Should we lower cholesterol as much as possible?
BMJ 2006; 332 doi: https://doi.org/10.1136/bmj.332.7553.1330 (Published 01 June 2006) Cite this as: BMJ 2006;332:1330All rapid responses
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Please forgive me for raking up a June posting, but it still bothers
me that a doctor should have to ask why Q10 lowering is actually harmful.
Now I am in no way criticising Dr de Woolf, because this information has
not received the enormous publicity that has been accorded to statins by
the drug companies, but has been kept very much under wraps.
Had Dr de Woolf asked why the inability to take in sufficient breath
and sufficient oxygen supply, he would have been laughed out of court, and
with good reason. But sufficient oxygen is totally necessary for the life
of the body because it is needed for the creation of energy to supply the
totality of individual systems which go to make up the whole.
This energy is only available to every individual cell, of whatever
function, through the electron transfer mechanism of that cell's Q10
molecule(s). While asphyxiation would destroy the body totally in a few
moments, a shortage of Q10 leaves cells without access to their energy
supply and death occurs cell by cell, but at the point where Q10 needed
renewal at the particular moment. These cells do not seem able to
regenerate, and permanent damage has taken place.
Heart, liver, kidneys and muscle have the greatest need for energy
and thus of Q10, but what else might be affected, insulin supply? thyroid?
all subject to pure chance effect of the moment, so creating the large
range of problems associated with statin use complained of by victims, and
the 6000 odd reports recorded by the yellow card system for simvastin plus
atorvastatin, not to mention about 60 deaths thought to have resulted.
I find it hard to believe that NICE, MHRA, and MRC, as guardians of
the patients' wellbeing, have not been aware of these matters which are
well documented, but the dissemination of the information to medical staff
has been totally neglected.
The lowering of Q10 also seems to affect its ability to replenish
itself, as a vulnerable 17 stage process is involved, so a long self-
destruct process is put into effect. The remark "it can't be due to the
statin, because it would have stopped when you stopped taking it" is not
valid, and the same applies to the reduction consequently of Carnitine,
necessary for energy production from fat in skeletal and heart muscle, and
permanent Secondary Carnitine Deficiency results, the cause of the muscle
pain side effect.
To add a note to "Surely some mistake" submitted by Prof.Alun Hughes,
if his hypothesis were true, the supply of cholesterol would not be
inhibited, as the recirculated CoA reductase would maintain its volume,
but we know that it is reduced, and Q10 along with it.
Competing interests:
Only as a badly damaged statin victim.
Competing interests: No competing interests
Dear Editor,
Ravskov et al discuss optimal cholesterol levels and more widespread use of statins.1 Over the counter (OTC) statins should also be considered in this debate.
In primary prevention of coronary heart disease (CHD), current guidelines recommend that high-risk patients (equivalent to CHD risk ≥ 15% using Framingham equations) should be prescribed a statin by their general practitioner (typically simvastatin 20-40mg).2 Royal Pharmaceutical Society of Great Britain (RPSGB) criteria for OTC simvastatin 10mg aim to target patients at moderate risk of CHD (10-year CHD risk 10-15%) using an assessment of age, sex and a count of CHD risk factors.3 Higher risk patients are also identified using RPSGB criteria, ideally including blood pressure (BP) and cholesterol checks (when available), and are advised to see a doctor.
We have investigated how accurately RPSGB criteria for OTC statins identify patients at moderate risk of CHD using data from the nationally representative Scottish Health Survey 1998 (SHS). The analysis included data from 2,760 people aged 40 to 74 years without cardiovascular disease (CVD) or diabetes, identifying those with 10-year CHD risk 10-15% using two methods – Framingham equations, and RPSGB criteria. Agreement between the two approaches was assessed using the kappa statistic (SPSS 11.5, Chicago). The analysis for RPSGB criteria was then repeated without taking BP and cholesterol readings into account.
