Prescriber August 2018 ❚ 13prescriber.co.uk

THERAPY FOCUS ■

Low-density lipoprotein (LDL) cholesterol, like blood pres-sure, is a very well-established, important modifiable risk

factor for the prevention of cardiovascular disease and natu-rally a leading target for a growing number of LDL cholester-ol-lowering therapeutic options.1-4 There is a diverse range of pharmacological lipid-regulating therapies available, but the current most commonly used options are high-intensity statin regimens involving atorvastatin (20–80mg daily), rosuvastatin (10–40mg daily) or simvastatin (80mg daily). These regimens are expected to reduce LDL cholesterol by over 40% in pri-mary prevention settings, while atorvastatin (80mg daily) is expected to reduce LDL cholesterol by over 50% in people with cardiovascular disease. In terms of the need for primary prevention, risk is ascer-tained by using the cardiovascular disease risk prediction algo-rithm QRISK®. The latest iteration of this tool (QRISK®3)5 was made available in 2017 (see Table 1 for a summary of included risk factors), but current NICE guidance refers to QRISK®2. In addition to those otherwise healthy individuals or type 2 diabetes patients receiving a ≥10%, 10-year cardiovascular risk score, patients to be considered for statin therapy (with-out measuring risk score) include those with type 1 diabetes, chronic kidney disease or established cardiovascular disease.6

Non-statin lipid-regulating agents, such as bile-acid seques-trants, the specific cholesterol absorption inhibitor ezetimibe, niacin (nicotinic acid) and fibrates have traditionally been far less effective in lowering LDL cholesterol and are not endorsed as first-line preventers of cardiovascular disease, where stat-ins set the standard. But a new breed of LDL cholesterol-low-ering agents, the proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors (represented by alirocumab and evo-locumab), has now disrupted this status quo by providing a non-statin therapeutic option that rivals LDL cholesterol lower-ing by statins.7-9

Can LDL cholesterol ever be lowered too much?DAVID LAIGHT

Current guidelines recommend reducing LDL cholesterol by specified amounts; however, a new treatment ‘lower is better’ paradigm advocates more dramatic LDL cholesterol reduction beyond current targets to maximise global cardiovascular risk benefits. This article examines the benefits and drawbacks of this approach.

SPL

■ THERAPY FOCUS l LDL cholesterol lowering

14 ❚ Prescriber August 2018 prescriber.co.uk

NICE currently recommends alirocumab and evolocumab for primary heterozygous-familial hypercholesterolaemia in individuals with LDL cholesterol persistently above treatment thresholds (either 3.5mmol/L or 5mmol/L depending on the presence or absence of cardiovascular disease, respec-tively), despite maximum tolerated lipid-lowering therapy.10,11 Furthermore, they are recommended as options for treating primary non-familial hypercholesterolaemia and mixed dys-lipidaemia, but only if there is cardiovascular disease (for example acute coronary syndrome, ischaemic stroke, coronary heart disease or peripheral artery disease) and only then if LDL cholesterol is persistently above 3.5 or 4mmol/L after lipid-lowering treatment, depending on the absolute level of cardiovascular risk. This use aligns with the relatively modest therapeutic aim of reducing LDL cholesterol to below specified thresholds, using whatever appropriate therapy is effective. However, a new treat-ment ‘lower is better’ paradigm advocates going much further in order to leverage the global cardiovascular risk benefits promised by dramatic LDL cholesterol reduction (to as low as 0.5mmol/L), especially in patients at highest cardiovascular risk.12-14

