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REVIEW ARTICLE
The benefits of statin therapy outweigh their side effects
Copyright (c) 2022 Slovenian Medical Journal. This work is licensed under a
Creative Commons Attribution-NonCommercial 4.0 International License.
The benefits of statin therapy outweigh their side effects
Koristi zdravljenja s statini odtehtajo njihove stranske učinke
Tadeja Sotler,1 Miran Šebeštjen,1,2
Abstract
Statins have been among the most commonly prescribed drugs in more than twenty years. By reducing LDL cholesterol, 
drugs from this group significantly reduce cardiovascular morbidity and mortality. Statins competitively inhibit the active 
site of the first and critical rate-limiting enzyme in the mevalonate pathway, HMG-CoA reductase. In addition to the effects 
on lowering LDL cholesterol, their mechanism of action is also responsible for most of the side effects. However, we do not 
have reliable data for that statement. The most common side effects, which are also the reason for discontinuing statin 
treatment, are related to muscle pain. The exact extent of the muscle adverse effects is not known, as we do not have a 
uniform definition of these side effects. Other side effects include newly onset of type 2 diabetes, hepatotoxicity, haemor-
rhagic stroke, and neurological disorders. Despite all these side effects, the benefits of statin treatment far outweigh these 
side effects. Despite new therapies to lower LDL cholesterol and thus reduce cardiovascular mortality, statin therapy will 
remain the first choice in both primary and secondary prevention for the next few years. The main drawback of the new 
therapies is that we do not have enough data on their long-term efficacy and safety. In any case, we should not neglect the 
economic aspect either, as the cost-effectiveness of statins is much higher compared to new drugs.
Izvleček
Zdravila iz skupine statinov so v zadnjih več kot 20 letih ena najpogosteje predpisovanih zdravil. Poleg znižanja koncen-
tracije holesterola LDL namreč zelo pomembno znižajo srčnožilno obolevnost in umrljivost. Statini kompetitivno zavirajo 
aktivno mesto reduktaze HMG-CoA prvega in ključnega hitrost omejujočega encima v mevalonatni poti. Ta mehanizem 
je poleg zmanjšanja vrednosti holesterola LDL najverjetneje odgovoren tudi za večino stranskih učinkov, čeprav za to ni 
zanesljivih dokazov. Najpogostejši stranski učinki, ki so tudi vzrok za prekinitev zdravljenja, so povezani z mišičnimi bo-
lečinami, čeprav natančne razširjenosti ne poznamo, saj ni enotne definicije teh stranskih učinkov. Drugi stranski učinki 
so še novo nastala sladkorna bolezen tipa 2, hepatotoksičnost, hemoragična možganska kap in nevrološke motnje. Vsem 
tem stranskim učinkom navkljub je korist zdravljenja s statini mnogo večja od navedenih stranskih učinkov. Kljub novim 
terapijam za znižanje holesterola LDL in zato zmanjšani srčnožilni umrljivosti bo terapija s statini še naslednjih nekaj let 
1 Department of Cardiology, University Medical Centre Ljubljana, Ljubljana, Slovenia
2 Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
Correspondence / Korespondenca: Miran Šebeštjen, e: miran.sebestjen@kclj.si
Key words: statins; cholesterol; cardiovascular events; adverse effects; toxicity
Ključne besede: statini; holesterol; srčnožilni dogodki; stranski učinki; toksičnost
Received / Prispelo: 13. 1. 2021 | Accepted / Sprejeto: 18. 1. 2022
Cite as / Citirajte kot: Sotler T, Šebeštjen M. The benefits of statin therapy outweigh their side effects. Zdrav Vestn. 2022;91(7–8):319–31. 
DOI: https://doi.org/10.6016/ZdravVestn.3217
eng slo element
en article-lang
10.6016/ZdravVestn.3217 doi
13.1.2021 date-received
18.1.2022 date-accepted
Cardiovascular system Srce in obtočila discipline
Review article Pregledni znanstveni članek article-type
The benefits of statin therapy outweigh their 
side effects 
Koristi zdravljenja s statini odtehtajo njihove 
stranske učinke article-title
The benefits of statin therapy outweigh their 
side effects 
Koristi zdravljenja s statini odtehtajo njihove 
stranske učinke alt-title
statins, cholesterol, cardiovascular events, 
adverse effects, toxicity
statini, holesterol, srčnožilni dogodki, stranski 
učinki, toksičnost kwd-group
The authors declare that there are no conflicts 
of interest present.
Avtorji so izjavili, da ne obstajajo nobeni 
konkurenčni interesi. conflict
year volume first month last month first page last page
2022 91 7 8 319 331
name surname aff email
Miran Šebeštjen 1,2 miran.sebestjen@kclj.si
name surname aff
Tadeja Sotler 1
eng slo aff-id
Department of Cardiology, 
University Medical Centre 
Ljubljana, Ljubljana, Slovenia
Klinični oddelek za kardiologijo, 
Interne klinike, Univerzitetni 
klinični center Ljubljana, 
Ljubljana, Slovenija
1
Faculty of Medicine, University 
of Ljubljana, Ljubljana, Slovenia
Katedra za interno medicino, 
Medicinska fakulteta, Univerza v 
Ljubljani, Ljubljana, Slovenija
2
Slovenian Medical Journallovenian Medical Journal
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1 Introduction
Statins are one of the most commonly prescribed 
drugs, reducing cardiovascular morbidity and mortal-
ity by lowering LDL cholesterol in both primary and 
secondary prevention (1). Randomized double-blind 
studies have shown that lowering LDL cholesterol by 1 
mmol/L reduces the relative risk of significant cardiovas-
cular events by 22% (2). Despite the widespread use of 
statins to lower LDL cholesterol and thus also to reduce 
cardiovascular morbidity and mortality, discontinuation 
and non-cooperation are very big problems. The reason 
for this is most often statin-induced muscle symptoms. 