Using Framingham equations, 1587 (58%) SHS participants aged 40 to 74 years were at low risk of CHD (10-year CHD risk <_10 _528="_528" _19="_19" were="were" at="at" moderate="moderate" risk="risk" of="of" chd="chd" _10-year="_10-year" _10-15="_10-15" and="and" _645="_645" _23="_23" high="high" _880515.="_880515." the="the" numbers="numbers" people="people" in="in" each="each" category="category" those="those" eligible="eligible" for="for" otc="otc" statins="statins" are="are" shown="shown" figure.="figure." using="using" rpsgb="rpsgb" criteria="criteria" including="including" bp="bp" cholesterol="cholesterol" _312="_312" _11="_11" shs="shs" participants="participants" agreement="agreement" about="about" which="which" was="was" less="less" than="than" that="that" expected="expected" by="by" chance="chance" when="when" compared="compared" with="with" framingham="framingham" equations="equations" kappa="kappa" _-0.1="_-0.1" p0.001="p0.001" _35="_35" _5="_5" high-risk="high-risk" would="would" have="have" been="been" identified="identified" as="as" being="being" statins.="statins." but="but" omitting="omitting" _766="_766" _28="_28" there="there" poor="poor" _0.2="_0.2" _250="_250" _39="_39" statins.br="statins.br"/>
In conclusion, large numbers of middle aged and elderly people would potentially be eligible for OTC statins. However, RPSGB criteria for OTC statins show little agreement with more commonly used Framingham equations. These findings introduce further complexity to the statin debate as up to 40% of high-risk patients could be under-treated with low dose statins, while people at low-risk could be exposed to the potential side-effects of statins unnecessarily. It would be preferable if the assessment for OTC statins included a full assessment of CVD risk using Framingham equations (or an alternative such as the SCORE system4) and BP and cholesterol measurement – but this would require additional training for some pharmacists.5
D Graham Mackenzie, Specialist Registrar in Public Health, Public Health Department, NHS Fife, Cameron House, Leven, KY8 5RG
Sarah H Wild, Senior Lecturer in Public Health and Epidemiology, Public Health Sciences, University of Edinburgh, Teviot Place, EH8 9AG
Philip Rutledge, Consultant in Medicines Management, Lothian NHS Board, 148 Pleasance, Edinburgh, EH8 9RS
Figure. CHD risk of SHS participants (n=2760). Those eligible for OTC statins using full RPSGB criteria are shown in black, and the additional participants identified after removing BP and cholesterol from the criteria are shown in white. Participants at moderate risk not identified using RPSGB criteria are shown in blue.
(a higher resolution version of this image can be viewed at http://www.doctors.net.uk/DocStore/DSView/Document.aspx?docid=427271)
References
- Ravnskov U, Rosch PJ, Sutter MC, Houston MC. Should we lower cholesterol as much as possible? BMJ 2006;332:1330 –2
- Wood DA et al. JBS 2: Joint British Societies' guidelines on prevention of cardiovascular disease in clinical practice Heart 2005;91:v1-v52
- OTC simvastatin practice guidance, concise version. http://www.rpsgb.org.uk/pdfs/otcsimvastatincardguid.pdf accessed 1/7/2006
- Conroy RM, Pyörälä K, Fitzgerald AP et al on behalf of the SCORE project group. Estimation of ten-year risk of fatal cardiovascular disease in Europe: the SCORE project. European Heart Journal 2003: 24; 987-1003
- Practice guidance on: sale of over-the-counter simvastatin. http://www.rpsgb.org.uk/pdfs/otcsimvastatinguid.pdf accessed 1/7/2006
Competing interests:
None declared
Competing interests: No competing interests
We agree with Ravnskov et al that little is known about the adverse
effects of high dose statins[1] but would also propose that little is
known about the long term safety of more modest doses used at present.
Lifetime use of statins may equate to therapy for thirty years or more.[2]
As stated by the authors, multi centre large-scale trials have established
efficacy of these agents but are much less reliable for detection of
infrequent serious adverse outcomes such as cancer.
Recent studies provide reassurance regarding the safety of statins
with respect to all-cause carcinogenicity in the short term[3,4] and up to
ten years.[5] However, whilst the length of post-marketing surveillance
remains quite short compared to the medically accepted latency period for
cancer of twenty years,[2] it seems prudent to establish systems examining
and linking large databases to allow extended follow-up for malignancy.