Importance of cholesterol to physiologyOver the years, cholesterol has picked up a clinical reputation as a pariah lipid, driving cardiovascular harms (the cholesterol hypothesis). However, it is also essential for a host of physio-logical functions such as the maintenance of cell membranes, the digestion of other dietary lipids (by providing bile salts)

and the support of steroid hormone production, including the generation of vitamin D following sunlight exposure. Cholesterol may also safeguard against malignancy and neurodegenerative disease.15,16 Such is the importance of an adequate supply of cholesterol that, in addition to being able to import circulating cholesterol as LDL cholesterol via the surface expression of LDL receptors and the process of receptor-mediated endocyto-sis, most cells can also synthesise it. Making cholesterol requires the enzyme HMG CoA reduc-tase, which catalyses the rate-limiting step of mevalonic acid production from HMG CoA (see Figure 1). This is the stage targeted by statins, which are HMG CoA reductase inhibitors, most clinically significantly in the liver. The subsequently upreg-ulated hepatic cell surface expression of LDL receptors leads to greater hepatic LDL cholesterol clearance from the circulation – one of the most effective ways of lowering LDL known. Starving the liver of cholesterol, by either preventing its enterohepatic recirculation as bile salts using bile-acid sequestrants or limit-ing its dietary absorption/biliary reabsorption with ezetimibe, acts in qualitatively the same fashion, but with a less dramatic impact on LDL cholesterol. Alirocumab and evolocumab acti-vate this hepatic LDL-lowering pathway in a complementary way, by blocking the action of the enzyme PCSK9 from binding to and tagging LDL receptors for intracellular degradation fol-lowing LDL receptor-mediated endocytosis. This results in more recycling of LDL receptors back to the cell surface (with the liver normally accounting for approximately 70% of tissue-expressed LDL receptors).

Cholesterol transportOther than non-esterified or free fatty acids, which are carried by circulating albumin, mass lipid transport in the blood is only made feasible by lipoproteins, which essentially provide emul-sification. These lipid droplets consist of a highly lipophilic fatty core (containing cholesteryl ester and triglycerides), encapsu-lated by an amphipathic monolayer envelope of phospholipids, in which is found cholesterol and proteins known as apolipo-proteins or apoproteins. Most lipoproteins feature several of these apoproteins (apoA–E) and these carry out a number of important enzyme regulatory and cell docking functions. However, LDL mainly features apoB100 and this is essential for LDL receptor-mediated endocytosis and tissue LDL choles-terol uptake. Dietary lipids, including both cholesterol and triglycerides, arrive in the blood via the lymphatics from the small intestine packaged as chylomicrons and this represents the ‘exogenous’ lipid pathway (see Figure 2). On the other hand, hepatically- produced lipids are exported into the circulation as very low-density lipoprotein (VLDL; representing the ‘endogenous’ pathway). Both these triglyceride-rich lipoproteins serve up fatty acids for uptake by extrahepatic tissues such as skeletal muscle and fat, following lipolysis by cell surface-expressed lipoprotein lipase. This route of blood triglyceride clearance in fact helps account for one of the major therapeutic lipid-lower-ing benefits of fibrates, through the increased expression of lipoprotein lipase.

• Age • Sex• Ethnicity• Postcode• Smoking status• Diabetes status• Angina or heart attack in first-degree relative <60 years• Chronic kidney disease (stage 3, 4 or 5)*• Atrial fibrillation• On blood pressure treatment• Migraines*• Rheumatoid arthritis• Systemic lupus erythematosus*• Severe mental illness*• On atypical antipsychotic medication*• On regular steroid tablets*• A diagnosis of or treatment for erectile dysfunction*• Cholesterol:HDL ratio• Systolic blood pressure• Standard deviation of at least two most recent systolic

blood pressure readings*• Body mass index

*Additions since QRISK®2

Table 1. QRISK®3 prediction algorithm cardiovascular risk factors5

Prescriber August 2018 ❚ 15prescriber.co.uk

LDL cholesterol lowering l THERAPY FOCUS ■

The triglyceride-depleted lipoprotein remnants are either entirely removed from the circulation by the liver in the case of chylomicron remnants; or partially cleared in the case of VLDL remnants (also known as intermediate-density lipoprotein [IDL]). Those remaining IDL not cleared by the liver are instead modified by hepatic lipase to become cholesterol-enriched LDL, which accounts for approximately 75% of cholesterol transport in the blood. Compared with other mammals, this in fact rep-resents an unusually large fraction of circulating cholesterol to be carried by LDL, reflecting the significant level of conversion of IDL to LDL.

