European Heart Journal (2024) 45, 647–650

https://doi.org/10.1093/eurheartj/ehad831

Global Spotlights

Celebrating the 90th birthday of the scientist

who discovered statins: Akira Endō

Downloaded from https://academic.oup.com/eurheartj/article/45/9/647/7512939 by guest on 02 March 2024

1 2,3 4,5
Stanisław Surma , Dimitri P. Mikhailidis , and Maciej Banach *
1
Faculty of Medical Sciences in Katowice, Medical University of Silesia, Medyków 18, 40-752 Katowice, Poland; 2Department of Surgical Biotechnology, Division of Surgery and Interventional
Science, University College London Medical School, University College London (UCL), London, UK; 3Department of Clinical Biochemistry, Royal Free Hospital Campus, UCL, London, UK;
4
Department of Preventive Cardiology and Lipidology, Medical University of Lodz (MUL), Rzgowska 281/289, Lodz 93-338, Poland; and 5Ciccarone Center for the Prevention of
Cardiovascular Disease, Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, 600 N. Wolfe St, Carnegie 591, Baltimore, MD 21287, USA

Dr Akira Endō—the father of
statins
In 1971, Dr Akira Endō (Figure 1A), working at the Sankyo company in
Tokyo, speculated that fungi not only contained antibiotics but also in­
hibitors of other processes, such as cholesterol metabolism. Over a
period of several years, he screened >6000 fungal cultures until a posi­
tive result emerged.1 This compound, which was named compactin
(mevastatin), came from the blue-green mould Penicillium citrinum
Pen-5 that was isolated from a rice sample collected at a grain shop
in Kyoto. Based on biochemical assays, compactin (mevastatin)
(Figure 1B) is the first known statin.1 On 14 November 2023,
Dr Akira Endō celebrated his 90th birthday. His discovery not only
made statins the gold standard for lipid-lowering treatment (LLT),
but also changed the natural history of cardiovascular (CV) disease
(CVD) treatment and prolonged the lives of patients, both in primary
and secondary cardiovascular prevention.2 For the past decades, statins
are the most commonly used ‘cardiology’ drugs in the world.2 After
over 50 years of natural ‘statin history’, we have prepared a SWOT
(strengths, weaknesses, opportunities, and threats) analysis to summar­
ize where we are and why we still underuse these drugs.
meta-analysis of 11 RCTs with 58 504 participants in primary preven­
tion. Acute coronary syndrome risk was reduced by 44%, major cere­
brovascular events by 22%, major coronary events by 33%, composite
CVD outcome by 29%, revascularizations by 35%, angina by 24%, and
CVD hospitalization by 26%.4 The use of statins in patients for second­
ary CVD prevention is associated with even more convincing results
with ACM risk reduced by 22%, CVD mortality by 31%, ACS by
38%, a need for coronary revascularization by 44%, and cerebrovascu­
lar events by 25%.5 Each reduction in serum low density lipoprotein
cholesterol (LDL-C) by 1 mmol/L (40 mg/dL) was associated with a
reduction in MACE risk by 12% (95% CI: 8%–16%) in the 1st year,
20% (16%–24%) in the 3rd year, 23% (18%–27%) in the 5th year,
and 29% (14%–42%) in the 7th year of LLT.6
Elevated LDL-C levels in younger people increase the risk of athero­
sclerotic cardiovascular disease (ASCVD) to a greater extent compared
with the same exposure in older people. This emphasizes the need to
control LDL-C at the earliest possible stage (=lifetime).2 More intensive
statin treatment allows for an additional 24% reduction in ASCVD risk
and by 10% ACM risk.2–6 Therefore, LLT with statins to be maximally
effective should be carried out in accordance with the following princi­
ples: ‘the lower the better’, ‘the longer the better’, and ‘the earlier the
better’.2