Such monitoring can also help ascertain whether any class effect or dose-
response exists and whether certain categories of carcinogenicity are
influenced by statins either favourably (as suggested by some case-control
studies) or deleteriously. These data linkage systems should include a
variety of stakeholders, among them regulatory authorities from different
countries and the pharmaceutical industry, all cooperating in the
provision of more robust information in this and other important areas of
pharmacovigilance. Recent issues surrounding the long term uncertainty of
COX-2 inhibitors and hormone replacement therapy have highlighted that
medication safety must be proven rather than assumed, especially for very
widely used medications utilised for long-term therapy.
Corresponding author: Steven Joseph Haas -
Steven.Haas@med.monash.edu.au
References
1. Ravnskov U, Rosch PJ, Sutter MC, Houston MC. Should we lower
cholesterol as much as possible? BMJ 2006;332(7553):1330-2.
2. Newman TB, Hulley SB. Carcinogenicity of lipid-lowering drugs.
JAMA 1996;275(1):55-60.
3. Baigent C, Keech A, Kearney PM, Blackwell L, Buck G, Pollicino C,
et al. Efficacy and safety of cholesterol-lowering treatment: prospective
meta-analysis of data from 90,056 participants in 14 randomised trials of
statins. Lancet 2005;366(9493):1267-78.
4. Kaye JA, Jick H. Statin use and cancer risk in the General
Practice Research Database. Br J Cancer 2004;90(3):635-7.
5. Strandberg TE, Pyorala K, Cook TJ, Wilhelmsen L, Faergeman O,
Thorgeirsson G, et al. Mortality and incidence of cancer during 10-year
follow-up of the Scandinavian Simvastatin Survival Study (4S). Lancet
2004;364(9436):771-7.
Competing interests:
Steven Joseph Haas has received assistance via an Australian National Health and Medical Research Council Public Health Postgraduate Research Scholarship, Scholarship application I.D. #237059. As corresponding author, Steven Joseph Haas had full access to all data in the study and had final responsibility for the decision to submit for publication.
Andrew Tonkin has received funding for studies and speakers fees from pharmaceutical industry companies including AstraZeneca, Bristol-Myers Squibb, Merck Sharp and Dohme, Pfizer, and Sankyo.
Mark Nelson has received funding for studies and consultancies from pharmaceutical industry companies including AstraZeneca, Bayer AG, Sanofi-Aventis, Sanofi-Synthelabo, Bristol-Myers Squibb, Merck Sharp and Dohme, and Pfizer.
John McNeil has served on advisory boards for Pfizer, GlaxoSmithKline, Johnson & Johnson, Bristol-Myers Squibb, Schering-Plough, Sanofi-Aventis, and Merck Sharp and Dohme.
Competing interests: No competing interests
Catey Shanahan wrote:
"Most doctors would be crazy to ask elderly women about dizziness,
fatigue, and forgetfulness because of course they're going to be dizzy,
tired, and forgetful sometimes, and just by asking, now you've got them
worried. Unless you also happen to have a potential solution for their
mild complaints (ie "you should stop your Lipitor, Mrs. Pumpernickle) you
just don't want to open that can of worms. But it seems to me we have a
nation of dizzy, achey, tired older middle aged and elderly men and women
who feel better after stopping the drug."
If you really think you are doing something for these patients, then
you have to ask them all these questions including those not on statins.
You could trying giving those not on statins, placebos or Lipitor and see
if you get an improvement. Don't underestimate the power of placebo or
jus talking to the patient.
Competing interests:
None declared
Competing interests: No competing interests
I have not done anything like a formal study, but I have an
opportunity to see many many patients on statins and ask them
nosy questions.
I am in private practice with two internists, one of whom is a statin
fanatic, even prescribing statins to elderly women with HDLs of 80
and LDLs of 130 or 140. She goes on vacation 3 months of the
year and I see her patients in that time, some for routine refills,
some for medical problems. When I'm in the mood, I scrounge
around asking them for potential statin side effects.
