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Statins
Patients and people are different
From Dr J. Blenkinsopp, MBChB,
MRPharmS
Your cover on 22 November 2003 poses the rhetorical question “are
OTC statins good for pharmacy and for patients?”. The answer to
the first part of that question will depend on a clear understanding
of the pharmacy role in tackling coronary heart disease and using the
word “patient” may not help in this. The intention of the
reclassification of simvastatin 10mg is to focus on people who are currently
well, but at moderately raised risk of CHD. This is more than a semantic
distinction: these people are not CHD patients currently and this underlines
the role that the pharmacist could play in reaching them.
CHD is such a common disease (the lifetime risk of developing it at age
40 years is 1 in 3 for a woman and 1 in 2 for a man) that some have advocated
a population-based approach with a “polypill” to achieve
the maximum reduction in its toll.1 In contrast, the sheer size of the
problem means that the NHS has had to prioritise treatment to those at
the greatest risk, including those that have already suffered a heart
attack and those (eg, with diabetes) at extremely high risk of a first
event. The role of self-care in reducing moderately raised CHD risk in
the population sits strategically between these two approaches and is
informed by both. Pharmacists should be reassured that in occupying this
ground they are supported by the evidence and expert opinion. In the
publication that launched the joint British guidelines on the treatment
of CHD the authors commented: “There is now evidence from randomised
controlled trials that for some risk factors intervention with drugs
significantly reduces the risk of CHD events, and all cause mortality,
in individuals with a risk as low as 6 per cent of such events over the
next 10 years.” In this context, the target population for pharmacy
self-care is likely to have a 10-year risk of a first coronary event
(CHD death or a non-fatal myocardial infarction) of 10–15 per cent;
if we included softer but meaningful endpoints such as unstable angina
their risk would be substantially greater.
The distinction between “patient” and “person” has
other implications: what may be the right management strategy for the
high-risk “patient” may not be optimal for the moderate risk “person”.
Until quite recently the 10mg strength of simvastatin was widely prescribed
by GPs. Following a wealth of evidence in high-risk populations — including
the ground-breaking Heart Protection Study in 20,000 Britons — there
has been a move to recommend the higher doses (eg, 40mg only in HPS)
used in these studies. This is entirely logical since for many of these
patients achieving the maximum reduction in low density lipoprotein cholesterol
(LDL-C) represents their best chance of significantly reducing their
CHD risk. But why should we adopt the same approach for individuals whose
moderate risk is derived primarily from their age and, for example, a
modifiable risk factor such as being overweight? In these people weight
loss and an increase in aerobic exercise can have a significant effect
on their risk proportionately much greater than that available to high
risk patients.
In adopting the more “holistic” model where 10mg of simvastatin
is one part of the programme of interventions offered, pharmacists should
not think that they are pharmacologically short-changing their customers.
The relationship between simvastatin dose and LDL-C reduction is log-linear:
a doubling of dose from 10mg to 20mg increases the relative reduction
of LDL-C from around 27 per cent to 32 per cent and doubling the dose
again to 40mg produces a further 5 per cent incremental improvement.
The absolute reduction of LDL-C achievable with 10mg simvastatin, if
sustained, will produce around a 30 per cent relative reduction in CHD
risk. This will produce a valuable absolute risk reduction in those at
moderate risk and if the individual also modifies risk behaviours the
benefits will be considerable.
In an essentially normal population it is reasonable to use the lowest
effective dose to achieve the proportionately greatest benefit. The rare
adverse events (eg, myositis) associated with statin use are dose-related
and linked in many cases to drug-drug interactions that increase statin
effects. The risk of such events with simvastatin 10mg is very low and
therefore the risk to benefit ratio for the self-medicating individual
is extremely favourable at this dose.
Advising “people” at risk of CHD in their efforts to remain
well and to help prevent them becoming CHD “patients” will
be a new role for pharmacists but one that they are well placed to play.
John Blenkinsopp
Principal Research Fellow
School of Pharmacy,
University of Bradford
(and chairman of the J&J/MSD Pharmacy Advisory Panel for the
proposed switch of Zocor Heart-Pro from POM to P)
Reference
1. Wald NJ, Law MR. A strategy to reduce cardiovascular disease by more
than 80%. BMJ 2003;326:1419–23.
Adverse effect on coenzyme Q10 levels
From Professor V. Preedy, FRCPath,
and Dr D. Mantle, FRCPath
Recent items in The Pharmaceutical Journal have highlighted moves by
the manufacturers of simvastatin (Johnson & Johnson/MSD), together
with Government agencies, to reclassify statin drugs from prescription-only
to pharmacy over-the-counter supply within six months (PJ, 22 November
2003, p699 and p705). Statins are potent inhibitors of
3-hydroxy-3-methylglutaryl coenzyme A reductase and the
rate-limiting enzyme in cholesterol biosynthesis. This action is not
selective, resulting in the inhibition of several non-sterol isoprenoid
end products, including coenzyme Q10. The effect of statins in lowering
coenzyme Q10 levels is well documented and should be a matter of concern
to clinicians and other health care professionals, in addition to their
better-known adverse effects (eg, myalgia, liver dysfunction, polyneuropathy).
Many of the adverse effects resulting from statin use can be rationalised
in terms of concomitant coenzyme Q10 depletion.
Coenzyme Q10 is a vitamin-like substance that plays a key role in normal
cell functioning, in cellular energy transduction (as an electron carrier
in mitochondrial oxidative phosphorylation), as a lipid-soluble free
radical scavenging antioxidant, and as a stabiliser of cell membranes.
Because of the continual high requirement for energy, coenzyme Q10 is
particularly important in the human cardiovascular system, as well as
in the normal function of the immune system. Coenzyme Q10 is obtained
partially from the diet, and partially via synthesis within the body;
levels decline with age, and are depleted in a number of disorders, particularly
cardiovascular disease.
Although coenzyme Q10 depletion may be tolerated in younger patients,
particularly in the short term, with the trend to use statins in higher
doses or in longer term treatment regimens, individuals are increasingly
at risk from the effects of statin induced coenzyme Q10 depletion (particularly
the elderly and those with chronic cardiovascular disease). Current prescribing
information for statins gives no specific warnings or guidelines regarding
coenzyme Q10 supplementation, although the pharmaceutical industry is
well aware of this problem (Merck has held two patents dating from 1990
relating to co-administration of statins and coenzyme Q10). However,
statin-induced coenzyme Q10 depletion is currently the subject of a citizen’s
petition to the US Food and Drug Administration, requiring manufacturers
to change the labelling of all statin drugs to recommend the use of coenzyme
Q10 supplementation. In addition, the marketing of statins in Canada
requires labelling warning of coenzyme Q10 depletion, and the possibility
that this “could lead to impaired cardiac function in patients
with borderline congestive heart failure”. It is possible that
the true therapeutic potential of statin drugs is being partially negated
by reduced coenzyme Q10 levels, and that co-administration of both substances
would lead to an even greater reduction in cardiovascular morbidity and
mortality. Oral supplementation of coenzyme Q 10 would be necessary,
as the latter is not available from the diet in sufficient amounts to
compensate for the depletion in levels induced by statins. Thus the statin
induced depletion of coenzyme Q10 could be completely prevented by
co-administration of coenzyme Q10 supplements, with no adverse effects
on statin cholesterol lowering or anti-inflammatory properties.
Victor Preedy
Department of Nutrition and Dietetics,
King’s College London
D. Mantle
School of Biology,
University of Newcastle
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