[S]trengths—statins improve [W]eaknesses—statin intolerance—

cardiovascular prognosis and
prolong life
Statins are the gold standard of lipid-lowering therapy and their use is
associated with improved CV outcomes (Figure 2). A meta-analysis of
94 000 patients in primary CV prevention showed that the use of
statins reduced the risk of: non-fatal acute coronary syndrome (ACS)
by 38%, CV mortality by 20%, all-cause mortality (ACM) by 11%, non-
fatal stroke by 17%, unstable angina by 25%, and composite major CV
events (MACE) by 26%.3 Similarly positive results were obtained in a
but is it really a significant problem
and weakness?
Statin intolerance (SI) should be reconsidered since they are one of the
best tolerated drugs in cardiology.2 However, due to lack of physician
and patient comprehensive knowledge, anti-statin movements from
the very beginning, media that prefer to unfavourably present statins,
and fake news, SI has been inappropriately considered as a weakness.
In this context, a study by Jones et al. found that the prevalence of mis­
information on statins on websites was 22.5%; this had a significant

* Corresponding author. Email: maciej.banach@icloud.com

© The Author(s) 2024. 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
648
Figure 1 A—Dr Akira Endō (source: https://pl.wikipedia.org/wiki/Akira_End%C5%8D; no permisision required); B—compactin (mevastatin)—the
first known statin discovered by Dr Akira Endō (public domain, no permission required).
impact since almost 60% of participants recommended that their rela­
tives ignore statin prescriptions. This study also showed that providing
information about the benefits and ways to deal with potential (rare)
side effects of statins significantly increased adherence.7
A drug that does not cause side effects has no effect at all. The reason
for not using statins is mostly the fear of intolerance, something we
call a drucebo effect that might be responsible for up to 90% of
SI cases.8 The world’s largest meta-analysis of 176 clinical studies,
including 4 143 517 patients showed that the overall prevalence of SI
worldwide is 9.1% (8.1%–10%), and when diagnosed with the approved
definitions, it was only 5.9%–7%.9 In other words, SI is in most of the
cases overdiagnosed, and 93% of patients on a statin can be treated ef­
fectively without any safety concerns.9 After ruling out the drucebo ef­
fect and excluding the risk factors and conditions that might increase SI
risk, any statin treatment can be continued in up to 98% of cases.2,9 The
most frequently reported side effects of statins (those with confirmed
causality) include statin-associated muscle symptoms (serious SAMS:
<0.1%), temporary elevation of liver enzymes (in most of the cases,
they return to normal levels after 4–8 weeks of therapy), and new-
onset diabetes (however, the risk is 5× less than CVD benefits asso­
ciated with statin therapy).8 In patients with a higher risk of SAMS
(e.g. polypharmacy) and a high risk of diabetes or with already existing
diabetes, pitavastatin might prove to be another option to optimize the
treatment of lipid disorders10 (Figure 2).
[O]pportunities—lipid-lowering
treatment based on statins allows
to reduce LDL-C levels by >85%
Recently, due to the ineffectiveness of LLT with only one-third to one-
fourth of patients reaching their LDL-C target, we have made a switch
from the high intensity statin therapy to intensive lipid-lowering com­
bination therapy.2 Depending on the therapeutic goal (determined
CardioPulse
Downloaded from https://academic.oup.com/eurheartj/article/45/9/647/7512939 by guest on 02 March 2024
individually for each patient based on CV risk and baseline LDL-C level),
a treatment with appropriate lipid-lowering potency is selected.2 The
use of combinations of lipid-lowering drugs allows to reduce LDL-C
level by >85% [strong statin in highest dose + ezetimibe + bempedoic
acid + proprotein convertase subtilisin/kexin type 9 (PCSK9) targeted
therapy approach].2 In patients at high to extremely high CVD risk,
the upfront lipid-lowering combination therapy not only allows to
achieve LDL-C targets more frequently, significantly reduces the num­
ber of side effects and the risk of discontinuation, but also reduces the
risk of CV outcomes [by 25% in 3-year follow-up; absolute risk reduc­
tion (ARR) 3.6%] and ACM (by 47%, ARR 4.7%).11 Therefore, LDL-C
goal achievement is possible for most patients (Figure 2).11
[T]hreats—lack of adherence to
statin therapy is an independent
cardiovascular disease risk factor
A lack of adherence to statin/lipid-lowering therapy and failure to
achieve therapeutic goals are common problems in clinical practice.8,11
The SANTORINI (Treatment of High and Very High riSk Dyslipidemic
pAtients for the PreveNTion of CardiOvasculaR Events) study showed
that in patients with high or very high CV risk, only 20.1% achieved their
target serum LDL-C level according to the 2019 ESC/EAS guidelines
(24% of high-risk patients and 18.6% of very high-risk patients, respect­
ively).12 Moreover, as many as 21.8% of patients did not receive any LLT
(23.5% and 21.1%, respectively), statin monotherapy was used by
54.3% of patients (58.4% and 52.5%, respectively), combined therapy
was used in 24% of patients (18.1% and 26.4%, respectively), and
most often, this was a combination of a statin and ezetimibe.12
Based on the available evidence, non-adherence to statin therapy,
which may result from statin-associated side effects, but also patient
non-compliance (because of lack of patient education and ineffective
communication), and physician inertia, is an independent CVD risk
CardioPulse 649

