Summary Istvan and Deisenhofer 2001) – This represents the

Summary

Introduction

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Preventative medication

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First statin approved in 1987 –

 

Epidemiological evidence linking elevated blood cholesterol (hyperlipidaemia)
to coronary heart disease (but scepticism over this despite animal models)
Framingham study? / Fredrickson (1967)

– (Gofman, n.d.)

– Circulating cholesterol – formation of atherosclerotic
plaques

-> suggests should target cholesterol pathway -> of
this pathway HMG-CoA reductase a good target for these reasons:

Scope of the problem – how many deaths?

 

Mechanism of Sterol Action

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Although dietary cholesterol can contribute to overall
levels, the major site of synthesis is hepatocytes in mammals

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The pathway for cholesterol biosynthesis is
complex and contains over 30 enzyme catalysed steps (see Fig. 1 for a reduced
version of the pathway). Statins target HMG-CoA reductase, which catalyses the conversion
(four electron reductive deacylation) of HMG-CoA to mevalonate. (E. S. Istvan and Deisenhofer 2001)

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This represents the committed step in
cholesterol biosynthesis and is the rate limiting enzyme.

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Statins inhibit this enzyme competitively with
respect to binding HMG-CoA but not to NADPH. All statins comprise a moiety
analogous to HMG linked to a rigid group varying in its hydrophobicity. X-ray
crystallography studies show that the HMG-like moiety occupies the active site
of the enzyme to sterically prevent the substrate from binding while the hydrophobic
group sits in a shallow groove

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These studies show that the HMG- like moiety
common to the statin molecules occupies the HMG binding site of the enzyme,
with the hydrophobic groups of the statins being positioned in a shallow groove
formed by rearrangement of the C-terminal residues of the enzyme that is only
present when these residues are disordered. (E. Istvan 2003). This sterically inhibits the
substrate entering and therefore reversibly inhibits cholesterol synthesis. Statins
bind with a nanomolar affinity, while the natural substrate has affinity in the
micromolar range. (Moghadasian 1999)

 

 

The SREBP/SCAP pathway

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Under normal cellular conditions, a reduction in
(plasma/hepatic) cholesterol levels activates a signalling cascade that
ultimately results in upregulation of LDL-receptor expression. through
regulated proteolysis and localisation of a transcription factor

 

Sterol response element binding proteins (SREBP)
are part of the family of basic-helix-loop-helix leucine zipper transcription
factors. Synthesised as inactive precursors bound to the ER.

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SREBPs must first be transported from the ER to
the Golgi

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The -NH2 terminal transcription factor domain is
released by sequential cleavage. Site 1 protease cleaves the and site 2 protease

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This translocates to the nucleus, where it binds
sterol
regulatory elements (SREs)

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Isoform specific functions – LDL-receptor. Identified
by over-expression of target genes in mice liver. Two genes encode the three
isoforms (Brown and Goldstein 1997)

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SCAP (SREBP cleavage activating protein) – has a
sterol sensing domain

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Raised expression of the LDL-receptor – more
displayed/decorate the cell surface – receptor mediated endocytosis –
internalisation lowers plasma concentration. Internalisation occurs via

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Receptor mediated endocytosis is constitutive –
no increase in rate, merely number

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Mutations in the gene for the LDL-R lead to a
disorder known as familial hypercholesterolemia. Heterozygous sufferers can be
treated with statins, but homozygotes cannot as there is no LDL-R to upregulate.

 

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Cholesterol in the bloodstream is insoluble, so
it must be transported in the form of a lipoprotein particle, of which there
are several varieties, classified on the basis of their density (first
distinguished by ultracentrifugation)

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Also raises expression of HMG-CoA reductase, but

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What is the evidence for the benefits of statins/lowering
cholesterol?

Currently statins are prescribed for two different groups of

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Landmark study was 4S (Scandinavian Simvastatin Survival Study Group 1994). Shows an overall reduction
in mortality and coronary mortality – secondary prevention, patients with
coronary heart disease studied (see also LIPID trial)

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Secondary prevention

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Primary prevention for cardiovascular disease –
good opportunity as long latency period. Treating patients with lipid-lowering
agents

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Good evidence for primary prevention being an
effective strategy: mutation in the PSCK9 gene associated with increased LDL
receptor -> decreases LDL -> lower CHD = effect of lower lifetime LDL(Cohen et al. 2006)

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Early primary prevention trial = WOSCOPS –
patients were hyperlipidemic but free of CVD

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2013 Cochrane review for primary prevention

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What is the current practice in prescribing statins?

