Mike V
Mon, Sep-24-07, 17:16
Hope this has not been posted before.
The Lancet 2006; 368:83-86 DOI:10.1016/S0140-6736(06)68971-X
Are statins analogues of vitamin D?David S GrimesMD a
Summary
There are many reasons why the dietary-heart-cholesterol
hypothesis should be questioned, and why statins might be
acting in some other way to reduce the risk of coronary heart
disease. Here, I propose that rather than being
cholesterol-lowering drugs per se, statins act as vitamin D
analogues, and explain why. This proposition is based on
published observations that the unexpected and unexplained
clinical benefits produced by statins have also been shown to
be properties of vitamin D. It seems likely that statins
activate vitamin D receptors. Back to top
During the late 19th century, conventional wisdom held that
masturbation was the cause of epilepsy, a more plausible
explanation than the previous notion that epilepsy was the
result of possession by the devil, and illness in general the
result of divine interference. Since bromide was thought to
reduce sexual desire, it became the logical treatment.
Although reasonably successful, bromide worked for reasons
that are different from the theory on which it was based. Can
the same be said of statins for heart disease? The emergence
of coronary heart disease (CHD) in the 20th century required
an explanation. Some had noted that cholesterol accumulated in
the walls of the arteries, and a process of accretion was
hence described as the major mechanism. Cholesterol was
assumed to originate from diet, and the diet-cholesterol-heart
hypothesis was established. The logical treatment was to
reduce dietary and serum cholesterol concentrations. Many
inconsistencies in this hypothesis have emerged and been
disregarded. In the London banking and transport study,1 for
example, men with the highest dietary cholesterol intake had
the lowest incidence of CHD. Furthermore, the results of the
Framingham study2 showed that raised concentrations of serum
cholesterol were predictive of CHD only in men younger than
age 55 years. Findings of studies from Honolulu3 and Paris4
suggest a protective effect of high serum cholesterol
concentrations, and the Leningrad paradox5 indicates that
those exposed to famine subsequently have a high incidence of
CHD, the opposite of what is expected. In Europe, populations
that consume a large amount of dietary fat and cholesterol
have a low incidence of CHD (the French paradox),6 and the
lowest incidence of CHD is seen in European nations with the
lowest consumption of wine and the most socioeconomic
deprivation (the Albanian paradox).7 Initial treatments to
reduce serum cholesterol were not effective. When introduced,
however, statins did greatly reduce serum cholesterol
concentrations by interfering with its synthesis; the
beneficial effects of statins in CHD have been assumed to be
the result of cholesterol-lowering, an assumption that I
believe is a serious mistake. Statins and the heart
The first statin trial was the Scandinavian Simvastatin
Survival Study
(4S),8 and its findings indicated a significant clinical
benefit from simvastatin. The results of the West of
Scotland Coronary Prevention Study (WOSCOPS)9 also showed
clinical benefit from statins (pravastatin) and of a
greater magnitude than expected; the mortality reduction
was about 35%, whereas the reduction in cholesterol
concentrations predicted a mortality reduction of only
25%. WOSCOPS9 showed no association between
cholesterol-lowering and clinical benefit,10 indicating
that cholesterol-lowering was not the mechanism by which
pravastatin reduced coronary events. In WOSCOPS, statins
lowered serum cholesterol concentrations, but also raised
concentrations of HDL cholesterol and lowered those of
serum triglyceride, indicating that inhibition of
3-hydroxy-3-methylglutaryl coenzyme A reductase was not
the only metabolic action. The clinical experiment of
cholesterol-lowering was thus intrinsically flawed, and
what must be understood is that 4S and WOSCOPS were trials
of statin therapy and not trials of cholesterol-lowering.
