Review Article

Risk and Benets of Statins in Glucose Control

Management of Type II Diabetes
Anthony Paulo Sunjaya1 Angela Felicia Sunjaya1 Samuel Halim, Sp.PD2 Frans Ferdinal, MSc3

1 Faculty of Medicine, Tarumanagara University, Jakarta, Indonesia
2 Department of Internal Medicine, Faculty of Medicine, Tarumanagara
University, Jakarta, Indonesia
3 Department of Biochemistry, Faculty of Medicine, Tarumanagara
University, Jakarta, Indonesia
Address for correspondence Anthony Paulo Sunjaya, Faculty of
Medicine, Tarumanagara University, Building J, Campus 1
Tarumanagara University, Jl. Letjen S. Parman No. 1, West Jakarta
11440, DKI Jakarta, Indonesia (e-mail: anthonysjy@yahoo.com).

Int J Angiol

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Abstract Worldwide statins are considered to be the rst-line pharmacological treatment for
dyslipidemia and reducing the risk of coronary heart disease. However, recently various
studies have shown its adverse effect on glucose control among diabetic patients and
the U.S. Food and Drug Administration have revised statin drug labels to include
information that increases in fasting serum glucose and glycated hemoglobin levels
have been reported. This systematic review objective is to evaluate the risks and benets
of statins in glucose control management of type 2 diabetes patients based on the 44
published journal articles included and obtained through MEDLINE full text, PubMed,
Keywords Science Direct, Pro Quest, SAGE, Taylor and Francis Online, Google Scholar, High Wire,
statins and Elsevier Clinical Key. Statins were found to affect glucose control through several
glucose control ways, namely, by affecting insulin production and secretion by -pancreatic cells, insulin
diabetes resistance, insulin uptake by the muscles and adipocytes and production of adipokines.
hypercholesterolemia Current evidence available shows that most of the statins give unfavorable side effects
insulin secretion with regards to glucose control among diabetic patients. A dose-dependent and time-
insulin sensitivity dependent effect was also observed in some statins which may be present among other
insulin resistance statins as well.

3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reduc-
tase inhibitors or better known as statins are a class of
medications widely known for decreasing low-density lipo-
protein cholesterol (LDL-C) and reducing the risk for coronary
heart disease and are considered the rst-line pharmacologi-
cal treatment and have become the cornerstone for the
management of dyslipidemia today.1,2 A total of 96.4% of
Europes and 96.1% of Americas population, 6.6% of them
diabetic, are currently eligible for statins following the 2013
American College of Cardiology/American Heart Association
(ACC/AHA) cholesterol guidelines lowered threshold rate of
atherosclerotic cardiovascular disease 10-year risk (7.5%)
required to start statin therapy.3,4 They are considered to
be the number one prescribed class of drugs and ranks third in
terms of sales worldwide. In 2013, the Centre for Disease
Control and Prevention reported that 32 million people in
total or approximately one out of four are consuming statins
in the United States.5
There are currently seven types of statins available in the
market: atorvastatin, uvastatin, lovastatin, pitavastatin,
pravastatin, rosuvastatin, and simvastatin. All statins are
cholesterol-lowering agents with the primary effect of reduc-
ing cardiovascular risks.6 However, adverse effects such as
myopathy, rhabdomyolysis, increased activity shown by liver
tests, acute renal failure, and incidence of type 2 diabetes
mellitus have been reported.7
Furthermore, the U.S. Food and Drug Administration
recently revised statin drug labels to include information
that increases in fasting serum glucose and glycated hemo-
globin levels have been reported with the use of statins which
was supported by a recent study showing that statin use is
associated with increased glycated hemoglobin (HbA1c)