Downloaded from https://academic.oup.com/eurheartj/article/45/9/647/7512939 by guest on 02 March 2024

Figure 2 SWOT analysis of lipid-lowering treatment with statins. LLT, lipid-lowering therapy; CV, cardiovascular; ACS, coronary acute syndrome;
CAD, coronary artery disease; MACE, major adverse cardiovascular events; SI, statin intolerance; SAMS, statin-associated muscle symptoms; AEs, ad­
verse events; NOD, new-onset diabetes; ASCVD, atherosclerotic cardiovascular disease; ACS, acute coronary syndrome; PAD, peripheral artery dis­
ease; HeFH, heterozygous familial hypercholesterolaemia; FDC, fixed dose combination; HIS, high intensity statin; EZE, ezetimibe; BA, bempedoic acid;
OBICE, obicetrapib; PCSK9m, proprotein convertase subtilisin/kexin 9 modulator

factor.8,11 A study involving 347 104 ASCVD patients on statins Declarations

showed that compared with the most adherent patients, the risk of
death increased by 8%–30% as adherence deteriorated.13 Another
study involving nearly 55 000 patients with ACS showed that 20% of
the participants were non-adherent to statin treatment during the first
year. This translated into a significantly higher risk of all-cause mortality
(by 71%) and CV mortality (by 62%).14 A systematic review indicated
that lack of adherence to statin treatment increased the risk of
ASCVD by up to 5 times, ACM by 2.5 times, while lack of persistent
treatment increases the risk of CVD and mortality by 1.7 times and
5 times, respectively2,8,11 (Figure 2).
Disclosure of Interest
S.S.: honoraria from: Novartis/Sandoz and Pro.Med.; D.P.M. has
nothing to disclose; M.B.: speakers bureau: Amgen, Daiichi Sankyo,
KRKA, Polpharma, Mylan/Viatris, Novartis, Novo-Nordisk, Pfizer,
Sanofi-Aventis, Teva, and Zentiva; consultant to Adamed, Amgen,
Daiichi Sankyo, Esperion, NewAmsterdam, Novartis, Novo-Nordisk,
and Sanofi-Aventis; grants from Amgen, Daiichi Sankyo, Mylan/Viatris,
Sanofi, and Valeant.

