect overall on breast cancer [RR 0.91

(0.80–1.05)], the use of hydrophobic

statins was associated with fewer

tumours [RR 0.82 (0.70–0.97);

p ¼ 0.02] (32). Larger benefits were

suggested in one study of colorectal

cancer with statins [RR ¼ 0.50

(0.43–0.61)] in contrast to fibrates [RR

1.08 (0.59–2.08)] (33). In contrast

other studies showed no effect on colo-

rectal cancer [RR 1.03 (0.85–1.26)]

(20) or breast cancer [RR 1.0 (0.6–

1.6)] (34). Overall meta-analyses show

no effect on statin therapy on rates of

common cancers.

Studies have continued in the haem-

atological tumours. Statins in vitro pro-

mote the differentiation and apoptosis

of haematological cells through their

isoprenoid actions (35). There is evi-

dence that statins improve the pheno-

type of lymphomas and early trials are

underway of statin therapy in chronic

lymphocytic leukaemia (36,37). In

registry studies the data are confusing.

In the EPILYMPH study statin ther-

apy, in contrast to other lipid-lowering

therapies [RR ¼ 0.75 (0.44–1.27)],

was associated with a reduced risk of

cancer [RR ¼ 0.61 (0.45–0.84)]

although this effect was independent of

treatment duration (38). In contrast,

others have noticed an increase in lym-

phoma with statins [RR 2.24 (1.36–

3.66); p ¼ 0.001] and ascribed this

to their immunosuppressive actions

(39). Thus, as yet, there is still no con-

sensus as to whether statin therapy will

be useful in the field of haemato-oncol-

ogy.

Despite early concerns raised in the

fibrate trials and initially as a result of

sampling artefacts in the early statin

trials, there is no evidence that statins

cause cancer. Unfortunately, despite

their isoprenoid actions and apoptotic

effects in vitro on tumour cells which

gave rise to later hopes of anti-tumour

actions for statins, there is no evidence

that they prevent it either in the vast

majority of tumours.

A. S. Wierzbicki

St Thomas’ Hospital, London, UK

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1024 EDITORIAL


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Lipid lowering, statins and cancer