Cholesterol: the good, the bad and the uglyCirculating cholesterol originally exported as VLDL (as a pre-cursor of LDL) is ultimately destined for uptake by tissues expressing surface LDL receptors. In contrast to this highly controlled, saturatable LDL cholesterol uptake pathway, LDL cholesterol scavenging by macrophages in the arterial wall represents an unregulated, unlimited cholesterol uptake pathway, which leads to foam cell formation and drives ath-erogenic lipid deposition. This unsurprisingly is the major reason for regarding LDL cholesterol as ‘bad’ circulating cho-lesterol in terms of both marking and mediating cardiovascu-lar risk.17 LDL’s poor reputation has been further tarnished by the discovery of a variant of LDL known as Lp(a), which features a modified form of apoB100 identified as apo(a) (produced by the liver) and which is considered to be espe-cially atherogenic (the ‘ugly’).18 On the other hand, ‘good’ blood cholesterol in the context of reduced cardio vascular risk, is conventionally associated with what is being trans-ported away from the periphery by high-density lipoprotein (HDL) in ‘reverse’, ie excess cholesterol returning to the liver to be cleared, out of harm’s way.19 In addition to lowering LDL

cholesterol, statins also modesty raise HDL and furthermore reduce triglyceride levels. This dichotomy of ‘good’ and ‘bad’ cholesterol in fact sim-ply reflects the pathological importance of the compartmen-talisation of cholesterol in the blood. This is further illustrated by now considering all non-HDL lipoproteins, not just LDL, as atherogenic. Indeed, non-HDL cholesterol is better associated with coronary atheroma progression than is LDL cholesterol.20

This places VLDL and IDL as well as Lp(a) and even chylomi-crons and their remnants firmly in the ‘bad’ cholesterol camp.

The current NICE recommendation is that non-HDL cholesterol (= total cholesterol minus HDL cholesterol) is reduced by more than 40% with high-intensity statin regimens for both primary and secondary prevention (see Table 2).6 Of course, given the unusually large contribution of LDL cholesterol to non-HDL cholesterol in man (see Table 3), lowering LDL cholesterol is likely to remain a principal clinical target for cardiovascular risk- modifying, lipid-regulating therapeutics. A related interesting question is whether LDL attributes such as size and density, and in particular particle quantity, for which LDL cholesterol level might simply be a proxy (ie high LDL cholesterol concentration tracks risk by reflecting high par-ticle number), are the really significant targets in lipid-regulating therapy. Small, dense (so-called ‘pattern B’) LDL are thought to represent an aggressively atherogenic phenotype, irrespective of LDL cholesterol level, while high particle number is likely to facilitate arterial wall lipid deposition and dyslipidaemia-driven atherogenesis. This suggests therapeutic efforts to improve LDL particle quality and reduce particle number, independently of reducing LDL cholesterol, may provide another legitimate treatment goal.

How low should LDL cholesterol go?Chasing down global cardiovascular risk by reducing LDL cho-lesterol to potentially extremely low levels (which is especially

• Statins are relatively safe and generally well-tolerated lipid-lowering agents with principal roles in the treatment of primary hypercholesterolaemia and mixed dyslipidaemia

• The treatment target for LDL cholesterol lowering in this context, either alone or in combination with other lipid-lowering therapies, typically involves reaching a specified threshold, which can be dependent on the presence or absence of cardiovascular disease and degree of cardiovascular risk

• In addition, high-intensity statin regimens are recommended in the management of LDL cholesterol as a modifiable cardiovascular risk factor in the primary and secondary prevention of cardiovascular disease

• The treatment target in this context is >40% reduction in non-HDL cholesterol

• The decision to offer statins for prevention is prompted by either a 10-year risk of heart attack or stroke of ≥10%, measured using the prediction QRISK® algorithm, or the presence of cardiovascular disease or other high-risk conditions