Unexpected benefits of statins
It is noteworthy that the participants treated with
pravastatin in WOSCOPS had a reduced incidence of diabetes
compared with controls.11 Additionally, when pravastatin was
given to recipients of heart transplants in an attempt to
reduce the likelihood of CHD, a reduction in the rate of
rejection and an increase in overall survival was noted,
irrespective of CHD status.12 The same pattern was seen in
recipients of kidney transplants.13 Clinical benefits of
statins have also been noted in a placebo-controlled trial14
of atorvastatin for rheumatoid arthritis. Furthermore,
simvastatin has been used successfully to treat patients with
multiple sclerosis.15 As with CHD, diabetes, rheumatoid
arthritis, and transplant rejection, the benefit noted with
respect to multiple sclerosis is independent of any effect on
serum cholesterol. Statins also have an effect on bone, and
women who take statins have a greater bone density than those
who do not.16 Moreover, the findings of the 10-year follow-up
study of participants in 4S17 indicate a significantly reduced
risk of cancer, particularly colorectal, lung, and prostate
cancer, in those who received simvastatin. Results of a
population study from Israel18 also show a greatly reduced
risk of colorectal cancer in those taking statins. In 1974,19
a group of illustrious diet-cholesterol-heart researchers
studied the association between cholesterol and cancer. They
noted that high serum cholesterol concentrations conferred
protection against colon cancer. The effects of statins
mentioned above hence present a major paradox: how can a drug
that lowers serum cholesterol concentrations reduce the risk
of colon cancer when high serum cholesterol concentrations
are, in fact, protective? A drug can act as a poison by
blocking normal metabolic processes, but to produce a
beneficial effect (other than antibacterial) we should assume
that it is switching on or enhancing a normal metabolic
process. I therefore suggest that statins mimic many of the
actions of vitamin D and can be considered analogues of
vitamin D.
Sunlight and vitamin D
Heart disease
In Europe, there is a higher rate of mortality from CHD in the
northern than in the southern countries, with the lowest rates
noted along the Mediterranean coast.20 This pattern suggests
that susceptibility to CHD is affected by duration of exposure
to sunlight. This notion is supported by findings from the
USA21,22 that the higher the altitude of residence, and hence
the greater the sunlight intensity, the lower the risk of
heart disease. Furthermore, the only dietary change that
consistently protects against CHD is an increase in
consumption of oily fish and fish oil, which contain large
amounts of vitamin D.23 In the Netherlands, mortality from CHD
was more than 50% lower in men who consumed at least 30 g of
fish per day than in those who did not eat fish.24 A similar
result was reported in women from a 16-year follow-up study in
the USA.25
Multiple sclerosis
Multiple sclerosis also shows a latitude gradient in Europe,
with the world's highest incidence reported in Scotland.26 The
risk of developing the disease is reduced by a third by
regular supplementation with vitamin D.27
Cancer
The risk of breast cancer and colon cancer is high in
northwest Europe and much lower in the Mediterranean
countries.28 And, in the UK, people die more readily from
cancer in the north than in the south of the country. After
being diagnosed, 34% of men with cancer and resident in
Oxfordshire survive for 5 years compared with 26% of those who
live in the northwest and Yorkshire. Men with stomach cancer
who live in London survive on average twice as long as those
who live in the northwest of England; the same applies to
bladder cancer.29 Patients with colon cancer also have a
greater chance of survival if they live in the south of
England rather than in the north.30 The benefits of sunshine
and vitamin D would explain these associations. Results of a
study31 done in 1941 in the USA and Canada showed that the
cancer death rates among residents of the most northern cities
were two and a half times those of the most southern cities.