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NICE guidelines updated in 2014

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Risk calculators used – give risk of having a
heart attack/stroke in next 10 years – jumping off point for primary prevention

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Advise prescription to people with risk over 10%
– up from 20% previously. The algorithm QRISK2 is used to assess risk. This
takes into account 15 different risk factors, with age given a particularly
high weight (Hippisley-Cox et al. 2008).  All adults, regardless of other risk factors,
will at some point become eligible for statin treatment.

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Following these guidelines, an estimated 11.8
million are eligible for statins (Ueda et al. 2017), representing 37% of the
population aged 30-84. However,

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Studies based on the 2008  guideline of ? 20% risk estimate that 69% of
people who meet the criteria are not prescribed statins. (van Staa et al. 2013)

Should statins be prescribed to patients at lower risk for
CVD?

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Cholesterol Treatment Trialists’ meta-analysis
suggests benefit for those with 10 year risk less than 10% – suggests need to
initiate discussion on expanding treatment (The effects of lowering LDL
cholesterol with statin therapy in people at low risk of vascular disease:
meta-analysis of individual data from 27 randomised trials)

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Need to prevent people from discontinuing statin
treatment as is common for primary prevention – (Vinogradova et al. 2016) – ‘A recent study using data
from CPRD showed that 47% of the patients prescribed statins as primary
prevention had at least 90 days of discontinued treatment during a median
follow-up time of 137 weeks’.

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Greater than 40% of statin users discontinue
their treatment at some point, over 70% of the discontinuers restart. (Vinogradova et al. 2016). Danger in prescribing
statins too early?

 

 

Statins for other diseases – Widening the scope

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Statins are well known to have pleiotropic
effects and have been proposed for diseases such as ….. This falls outside the
scope of this essay.

 

Adverse effects :

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Meta-analysis: increase in absolute risk of
diabetes of 0.5%

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Muscle pain

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Claims of over-medicalisation: should we instead
be encouraging people to lose weight/stop smoking etc?

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Controversy – liken to MMR

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https://www.theguardian.com/society/2016/jun/28/statins-controversy-uk-people-stop-taking-pills-heart-attack-stroke

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Need improved communications between prescribers
and patients

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200,000 Britons stopped taking statins after
controversy

Effect of the media:

In a six-month timeframe (1 October 2013 – 31 March 2014),
67 articles were published in the news media containing references to statins.
The ratio of negative to positive coverage was greater than 2:1 overall, with an
even greater bias towards negative in the right-wing press. (Chisnell et al. 2017).

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This reporting does not reflect the quality of
the study, all trials are portrayed equally

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This preponderance of negative press coverage
may not only be discouraging people from beginning/continuing statin treatment,
but may also be influencing the adverse effects experienced.

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Blind trial followed by non-blinded

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What proportion are genuinely caused by the drug
– media hype/statins given to older people likely to suffer these symptoms
anyway – raised awareness leads them to blame statins

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Link this to nocebo effects

 

Some concerns over increased
statin prescriptions are a fear of risk compensation, whereby people become
less careful when they feel safer

Clinical studies disagree about
the extent to which statin use impacts healthy behaviour:

Study

Findings

Sugiyama et al, 2007
USA

Caloric and fat intake increase in statin users over time, leading to
a faster rate of BMI increase than in non-statin users.

Lee et al, 2015
USA

Statin use was associated with modestly lower
physical activity among community-living men, even after accounting for
medical history and other potentially confounding factors

Lofgren et al, 2007
USA

Caloric intake did not vary significantly between statin users and
non-users.

Lytsy et al, 2012 Sweden

statin users were more likely to understand the importance of CVD
risk reduction and were more likely to undertake lifestyle modification

Johal et al, 2017
Australia

Statin users had lower saturated fat intake than non- users. However,
there was no difference in smoking status, exercise levels or alcohol consumption
between statin users and non-users after

Table 1 – A summary of some
recent papers regarding the lifestyle choices of patients prescribed statins – (Sugiyama et al. 2007; Lee et al. 2015; Lofgren 2007;
Lytsy, et al. 2012; Johal et al. 2017)

Dietary choices/sedentary lifestyle
– risk compensation

Over-medicalisation

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Over-treating older patients

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Load on GPs/NHS – takes time away from other
patients – each GP would need to prescribe around 200 more patients each (Ueda et al. 2017)

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Over the counter a solution?

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Is this the future of preventative medicine –
compare to immunisation