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Risks and Benefits of Statins Sunjaya et al.
levels.8,9 This review aims to determine whether statins incur
a cost or a benet to glucose control.
Materials and Methods
Participants
Studies that had patients diagnosed with type 2 diabetes
mellitus and using statins were included. Ideally, diabetes in
the studies should be dened following guidelines provided
either by the International Diabetic Federation, American
Diabetes Association, or PERKENI (Perkumpulan Endokrino-
logi Indonesia).
Data Source
The databases searched to obtain the articles included MED-
LINE full text, PubMed, Science Direct, Pro Quest, SAGE, Taylor
and Francis Online, Google Scholar, High Wire, and Elsevier
Clinical Key. The search strategies used included availability
of full text written in English from January 1, 2000 to till date.
Keywords used were glucose control or synonyms OR
diabetes or synonyms AND statins. When multiple articles
for a single study was found, the most recent publication was
used. Relevance of studies was assessed by using an approach
based on title, abstract, and full text.
Study Selection
Studies were included if they were original studies and if they
have a randomized controlled trial (RCT) and cohort study
design. In addition, studies were included if (1) they were
done on patients or animals with continuous statin treatment
of any dose, (2) parameters related to glucose control were
reported, (3) studies compare patients/animals treated with
statins versus placebo, or (4) studies comparing patients/
animals treated with one type of statin versus another type
with placebo as control. The rest were excluded from this
review.
Results
Our initial search resulted in 5,069 articles found, of which
4,968 were excluded on the basis of title and abstract. Of the
remaining 101, 57 were excluded because they did not meet
the inclusion criteria or were duplicated publications. Finally,
44 articles were found that fullled all of our inclusion
criteria, 7 of which were experimental studies and the
remaining 37 were clinical studies.
Sample sizes vary in between studies ranging from 10 to
6,770 with a follow-up duration in between 4 weeks10 and
5 years.11 Majority of them were RCTs with two cohort
studies9,12 included. A total of 27,966 subjects were found
in the clinical studies.
The animal studies included had a sample size ranging
from 6 to 60 with a follow-up time between 3 and
52 weeks.1315 A total of 138 subjects were found in the
animal studies.
The outcomes of interest were changes in blood glucose
and HbA1c level, reported impacts on diabetes either improv-
ing, worsening or no change, the adverse effects reported,
International Journal of Angiology
diabetes complications and overall effect on mortality as well
as morbidity of participants. The majority of studies were
published from 2010 onwards and conducted in Western
Countries and Japan with one from Taiwan16 and one from
India.13
It must be noted that the studies included were based on
published reports and take into account that studies report-
ing positive effects are more readily accepted to be published
as compared with studies reporting negative effects.
Discussion
It is widely known that insulin resistance in muscle as well as
liver and -cell failure represent the core pathophysiologic
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defects in type 2 diabetes (triumvirate). However, other mech-
anisms have been identied as metabolic defects present in type
2 diabetes representing various roles in the development of
glucose intolerance in type 2 diabetic individuals. Together,
these eight players consisting of the fat cell (accelerated lipolysis),
gastrointestinal tract (incretin deciency/resistance), -cell
(hyperglucagonemia), kidney (increased glucose reabsorption),
brain (insulin resistance) in addition to the triumvirate comprise
to form the ominous octet.17
An ongoing discussion has opened up on whether statins
exert any inuence on glucose metabolism and the patho-
physiology of type 2 diabetes (ominous octet).17 On this part,
numerous health institutions have created clinical guidelines
on statin use for patients suffering from type 2 diabetes which
are still used today. In Indonesia, PERKENI 2011 clinical
guidelines recommend diabetic patients over the age of
40 years the use of statin therapy to reduce levels of LDL-C
as much as 30 to 40% of its initial measurement. Patients of
less than 40 years of age with acute coronary syndrome or in
higher risks of cardiovascular disease which cannot be
improved by lifestyle changes are also included in this
category provided an observation of the risks of side effects
are done.18
In 2015, the American Diabetes Association revised its
guidelines in statin use for diabetic patients to align with the
ACC/AHA 2013 guidelines resulting in patients over the age of
40 and beyond, regardless of whether CVD risks or overt CVD
are present will be required to take moderate-to-high statin
therapy in addition to lifestyle therapy.19
Potential Mechanisms of Action
Effect of Statins on Insulin Production and Secretion by -
Pancreatic Cells
Statins are responsible for the inhibition of de novo synthesis
of cholesterol, which caused the LDL-C receptors present in
the pancreatic cells to increase their uptake of LDL-C which
resulted in the increased production of plasma-derived LDL-C
which held several key differences as compared with de novo
synthesized cholesterol. The oxidation of plasma-derived
LDL-C is known to induce the intracellular response system
of the body, leading to inammatory consequences which can
lead to impaired insulin secretion. In this case, statins instead
provide a benecial effect by improving insulin resistance