Table 2. LDL cholesterol lowering with statins: prescribing summary

acetyl CoAacetoacetyl CoA

3-hydroxy-3-methyl-glutaryl-CoA (HMG CoA)

HMG CoA reductase

mevalonic acid

cholesterol

Figure 1. Simplified pathway of cholesterol synthesis

■ THERAPY FOCUS l LDL cholesterol lowering

16 ❚ Prescriber August 2018 prescriber.co.uk

of relevance to patients at highest risk), naturally raises impor-tant concerns about the health consequences of iatrogenic hypocholesterolaemia. This, of course, is with regard to choles-terol’s multiple and essential physiological intracellular roles. However, there are indications that the clinical prospect of pro-foundly reducing circulating LDL cholesterol may not be quite so alarming. This is in view of observations in populations with very low LDL cholesterol levels, for example neonates, traditional hunter-gatherer populations and individuals with hypobeta-lipoproteinaemia (where LDL production is limited) or PCSK9 loss of function mutations (with a naturally high expression of hepatic LDL receptors), which suggest that very low levels are tolerable and for long periods.21 Furthermore, investigations, including a meta-analysis looking at the safety and efficacy of more intensive LDL cholesterol reduction, have indicated that cardiovascular benefits are safely achievable.12,22

Such observations serve to eschew conventional fixed notions of LDL cholesterol treatment thresholds or desirable levels (see Table 3 for desirable lipid levels in adults suggested by NHS and Heart UK).23 Moreover, misgivings about potential harms arising from extremely low LDL cholesterol might need to be weighed against the anticipated cardiovascular benefit in individuals at high risk, such as in a secondary prevention setting. Indeed, reducing LDL cholesterol to the ‘lower normal’ boundary of 0.52mmol/L based on epidemiological findings

(ie some six-times lower than the declared desirable limit in healthy adults – see Table 3), might be suggested as justifi-able in patients at highest cardiovascular risk with extensive atherosclerosis.21 This all reinforces the impression that LDL cholesterol reduction, at least with statins, is a cardiovascular ‘gift that keeps on giving’ and furthermore that lower LDL cho-lesterol really is better. In this clinical picture, only the incidence of statin side-effects might be expected to impose a major lim-itation on LDL cholesterol lowering in highest risk patients. However, the lowest safe or tolerated LDL cholesterol level has yet to be determined.

Role of statins in lowering LDL cholesterol beyond current targetsNotwithstanding the clinical supremacy of intensive statin therapy, there may still be a question of exactly how best to pursue dramatic reductions in LDL cholesterol. Despite offer-ing clear lipid-lowering and other pleiotropic cardiovascular benefits,13,24 the use of intensive statins runs into potential problems with the (admittedly rare but serious) risks pre-sented by myopathy, myositis, rhabdomyolysis and hepato-toxicity, as well as the more common phenomenon of statin intolerance. The nature of this intolerance is in fact an ongo-ing area of contention, as it has been suggested that sta-tin-associated muscle symptoms (SAMS) may not necessarily be related to pharmacological statin effects.25 Nevertheless,

Lp(a)

clearance

chylomicrons

chylomicron remnants

‘forward’ cholesterol transport

VLDL

VLDL remnants (IDL)

LDL

clearance

clearance

Liver

Gut

Extrahepatic tissue, eg muscle, fat, endocrine

Figure 2. Lipid transport by non-HDL, atherogenic lipoproteins

Prescriber August 2018 ❚ 17prescriber.co.uk

LDL cholesterol lowering l THERAPY FOCUS ■

non-adherence to statins in the face of considerable levels of intolerance, coupled with large variability in patient LDL cholesterol-lowering responses, are already thought to con-tribute to a state of suboptimal LDL cholesterol control and cardiovascular risk management.26,27 Furthermore, lipid-low-ering with statins has been linked with haemorrhagic stroke, dementia, cancer and diabetes and even an increased risk of death from violent causes.28