Conclusions
Statins, which were developed after the discovery by Dr Akira Endō,
revolutionized medicine and proved to be the most effective treatment
for reducing the risk associated with ASCVD and prolonging life.
Despite this evidence, these drugs are underused. This situation can
only be changed by improving the knowledge of patients and prescri­
bers regarding the importance of using statins in patients with CVD.
Knowledge regarding how to deal with SI is also critically important.
References
1. Endo A. A historical perspective on the discovery of statins. Proc Jpn Acad Ser B Phys Biol
Sci 2010;86:484–93. https://doi.org/10.2183/pjab.86.484
2. Banach M, Surma S. A look to the past—what has had the biggest impact on lipids in the
last four decades? A personal perspective. Arch Med Sci 2023;19:559–64. https://doi.org/
10.5114/aoms/166256
3. Yebyo HG, Aschmann HE, Kaufmann M, Puhan MA. Comparative effectiveness and
safety of statins as a class and of specific statins for primary prevention of cardiovascular
disease: a systematic review, meta-analysis, and network meta-analysis of randomized
trials with 94,283 participants. Am Heart J 2019;210:18–28. https://doi.org/10.1016/j.
ahj.2018.12.007
650
4. Singh BM, Lamichhane HK, Srivatsa SS, Adhikari P, Kshetri BJ, Khatiwada S, et al. Role of
statins in the primary prevention of atherosclerotic cardiovascular disease and mortality
in the population with mean cholesterol in the near-optimal to borderline high range: a
systematic review and meta-analysis. Adv Prev Med 2020;2020:6617905. https://doi.org/
10.1155/2020/6617905
5. Ma W, Pan Q, Pan D, Xu T, Zhu H, Li D. Efficacy and safety of lipid-lowering drugs of
different intensity on clinical outcomes: a systematic review and network meta-analysis.
Front Pharmacol 2021;12:713007. https://doi.org/10.3389/fphar.2021.713007
6. Wang N, Woodward M, Huffman MD, Rodgers A. Compounding benefits of
cholesterol-lowering therapy for the reduction of major cardiovascular events: system­
atic review and meta-analysis. Circ Cardiovasc Qual Outcomes 2022;15:e008552. https://
doi.org/10.1161/CIRCOUTCOMES.121.008552
7. Jones NM, Mukamel DB, Malik S, Greenfield RS, Reikes A, Wong ND, et al. The costs
outweigh the benefits: seeing side-effects online may decrease adherence to
statins. BMC Med Inform Decis Mak 2020;20:197. https://doi.org/10.1186/s12911-020-
01207-w
8. Penson PE, Bruckert E, Marais D, Reiner Ž, Pirro M, Sahebkar A, et al. Step-by-step
diagnosis and management of the nocebo/drucebo effect in statin-associated
muscle symptoms patients: a position paper from the International Lipid Expert
Panel (ILEP). J Cachexia Sarcopenia Muscle 2022;13:1596–622. https://doi.org/10.1002/
jcsm.12960
CardioPulse
9. Bytyçi I, Penson PE, Mikhailidis DP, Wong ND, Hernandez AV, Sahebkar A, et al.
Prevalence of statin intolerance: a meta-analysis. Eur Heart J 2022;43:3213–23.
https://doi.org/10.1093/eurheartj/ehac015
10. Banach M, Surma S, Reiner Z, Katsiki N, Penson PE, Fras Z, et al. Personalized manage­
ment of dyslipidemias in patients with diabetes—it is time for a new approach (2022).
Cardiovasc Diabetol 2022;21:263. https://doi.org/10.1186/s12933-022-01684-5
11. Banach M, Surma S, Toth PP. 2023: the year in cardiovascular disease—the year of new
and prospective lipid lowering therapies. Can we render dyslipidemia a rare disease by
2024? Arch Med Sci 2023;19:1602–15. https://doi.org/10.5114/aoms/174743
12. Ray KK, Haq I, Bilitou A, Manu MC, Burden A, Aguiar C, et al. Treatment gaps in the
implementation of LDL cholesterol control among high- and very high-risk patients in
Europe between 2020 and 2021: the multinational observational SANTORINI study.
Lancet Reg Health Eur 2023;29:100624. https://doi.org/10.1016/j.lanepe.2023.100624
13. Rodriguez F, Maron DJ, Knowles JW, Virani SS, Lin S, Heidenreich PA. Association of
statin adherence with mortality in patients with atherosclerotic cardiovascular disease.
JAMA Cardiol 2019;4:206–13. https://doi.org/10.1001/jamacardio.2018.4936
14. Khalaf K, Johnell K, Austin PC, Tyden P, Midlöv P, Perez-Vicente R, et al. Low adherence
Downloaded from https://academic.oup.com/eurheartj/article/45/9/647/7512939 by guest on 02 March 2024
to statin treatment during the 1st year after an acute myocardial infarction is associated
with increased 2nd-year mortality risk-an inverse probability of treatment weighted
study on 54 872 patients. Eur Heart J Cardiovasc Pharmacother 2021;7:141–7. https://
doi.org/10.1093/ehjcvp/pvaa010