through their anti-inammatory effects. It is believed that the
usage of statins increase the amounts of nitric oxides in an
effort to improve endothelial function which in turn activates
calpain (a calcium-dependent protease) leading to cellular
apoptosis.20,21
The mevalonate pathway or HMG-CoA reductase pathway
is an important cellular metabolic pathway which plays a key
role in synthesizing sterol isoprenoids, such as cholesterol
and nonsterol isoprenoids.22 Statins are able to reduce gly-
cemic control as they block the production of several metab-
olites usually produced during cholesterol synthesis in the
mevalonate pathway, such as isoprenoids, geranylgeranyl
pyrophosphate (GGPP), farnesyl pyrophosphate (FPP), and
ubiquinone (coenzyme Q10, CoQ10) which are determining
factors in glucose uptake as well as insulin levels.23,24
Statins also block other products formed in the process of
the biosynthetic pathway of cholesterol with the greater
impact falling upon dolichol, FPP, GGPP, and CoQ10 (ubiqui-
none). Dolichol is a cofactor necessary for intracellular mem-
brane-bound receptor processing. Isoprenoids (FPP and
GGPP) are known to improve glucose uptake through glucose
transporter 4 (GLUT 4). A downregulation of GLUT4 would
impair insulin action and will cause insulin resistance.25
Under statin, CoQ10 (ubiquinone), which is responsible in
the electron-transfer system in the mitochondria was associ-
ated with a decrease in nutrient-related insulin secretion by
the cells due to reduced adenosine triphosphate. In addition
to these effects, statins are known to decrease insulin secre-
tion due to its consequences on systolic Ca2 which has been
linked to the endogenous cholesterol functions in cells by
the functional activity of Ca2 channels and thus was able to
reduce Ca2-dependent insulin secretion by blocking this
signaling (Fig. 1).24
Effect of Statins on Tissue Insulin Sensitivity (Adipocytes
and Adipokines)
The exact role of statins on adipose has been a highly
debatable issue, but has mostly demonstrated a major effect
Fig. 1 Statin and its possible effects on the mevalonate pathway.21
Risks and Benefits of Statins Sunjaya et al.
on the cellular physiology of the adipocyte in multiple
levels.26 White adipose tissue is responsible for the secretion
of an array of signaling molecules termed as adipokines,
which include leptin, adiponectin, resistin, and visfatin.
Adipokines could lead to an inammatory response in the
adipose tissue which could play a role in the development of
insulin resistance. A dysfunction of adipokines can be impli-
cated with obesity, type 2 diabetes, and the increased risk of
cardiovascular disease27,28 (Table 1).
Effect of Statins on Adipose Tissue
The plasma membrane of the adipose tissue contains distinct
regions of lipid storage known as lipid rafts and caveolae.
Caveolae are unique forms of lipid rafts due to their expres-
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sion of Cav proteins (Cav-1 and Cav-2), a family of integral
membrane proteins that are the principal components of the
caveolae forming small, bulb-shaped invaginations of the
plasma membrane. Caveolae plays a role in fatty acid trans-
port and is linked to the transduction of lipid-linked signaling
proteins present in adipocytes. Statins have been proven to
provide an inhibitory effect on the caveolae formation
through low Cav-1 levels. Although statins increased the
number of caveolae present, there is a reduced number of
the typical bulb-like caveolar structures and instead a buildup
of caveolar vesicles thus affecting adiponectin levels. As
adiponectin levels and Cav-1 positively correlate each other,
when statins inhibit the Cav-1 expression and proper forma-
tion of caveolar structure, the mechanism on the secretion of
adiponectin is disrupted thus reducing its circulation levels
though studies show that total adiponectin levels (intracellu-
lar and in circulation) remain mostly unchanged.26
Adipocyte maturation/differentiation is a process all
preadipocytes must undergo before they can secrete insulin-
sensitizing hormones along with GLUT4 translocation and