Almost without exception they have minor complains that could
certainly be attributed to statins. By minor I mean subtle
forgetfullness, vague muscle fatigue at the end of the day, mild
disequilibrium; the type of stuff they probably wouldn't have told
me about had I not specifically asked. A small minority of these
have severe muscle aches and are miserable and dying to stop
the drug if only it were "safe."
Many of these patients become my patients because they don't
want to have to go back onto the statin again.
Of the hundred or so of my statin-loving coworker's statin-using
patients whom I have seen over the past two and one half years
since she joined our clinic, I would guess about three or four
definitively denied having any symptoms, but I didn't question all
one hundred well enough to be sure it was only those few--it could
have been lots more. But my general, vague and possibly
biased, impression is that it's the exception not the rule for people
to deny potential statin caused symptoms began after starting their
statins.
Most doctors would be crazy to ask elderly women about
dizziness, fatigue, and forgetfulness because of course they're
going to be dizzy, tired, and forgetful sometimes, and just by
asking, now you've got them worried. Unless you also happen to
have a potential solution for their mild complaints (ie "you should
stop your Lipitor, Mrs. Pumpernickle) you just don't want to open
that can of worms. But it seems to me we have a nation of dizzy,
achey, tired older middle aged and elderly men and women who
feel better after stopping the drug.
Competing interests:
None declared
Competing interests: No competing interests
Ravnskov and his colleagues (1) have to be congratulated on
their article stating that statins have more side effects than usually
claimed.
They highlight selection bias and scientific mishandling of data
as possible sources for this misconception.
Selection Bias: The main statin studies exclude patients with
concomitant diseases ( mainly cancer and COPD). Additionally, some
studies like TNT (2) and HPS (3) exclude all patients who had side
effects with statin medication in the pre run. The reported low
number of patients with side effects therefore refers to those
patients only who did not have side effects in the first place and
were not excluded from the main trial.
Scientific Mishandling: PROSPER (4) showed a small but significant
increase in cancer incidence with Pravastatin treatment. The result
was buried in a makeshift meta analysis of unmatched trials.
Where does it leave us? What are the medical, ethical and legal
implications when we know that benefits from statin therapy for
the individual patient are small and fraught with problems. Should
UK General Practitioners receive ,quality payments’ by spending
approximately 4 – 6% of the total UK drug budget on drugs with growing
concerns about safety and tolerability. Could this money be better
spend on health promotion relating to life style changes ? (
Explanation for the Non-British readers : GPs in the UK receive so
called quality payments for reaching certain targets like putting
patients on statins etc.)
I seriously hope, that the article by Ravnskov et al. will start
a discussion of evidence.
1) Ravnskov U, Rosch PJ, Sutter MC, Houston MC. Should we lower
cholesterol as much as possible? BMJ 2006; 332:130-1332
2) LaRosa JC, Grundy SM, Waters DD, Shear S, Barter P, Fruchart J et al.
Intensive lipid lowering with atorvastatin in patients with stable
coronary disease. N Engl J Med 2005; 352: 1425 - 1435
3) Heart Protection Study Collaborative Group. MRC/BHF Heart Protection
Study of cholesterol lowering with Simvastatin in 20,536 high risk
individuals: a randomised placebo controlled trial. Lancet 2002; 360: 7-
22.
4) Shepherd J, Blauw GJ, Murphy MB, Bollen EL, Buckley BM, Cobbe SM et al.
Pravastatin in elderly individuals at risk of vascular disease (PROSPER):
a randomized controlled trial. Lancet 2002 ; 360: 1623 - 30
Competing interests:
None declared
Competing interests: No competing interests
that statins occupy, with various permanency, the active site in the enzyme
resulting in reduced production of mevalonate, the 6 carbon precursor to
the 5 carbon group based isoprenoid family. While interesting, the
point is not how statins don't work but if or why they don't.