Other, significantly fewer common causes are diabetes, 
neurological and neurocognitive effects, and hepato- 
and nephrotoxicity (3). The patient’s attitude towards 
the drug depends mainly on their experience and beliefs. 
Figure 1: Schematic representation of the positive and adverse effects of statins. The numbers shown represent absolute 
values.
Negative beliefs about the drug are an even greater rea-
son for non-cooperation than other factors, such as the 
price of the drug. A study examining the opinions of 
statin users on social networks has shown that patients 
are most often concerned because they do not trust 
drug manufacturers and because they believe statins are 
harmful or that they do more harm than good (4). The 
purpose of this review article is to describe both the pos-
itive and negative sides of statin therapy and the possible 
mechanisms of their action (Figure 1, Table 1).
2 Treatment guidelines
In the latest ESC/EAS guidelines for the management 
of dyslipidaemias from 2019, one of the most important 
ostala prva izbira tako pri primarni kot tudi sekundarni preventivi, saj še ni dovolj podatkov o dolgoročni učinkovitosti in 
predvsem varnosti novih zdravil. Nikakor pa ne smemo zanemariti niti ekonomskega vidika, saj je stroškovna učinkovitost 
statinov v primerjavi z novimi zdravili zaenkrat še mnogo večja.
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The benefits of statin therapy outweigh their side effects
Positive effects Adverse effects
Statin-induced effects:
• reduction of cardiovascular morbidity and mortality;
• improvement of endothelial dysfunction;
• stabilization of atherosclerotic plaques;
• anti-inflammatory effects;
• immunomodulatory effects;
• antithrombotic effects;
• reduction of the risk of dementia;
• beneficial effects on bone metabolism.
Statin-induced effects:
• myalgia;
• toxic myopathy;
• immune-mediated myopathy;
• rhabdomyolysis.
Type 2 diabetes.
Neurological and neurocognitive effects:
• haemorrhagic stroke;
• cognitive decline;
• peripheral neuropathy;
• depression;
• confusion and memory loss;
• aggressiveness;
• personality changes.
Hepatotoxicity.
Nephrotoxicity.
Table 1: Positive and adverse effects of statins.
innovations was a change in therapy goals. Target values 
for lowering LDL cholesterol, which is still the main goal 
of dyslipidaemia management, are even lower, except in 
patients at low cardiovascular risk. The recommended 
reduction in LDL cholesterol level in the group of pa-
tients at very high cardiovascular risk is more than 50% 
or below 1.4 mmol/L, in the high-risk group it is more 
than 50% or below 1.8 mmol/L, and in the moderate-risk 
group the target is less than 2.6 mmol/L. Lower LDL cho-
lesterol target values therefore also mean higher treat-
ment intensity. The guidelines state that statin therapy 
reduces LDL cholesterol by up to 50% and can be used 
in combination with other cholesterol-lowering drugs. 
A 1 mmol/L reduction in LDL cholesterol with statins is 
associated with a 22% reduction in the incidence of sig-
nificant cardiovascular events, a 23% reduction in coro-
nary events, a 17% reduction in coronary death, a 17% 
reduction in stroke incidence, and a 10% reduction in 
all-cause mortality. The beneficial effects are most pro-
nounced in the first year of treatment. The choice of sta-
tin depends on the cardiovascular risk and therapy goals 
of the individual patient, but the response to treatment, 
associated diseases, and the use of other drugs should al-
ways be considered. The guidelines state a strategy for a 
sequential drug introduction (first high-intensity statin 
therapy, then ezetimibe, and finally a PCSK9 inhibitor) 
and mention the possibility of directly adding a PCSK9 
inhibitor to statins. If LDL cholesterol target values are 
not reached at the highest statin dose the patient still tol-
erates, a combination with ezetimibe is recommended. 
Combination with a PCSK9 inhibitor is advised in sec-
ondary prevention in patients at very high cardiovascu-
lar risk who do not reach LDL cholesterol target values 
at the highest statin and ezetimibe doses. The guidelines 
also recommend statins as the first drug of choice to re-
duce cardiovascular risk in patients with hypertriglyce-
ridaemia, but are not effective in some specific patient 
groups, such as patients with heart failure and those with 
haemodialysis (5).
The analysis of 19 studies conducted for the US Food 
and Drug Administration (FDA) included 71,344 pa-
tients treated with various statins in primary and sec-
ondary prevention over a period of six months to six 
years. They found that in a group ranging from eight to 
286 patients, 72 patients needed to be treated to prevent 
any cardiovascular event. To prevent one heart attack 
in groups ranging from 45 to 263 patients, 123 patients 
had to be treated. One study stated that only 11 patients 
needed to be treated to prevent one stroke. However, ex-
cluding this study, others found that the number of pa-
tients needed to be treated to prevent one such event was 
263 patients in groups ranging from 92 to 625 patients. 
All of these studies have shown that diabetes occurred in 
every 99th subject (6).
3 Mechanism of action of statins
The most important effects of statins are lowering 
LDL cholesterol and thus reducing cardiovascular mor-
bidity and mortality. Statins competitively inhibit the ac-
tive site of the first and key rate-limiting enzyme of the 
mevalonate pathway, HMG-CoA reductase. Inhibition 
of this site prevents access to the substrate, thus inhib-
iting the conversion of HMG-CoA to mevalonic acid. 