A recent literature survey incorporating data from ran-domised controlled trials and genetic studies, while confirm-ing a modest risk of new-onset diabetes with statins, came to the overall conclusion that long-term statin therapy is indeed safe with a low risk of clinically relevant adverse events.29 Moreover, this risk is thought to be far outweighed by estab-lished cardiovascular benefits. This pronouncement may still not be enough to allay all the controversy surrounding the decision by NICE to recommend treatment with a high-intensity statin regimen at the lower, primary prevention threshold of ≥10% cardiovascular 10-year risk6 with respect to expanding the statin-medicated population. It is also important to note here that there remains some dissent from the mainstream view that statins are a largely unqualified therapeutic good and even some disillusionment with the whole conventional cholesterol hypothesis.30 However, while the advocacy of statin use in primary preven-tion remains contentious, especially in low-risk groups,31 their use in secondary prevention settings is generally considered favourable from the perspective of an increasingly advanta-geous risk/benefit ratio. This naturally aligns with the obser-vation that subjects at highest absolute cardiovascular risk, and with the most severe disturbance in LDL cholesterol, have much to gain from LDL cholesterol-lowering intervention with statins.13,32,33 Furthermore, such gains may not be limited to primary and secondary prevention, as apparently healthy indi-viduals without known cardiovascular risk factors still appear to derive a cardiovascular benefit associated with LDL cholesterol lowering below normal values with statins in the setting of pri-mordial prevention.34 This may possibly also reflect the actions of statins to, for example, stabilise atherosclerotic plaques, improve vascular endothelial function and reduce inflammation and thrombosis. Such pleiotropic effects might therefore help to chip away at unaccounted for or residual cardiovascular risk, as well as ameliorating predictable risk by LDL cholesterol low-ering.

Optimising lipid-lowering therapyOf course, the optimal choice of prescribed LDL cholesterol-low-ering intervention(s) should be personalised, based on factors such as drug efficacy, tolerability, polypharmacy, co-morbidities and patient safety profile, and informed patient preference. In addition to whatever may be achieved by lifestyle change and statins, any future adherence to a ‘lower is better’ clini-cal approach to LDL cholesterol control (especially in those patients at highest cardiovascular risk) will likely require a much greater role for add-on or alternative therapies that can fur-ther upregulate hepatic LDL receptors.7,9,26,35 Interestingly in

this regard, a recent change to the marketing authorisation for the PCSK9 inhibitor evolocumab means that it is now also licensed in adults with established atherosclerotic cardiovascu-lar disease to reduce cardiovascular risk (as add-on therapy to a maximum tolerated dose of a statin).36 However, NICE is yet to appraise its use for this indication. Here, the PCSK9 inhibitors might be expected to do an even better job at targeting non-HDL cholesterol by virtue of reduc-ing Lp(a).18 Furthermore, importantly, cardiovascular benefits related to LDL cholesterol reduction via the hepatic upregula-tion of LDL receptors are reported to be equivalent to those offered by statins.37 While the inherently higher acquisition costs of monoclonal antibody therapies may cause concern about any potential future wider use of current PCSK9 inhibitors in aggressively pursuing even lower LDL cholesterol than that managed by high-intensity statins alone, this probably needs to considered in the context of the broader economic benefits expected to arise from the anticipated additional prevention of cardiovascular outcomes.

So does LDL cholesterol lowering have its limits?LDL cholesterol-lowering, primarily achieved with the generally well tolerated and relatively safe statins, clearly has an ongo-ing fundamental part to play in helping reduce the incidence of heart attack or stroke in a range of individuals at increased cardiovascular risk. The central importance to primary and sec-ondary prevention accorded to LDL cholesterol lowering likely reflects the importance of improvements in the cholesterol:HDL ratio, which of course represents one of the most clinically sig-nificant modifiable risk factors included in the QRISK® prediction algorithm (see Table 1). However, it is interesting to consider that this single QRISK® lipid risk factor continues to be diluted by the addi-tion of new, non-lipid risk factors (see Table 1). Furthermore, there is a plethora of emerging novel, non-traditional cardio-vascular risk factors38 that are no doubt yet to be considered for inclusion in risk prediction algorithms. This may therefore

