Statins versus Vitamin D (long but interesting hypothesis)

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.
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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

1. Morris JN, Marr JW, Clayton DG. Diet and heart: a postscript. BMJ 1977;
2: 1307-1314.
2. Kannel WB, Castelli WP, Gordon T. Cholesterol in the prediction of
atherosclerotic disease: new perspectives based on the Framingham study. Ann
Intern Med 1979; 90: 85-91. MEDLINE
3. Schatz IJ, Masaki K, Yano K, Chen R, Rodriguez BL, Curb JD. Cholesterol
and all-cause mortality in elderly people from the Honolulu Heart Program: a
cohort study. Lancet 2001; 358: 351-355. Abstract | Full Text | PDF (82 KB)
| MEDLINE | CrossRef
4. Forette B, Tortrat D, Wolmark Y. Cholesterol as risk factor for mortality
in elderly women. Lancet 1989; 333: 868-870. CrossRef
5. Sparén P, Vågerö D, Shestov DB, et al. Long term mortality after severe
starvation during the siege of Leningrad: prospective cohort study. BMJ
2004; 328: 11-14. CrossRef
6. Renaud S, De Lorgeril M. Wine, alcohol, platelets, and the French paradox
for coronary heart disease. Lancet 1992; 339: 1523-1526. MEDLINE | CrossRef
7. Gjonça A, Bobak M. Albanian paradox, another example of protective effect
of Mediterranean lifestyle?. Lancet 1997; 350: 1815-1817. Abstract | Full
Text | PDF (68 KB) | MEDLINE | CrossRef
8. Scandinavian Simvastatin Survival Study Group. Randomised controlled
trial of cholesterol lowering in 4444 patients with coronary heart disease:
the Scandinavian Simvastatin Survival Study (4S). Lancet 1994; 344:
1383-1389. MEDLINE
9. 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
10. 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
11. 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.
12. 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
13. 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
14. 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
15. 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
16. 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
17. 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
18. Poytner JN, Gruber SB, Higgins PDR, et al. Statins and risk of
colorectal cancer. N Engl J Med 2005; 352: 2184-2192. CrossRef
19. Rose G, Blackburn H, Keys A, et al. Colon cancer and cholesterol. Lancet
1974; 1: 181-183. MEDLINE | CrossRef
20. Grimes DS, Hindle E, Dyer T. Sunlight, cholesterol and coronary heart
disease. Q J Med 1996; 89: 579-589.
21. 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
22. 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
23. 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.
24. 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
25. 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
26. Kurtzke JF. A reassessment of the distribution of multiple sclerosis.
Acta Neurologica Scand 1975; 51: 137-157.
27. Munger KL, Zhang SM, O'Reilly E, et al. Vitamin D intake and incidence
of multiple sclerosis. Neurology 2004; 62: 60-65.
28. 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:.
29. Silman AJ, Evans SJW. Regional differences in survival from cancer.
Community Med 1991; 3: 291-297. MEDLINE
30. Coleman MP, Babb P, Damiecki P, et al. Cancer survival trends in England
and Wales, 1971-1995: deprivation and NHS region. London: Stationery Office,
1999:.
31. Apperly FL. The relationship of solar radiation to cancer mortality in
North America. Cancer Res 1941; 1: 191-195.
32. 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
33. 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
34. 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
35. 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.
36. Matthews DR, Spivey RS, Kennedy I. Coffee consumption as trigger for
diabetes in childhood. BMJ 1990; 300: 1012. MEDLINE
37. 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
38. 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;
358: 1500-1503. Abstract | Full Text | PDF (77 KB) | MEDLINE | CrossRef
39. 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
40. Kröger H, Penttila IM, Alhava EM. Low serum vitamin D metabolites in
women with rheumatoid arthritis. Scand J Rheumatol 1993; 22: 172-177.
MEDLINE
41. 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.
42. 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.
43. Thomas MG, Teb*** 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
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Affiliations

a. Blackburn Royal Infirmary, Blackburn, Lancashire BB6 8HE, UK


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