European Heart Journal (2023) 00, 1–3 EDITORIAL

https://doi.org/10.1093/eurheartj/ehad324

Statins revisited: therapeutic applications

beyond lipid lowering?

Downloaded from https://academic.oup.com/eurheartj/advance-article/doi/10.1093/eurheartj/ehad324/7198202 by guest on 23 June 2023

1,2,3 4 1,2
Lina Badimon *, Guiomar Mendieta , and Gemma Vilahur
1
Cardiovascular Program-ICCC, IR-Hospital de la Santa Creu i Sant Pau, IIB-SantPau, Av. S. Antoni M. Claret, 167, ES-08025 Barcelona, Spain; 2Centro de Investigación Biomédica en Red de
Enfermedades Cardiovasculares (CIBERCV CB16/11/00226), Spain; 3Cardiovascular Research Chair, Autonomous University of Barcelona, Barcelona, Spain; and 4Cardiology Hospital
Clinic, IDIBAPS, Barcelona, Spain

This editorial refers to ‘Statin loading before coronary artery bypass grafting: a randomized trial’, by O.J. Liakopoulos et al.,
https://doi.org/10.1093/eurheartj/ehad238.

Graphical Abstract

3-hydroxy-3-methylglutaryl-CoA
(HMG-CoA)

Statins
HMG-CoA
2NADPH+2H
Reductase

2NADP+
Loading dosages Oral dosages
CoA-SH

Cholesterol Mevalonate
Intravenous
administration ? Prenylation
of statin G-proteins Hypolipidemic
Statins lipophilicity effects
Statin bioavailability
Statins half-life
Myocardial
Pleiotropic
Inflammation effects
infarction
damage

Thrombosis

Atherosclerotic plaque
stabilization
Immunomodulation Endothelial function Oxidative stress

Pleiotropic effects of statins: impact of statin dosages.