Lipid fraction Level (mmol/L)

Total cholesterol ≤5 (≤4 if high risk)

LDL cholesterol ≤3 (≤2 if high risk)

Non-HDL cholesterol ≤4

HDL cholesterol >1 (men)>1.2 (women)

Triglycerides <1.7 (fasting)<2.3 (non-fasting)

Total cholesterol: HDL cholesterol ratio

<4

Table 3. NHS/Heart UK desirable lipid values in adults23

■ THERAPY FOCUS l LDL cholesterol lowering

18 ❚ Prescriber August 2018 prescriber.co.uk

suggest at least a theoretical limit to what LDL cholesterol (or non-HDL cholesterol) reduction alone can achieve – however profound, however achieved and however well tolerated – in terms of reducing either predictable or residual cardiovascu-lar risk.

References1. Pedersen TR. The success story of LDL cholesterol lowering. Circ Res 2016;118:721–31.2. Wadhera RK, et al. A review of low-density lipoprotein cholesterol, treatment strategies, and its impact on cardiovascular disease morbid-ity and mortality. J Clin Lipidol 2016;10:472–89.3. Drexel H. Statins, fibrates, nicotinic acid, cholesterol absorption inhibitors, anion-exchange resins, omega-3 fatty acids: which drugs for which patients? Fund Clin Pharmacology 2009;23:687–92.4. Kreisberg RA, Oberman A. Medical management of hyperlipidemia/dyslipidemia. J Clin Endocrinol Metab 2003;88:2445–61.5. ClinRisk. QRISK®3-2017 risk calculator. Available from: https://qrisk.org/three/ [accessed 19 July 2018].6. National Institute for Health and Care Excellence. Cardiovascular disease: risk assessment and reduction, including lipid modification. CG181. July 2014 (updated September 2016). Available from: https://www.nice.org.uk/guidance/cg181 7. Chaplin S. PCSK9 inhibitors: when statins aren’t enough. Prescriber 2017;28(10):21–6.8. Scherer DJ, et al. Targeting low-density lipoprotein cholesterol with PCSK9 inhibitors. Int Med J 2017;47:856–65.9. Sabatine MS, et al. Evolocumab and clinical outcomes in patients with cardiovascular disease. New Engl J Med 2017;376:1713–22.10. National Institute for Health and Care Excellence. Evolocumab for treating primary hypercholesterolaemia and mixed dyslipidaemia. TA394. June 2016. https://www.nice.org.uk/guidance/ta39411. National Institute for Health and Care Excellence. Alirocumab for treating primary hypercholesterolaemia and mixed dyslipidaemia. TA393. June 2016. https://www.nice.org.uk/guidance/ta39312. McCormack T, et al. Very low LDL-C levels may safely provide addi-tional clinical cardiovascular benefit: the evidence to date. Int J Clin Pharmacy 2016;70:886–97.13. Whayne TF. Assessment of low-density lipoprotein targets. Angiology 2012;64:411–6.14. Bandyopadhyay D, et al. Safety and efficacy of extremely low LDL-cholesterol Levels and Its Prospects in Hyperlipidemia Management. J Lipids 2018. DOI: https://doi.org/10.1155/2018/859805415. Petrov AM, et al. Cholesterol in the pathogenesis of Alzheimer’s, Parkinson’s diseases and autism: link to synaptic dysfunction. Acta Naturae 2017;9:26–37.16. Katzke V, et al. Blood lipids and lipoproteins in relation to inci-dence and mortality risks for CVD and cancer in the prospective EPIC–Heidelberg cohort. BMC Medicine 2017;15. DOI: https://doi.org/10.1186/s12916-017-0976-417. Elshourbagy NA, et al. Cholesterol: the good, the bad, and the ugly – therapeutic targets for the treatment of dyslipidemia. Med Princ Pract 2014;23:99–111.18. Tsimikas S. A test in context: lipoprotein(a): diagnosis, prognosis, con-troversies, and emerging therapies. J Am Coll Cardiol 2017;69:692–711.19. Rye K-A, Barter PJ. Cardioprotective functions of HDLs. J Lipid Res 2014;55:168–79.20. Puri R, et al. Non-HDL cholesterol and triglycerides: implications for coronary atheroma progression and clinical events. Arterioscler Thromb Vasc Biol 2016;36:2220–8.

