Summary Istvan and Deisenhofer 2001) – This represents the

SummaryIntroduction-       Preventative medication-       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 atheroscleroticplaques -> suggests should target cholesterol pathway -> ofthis pathway HMG-CoA reductase a good target for these reasons:Scope of the problem – how many deaths? Mechanism of Sterol Action –       Although dietary cholesterol can contribute to overalllevels, the major site of synthesis is hepatocytes in mammals –       The pathway for cholesterol biosynthesis iscomplex and contains over 30 enzyme catalysed steps (see Fig. 1 for a reducedversion of the pathway). Statins target HMG-CoA reductase, which catalyses the conversion(four electron reductive deacylation) of HMG-CoA to mevalonate.

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(E. S. Istvan and Deisenhofer 2001)-       This represents the committed step incholesterol biosynthesis and is the rate limiting enzyme.-       Statins inhibit this enzyme competitively withrespect to binding HMG-CoA but not to NADPH. All statins comprise a moietyanalogous to HMG linked to a rigid group varying in its hydrophobicity. X-raycrystallography studies show that the HMG-like moiety occupies the active siteof the enzyme to sterically prevent the substrate from binding while the hydrophobicgroup sits in a shallow groove-       These studies show that the HMG- like moietycommon to the statin molecules occupies the HMG binding site of the enzyme,with the hydrophobic groups of the statins being positioned in a shallow grooveformed by rearrangement of the C-terminal residues of the enzyme that is onlypresent when these residues are disordered.

(E. Istvan 2003). This sterically inhibits thesubstrate entering and therefore reversibly inhibits cholesterol synthesis. Statinsbind with a nanomolar affinity, while the natural substrate has affinity in themicromolar range. (Moghadasian 1999)  The SREBP/SCAP pathway-       Under normal cellular conditions, a reduction in(plasma/hepatic) cholesterol levels activates a signalling cascade thatultimately results in upregulation of LDL-receptor expression. throughregulated 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 transcriptionfactors. Synthesised as inactive precursors bound to the ER. –       SREBPs must first be transported from the ER tothe Golgi-       The -NH2 terminal transcription factor domain isreleased by sequential cleavage.

Site 1 protease cleaves the and site 2 protease-       This translocates to the nucleus, where it bindssterolregulatory elements (SREs) –       Isoform specific functions – LDL-receptor. Identifiedby over-expression of target genes in mice liver. Two genes encode the threeisoforms (Brown and Goldstein 1997)-       SCAP (SREBP cleavage activating protein) – has asterol sensing domain-       Raised expression of the LDL-receptor – moredisplayed/decorate the cell surface – receptor mediated endocytosis –internalisation lowers plasma concentration. Internalisation occurs via –       Receptor mediated endocytosis is constitutive –no increase in rate, merely number-       Mutations in the gene for the LDL-R lead to adisorder known as familial hypercholesterolemia. Heterozygous sufferers can betreated with statins, but homozygotes cannot as there is no LDL-R to upregulate. –       Cholesterol in the bloodstream is insoluble, soit must be transported in the form of a lipoprotein particle, of which thereare several varieties, classified on the basis of their density (firstdistinguished by ultracentrifugation)-       Also raises expression of HMG-CoA reductase, but-         What is the evidence for the benefits of statins/loweringcholesterol?Currently statins are prescribed for two different groups of-       Landmark study was 4S (Scandinavian Simvastatin Survival Study Group 1994).

Shows an overall reductionin mortality and coronary mortality – secondary prevention, patients withcoronary heart disease studied (see also LIPID trial)-       Secondary prevention –       Primary prevention for cardiovascular disease –good opportunity as long latency period. Treating patients with lipid-loweringagents –       Good evidence for primary prevention being aneffective strategy: mutation in the PSCK9 gene associated with increased LDLreceptor -> decreases LDL -> lower CHD = effect of lower lifetime LDL(Cohen et al. 2006)-       Early primary prevention trial = WOSCOPS –patients were hyperlipidemic but free of CVD-       2013 Cochrane review for primary prevention-         What is the current practice in prescribing statins?-       NICE guidelines updated in 2014-       Risk calculators used – give risk of having aheart attack/stroke in next 10 years – jumping off point for primary prevention-       Advise prescription to people with risk over 10%- up from 20% previously. The algorithm QRISK2 is used to assess risk.

Thistakes into account 15 different risk factors, with age given a particularlyhigh weight (Hippisley-Cox et al. 2008).  All adults, regardless of other risk factors,will at some point become eligible for statin treatment.

–       Following these guidelines, an estimated 11.8million are eligible for statins (Ueda et al. 2017), representing 37% of thepopulation aged 30-84. However,-       Studies based on the 2008  guideline of ? 20% risk estimate that 69% ofpeople who meet the criteria are not prescribed statins. (van Staa et al. 2013)Should statins be prescribed to patients at lower risk forCVD?-       Cholesterol Treatment Trialists’ meta-analysissuggests benefit for those with 10 year risk less than 10% – suggests need toinitiate discussion on expanding treatment (The effects of lowering LDLcholesterol with statin therapy in people at low risk of vascular disease:meta-analysis of individual data from 27 randomised trials)-       Need to prevent people from discontinuing statintreatment as is common for primary prevention – (Vinogradova et al. 2016) – ‘A recent study using datafrom CPRD showed that 47% of the patients prescribed statins as primaryprevention had at least 90 days of discontinued treatment during a medianfollow-up time of 137 weeks’.-       Greater than 40% of statin users discontinuetheir treatment at some point, over 70% of the discontinuers restart.

(Vinogradova et al. 2016). Danger in prescribingstatins too early?   Statins for other diseases – Widening the scope-       Statins are well known to have pleiotropiceffects and have been proposed for diseases such as ….. This falls outside thescope of this essay.

 Adverse effects :-       Meta-analysis: increase in absolute risk ofdiabetes of 0.5%-       Muscle pain-       Claims of over-medicalisation: should we insteadbe encouraging people to lose weight/stop smoking etc?-       Controversy – liken to MMR-       https://www.theguardian.com/society/2016/jun/28/statins-controversy-uk-people-stop-taking-pills-heart-attack-stroke-       Need improved communications between prescribersand patients –       200,000 Britons stopped taking statins aftercontroversy 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 aneven greater bias towards negative in the right-wing press. (Chisnell et al. 2017).-       This reporting does not reflect the quality ofthe study, all trials are portrayed equally –       This preponderance of negative press coveragemay not only be discouraging people from beginning/continuing statin treatment,but may also be influencing the adverse effects experienced.

–       Blind trial followed by non-blinded-       What proportion are genuinely caused by the drug– media hype/statins given to older people likely to suffer these symptomsanyway – raised awareness leads them to blame statins-       Link this to nocebo effects Some concerns over increasedstatin prescriptions are a fear of risk compensation, whereby people becomeless careful when they feel safer Clinical studies disagree aboutthe 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 somerecent 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 compensationOver-medicalisation-       Over-treating older patients-       Load on GPs/NHS – takes time away from otherpatients – each GP would need to prescribe around 200 more patients each (Ueda et al. 2017)-       Over the counter a solution?-       Is this the future of preventative medicine –compare to immunisation