In the liver, cholesterol synthesis is reduced, which leads 
to increased production of microsomal HMG-CoA 
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reductase and increased expression of LDL receptors on 
the cell surface. This leads to an increased removal of 
LDL from the bloodstream and thus a 20-55% reduction 
in LDL levels in it. In addition to lowering LDL levels 
and reducing cardiovascular morbidity and mortality, 
statins are thought to have additional pleiotropic ef-
fects not related to lipids. These include improving en-
dothelial function, stabilizing atherosclerotic plaques, 
anti-inflammatory, immunomodulatory and antithrom-
botic effects, effects on bone metabolism, and reduced 
risk of dementia. Analysis of some studies has shown 
that statins reduce the risk of cardiovascular events to a 
greater extent than just by lowering LDL cholesterol lev-
els, and that they increase survival even in patients who 
had had a heart attack and who have normal cholesterol 
levels (7). There are therefore lipid-dependent and lip-
id-independent mechanisms that contribute to the clin-
ically beneficial effects of statins. Inhibition of HMG-
CoA reductase also reduces the production of non-sterol 
mevalonate derivatives. The most important non-sterol 
mevalonate derivatives are farnesyl and geranylgeranyl 
pyrophosphate, which play a key role in protein pre-
nylation and in inhibiting the synthesis of isoprenoid 
intermediates in the mevalonate pathway (8). Posttrans-
lational protein prenylation, which modifies proteins 
into more hydrophobic molecules, is important for cell 
signalling, differentiation, growth regulation, and mem-
brane transport. Non-sterol mevalonate derivatives are 
thought to be responsible, among others, for the effect 
of statins on some key reactions in the coagulation and 
fibrinolysis cascade (9).
The active ingredient of statins is a modified portion 
of 3,5-dihydroxyglutaric acid, which is structurally sim-
ilar to the endogenous substrate, HMG-CoA, and the 
mevaldyl-CoA transition state intermediate. The ring 
substituents determine the solubility and pharmacolog-
ical properties of the statin (10,11). Atorvastatin, lovas-
tatin, simvastatin, and fluvastatin are lipophilic and are 
metabolized by the cytochrome P450 system. Pravastatin 
and pitavastatin are hydrophilic and due to this property 
undergo minimal metabolism in the liver. Rosuvastatin 
is somewhere in the middle in terms of these properties 
(12).
4 Statin toxicity
The most common toxic effects are statin-associ-
ated muscle symptoms (SAMS) (13,14). The exact fre-
quency of these side effects is unknown. According to 
the results of cross-sectional studies, muscle symptoms 
occur in 10–15% of patients (15-18), and some clinical 
registries describe as much as 30% incidence of muscle 
symptoms (14,16). In randomized, double-blind, place-
bo-controlled studies, the incidence of these symptoms 
in 1.5–5% of subjects were definitely underestimated, as 
patients with a history of statin intolerance were exclud-
ed from these studies before randomization or during 
the induction period (14,15,19,20). However, it is also 
difficult to determine the exact incidence, as there is no 
single definition for muscle symptoms. Other side ef-
fects of statin therapy include the onset of type 2 dia-
betes, neurological and cognitive effects, hepatotoxicity, 
impaired renal function, and other less common side 
effects (21). 
Statin toxicity is thought to be a result of inhibition 
of the HMG-CoA reductase enzyme, direct cellular and 
subcellular effects, or a combination of both (22). Other 
possible causes include genetic factors, interactions with 
other drugs, vitamin D levels, and other metabolic or im-
mune effects (15). Regardless of the mechanism, the end 
result is a change in the bioavailability and activity of the 
drug (23). The main predisposing factors are age due to 
the likely presence of several other diseases (renal or he-
patic dysfunction), concomitant use of other drugs that 
may affect statin function, decreased body weight, and 
cognitive impairment (17). The only side effects clearly 
demonstrated in randomized double-blind studies were, 
in addition to haemorrhagic stroke, muscle symptoms 
and type 2 diabetes. However, the absolute risk of these 
side effects is small compared to the absolute benefits of 
statin therapy (Table 2).
5 Statin-associated muscle symptoms
Muscle symptoms are by definition muscle pain, 
tension or muscle weakness together with an increase 
in creatinine kinase (CK) concentration to at least ten 
times the upper limit of normal (24). The most severe 
form of muscle damage is rhabdomyolysis, which can 
also lead to acute renal failure or exacerbation of chronic 
renal failure mainly due to increased concentrations of 
myoglobin in the blood (25).
Myopathies are rare in patients without associated 
diseases, although the relative risk of muscle pain is high 
(25). However, the absolute risk is very small, occurring 
in one patient per 10,000 patients treated for one year, 
while the incidence of rhabdomyolysis is two to three 
patients per 100,000 patients treated for one year (26). 
From a clinical point of view, muscle symptoms can be 
divided into four groups: rhabdomyolysis with a high 
concentration of CK (> 100 times the upper limit of 
normal (ULN)), myoglobinuria and renal impairment; 
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The benefits of statin therapy outweigh their side effects
Legend: CI – confidence interval; HPS – Heart Protection Study; JUPITER – Justification for the Use of Statins in Primary 
Prevention: an Intervention Trial Evaluating Rosuvastatin trial; CHD – coronary heart disease; MI – myocardial infarction; 
PAD – peripheral artery disease; PROSPER – Prospective Study of Pravastatin in the Elderly at Risk; SEARCH – Study of the 
Effectiveness of Additional Reductions in Cholesterol and Homocysteine; SPARCL – Stroke Prevention by Aggressive Reduction 
in Cholesterol Levels; CD – cardiovascular disease; TIA – transient ischaemic attack.