21. Whayne TF. Low-density lipoprotein cholesterol (LDL-C): how low? Curr Vasc Pharmacol 2017;15:374–79.22. Cholesterol Treatment Trialists’ (CTT) Collaboration. Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials. Lancet 2010;376:1670–81.23. Cholesterol Matters. Understanding cholesterol levels. Available from: https://www.cholesterolmatters.co.uk/cholesterol/understand-ing-cholesterol-levels; Diabetes.co.uk. Total cholesterol to HDL ratio calculator. Available from: www.diabetes.co.uk/cholesterol-to-hdl- ratio-calculator.html24. Collins R, et al. Interpretation of the evidence for the efficacy and safety of statin therapy. Lancet 2016;388:2532–61.25. Pedro-Botet J, Rubiés-Prat J. Statin-associated muscle symptoms: beware of the nocebo effect. Lancet 2017;389:2445–6.26. Krähenbühl S, et al. Unmet needs in LDL-C lowering: when statins won’t do! Drugs 2016;76:1175–90.27. Boekholdt SM, et al. Very low levels of atherogenic lipoproteins and the risk for cardiovascular events: a meta-analysis of statin trials. J Am Coll Cardiol 2014;64:485–94.28. Stein EA, et al. Targeting LDL: is lower better and is it safe? Best Pract Res Clin Endocrin Metab 2014;28:309–24.29. Mach F, et al. Adverse effects of statin therapy: perception vs. the evidence – focus on glucose homeostasis, cognitive, renal and hepatic function, haemorrhagic stroke and cataract. Eur Heart J 2018;39:2526–39.30. Malhotra A, et al. More clarity needed on the true benefits and risks of statins. Prescriber 2016;27(12):15–7.31. Abramson JD, et al. Should people at low risk of cardiovascular disease take a statin? BMJ 2013;347:f6123.32. Vallejo-Vaz AJ, et al. Low-density lipoprotein cholesterol lowering for the primary prevention of cardiovascular disease among men with primary elevations of low-density lipoprotein cholesterol levels of 190 mg/dL or above: analyses from the WOSCOPS 5-year randomised trial and 20-year observational follow-up. Circulation 2017;136:1878–91.33. Maki KC, Dicklin MR. Assessing cardiovascular disease risk and responses to preventive therapies in clinical practice. Curr Atheroscler Rep 2018;20:23.34. Fernández-Friera A, et al. Normal LDL-cholesterol levels are asso-ciated with subclinical atherosclerosis in the absence of risk factors. J Am Coll Cardiol 2017;70:2979–91.35. Steg PG, Ducrocq G. Future of the prevention and treatment of coronary artery disease. Circ J 2016;80:1067–72.36. European Medicines Agency. Repatha. Available from: http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/ medicines/003766/smops/Positive/human_smop_001272.jsp&mid=WC0b01ac058001d127 [accessed 20 July 2018].37. Silverman MG, et al. Association between lowering LDL-C and car-diovascular risk reduction among different therapeutic interventions. JAMA 2016;316:1289–97.38. Whayne TF. Non-traditional cardiovascular risk markers in the era of established major risk factors and multiple guidelines. Curr Vasc Pharmacol 2018;16. DOI: 10.2174/1570161116666180123112956.

Declaration of interestsNone to declare.

David Laight is a Principal Lecturer in Pharmacology in the School of Pharmacy and Biomedical Sciences, University of Portsmouth