An extensive study32 of more than 5000 locations in the USA
has shown that incidence rates of cancer are lowest where
ultraviolet light exposure is greatest. Bladder, breast,
colon, kidney, oesophageal, ovarian, prostate, rectal,
stomach, and uterine cancers, and non-Hodgkin lymphoma are
associated with low exposure to ultraviolet light.32 In the
USA, cancer of the prostate has an increasing incidence with
distance from the equator, suggesting a protective effect of
sunshine. The incidence is highest in the eastern states and
lowest in the west.33 This is exactly the same as with CHD,
and is probably the result of a high altitude being protective
because of greater ultraviolet light exposure. The association
between prostate cancer and insufficient access to ultraviolet
light has also been noted in the UK,34 with men exposed to low
levels of ultraviolet light developing cancer at a younger age
than those exposed to high levels (median age 67·7 years vs
72·1 years). In a study35 of 456 people with early-stage lung
cancer who had undergone surgery, those diagnosed and operated
on in the summer, spring, or autumn had a significantly higher
5-year survival rate than those diagnosed and operated on in
the winter. The survival rate was 29% in those who took no
vitamin D supplements and had treatment in the winter compared
with 72% in those who took vitamin D supplements and were
treated in the summer.35
Diabetes
The international distribution of diabetes in children is very
similar to that of CHD, with incidence increasing with
distance from the equator,36 again suggesting a protective
effect of sunlight and vitamin D. Furthermore, children of
women who do, compared with those who do not, take cod liver
oil during pregnancy have a reduced incidence of type 1
diabetes.37 The findings of a retrospective study,38
undertaken in Finland and involving 10?821 children born in
1966, indicate that the incidence of diabetes in adulthood is
almost ten times higher in those who do not, compared with
those who do, take vitamin D supplements in childhood. The
benefit of vitamin D supplementation during infancy has been
further strengthened by the findings of a large study
undertaken in Norway.39
Rhematoid arthritis
Kröger and colleagues40 noted that 16% of 143 women with
rheumatoid arthritis, compared with the general population,
had very low concentrations of serum calcidiol. During the
winter, 73% had levels of calcitriol below the seasonally
adjusted normal range and the lowest levels were in patients
with very active disease. In another study,41 of 19 patients
with rheumatoid arthritis given vitamin D supplements, nine
reported a complete remission of symptoms, and eight a
satisfactory response. Inflammatory markers also improved: the
mean erythrocyte sedimentation rate fell by 43% and the mean
concentrations of C-reactive protein by 52%. This study is a
small one but although far from conclusive the results conform
to a pattern that should not be ignored.
Testing of my hypothesis
In view of the above, there is a striking similarity between
the benefits of vitamin D and the benefits of statin therapy.
I believe that the unexpected and unexplained beneficial
effects of statin therapy might be mediated by activation of
vitamin D receptors by this group of drugs. This hypothesis
is, in theory, easy to test. A prospective study should be
undertaken in cancer treatment and prevention, with a
factorial design, so that patients receive statins, vitamin D,
a combination of statins and vitamin D, or placebo. A similar
outcome in the three treatment groups would lend support to
the suggestion of statins acting via vitamin D receptors. If
vitamin D and statins are activating the same receptors, then
if both are given in sub-maximum doses, the two together would
have a greater effect than each individually. Intervention
studies should also be undertaken to look at the relapse rates
of established illnesses, including CHD, multiple sclerosis,
and rheumatoid arthritis, comparing statins and vitamin D. The
difficulty in doing these studies is that we know only the
minimum dose of vitamin D necessary to prevent and heal
rickets: we do not know the dose necessary to increase to a
maximum the other effects, especially those that enhance
immune competence. The same applies to statins: their effect
on serum cholesterol concentrations is easy to measure, but we
do not know what to measure as a biochemical surrogate for the
other effects, again probably those enhancing immune
competence. As such, a range of treatment doses of vitamin D
and statins need to be investigated. Additionally, clinical
trials of established treatments-eg, statins for CHD-are
difficult to design because of the ethics of not giving an
established medication (a statin), but in place a trial
medication (vitamin D). Comparisons with vitamin D supplements
could be undertaken, but only once the optimum dose of vitamin
D has been established. Colonic mucosa and colonic cancer
cells contain vitamin D receptors,42 strengthening my
suggestion that vitamin D is biologically active in these
tissues. Furthermore, vitamin D has an inhibitory effect on
colonic carcinoma cell lines.43 Do statins have a similar
effect? In-vitro experiments are one way that the effects of
statins on vitamin D receptors could be investigated directly.
Conclusion
Anomalous results, such as the unexpected benefits of statins
detailed here, lead to the advancement of science. Such an
opportunity for research should not be overlooked. Statins
should be looked at objectively and the
diet-cholesterol-heart hypothesis on which the treatment was
based disregarded. Statins have been described as wonder
drugs because of their unexpected benefits; my hypothesis
gives an opportunity for new thinking. The explanation of
statins as analogues of vitamin D, if correct, would be
reassuring to the millions of people who take them every day.
Finally, sunlight and vitamin D might at last be recognised
for their widespread health benefits.
Conflict of interest statement I declare that I have no
conflict of interest.