Clearly, when there is mathematical certainty from 2 meta analysis [JAMA
and JACC 2004, ref's in (1)] that women don't have a mortality benefit
from a statin or, in secondary prevention, no benefit in myocardial infarction
one has to come with answers why this might be. Why PROSPER found
no mortality benefit in over 70 year olds also needs to be answered first
and, I suggest, before we argue method of action or side-effects from any
dose.
I suggest there may be an 'event' benefit in statins in younger males
since statins mimic nitroglycerin [promote the NO-synthase pathway] and
thus lower the rate of 'classic' male stable angina symptoms, arguably
not ever a fatal condition but certainly one that can send one to the cath-lab
while in a trial. Pharmacologists should split out this statin effect as a confounder in combined endpoint studies and then we can see if anyone really benefits from impeding the mevalonate pathway and that affects every
system in the body.
Regarding the 'lower is better' concept, the 1/4 million patient-year observational J-LIT study (2) showed that simvastatin 'hyper-responders'
achieving the LDL levels the various guidelines propose had significantly greater mortality than those remaining near total cholesterol 6 ± 0.5
mmol/L and LDL 4 ± 0.8 mmol/L [J-LIT
graphs from table 5 Medline 12499611]
Eddie Vos- vos{at}health-heart.org
1.) Vos E, Rose CP. Questioning
the benefits of statins. CMAJ Nov 8, 2005; 173 (10). doi:10.1503/cmaj.1050120.
2.) Matsuzaki M, Kita T, Mabuchi H, Matsuzawa Y, Nakaya N, Oikawa S
et al Large
scale cohort study of the relationship between serum cholesterol concentration
and coronary events with low-dose simvastatin therapy in Japanese patients
with hypercholesterolemia. Circ J. 2002 Dec;66(12):1087-95.
Competing interests:
None declared
Competing interests: No competing interests
Ravnskov et al. raise concerns about the safety of high-dose statins
[1].
A recent retrospective analysis of pooled data from 49 clinical
trials of atorvastatin (n=14,236 patients) has shown that the incidence of
treatment-associated adverse events for high-dose atorvastatin (80 mg) is
similar to that of atorvastatin at a dose of 10 mg and placebo. Based on
this analysis, the safety profile of atorvastatin at the highest dose is
supported [2].
However, a recent meta-analysis (n=71,108) of randomized controlled
trials have shown that atorvastatin is associated with the greatest risk
of adeverse events among atorvastatin, fluvastatin, lovastatin,
simvastatin, and pravastatin [3].
On the other hand, though we analyzed the incidence of
rhabdomyolysis, based on Japanese post-marketing survey for pitavastatin
as a new statin [4], the incidence was 0 (95% CI: 0-12.9) per 10,000
person-years in monotherapy of pitavastatin (n=7,880). Furthermore,
pitavastatin (2 mg/day) decreased the risk of any adverse events
significantly compared with simvastatin (20 mg/day) in (p=0.015 by using
Fisher exact test), though the mean rate of low density lipoprotein (LDL)
cholesterol reduction was not significantly different (pitavastatin:
38.2%, simvastain: 39.4%) [5]. Therefore, these studies indicate the rate
of adverse events differs among statins.
On the other hand, though we think that there are the benefits of
high-dose statins in the secondary prevention of cardiovascular diseases,
the benefits are not sufficiently shown in the primary prevention of
cardiovascular diseases. Furthermore, the worries about the increase of
high-dose statins-related adverse events remain even in the secondary
prevention of cardiovascular diseases [1].
Therefore, statins should be used, considering the difference of the
rate of adverse events among statins in the primary or the secondary
prevention of cardiovascular diseases. Furthermore, it should be still
avoided to use high-dose statins in the primary prevention of
cardiovascular diseases.
References:
[1] Ravnskov U, Rosche PJ, Sutter MC and Houston MC. Should we lower
cholesterol as much as possible ? BMJ 2006;332:1330-1332.
[2] Newman C, Tsai J, Szarek M, Luo D, Gibson E, Comparative safety
of atorvastatin 80 mg versus 10 mg derived from analysis of 49 completed
trials in 14,236 patients, Am J Cardiol 2006;97: 61-67.