therefore directly affects insulin resistance. An accumulation of
undifferentiated adipocyte may lead to an increased insulin
resistance and the risk of the development of statin-induced
diabetes. Not many studies have been performed on the
International Journal of Angiology
Risks and Benefits of Statins Sunjaya et al.
Table 1 Statins effects on various adipocytes affecting molecules
Molecule Physiological effects
Adiponectin Hepatic glucose production
" Insulin secretion26,29
Visfatin Mimics the effects of insulin binding the insulin
receptor providing hypoglycemic effects30
Resistin " Blood glucose
" Glycogenolysis
" Gluconeogenesis
Leptin Effects on insulin signaling and hepatic glucose production29
Performs a similar function as compared with insulin32
potential mechanism and the implications of statins toward it.
Peroxisome proliferator activated receptor gamma and CCAAT/
enhancer-binding protein(C/EBPs) are the two main transcrip-
tion factors associated with adipocyte differentiation, both
which decreased in levels following statin treatment. C/EBP-
decient cells are linked to increase to normal levels of GLUT4
but reduced expression of insulin receptor (IR) and insulin
receptor substrate (IRS-1) which increased upon statin therapy.
However, some studies also showed no effect on adipocyte
differentiation occurring upon consuming statins.25
Obesity has been known to give rise to a state of chronic,
low-grade inammation that contributes to insulin resistance
and type 2 diabetes. Macrophages present in the adipose
tissue possess several proinammatory cytokines such as
tumor necrosis factor (TNF)- that inhibit insulin action along
with adiponectin production in adipocyte thus leading to
risks of inammation. Statins, with their anti-inammatory
properties, is able to reduce macrophage accumulation in
atherosclerotic plaque and lower levels of proinammatory
cytokines such as TNF- mostly through a direct effect
through the liver (Fig. 2).26,33
Effect of Statins on Insulin Resistance (HOMA-IR Levels)
The homeostatic model assessment (HOMA)-IR is a method used
to quantify insulin resistance and cell function. Insulin resis-
Fig. 2 Statins other effects on adipose tissue. 26,33
International Journal of Angiology
Statins effects
Decreased by atorvastatin, simvastatin
Neutral or increase by atorvastatin, pravastatin,
simvastatin, uvastatin24,25
Downregulation by rosuvastatin, atorvastatin
Neutral effect by simvastatin24,31
Little or no effect by statins
(mostly atorvastatin studies)24,29
Suppression by rosuvastatin, simvastatin,
and atorvastatin
Neutral effect by pravastatin, atorvastatin,
simvastatin24,25
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tance is often associated with the progression of atherosclerosis
and coronary heart disease. Although, a high majority of studies
have shown that statins provide an increment in HOMA-IR,
others (rosuvastatin, simvastatin) have also demonstrated a
decrease or no change in insulin resistance. The mechanisms
by which statins affect insulin resistance are multifactorial. One
possibility is the decrease of several important metabolites
produced in the mevalonate pathway which has been linked
to the protein, GLUT4 in 3T3L1 adipocytes, thus augmenting
glucose uptake. Lipophilic statins have also been argued to
penetrate the cell membrane more than its hydrophilic counter-
part and are likely to possess more extrahepatic effects.34
A study has also shown that statins could induce insulin
resistance through inammasome activation. This works by
activating NLRP3 inammasome in the presence of a priming
agent lipopolysaccharide, which induces the secretion of
interleukin (IL)-1 (catabolin) leading to caspase-1 activation
and the subsequent insulin resistance in fat. NLRP3 inam-
masome is a protein present in the macrophages as well as the
adipose tissue in humans, which plays a role in inammation
and apoptosis. However, it was later proven that caspase-1
activation without the appearance of IL-1 is sufcient to
impair insulin signaling in adipocyte causing insulin resis-
tance.35 However, statins could also reduce insulin resistance
through the lowering of triglyceride levels. Triglycerides have