References
5. Morris JN, Marr JW, Clayton DG. Diet and heart: a
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6: 1307-1314.
7. Kannel WB, Castelli WP, Gordon T. Cholesterol in the
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8. Schatz IJ, Masaki K, Yano K, Chen R, Rodriguez BL, Curb
JD. Cholesterol and all-cause mortality in elderly people
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11. Renaud S, De Lorgeril M. Wine, alcohol, platelets, and the
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13. Scandinavian Simvastatin Survival Study Group. Randomised
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14. Shepherd J, Cobbe SM, Ford I, et alfor the West of
Scotland Coronary Prevention Study Group. Prevention of
coronary heart disease with pravastatin in men with
hypercholesterolaemia. N Engl J Med 1995; 333: 1301-1307.
MEDLINE | CrossRef
15. Packard CJfor West of Scotland Coronary Prevention Group.
Influence of pravastatin and plasma lipids on clinical
events in the west of Scotland coronary prevention study
(WOSCOPS). Circulation 1998; 97: 1440-1445. MEDLINE
16. Freeman DJ, Norrie J, Sattar N, et al. Pravastatin and the
development of diabetes mellitus; evidence for a
protective treatment effect in the west of Scotland
coronary prevention study. Circulation 2001; 103: 357-362.
17. Kobashigawa JA, Katznelson S, Laks H, et al. Effect of
pravastatin on outcomes after cardiac transplantation. N
Engl J Med 1995; 333: 621-627. MEDLINE | CrossRef
18. Katznelson S, Wilkinson AH, Kobashigawa JA, et al. The
effect of pravastatin on acute rejection after kidney
transplantation: a pilot study. Transplantation 1996; 61:
1469-1474. MEDLINE
19. McCarey DW, McInnes IB, Madhok R, et al. Trial of
atorvastatin in rheumatoid arthritis (TARA): double-blind,
randomised placebo-controlled trial. Lancet 2004; 363:
2015-2021. Abstract | Full Text | PDF (101 KB) | CrossRef
20. Vollmer T, Key L, Durkalski V, et al. Oral simvastatin
treatment in relapsing-remitting multiple sclerosis.
Lancet 2004; 363: 1607-1608. Abstract | Full Text | PDF
(59 KB) | CrossRef
21. Edwards CJ, Hart DJ, Spector TD. Oral statins and
increased bone-mineral density in postmenopausal women.
Lancet 2000; 355: 2218-2219. Abstract | Full Text | PDF
(59 KB) | MEDLINE | CrossRef
22. Strandberg TE, Pyörälä K, Cook TJ, et alfor the 4S group.
Mortality and incidence of cancer during 10-year
follow-up of the Scandinavian Simvastatin Survival Study.
Lancet 2004; 364: 771-777. Abstract | Full Text | PDF
(101 KB) | CrossRef
23. Poytner JN, Gruber SB, Higgins PDR, et al. Statins and
risk of colorectal cancer. N Engl J Med 2005; 352:
2184-2192. CrossRef
24. Rose G, Blackburn H, Keys A, et al. Colon cancer and
cholesterol. Lancet 1974; 1: 181-183. MEDLINE | CrossRef
25. Grimes DS, Hindle E, Dyer T. Sunlight, cholesterol and
coronary heart disease. Q J Med 1996; 89: 579-589.
26. Mortimer EA, Monson RR, MacMahon B. Reduction in mortality
from coronary heart disease in men residing at high
altitude. N Engl J Med 1977; 296: 581-585. MEDLINE
27. Voors AW, Johnson WD. Altitude and arteriosclerotic heart
disease mortality of white residents of 99 of the 100
largest cities in the United States. J Chronic Dis 1979;
32: 157-162. MEDLINE | CrossRef
28. Burr ML, Fehily AM, Gilbert JF, et al. Effects of changes
in fat, fish, and fibre intakes on death and myocardial
reinfarction: diet and reinfarction trial (DART). Lancet
1989; 3342: 757-761.
