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Frontiers in Lipid Lowering Therapy: To Statins and Beyond

  • Arindam Chaudhuri
    Correspondence
    Bedfordshire–Milton Keynes Vascular Centre, Bedfordshire Hospitals NHS Foundation Trust, Kempston Road, Bedford, MK42 9DJ, UK.
    Affiliations
    Bedfordshire–Milton Keynes Vascular Centre, Bedfordshire Hospitals NHS Foundation Trust, Bedford, UK
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Open ArchivePublished:September 28, 2020DOI:https://doi.org/10.1016/j.ejvs.2020.08.051
      “Best medical treatment” are the bywords in the management of peripheral arterial disease (PAD), with lipid lowering therapy (LLT) prescribed de rigueur for arteriopaths. Typical LLT options comprise statins (more accurately, “vastatins”), which are effective in reducing all lipid profile fractions, including triglycerides (TGs) and low density lipoprotein-cholesterol (LDL-C), where attention is focused.
      • Behr P.E.B.
      • Moriguchi E.H.
      • Castro I.
      • Bodanese L.C.
      • Dutra O.P.
      • Leaes P.E.
      • et al.
      Indications of PCSK9 inhibitors for patients at high and very high cardiovascular risk.
      ,
      • Bhatt D.L.
      • Steg P.G.
      • Miller M.
      • Brinton E.A.
      • Jacobson T.A.
      • Ketchum S.B.
      • et al.
      Cardiovascular risk reduction with icosapent ethyl for hypertriglyceridemia.
      Statins represent a change from prior yet complementary LLT such as fibrates,
      • Jun M.
      • Foote C.
      • Lv J.
      • Neal B.
      • Patel A.
      • Nicholls S.J.
      • et al.
      Effects of fibrates on cardiovascular outcomes: a systematic review and meta-analysis.
      and gut absorption inhibitors like ezetimibe.
      • Nutescu E.A.
      • Shapiro N.L.
      Ezetimibe: a selective cholesterol absorption inhibitor.
      The benefits clearly seem to outweigh the disadvantages,
      • Mihaylova B.
      • Emberson J.
      • Blackwell L.
      • Keech A.
      • Simes J.
      • et al.
      Cholesterol Treatment Trialists' Collaborators
      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.
      and the side effect profile (focused currently on statins) exaggerated in the press.
      However, lipid control is not a panacea. The high density lipoprotein cholesterol ratio, considered an index of “protection” or severity of dyslipidaemia is not a useful target for reducing cardiovascular (CV) outcomes.
      • Kaur N.
      • Pandey A.
      • Negi H.
      • Shafiq N.
      • Reddy S.
      • Kaur H.
      • et al.
      Effect of HDL-raising drugs on cardiovascular outcomes: a systematic review and meta-regression.
      The benefits of statin therapy in PAD were thought to be a surrogate for improved cardiac outcomes, potentially confounded by the use of antiplatelet agents. However, a dose dependent reduction in amputation rates in patients with PAD has been noted,
      • Aday A.W.
      • Everett B.M.
      Statins in peripheral artery disease.
      and high dose statins seem to provide direct benefits in terms of preventing recurrent stroke.
      • Sillesen H.
      • Amarenco P.
      • Hennerici M.G.
      • Callahan A.
      • Goldstein L.B.
      • Zivin J.
      • et al.
      Atorvastatin reduces the risk of cardiovascular events in patients with carotid atherosclerosis: a secondary analysis of the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trial.
      However, in reality statin prescribing can be patchy.
      • Aday A.W.
      • Everett B.M.
      Statins in peripheral artery disease.
      Meanwhile, the world of lipid biology and lipid lowering pharmacology has moved on, focusing on those for whom statins are unsuitable, but who yet pose high CV risk; such patients are typically managed in dedicated familial hyperlipidaemia (FH) clinics. 3-Hydroxy-3-methylglutaryl co-enzyme A reductase is no longer the primary target. So called novel targets such as the Niemann–Pick C1 like 1 protein receptors on the small intestinal brush border overlap as a target for ezetimibe.
      • Gong Y.Z.
      • Sun S.W.
      • Yuan H.Y.
      • Xie X.J.
      • Tuo Q.H.
      • Yang X.F.
      • et al.
      Ezetimibe-mediated protection of vascular smooth muscle cells from cholesterol accumulation through the regulation of lipid metabolism-related gene expression.