Study
(reference)
Subjects 
(age)
Intervention Impact on 
cardiovascular 
events (ratio of 
prospects (95% 
CI))
Muscle 
symptoms
(% of 
patients)
Diabetes Neurological side 
effects
SEARCH
(25)
12,064 
survivors of MI 
(ages 18–80)
80 mg 
simvastatin 
daily versus 20 
mg simvastatin 
daily
Coronary events
(0.94 (0.88–1.01))
stroke
(0.85 (0.60–1.21))
myopathy 53 
(1%) versus 
two (0.03%)
not studied haemorrhagic 
stroke (odds ratio 
(0.91 CI (0.77–1.09))
HPS
(26)
20,536 patients 
with CHD, PAD 
or diabetes 
(ages 40–80)
40 mg 
simvastatin 
daily versus 
placebo 
Coronary events
(0.73 (0.76–0.97))
stroke
(0.75 (0.66–0.85))
myalgia 32.9% 
versus 33.2%
not studied haemorrhagic 
stroke 51 (0.5%) 
versus 53 (0.5%)
JUPITER
(33)
17,802 healthy 
subjects
20 mg 
rosuvastatin 
daily versus 
placebo
MI (0.46 (0.30–
0.70))
stroke
(0.52 (0.34–0.97))
total mortality
(0.80 (0.67–0.97))
muscle 
weakness 
or pain 1421 
(16%) versus 
1375 (15.4%)
newly 
discovered 
270 (3%) 
versus 216 
(2.4%)
not studied
SPARCL
(56)
4,731 patients 
who had had a 
stroke or TIA
80 mg 
atorvastatin 
daily versus 
placebo
Stroke
(0.97 (0.66–0.95))
significant 
coronary event 81 
(3.4%) versus 120 
(5.1%)
myalgia 129 
(5.5%) versus 
141 (6.0%) 
myopathy 
0.3% in both 
groups
not studied haemorrhagic 
stroke 55 (2.3%) 
versus 33 (1.4%)
PROSPER
(57,58,59)
5,804 patients 
with a history 
of CD or risk 
factors (70–82 
years)
40 mg 
pravastatin 
daily versus 
placebo
death due to CHD 
and MI
(0.81 (0.96–0.94))
stroke
(0.96 (0.79–1.16))
myalgia 36 
(1.2%) versus 
32 (1.1%)
not studied no differences 
between the groups
Table 2: Overview of the most important research on the effect of statins on cardiovascular events and the most common 
side effects.
myalgia or mild increase in CK (< five-fold ULN); 
self-limiting toxic statin myopathy (CK values between 
10 and 100 ULN); myositis or immune-mediated necro-
tising myopathy with HMG-CoA reductase antibodies 
and CK values between 10 and 100 times ULN (27).
Regardless of the definition, muscle symptoms usu-
ally manifest as symmetrical weakness of large proximal 
muscles primarily of the lower limbs. Symptoms occur 
at rest or shortly after physical activity and usually occur 
within one month after starting treatment or after in-
creasing the dose (15,22). Phenotypically, seven progres-
sively inferior, statin-associated myotoxic phenotypes 
were proposed. They begin with asymptomatic CK el-
evation and include tolerable and intolerable myalgia, 
myopathy, severe myopathy, rhabdomyolysis, and im-
mune-mediated necrotizing myositis (28).
Due to the ability to nonselectively diffuse into the ex-
trahepatic tissues such as skeletal muscle, muscle symp-
toms are more common in lipophilic statins such as sim-
vastatin, atorvastatin, and lovastatin (15,21). In contrast, 
hydrophilic statins, which are represented by pravastatin 
and fluvastatin, have a lower ability to penetrate mus-
cles and therefore a lower risk of muscle symptoms (15). 
Up to 60% of muscle symptoms are associated with the 
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concomitant use of statins with drugs metabolized by 
the same hepatic cytochrome P450 (22). Some believe 
that the greatest risk for muscle symptoms is previous 
myopathy with another statin, treatment with high-dose 
statins, a history of unexplained seizures or elevated CK 
values in personal history, a family history of muscle 
symptoms with lipid-lowering therapy, and untreated 
hypothyroidism (29). Other risk factors include female 
gender, age over 80, impaired liver or kidney function, 
alcoholism, consumption of grapefruit juice, vitamin D 
deficiency, low body mass index, and excessive physical 
activity.
The SEARCH study (30) reported more than 10 
times more myopathies in patients treated with 80 mg 
simvastatin daily than those treated with 20 mg daily, 
and the Heart Protection Study (HPS) reported one case 
per 1,000 or 10,000 patients treated with 40 mg daily for 
one year (31). Therefore, prescribing the highest doses in 
all patients is no longer recommended. Regulatory data-
bases also contain a large number of reports of muscle 
symptoms at high doses of atorvastatin, but these data 
are very biased and the absolute risk of muscle symp-
toms even at the highest dose is actually very low (32).
In the HPS study comparing 40 mg simvastatin dai-
ly with placebo, there was a relative risk for any form 
of myalgia of 0.99 (95% confidence interval, 0.95–1.03) 
regardless of creatinine kinase, while the relative risk of 
myalgia in patients with creatine kinase levels was more 
than four times the upper limit of normal, 1.7 (95% con-
fidence interval, 0.9–3.1). In patients whose creatinine 
kinase levels were increased more than 10-fold above the 
upper limit of normal, the relative risk was 2.5 (95% con-
fidence interval, 0.8-8.0) (31).