29. Kromhout D, Bosschieter EB, Coulander C de L. The inverse
relation between fish consumption and 20-year mortality
from coronary heart disease. N Engl J Med 1985; 312:
1205-1209. MEDLINE
30. Hu FB, Bronner L, Willett WC, et al. Fish and omega-e
fatty acid intake and risk of coronary heart disease in
women. JAMA 2002; 287: 1815-1821. MEDLINE | CrossRef
31. Kurtzke JF. A reassessment of the distribution of multiple
sclerosis. Acta Neurologica Scand 1975; 51: 137-157.
32. Munger KL, Zhang SM, O'Reilly E, et al. Vitamin D
intake and incidence of multiple sclerosis. Neurology
2004; 62: 60-65.
33. Parkin DM, Whelan SL, Ferlay J, Teppo L, Thomas DB. Cancer
in five continents VIII. International Association of
Cancer Registries (IACR). Scientific publication number
155. Lyon: IACR, 2002:.
34. Silman AJ, Evans SJW. Regional differences in survival
from cancer. Community Med 1991; 3: 291-297. MEDLINE
35. Coleman MP, Babb P, Damiecki P, et al. Cancer survival
trends in England and Wales, 1971-1995: deprivation and
NHS region. London: Stationery Office,
36:.
37. Apperly FL. The relationship of solar radiation to cancer
mortality in North America. Cancer Res 1941; 1: 191-195.
38. Grant WB. An estimate of premature cancer mortality in the
US due to inadequate doses of solar ultraviolet-B
radiation. Cancer 2002; 94: 1867-1875. MEDLINE | CrossRef
39. Hanchette CL, Schwartz GG. Geographical patterns of
prostate cancer mortality: evidence for a protective
effect of ultraviolet radiation. Cancer 1992; 70:
2861-2869. MEDLINE | CrossRef
40. Luscombe CJ, Fryer AA, French ME, et al. Exposure to
ultraviolet radiation: association with susceptibility and
age at presentation with prostate cancer. Lancet 2001;
358: 641-642. Abstract | Full Text | PDF (61 KB) | MEDLINE
| CrossRef
41. Zhou W, Suk R, Liu G, et al. Vitamin D predicts overall
survival in early stage non-small cell lung cancer
patients. American Association for Cancer Research April
16-20, 2005, abstract LB-231.
42. Matthews DR, Spivey RS, Kennedy I. Coffee consumption
as trigger for diabetes in childhood. BMJ 1990; 300:
1012. MEDLINE
43. Stene LC, Ulriksen J, Magnus P, Joner G. Use of cod liver
oil during pregnancy associated with lower risk of type 1
diabetes in the offspring. Diabetologia 2000; 43:
1093-1098. MEDLINE | CrossRef
44. Hyppönen E, Läärä E, Reunanen A, Järvelin M-R, Virtanen
SM. Intake of vitamin D and risk of type 1 diabetes: a
birth-cohort study. Lancet 2001;
45: 1500-1503. Abstract | Full Text | PDF (77 KB) | MEDLINE
| CrossRef
46. Stene LC, Joner Gfor the Norwegian Childhood Diabetes
Study Group. Use of cod liver oil during the first year of
life is associated with lower risk of childhood-onset type
1 diabetes: a large population-based case-control trial.
Am J Clin Nutr 2003; 78: 1128-1134. MEDLINE
47. Kröger H, Penttila IM, Alhava EM. Low serum vitamin D
metabolites in women with rheumatoid arthritis. Scand J
Rheumatol 1993; 22: 172-177. MEDLINE
48. Andjelovic Z, Vojinovic J, Pejnovic N, et al. Disease
modifying and immunomodulatory effects of high dose 1?
(OH) D3 in rheumatoid arthritis patients. Clin Exp
Rheumatol 1999; 17: 452-456.
49. Kane KF, Langman MJS, Williams GR. Vitamin D3 and retinoid
X receptor mRNAs are expressed in human colorectal mucosa
and neoplasms. Gut 1994; 35 (suppl): S2.