The opinions expressed in this article are not necessarily those of the Editors of the European Heart Journal or of the European Society of Cardiology.
*
Corresponding author: Tel: +34 93 556 58 80, Fax: +34 93 556 55 59, Email: LBadimon@santpau.cat
© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com
2 Editorial
Statins reduce hepatic cholesterol synthesis through the competitive in-
hibition of 3-hydroxy-3-methylglutaryl coenzyme A reductase
(HMG-CoAR), the rate-limiting enzyme in cholesterol biosynthesis.
The reduction in intracellular cholesterol promotes increased LDL re-
ceptor expression at the surface of the hepatocytes, which in turn re-
sults in an increased uptake of LDL from the blood, thereby reducing
LDL plasma concentrations. The latest European Society of
Cardiology and European Atherosclerosis Society Guidelines on
Dyslipidaemia clearly recognize that lowering LDL-cholesterol levels
is the most important pharmacological intervention to mitigate athero-
sclerotic cardiovascular (CV) events.1 Indeed, statin efficacy in both the
primary and secondary prevention of coronary heart disease (CHD)
has been demonstrated in numerous landmark clinical trials.2
However, the benefits derived from treatment with statins are great-
er than might be expected from changes in plasma lipid levels alone, po-
tentially due to their associated ‘pleiotropic’ effects, which go beyond
plasma cholesterol lowering. The purported effects of statin pleiotrop-
ism include improved endothelial function, enhanced atherosclerotic
plaque stability, decreased oxidative stress and inflammation, inhibition
of the thrombogenic response and modulation of the immune system,
and other systems (central nervous system and bone).3 These pleio-
tropic effects were evidenced in vitro and in experimental in vivo studies
performed using high statin doses, bringing about the concept of oral
statin loading doses to reproduce the experimentally observed benefits
in the clinical setting. Numerous clinical studies have investigated these
biologically plausible effects with modest success, showing trends to-
ward greater benefit (statin loading before percutaneous coronary re-
vascularization; i.e. ARMYDA-RECAPTURE and SECURE-PCI trials).4,5
Moreover, in the Statin Therapy in Cardiac Surgery (STICS) trial, a
20 mg oral dose of statin given 8 days before and 5 days after coronary
artery bypass grafting (CABG) surgery in statin-naive patients showed
neutral effects.6 In this issue of the European Heart Journal,
Liakopoulos et al.7 report on the results of the randomized, double-
blind, placebo-controlled START-CABG trial, where the effects of sta-
tin loading 12 and 2 h before surgical revascularization in patients
chronically treated with different statins (simvastatin, atorvastatin, pra-
vastatin, and fluvastatin) were investigated. Loading doses were the
maximal daily doses of the prescribed statin. The authors, who are to
be commended on their work in this investigator-initiated trial, report
that a statin loading dose before CABG failed to reduce primary and
secondary outcomes. The primary outcome, major adverse cardio-
cerebral events (MACCE), was a composite consisting of all-cause mor-
tality, myocardial infarction, and a cerebrovascular event within 30 days
after surgery. The secondary endpoints included a composite of cardiac
death and myocardial infarction (MACE), myocardial injury, and death
within 12 months.
Together with the STICS trial,6 which tested the effect of 8 days pre-
and 5 days post-treatment with rosuvastatin (20 mg daily oral doses)
and showed no clinical benefit, the neutral results of the
START-CABG trial7 further suggest that peri-procedural treatment
with statins does not provide any additional benefits to post-CABG
outcomes.
That being said, perhaps we should re-address the issue and
examine whether we are using statins in the right way. Have the
studies performed thus far assessed statin interventions appropriate-
ly so as to adequately capture their treatment effects on patient
outcomes?
The scientific understanding of the mechanism of action of statins,
beyond their cholesterol-lowering properties, has grown considerably
over the last years. The benefits of their pleiotropic effects have been
attributed to the inhibition of isoprenylation, an effect that can be at-
tained at different levels depending on the type and pharmacokinetic
profile of the statin in use (Graphical Abstract).
Statin inhibition of mevalonate synthesis prevents isoprenoid inter-
mediate synthesis, including farnesylpyrophosphate (FPP) and geranyl-
geranylpyrophosphate (GGPP).3 These intermediates serve as
important lipid attachments for the post-translational modification of
intracellular small G-proteins such as Ras, Rho, and Rac and their down-
stream effectors. Inhibition of these GTP proteins may be an important
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mechanism contributing to the pleiotropic effects of statins. Target cel-
lular and molecular points far beyond LDL lowering-mediated effects
have been identified and the statin doses required are higher than those
for lipid lowering in chronic CV disease (CVD) prevention.
In addition, statins are not all equal when it comes to pleiotropic ac-
tions. In order to effectively inhibit an acutely triggered pathological
process (ischaemia, inflammation, oxidative processes, reperfusion in-
jury, etc.), a threshold amount of drug is required at its initiation.
Understanding drug pharmacology is key to uncover the full potential
of these drugs.8 Displaying variable degrees of lipophilicity, the more
hydrophilic types (rosuvastatin and pravastatin) require activated
carrier-mediated transport with organic anion-transporting polypep-
tide 1B1 and are more liver selective (statin transporters are not pre-
sent in all tissues), whereas lipophilic statins (lovastatin, simvastatin,
fluvastatin, atorvastatin, and pitavastatin) cross cell membranes mainly
through passive diffusion.8,9
Statin oral bioavailability differs according to their chemical structure,
and it is generally low, ranging from ∼5% for simvastatin, to 10–12% for
atorvastatin and to 20% for rosuvastatin. In addition, statins bind to
plasma proteins, and therefore the amount of pharmacologically active
drug is low after oral dosing, peaking within 3 h after administration.
These pharmacokinetic properties explain the lack of sufficient levels
of active drug to halt the aforementioned pathological processes
upon oral administration.8 Given these pharmacological caveats, it
may not be possible for oral administration of statins to achieve these
pleiotropic effects.
Recent experimental studies in a pre-clinical animal model have
demonstrated that the heart is best protected against ischaemia
through the administration of an intravenous formulation of modi-
fied atorvastatin given during ischaemia and prior to revasculariza-
tion.10–12 However, this novel strategy needs to be proven in
human studies.
Unexpectedly, in the STICS trial6 of peri-operative rosuvastatin
therapy, adverse kidney effects in the rosuvastatin-allocated patient
arm were detected. The authors have investigated the mechanism
of post-operative acute kidney injury found in the trial and have re-
ported their findings in the article by Wijesurendra et al. also pub-
lished in the current issue of the journal.13 Renal function was
adversely affected and an increase in different inflammatory and kid-
ney injury-related biomarkers was found. Interestingly, rosuvastatin
effects on kidney function were observed right after its approval.
While in 2004 there was a controversy on this respect in The
Lancet,14 later on effects were found to vary according to the type
of patient under treatment. CVD frequently co-exists with chronic
kidney disease (CKD), and patients with CVD and CKD are at
very high risk of CVD events. Statins are the first-line lipid-lowering
therapy in patients with CVD and CKD, although rosuvastatin needs
dose adjustments based on renal function, whereas atorvastatin does
not.15 Indeed, rosuvastatin is generally not recommended for chronic
lipid lowering in patients with severe kidney disease. It is interesting
that in patients undergoing elective cardiac surgery only an 8-day
Editorial
pre-treatment and 5-day post-treatment with oral 20 mg rosuvasta-
tin exacerbated renal injury.
While the potential benefit of intravenous statin treatment regimens
intended to inhibit cellular and molecular events in ischaemia- and
revascularization-induced organ damage in association with percutan-
eous coronary intervention and surgical procedures remains to be in-
vestigated in the clinical setting, the deleterious effects of rosuvastatin
on acute kidney injury detected in the STICS trial are of clinical rele-
vance and should be taken into consideration in the management of
CABG patients.
Funding
This work was supported by the Spanish Ministry of Economy and
Competitiveness of Science and Agencia Estatal de Investigación (AEI
/10.13039/501100011033-[PID2019-107160RB-I00]) to L.B.; AEI /10.13039/
501100011033-PID2021-128891OB-I00 to G.V; CIBERCV CB16/11/00411
to L.B.) cofounded by “Fondo Europeo de Desarrollo Regional (FEDER):
A way of making Europe”. Secretaria d’Universitats i Recerca del
Departament d’Empresa i Coneixement de la Generalitat de Catalunya
[2017 SGR 1480]. We thank Fundación Jesus Serra and Fundación de
Investigación Cardiovascular, Barcelona, for their continuous support.
Conflict of interest
L.B. declares speaker or consultant honoraria from Sanofi, NovoNordisk,
and Ionnis. L.B. and G.V. have founded the Spin-offs Glycardial
Diagnostics SL. and Ivastatin Therapeutics SL. G.M. declares being a mem-
ber of the Steering Committee of the Hermes NovoNordisk trial.
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