Vitamin D deficiency has been independently associ-
ated with muscle weakness and severe myopathy. There 
is a hypothesis that vitamin D deficiency may exacerbate 
statin-induced myopathy. In vitamin D deficiency, CY-
P3A4 is directed to the hydroxylation pathway of vitamin 
D, which reduces the amount of this metabolite available 
for statin metabolism, which could increase statin tox-
icity. Ahmed et al. investigated the association between 
low vitamin D levels and myalgia in patients receiving 
statins and the regulation of myalgia with vitamin D re-
placement while patients continued to receive statins. 
Patients with vitamin D deficiency were treated with 
50,000 units of ergocalciferol per week for 12 weeks. Pa-
tients with myalgia receiving statins were found to have 
lower serum vitamin D levels than patients without my-
algia receiving statins. Vitamin D replacement improved 
muscle symptoms in 92% of patients who were receiv-
ing statins and had myalgia and concomitant vitamin D 
deficiency (33).
Calcium plays a key role in the contraction and relax-
ation of skeletal muscle, so it is one of the important fac-
tors in the formation of SAMS, which includes muscle 
spasms and cramps. The main pump that allows calcium 
to be re-absorbed into the sarcoplasmic reticulum is the 
sarco-endoplasmic reticulum calcium ATPase (SERCA). 
When SERCA activity was observed in statin users, ac-
tivity was found to be 30% higher in asymptomatic statin 
users than in subjects not receiving statin; however, there 
was no difference between statin users with or without 
symptoms (34). Increased SERCA activity may impair 
calcium homeostasis and does not occur as a compen-
satory mechanism, and its content in skeletal muscle has 
been shown to decrease after five weeks of endurance 
training. Therefore, if increased SERCA activity contrib-
utes to impaired calcium homeostasis, as shown in statin 
users, physical activity could benefit such patients (35).
Coenzyme Q10 (CoQ10) is a fat-soluble vitamin-like 
substance that, when reduced to ubiquinol, protects cells 
against free radical-induced oxidative stress and is in-
volved in the electron transport in the respiratory chain. 
Several studies have found that plasma concentrations 
of coenzyme Q10 are reduced in statin users. Coenzyme 
Q10 replacement has therefore been suggested for the 
treatment of SAMS. However, studies have shown that 
despite the effective increase in serum concentrations 
of coenzyme Q10, SAMS occurred as often when coen-
zyme Q10 was replaced as when it was not. Here, too, the 
occurrence of SAMS has been shown to be multifactori-
al and unlikely to be related solely to the effect of statins 
on coenzyme Q10 (36,37).
6 Statins and diabetes
The incidence of new-onset type 2 diabetes with sta-
tin therapy is higher in patients with pre-existing risk 
factors such as increased body mass index, higher levels 
of glycated haemoglobin and impaired glucose tolerance. 
No differences have been observed between hydrophilic 
and lipophilic statins, but it appears to be more common 
in elderly patients and those taking high doses of statins 
(15). The exact mechanisms by which statins trigger 
type 2 diabetes are unknown, but there may be direct 
and indirect effects, including effects on body weight, 
adipocyte differentiation, blood glucose homeostasis via 
gluconeogenesis and insulin signalling pathway, changes 
in concentration and activity of adiponectin and leptin 
as well as with impaired β-cell function (17,38-40). In 
understanding the effect of statins on the development 
of diabetes, it would be helpful to know whether the risk 
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The benefits of statin therapy outweigh their side effects
of developing diabetes during statin therapy is related 
to the specific action of statins, that is, the inhibition of 
HMG-CoA reductase, or due to other statin effects.
In 18 studies involving 12,725 patients, they found 
an average LDL cholesterol reduction of 0.89 mmol/L, 
while the risk of developing diabetes increased by 10% 
compared to the control group. These studies included 
all statins currently on the market, except rosuvastatin. It 
has been calculated that the risk of developing statin-in-
duced diabetes was 0.1% per year, and that the reduction 
in cardiovascular events was 0.42% per year (41).
Despite the increased risk of developing diabetes 
with statin therapy, the benefit of reducing significant 
coronary events outweighs the potential side effects. In 
the JUPITER study (Justification for the Use of Statins 
in Primary Prevention: An Intervention Trial Evaluat-
ing Rosuvastatin trial), which included 17,802 patients 
without known cardiovascular disease, glycated haemo-
globin was slightly higher than placebo after two years of 
use in the group receiving rosuvastatin (5.9 versus 5.8), 
which was statistically significant (42,43). There was also 
a quarter more newly diagnosed diabetes, which was al-
so statistically significant (3.0% vs. 2.4%). Meta-analyses 
have shown that a standard dose of a statin increases the 
risk of developing type 2 diabetes by 10%, and higher 
doses, including rosuvastatin 20 mg used in the JUPI-
TER study, by a further 10% (44,45). Type 2 diabetes 
usually occurs soon after starting statin therapy, and the 
risk does not increase with continued treatment. Diabe-
tes usually occurs in patients with already expressed risk 
factors such as increased body mass index, increased 
levels of glycated haemoglobin, or impaired glucose tol-
erance (42,46,47).
A retrospective study of 12,725 patients with type 2 
diabetes compared for 3 years the HbA1c levels at six-
month intervals between patients who had been treated 
with statin in the past and patients who did not receive 
statins but were starting insulin therapy. In the first six 
months, patients who had received statins in the past 
had a 0.26% decrease in HbA1c, and the decrease was 
0.34% in patients who were not receiving statins. A sim-
ilar and statistically significant change between HbA1c 
values was seen even after 12 months. There was a de-
crease of 0.29% in patients who had received statins in 
the past and a decrease of 0.37% in patients who were 
not receiving statins. Patients who had received statins 
in the past had higher HbA1c levels after three years. A 
conclusion was made that patients with type 2 diabetes 
treated with insulin who had received statins in the past 
experienced a decrease in insulin sensitivity, making in-
sulin treatment less effective in lowering HbA1c (48).