50. Thomas MG, Tebbutt S, Williamson RCN. Vitamin D and its
metabolites inhibit cell proliferation in human rectal
mucosa and a colon cancer cell line. Gut 1992; 33:
1660-1663. MEDLINE Back to top
Affiliations
a. Blackburn Royal Infirmary, Blackburn, Lancashire BB6 8HE,
UK
The Lancet 2006; 368:83-86 DOI:10.1016/S0140-6736(06)68971-X
Are statins analogues of vitamin D?David S GrimesMD a
Summary
There are many reasons why the dietary-heart-cholesterol
hypothesis should be questioned, and why statins might be
acting in some other way to reduce the risk of coronary heart
disease. Here, I propose that rather than being
cholesterol-lowering drugs per se, statins act as vitamin D
analogues, and explain why. This proposition is based on
published observations that the unexpected and unexplained
clinical benefits produced by statins have also been shown to
be properties of vitamin D. It seems likely that statins
activate vitamin D receptors. Back to top
During the late 19th century, conventional wisdom held that
masturbation was the cause of epilepsy, a more plausible
explanation than the previous notion that epilepsy was the
result of possession by the devil, and illness in general the
result of divine interference. Since bromide was thought to
reduce sexual desire, it became the logical treatment.
Although reasonably successful, bromide worked for reasons
that are different from the theory on which it was based. Can
the same be said of statins for heart disease? The emergence
of coronary heart disease (CHD) in the 20th century required
an explanation. Some had noted that cholesterol accumulated in
the walls of the arteries, and a process of accretion was
hence described as the major mechanism. Cholesterol was
assumed to originate from diet, and the diet-cholesterol-heart
hypothesis was established. The logical treatment was to
reduce dietary and serum cholesterol concentrations. Many
inconsistencies in this hypothesis have emerged and been
disregarded. In the London banking and transport study,1 for
example, men with the highest dietary cholesterol intake had
the lowest incidence of CHD. Furthermore, the results of the
Framingham study2 showed that raised concentrations of serum
cholesterol were predictive of CHD only in men younger than
age 55 years. Findings of studies from Honolulu3 and Paris4
suggest a protective effect of high serum cholesterol
concentrations, and the Leningrad paradox5 indicates that
those exposed to famine subsequently have a high incidence of
CHD, the opposite of what is expected. In Europe, populations
that consume a large amount of dietary fat and cholesterol
have a low incidence of CHD (the French paradox),6 and the
lowest incidence of CHD is seen in European nations with the
lowest consumption of wine and the most socioeconomic
deprivation (the Albanian paradox).7 Initial treatments to
reduce serum cholesterol were not effective. When introduced,
however, statins did greatly reduce serum cholesterol
concentrations by interfering with its synthesis; the
beneficial effects of statins in CHD have been assumed to be
the result of cholesterol-lowering, an assumption that I
believe is a serious mistake. Statins and the heart
The first statin trial was the Scandinavian Simvastatin
Survival Study
(4S),8 and its findings indicated a significant clinical
benefit from simvastatin. The results of the West of
Scotland Coronary Prevention Study (WOSCOPS)9 also showed
clinical benefit from statins (pravastatin) and of a
greater magnitude than expected; the mortality reduction
was about 35%, whereas the reduction in cholesterol
concentrations predicted a mortality reduction of only
25%. WOSCOPS9 showed no association between
cholesterol-lowering and clinical benefit,10 indicating
that cholesterol-lowering was not the mechanism by which
pravastatin reduced coronary events. In WOSCOPS, statins
lowered serum cholesterol concentrations, but also raised
concentrations of HDL cholesterol and lowered those of
serum triglyceride, indicating that inhibition of
3-hydroxy-3-methylglutaryl coenzyme A reductase was not
the only metabolic action. The clinical experiment of
cholesterol-lowering was thus intrinsically flawed, and
what must be understood is that 4S and WOSCOPS were trials
of statin therapy and not trials of cholesterol-lowering.