[3] Silva MA, Swanson AC, Gandhi PJ, Tataronis GR, Statin-related
adverse events: a meta-analysis. Clin Ther 2006;28:26-35.
[4] Kurihara Y., Douzono S.,Fujita S., Kakuda T., Nachi S., Uematsu
H. Interim Report, 8083 Patients on the Drug Use Investigation of
Pitavastatin (LIVALO Tablet), Jpn Pharmacol Ther 2006;34:317-326. (in
Japanese)
[5] Park S, Kang HJ, Rim SJ, et al, A randomized, open-label study to
evaluate the efficacy and safety of pitavastatin compared with simvastatin
in Korean patients with hypercholesterolemia, Clin Ther 2005;27:1074-1082.
Competing interests:
None declared
Competing interests: No competing interests
Ravnskov et al., state that 'all statins inhibit the synthesis of
hydroxymethylglutaryl coenzyme A (HMG CoA) reductase, an enzyme involved
in synthesis of the precursor of cholesterol'. This is incorrect. Statins
act as inhibitors of hydroxymethylglutaryl coenzyme A reductase and reduce
synthesis of mevalonate from HMG CoA. The consequent reduction in
cholesterol synthesis leads to upregulation of receptors for low density
lipoprotein (LDL) and a resultant increase in uptake of this lipoprotein
(largely by the liver) and reduced circulating LDL. In fact use of statins
is associated with increased amounts of HMG CoA reductase as a result of
reduced negative feedback on synthesis (1).
1. Brown MS, Goldstein JL. Multivalent feedback regulation of HMG CoA
reductase, a control mechanism coordinating isoprenoid synthesis and cell
growth. J Lipid Res. 1980;21:505-17.
Competing interests:
None declared
Competing interests: No competing interests
Further evidence that higher statin doses are ineffective
In
their recent subgroup analysis of the TNT trial Deedwania and coworkers found
that coronary patients with the metabolic syndrome gained more benefit from
high-dose atorvastatin therapy than coronary patients without, but they didn´t
mention that the latter group gained no benefit at all (table 1). The small
differences between the low-dose and the high-dose groups were far from
significant in this subgroup implying that there is no reason to increase
atorvastatin by eight times in the absence of the metabolic syndrome.
As total mortality was unchanged in all
subgroups, the question is if the significant, but small reduction of non-fatal
events in the patients with the metabolic syndrome offsets possible long-term
side effects. Of special concern is the risk of peripheral neuropathy.
In one study the odds ratio for that risk in patients treated with
statins for longer than two years was 26.4 (17.8-45.4)2 and in
another one polyneuropathy was seen in five of 50 cardiology clinic patients
after 28 months of treatment.3 Most likely the risk is even larger in
diabetic patients, and as the symptoms may be seen as part of their disease and
not as a side effect of the treatment this tormenting plague may become
permanent.
Event
rate (%)
10
mg of Atorvastatin
80
mg of Atorvastatin
Major
cardiovascular events
181/2186
(8.3)
172/2231
(7.7)
Major
coronary events
138/2186
(6.3)
134/2231
(6.0)
All-cause
mortality
104/2186
(4.8)
114/2231
(5.1)
Table
1. Primary outcomes in the TNT trial in patients with coronary heart disease
after exclusion of patients with the metabolic syndrome.
References
P, Barter P, Carmena R, et al. Reduction of low-density lipoprotein
cholesterol in patients with coronary heart disease and metabolic syndrome:
analysis of the Treating to New Targets study. Lancet
2006;368:919-28.
D, Jeppesen U, Andersen M, Garcia Rodriguez LA, Hallas J, Sindrup SH.
Statins and risk of polyneuropathy: a case-control study. Neurology
2002;58:1333-7.
PH, Langsjoen JO, Langsjoen AM, Lucas LA. Treatment
of statin adverse effects with supplemental Coenzyme Q10 and statin drug
discontinuation. Biofactors
2005;25:147-52.
Competing interests:
None declared
Competing interests: No competing interests