The clinical significance of the increase in the inci-
dence of type 2 diabetes with statin therapy is not entire-
ly clear, as the reduction in cardiovascular morbidity and 
mortality significantly exceeds the increase in morbidity 
and mortality associated with diabetes. The incidence 
of new-onset diabetes in primary prevention is around 
1% per year (44), which is around 10–20 new diabetics 
per 10,000 statin-taking patients per year. If the assump-
tion, that this is associated with a doubling of the risk 
of cardiovascular disease is made (same as in the case 
of spontaneous diabetes) (49), then 10,000 patients in 
primary prevention with a 5 to 10% risk in five years of 
treatment would have five to ten cardiovascular events. 
Despite this side effect, lowering LDL cholesterol by 1 to 
2 mmol/L in the same patient population prevents 150 
to 300 identical events, despite the potentially detrimen-
tal effect of new-onset diabetes (50-52).
7 Hepatotoxicity
Statin therapy may result in a mild increase in trans-
aminases, which rarely presents a clinically significant 
hepatic impairment. Elevations in transaminases occur 
in approximately 3% of patients, usually within the first 
year of initiation of therapy, and resolve spontaneously 
despite continued statin use (53-55). Hepatotoxicity is 
most likely a feature of all statins and is associated with 
an increase in their dose (56,57).
An increase in transaminases alone, but without an 
increase in bilirubin, is not unequivocally associated 
with clinically or pathologically significant hepatocyte 
damage (58). An even bigger problem is the fact that 
there is no uniform definition of drug-induced liver in-
jury (DILI).
The exact mechanism of action of DILI is unknown, 
but in vitro models have shown dose- and time-depen-
dent mitochondrial dysfunction due to statins. In mito-
chondria, there is thought to be a significant increase in 
mitochondrial superoxide, which is one of the important 
cytotoxic and signalling mediators in mitochondrial or 
hepatic injury. Another important reason for statin-in-
duced hepatotoxicity is that statins cause apoptosis. 
Cerivastatin was withdrawn from the market in 2001 due 
to DILI. Other possible mechanisms of hepatotoxicity 
are inhibition of respiratory chain enzymes, mitochon-
drial membrane depolarization, and release of calcium 
ions (59). The incidence of statin-induced liver injury 
is higher when using statins at maximum doses with 
other lipid-lowering drugs such as fibrates, other hep-
atotoxic drugs, or drugs with similar enzyme pathways, 
or when used in the elderly and people with significant 
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liver or kidney injury (59). Drug-induced liver injury is 
relatively rare, with elevated levels of biomarkers of liver 
injury such as alanine aminotransferase (ALT), aspartate 
aminotransferase (AST), gamma-glutamyl transferase 
(GGT), total serum bilirubin, and alkaline phosphatase 
(ALP) being observed (38). Therefore, active monitor-
ing of liver tests in asymptomatic patients is not recom-
mended in this context. Elevated liver enzymes can be 
misleading given the actual extent of liver injury. Despite 
elevated liver enzymes, hepatic adverse reactions are ra-
re. Action is required when symptoms of hepatotoxicity 
such as fatigue, weakness, loss of appetite, yellowing of 
the skin or eyes, and dark urine occur (60). A meta-anal-
ysis of 135 randomized controlled trials of 246,000 pa-
tients receiving atorvastatin, lovastatin, and simvastatin 
showed that 50% of patients were at increased risk for el-
evated transaminases compared with placebo. However, 
there was only a slight increase in values, which did not 
necessarily mean serious adverse reactions for the liver 
and usually stabilized over time (61). Statin-induced liv-
er abnormalities have therefore not been demonstrated 
and are equally common in statin-treated patients and 
placebo-treated patients. Monitoring of liver enzymes is 
required when liver dysfunction is present or statins are 
combined with other hepatotoxic drugs. It is important 
not to reduce or discontinue statin therapy if liver test 
values remain below three times the upper limit of nor-
mal (62).
8 Neurological disorders
The most important and most common neurologi-
cal disorder is intracerebral haemorrhage. Other neu-
rological disorders for which we have somewhat less 
data are cognitive decline, peripheral neuropathy, de-
pression, confusion, and memory loss, aggression, and 
personality changes (21). In observational studies, cho-
lesterol levels were negatively associated with haemor-
rhagic stroke, especially in patients with elevated arterial 
blood pressure (63-65). In a randomized, double-blind 
SPARCL study of 4,731 patients who recovered from 
cerebrovascular disease, atorvastatin 80 mg statistically 
significantly reduced ischaemic cerebrovascular events 
by 21%, but also resulted in a significant increase in hae-
morrhagic events by 40% (66). When these results are 
combined with other results from other studies from the 
CTT meta-analysis (1), the risk of a haemorrhagic car-
diovascular event increases by 21% when LDL choles-
terol is reduced by 1 mmol/L. However, the reduction in 
the risk of all cerebrovascular events with statin therapy 
is greater than the risk of haemorrhagic stroke (52,66). 
Ribe et al. conducted the largest study to date on the 
association between statin use and the risk of cerebral 
haemorrhage in patients who have already had a stroke. 