Unexpected benefits of statins
It is noteworthy that the participants treated with
pravastatin in WOSCOPS had a reduced incidence of diabetes
compared with controls.11 Additionally, when pravastatin was
given to recipients of heart transplants in an attempt to
reduce the likelihood of CHD, a reduction in the rate of
rejection and an increase in overall survival was noted,
irrespective of CHD status.12 The same pattern was seen in
recipients of kidney transplants.13 Clinical benefits of
statins have also been noted in a placebo-controlled trial14
of atorvastatin for rheumatoid arthritis. Furthermore,
simvastatin has been used successfully to treat patients with
multiple sclerosis.15 As with CHD, diabetes, rheumatoid
arthritis, and transplant rejection, the benefit noted with
respect to multiple sclerosis is independent of any effect on
serum cholesterol. Statins also have an effect on bone, and
women who take statins have a greater bone density than those
who do not.16 Moreover, the findings of the 10-year follow-up
study of participants in 4S17 indicate a significantly reduced
risk of cancer, particularly colorectal, lung, and prostate
cancer, in those who received simvastatin. Results of a
population study from Israel18 also show a greatly reduced
risk of colorectal cancer in those taking statins. In 1974,19
a group of illustrious diet-cholesterol-heart researchers
studied the association between cholesterol and cancer. They
noted that high serum cholesterol concentrations conferred
protection against colon cancer. The effects of statins
mentioned above hence present a major paradox: how can a drug
that lowers serum cholesterol concentrations reduce the risk
of colon cancer when high serum cholesterol concentrations
are, in fact, protective? A drug can act as a poison by
blocking normal metabolic processes, but to produce a
beneficial effect (other than antibacterial) we should assume
that it is switching on or enhancing a normal metabolic
process. I therefore suggest that statins mimic many of the
actions of vitamin D and can be considered analogues of
vitamin D.
Sunlight and vitamin D
Heart disease
In Europe, there is a higher rate of mortality from CHD in the
northern than in the southern countries, with the lowest rates
noted along the Mediterranean coast.20 This pattern suggests
that susceptibility to CHD is affected by duration of exposure
to sunlight. This notion is supported by findings from the
USA21,22 that the higher the altitude of residence, and hence
the greater the sunlight intensity, the lower the risk of
heart disease. Furthermore, the only dietary change that
consistently protects against CHD is an increase in
consumption of oily fish and fish oil, which contain large
amounts of vitamin D.23 In the Netherlands, mortality from CHD
was more than 50% lower in men who consumed at least 30 g of
fish per day than in those who did not eat fish.24 A similar
result was reported in women from a 16-year follow-up study in
the USA.25
Multiple sclerosis
Multiple sclerosis also shows a latitude gradient in Europe,
with the world's highest incidence reported in Scotland.26 The
risk of developing the disease is reduced by a third by
regular supplementation with vitamin D.27
Cancer
The risk of breast cancer and colon cancer is high in
northwest Europe and much lower in the Mediterranean
countries.28 And, in the UK, people die more readily from
cancer in the north than in the south of the country. After
being diagnosed, 34% of men with cancer and resident in
Oxfordshire survive for 5 years compared with 26% of those who
live in the northwest and Yorkshire. Men with stomach cancer
who live in London survive on average twice as long as those
who live in the northwest of England; the same applies to
bladder cancer.29 Patients with colon cancer also have a
greater chance of survival if they live in the south of
England rather than in the north.30 The benefits of sunshine
and vitamin D would explain these associations. Results of a
study31 done in 1941 in the USA and Canada showed that the
cancer death rates among residents of the most northern cities
were two and a half times those of the most southern cities.