      Many more options now present themselves for managing dyslipidaemia.
      Cholesterol absorption inhibitors, such as plant stanols (phytosterols and phytostanols) are available in supermarkets. Although apparently effective only in reducing serum cholesterol, studies indicate additional LDL-C reductions with high dose intake.
      • Gupta A.K.
      • Savopoulos C.G.
      • Ahuja J.
      • Hatzitolios A.I.
      Role of phytosterols in lipid-lowering: current perspectives.
      They may interfere with absorption of fat soluble vitamins. Pancreatic lipase inhibitors like orlistat are commercially available in slimming packages or via the UK National Health Service as part of obesity management programmes. Their additional lipid lowering effects, particularly in diabetics, are recognised but they do not form part of standard LLT.
      • Filippatos T.D.
      • Mikhailidis D.P.
      Lipid-lowering drugs acting at the level of the gastrointestinal tract.
      Bile acid sequestrants are not in mainstream use, but the newer colesevelam is specified for FH with or without a concomitant statin. Omega 3 fatty acids are another group being trialled
      • Bhatt D.L.
      • Steg P.G.
      • Miller M.
      • Brinton E.A.
      • Jacobson T.A.
      • Ketchum S.B.
      • et al.
      Cardiovascular risk reduction with icosapent ethyl for hypertriglyceridemia.
      ; eicosapentaenoic acid supplements are approved by the US Food and Drug Administration (FDA).
      • Cassagnol M.
      • Ezzo D.
      • Patel P.N.
      New therapeutic alternatives for the management of dyslipidemia.
      These fraction-specific approaches focus on associations between elevated TG levels and CV events.
      • Bhatt D.L.
      • Steg P.G.
      • Miller M.
      • Brinton E.A.
      • Jacobson T.A.
      • Ketchum S.B.
      • et al.
      Cardiovascular risk reduction with icosapent ethyl for hypertriglyceridemia.
      Specific very low density lipoprotein inhibitors like the microsomal triglyceride transfer protein inhibitor lomitapide are FDA approved for FH. Others, like mipomersen (an antisense apolipoprotein B synthesis inhibitor), have been approved as statin alternatives.
      • Cassagnol M.
      • Ezzo D.
      • Patel P.N.
      New therapeutic alternatives for the management of dyslipidemia.
      The most recent alternatives include a LDL specific immunological approach via the serine protease proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors,
      • Behr P.E.B.
      • Moriguchi E.H.
      • Castro I.
      • Bodanese L.C.
      • Dutra O.P.
      • Leaes P.E.
      • et al.
      Indications of PCSK9 inhibitors for patients at high and very high cardiovascular risk.
      which reduce LDL receptor loss, promoting LDL clearance, presenting an alternative for those at high CV risk with poorly controlled hyperlipidaemia either on statins or who are statin intolerant. Although expensive, LDL and CV adverse event reductions are impressive.
      • Behr P.E.B.
      • Moriguchi E.H.
      • Castro I.
      • Bodanese L.C.
      • Dutra O.P.
      • Leaes P.E.
      • et al.
      Indications of PCSK9 inhibitors for patients at high and very high cardiovascular risk.
      Evolocumab (two weekly dosing) and alirocumab (four weekly dosing) provide attractive injectable examples and are FDA/National Institute of Health and Care Excellence approved.
      • Achimastos A.
      • Alexandrides T.
      • Alexopoulos D.
      • Athyros V.
      • Bargiota A.
      • Bilianou E.
      • et al.
      Expert consensus on the rational clinical use of proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors.
      Most recently, a combination of ezetimibe and an adenosine triphosphate citrate lyase inhibitor, bempedoic acid,
      • Ballantyne C.M.
      • Banach M.
      • Mancini G.B.J.
      • Lepor N.E.
      • Hanselman J.C.
      • Zhao X.
      • et al.
      Efficacy and safety of bempedoic acid added to ezetimibe in statin-intolerant patients with hypercholesterolemia: a randomized, placebo-controlled study.
      received FDA approval.
      Therefore, while LLT is established, on a planet with an increasing burden of ageing people and obesity, a correspondingly increasing prevalence of diabetes, and cardiac and vascular disease, the push through newer frontiers in the universe of LLT continues. What is not yet known is how these newer therapies will specifically impact on some specific vascular outcomes (e.g., for PAD), particularly when addressing fraction targeted therapies, and thus more specific research is now needed in this context.

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