More than 55,000 patients were included who started 
statin therapy after their first intracerebral haemorrhage 
or ischaemic stroke. They found that the risk of cerebral 
haemorrhage was similar in patients treated with statins 
and in those who did not receive statins, regardless of 
the type of stroke. However, in the subgroup of patients 
who have previously suffered an ischaemic stroke, the 
risk is even lower. It was also found that many patients 
receiving statins start treatment with other drugs after a 
stroke, which could have a significant effect on the risk 
of stroke (67).
Regarding the risk of haemorrhagic transformation, 
a retrospective study was performed comparing patients 
previously treated with statins, patients who started sta-
tin therapy within 3 days after ischaemic stroke, and 
with patients who were not receiving statins. They found 
that statin therapy was not associated with early haem-
orrhagic complications and that statin therapy had not 
previously affected the treatment of ischaemic stroke 
with thrombolysis. Early introduction of statins after 
ischaemic stroke is also not associated with an increased 
risk of intracerebral haemorrhage (68).
The role of statins in the development of peripheral 
neuropathy has not yet been clearly demonstrated, and 
changes in the integrity of cell membranes of neurons, 
whose important building block is cholesterol, have been 
described as a possible mechanism. Statins could also af-
fect energy use in neurons by inhibiting coenzyme Q10 
(69). According to studies conducted so far, treatment 
with statins could cause changes in peripheral nerves. 
But in most cases, these changes do not cause clinically 
significant symptoms (70).
Cognitive functions during statin therapy were close-
ly monitored in the PROSPER study, which included 
5,804 patients aged 72 to 80 years (71-73). Cognitive 
function was found to be unaffected by treatment with 
40 mg pravastatin. Potential memory impairment was 
closely monitored in the Heart Protection Study (HPS), 
which followed 20,536 patients taking 40 mg simvastatin 
daily or placebo for 5 years. It turned out that there were 
no differences between the groups (31).
It is not entirely clear whether these disorders are 
caused by the direct action of statins, as the blood-brain 
barrier selectively permeates so that the brain is self-reli-
ant in endogenous cholesterol synthesis (38). Lipophilic 
statins are thought to pose a higher risk due to a greater 
chance of permeating the blood-brain barrier, but these 
effects are not necessarily specific for statins, but may 
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REVIEW ARTICLE
The benefits of statin therapy outweigh their side effects
be due to low cholesterol (10). Lower serum lipid levels 
could adversely affect the formation of cell membranes 
of neurons, myelin sheaths, and nerve synapses. When 
less cholesterol is available for neurons, this can contrib-
ute to a decrease in serotonin activity through decreased 
receptor expression, which can result in behavioural 
changes and psychiatric adverse effects (72).
9 Other statin-related side effects
Other statin-related side effects include: cataracts, 
gastrointestinal disorders, urogenital disorders, gynae-
comastia, and reproductive disorders. Most are thought 
to result from reduced formation of intermediates and 
end products of the mevalonate pathway. Thyroid diseas-
es that are not thought to be statin-related may contrib-
ute to statin intolerance, especially in muscle symptoms 
(17). Meta-analyses have not shown significant effects of 
statins or lower cholesterol levels using statin on cataract 
development or prevention. In vitro studies have shown 
that atorvastatin promotes phagocytosis and reduces 
inflammation in the retinal pigment epithelium, which 
may protect against age-related macular degeneration 
(74). Statins could be associated with lowering androgen 
as they inhibit the formation of the substrate required 
for local synthesis. One study found an increased risk of 
gynaecomastia during statin therapy (75).
10 Timing of statin administration
Due to the different half-lives of statins, especially 
those with a short half-life, the effect is highly depen-
dent on the time of ingestion. Cholesterol biosynthe-
sis changes during the day, peaking between midnight 
and five o’clock in the morning, so the action of statins 
during this time can greatly affect the patient’s lipid pro-
file. Statins with a short half-life, such as simvastatin, 
pravastatin, lovastatin, and fluvastatin, should be taken 
by patients in the evening for best results. Statins with 
longer half-lives, such as atorvastatin and rosuvastatin 
are not affected by the timing of administration (76,77). 
However, there are no data on whether the time of inges-
tion and concomitant consumption of food affects the 
occurrence and severity of side effects.
11 Drug interactions
Interactions between different drugs occur when 
previous or concomitant administration of one drug 
changes the pharmacokinetics or pharmacodynamics 
of the other drug and therefore the effects of the drugs 
are different than would be expected from each indi-
vidual drug. This may lead to a change in the effective-
ness or toxicity of one or both drugs. Their effect may 
be additive, synergistic, or antagonistic, and there may 
be changes in the absorption, distribution, metabolism, 
or excretion of the drug. The most clinically important 
drug interactions are pharmacokinetic and are often due 
to the induction or inhibition of enzymes and transport-
ers involved in drug metabolism. Most statins undergo 
microsomal metabolism by the CYP450 isoenzymes and 
are recognized by transporters in the liver, intestine, and 
kidney (78). Some genetic variants may contribute to 
statin toxicity by mutations in genes with the transcrip-
tion for proteins that regulate pharmacokinetics (recep-
tors, transporters and enzymes) and pharmacodynam-
ics of statins (muscle enzymes) (17). Genetic variants in 
CYP450 enzyme activity may affect statin interactions 
with other drugs, while genetic variants in membrane 
transporters may affect hepatic uptake, circulating con-
centration, and peripheral tissue exposure (38).
The most common drugs that may interact with 
statins are glucocorticoids, antipsychotics, HIV prote-
ase inhibitors, azoles, immunosuppressants, macrolides, 
calcium channel blockers, and drugs that affect lipids 
such as gemfibrozil. Additional reactions can also be 
caused by alcohol, opioids, and cocaine (22).