An extensive study32 of more than 5000 locations in the USA
has shown that incidence rates of cancer are lowest where
ultraviolet light exposure is greatest. Bladder, breast,
colon, kidney, oesophageal, ovarian, prostate, rectal,
stomach, and uterine cancers, and non-Hodgkin lymphoma are
associated with low exposure to ultraviolet light.32 In the
USA, cancer of the prostate has an increasing incidence with
distance from the equator, suggesting a protective effect of
sunshine. The incidence is highest in the eastern states and
lowest in the west.33 This is exactly the same as with CHD,
and is probably the result of a high altitude being protective
because of greater ultraviolet light exposure. The association
between prostate cancer and insufficient access to ultraviolet
light has also been noted in the UK,34 with men exposed to low
levels of ultraviolet light developing cancer at a younger age
than those exposed to high levels (median age 67·7 years vs
72·1 years). In a study35 of 456 people with early-stage lung
cancer who had undergone surgery, those diagnosed and operated
on in the summer, spring, or autumn had a significantly higher
5-year survival rate than those diagnosed and operated on in
the winter. The survival rate was 29% in those who took no
vitamin D supplements and had treatment in the winter compared
with 72% in those who took vitamin D supplements and were
treated in the summer.35
Diabetes
The international distribution of diabetes in children is very
similar to that of CHD, with incidence increasing with
distance from the equator,36 again suggesting a protective
effect of sunlight and vitamin D. Furthermore, children of
women who do, compared with those who do not, take cod liver
oil during pregnancy have a reduced incidence of type 1
diabetes.37 The findings of a retrospective study,38
undertaken in Finland and involving 10?821 children born in
1966, indicate that the incidence of diabetes in adulthood is
almost ten times higher in those who do not, compared with
those who do, take vitamin D supplements in childhood. The
benefit of vitamin D supplementation during infancy has been
further strengthened by the findings of a large study
undertaken in Norway.39
Rhematoid arthritis
Kröger and colleagues40 noted that 16% of 143 women with
rheumatoid arthritis, compared with the general population,
had very low concentrations of serum calcidiol. During the
winter, 73% had levels of calcitriol below the seasonally
adjusted normal range and the lowest levels were in patients
with very active disease. In another study,41 of 19 patients
with rheumatoid arthritis given vitamin D supplements, nine
reported a complete remission of symptoms, and eight a
satisfactory response. Inflammatory markers also improved: the
mean erythrocyte sedimentation rate fell by 43% and the mean
concentrations of C-reactive protein by 52%. This study is a
small one but although far from conclusive the results conform
to a pattern that should not be ignored.
Testing of my hypothesis
In view of the above, there is a striking similarity between
the benefits of vitamin D and the benefits of statin therapy.
I believe that the unexpected and unexplained beneficial
effects of statin therapy might be mediated by activation of
vitamin D receptors by this group of drugs. This hypothesis
is, in theory, easy to test. A prospective study should be
undertaken in cancer treatment and prevention, with a
factorial design, so that patients receive statins, vitamin D,
a combination of statins and vitamin D, or placebo. A similar
outcome in the three treatment groups would lend support to
the suggestion of statins acting via vitamin D receptors. If
vitamin D and statins are activating the same receptors, then
if both are given in sub-maximum doses, the two together would
have a greater effect than each individually. Intervention
studies should also be undertaken to look at the relapse rates
of established illnesses, including CHD, multiple sclerosis,
and rheumatoid arthritis, comparing statins and vitamin D. The
difficulty in doing these studies is that we know only the
minimum dose of vitamin D necessary to prevent and heal
rickets: we do not know the dose necessary to increase to a
maximum the other effects, especially those that enhance
immune competence. The same applies to statins: their effect
on serum cholesterol concentrations is easy to measure, but we
do not know what to measure as a biochemical surrogate for the
other effects, again probably those enhancing immune
competence. As such, a range of treatment doses of vitamin D
and statins need to be investigated. Additionally, clinical
trials of established treatments-eg, statins for CHD-are
difficult to design because of the ethics of not giving an
established medication (a statin), but in place a trial
medication (vitamin D). Comparisons with vitamin D supplements
could be undertaken, but only once the optimum dose of vitamin
D has been established. Colonic mucosa and colonic cancer
cells contain vitamin D receptors,42 strengthening my
suggestion that vitamin D is biologically active in these
tissues. Furthermore, vitamin D has an inhibitory effect on
colonic carcinoma cell lines.43 Do statins have a similar
effect? In-vitro experiments are one way that the effects of
statins on vitamin D receptors could be investigated directly.
Conclusion
Anomalous results, such as the unexpected benefits of statins
detailed here, lead to the advancement of science. Such an
opportunity for research should not be overlooked. Statins
should be looked at objectively and the
diet-cholesterol-heart hypothesis on which the treatment was
based disregarded. Statins have been described as wonder
drugs because of their unexpected benefits; my hypothesis
gives an opportunity for new thinking. The explanation of
statins as analogues of vitamin D, if correct, would be
reassuring to the millions of people who take them every day.
Finally, sunlight and vitamin D might at last be recognised
for their widespread health benefits.
Conflict of interest statement I declare that I have no
conflict of interest.
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Affiliations
a. Blackburn Royal Infirmary, Blackburn, Lancashire BB6 8HE,
UK