12 Statins and grapefruit juice
Since the incidental discovery of interactions of 
grapefruit juice with certain drugs in 1989, interac-
tions with about 85 drugs, including statins, have been 
identified. The main compounds in grapefruit juice that 
cause statin interactions are furanocoumarin bergamot-
tin and its derivative 6’,7’-dihydroxybergamottin. The 
compounds inactivate CYP3A4, a key enzyme in the 
metabolism of some statins. Studies have shown that 
the concentration of this enzyme in the gastrointestinal 
tract is reduced by 50% within four hours after drinking 
grapefruit juice. Inactivation of CYP3A4 in the gastro-
intestinal tract affects presystemic metabolism of statins 
and thus increases their systemic availability. This effect 
occurs only with statins metabolized by CYP3A4, name-
ly lovastatin, simvastatin, and atorvastatin. Fluvastatin, 
rosuvastatin, and pravastatin are unaffected as they are 
metabolized by other enzymes. The effect of grapefruit 
juice on statins drops to 10% of the maximum value 24 
hours after drinking it, which means that the half-life 
of the effect of grapefruit juice is seven to eight hours. 
For statins with relatively short half-lives, such as sim-
vastatin and lovastatin, drinking grapefruit juice in the 
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evening when patients also take statin means half the ef-
fect of drinking juice in the morning (79).
13 »Nocebo« effect
The placebo effect is the beneficial effect on health 
that results from positive expectations during treatment. 
In contrast, the nocebo effect is the detrimental effect 
on health resulting from negative expectations during 
treatment. The effects of nocebo and placebo on statin 
therapy were investigated in three randomized studies: 
ASCOT, ODYSSEY ALTERNATIVE, and GAUSS-3. 
The results have demonstrated the effect of nocebo in 
the placebo groups and have shown that about 20% of 
patients receiving atorvastatin were in fact intolerant of 
it (80).
In two large studies, the development of SAMS was 
observed in patients with statin intolerance. Patients 
were divided into two groups, one receiving PCSK9 
inhibitors and the other ezetimibe. The mechanism of 
action of both drugs is different from the mechanism 
of action of statins, so apart from the nocebo effect, no 
other explanation has been found for the occurrence of 
this side effect (81,82).
After discontinuation of statin therapy until symp-
toms have resolved, the time of resuming treatment is 
crucial for the long-term reduction of the risk of ath-
erosclerotic cardiovascular disease. More than 70% of 
patients who discontinued treatment due to adverse re-
actions are expected to reattempt statin therapy. Such 
patients are offered the option of re-initiating treatment 
with the same statin dose, possibly at less frequent in-
tervals (e.g. every other day), at a lower dose, or with a 
different statin. If symptoms persist for more than two 
months after discontinuing statin therapy, other causes 
should be assessed (hypothyroidism, rheumatic diseas-
es, etc.) (80).
14 Conclusion
The true prevalence of statin intolerance is still not 
fully understood, but discontinuation of treatment and 
non-cooperation are a major clinical problem. There are 
many mechanisms to explain statin toxicity and intoler-
ance, and a major obstacle to detecting these patients is 
the lack of a clear definition and, above all, a biochem-
ical marker to identify or even predict which patients 
will develop intolerance or toxicity. However, the vast 
majority of statin side effects cannot be attributed to just 
one factor, but to the intertwining of the various mech-
anisms previously described. Given the relatively high 
effect on reducing cardiovascular morbidity and mor-
tality and the very low absolute risk of side effects, as 
well as their cost-effectiveness, statins are likely to be 
the first drug of choice for the treatment of dyslipidae-
mia for at least some time. However, further research is 
needed to find one or more biochemical markers to help 
us identify patients more likely to have side effects. On 
the other hand, of course, we need alternative solutions 
that will enable the treatment of patients with proven 
adverse effects, which are, nevertheless, rare. Despite 
the fact that there are drugs that reduce the effect of PC-
SK9 with antibodies and its synthesis, statins in patients 
with elevated LDL cholesterol in both primary and sec-
ondary prevention are likely to remain the first choice 
for some time. There is still insufficient data on the long-
term efficacy and safety of new drugs.
Conflict of interest
None declared.
Acknowledgment
We, the authors, would like to thank Katja Bizilj, 
Bachelor’s degree in Slovene language and literature 
and dr. Christopher Berrie for the language review. The 
image was prepared with the MindtheGraph software 
(https://mindthegraph.com/).
List of Abbreviations
ALP = alkaline phosphatase
ALT = alanine aminotransferase
ASCOT = Anglo-Scandinavian Cardiac Outcomes Trial
AST = aspartate aminotransferase
CK = creatine kinase
CTT = Cholesterol Treatment Trialists
CYP3A4 = cytochrome P450 3A4
CYP450 = cytochrome P450
DILI = drug induced liver injury
EAS = European Atherosclerosis Society
ESC = European Society of Cardiology
FDA = Food and Drug Administration
GAUSS-3 = Goal Achievement After Utilizing an An-
ti-PCSK9 Antibody in Statin Intolerant Subjects 3
GGT = gamma-glutamyl transferase
HIV = human immunodeficiency virus
HMG-CoA = hydroxymethylglutaryl-coenzyme A
HPS = Heart Protection Study
IDL = intermediate-density lipoprotein
JUPITER = Justification for the Use of Statins in Primary 
Prevention: An Intervention Trial Evaluating Rosuvasta-
tin trial
LDL = low-density lipoprotein
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The benefits of statin therapy outweigh their side effects
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