been known to impair insulin action during its infusion
(activity of the Randle cycle) after 3 to 4 hours. An improve-
ment in insulin sensitivity was detected on the usage of
statins due to its hypotriglyceridemic effect.24
On the other hand, the effect of statin can also be shown to
be inhibitory. GLUT4 is an insulin-regulated glucose trans-
porter that moves from its intracellular storage to the plasma
membrane through the initiation of insulin-receptor tyrosine
kinase phosphorylation. IRS-1 undergoes phosphorylation to
insulin or insulin growth factor which binds to the IR which
creates a chain reaction through the PI3K/AKT pathway
resulting in GLUT4 translocation to the plasma membrane.
Studies have shown that statins downregulate the activation
of small GTPases, which are involved in GLUT4 expression in
the plasma membrane through the altered intracellular insu-
lin signal transduction (Fig. 3).24,25
Effect of Statins on Skeletal Muscle
The most complication in the usage of statins is some degree
of skeletal myopathy though the degree of complications can
range from myositis (inammation of the muscles) to rhab-
domyolysis (breakdown of muscle tissue that releases the
muscle ber content into the blood).36
The mechanism of statin-induced myopathy has still been
much theorized but it is widely agreed that multiple factors
contribute to this. Statins reduce LDL-C by altering the
mevalonate pathway at the cost of the formation of several
important products, the mitochondrial cofactor and CoQ10
(ubiquinone) being associated the most with muscle
symptoms. The ubiquinone, a metabolite produced in the
mevalonate pathway is involved in electron transport during
oxidative phosphorylation in the mitochondria (OXPHOS).
Statin treatment may result in the impaired mitochondrial
oxidative metabolism as well as energy production. A lower
capacity of OXPHOS has been linked with the usage of statins
in several studies.37
Fig. 3 Statins effects on insulin resistance. 24,25,34,35
Risks and Benefits of Statins Sunjaya et al.
Other than the mevalonate pathway, the ubiquitin-pro-
teasome pathway (UPP), a principal mechanism for protein
catabolism in the mammalian cytosol and nucleus is also
adversely affected. The UPP plays an important role in the
structural integrity of the skeletal muscle and is responsible
for the degradation and repair of many skeletal muscle
proteins. One of the enzymes produced in the atrophy process
is an ubiquitin protein ligase known as atrogin-1 which
increased and is often associated with muscle wasting other
than disease or fasting. Statin-induced apoptosis could also
occur via calpain (stimulates programmed cell death), the
repression of the antiapoptosis gene (Birc4) and the activa-
tion of proapoptosis gene (Car). Finally, statins alter Ca2
homeostasis increasing systolic Ca2 which might impair
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sarcoplasmic reticulum calcium cycling.38,39
The mechanism of statin-induced myopathy has still been
much theorized but it is widely agreed that multiple factors
contribute to this as shown in the gure below (Fig. 4).
Effects of Various Statins on Glucose Control
The effect of statins on glucose control among diabetic patients
has been extensively evaluated by numerous clinical trials.
Atorvastatin
Experimental data: Several studies which evaluate the effect
of atorvastatin treatment on glucose control in experimental
animal model were found. Both Suzuki et al and Ahmed et al
reported that atorvastatin improved glucose control, decreas-
ing plasma glucose levels, plasma insulin levels as well as a
reduction in insulin resistance index among diabetic mice
models treated with atorvastatin.13,40 Whereas, Aguirre et al
reported no signicant change in serum glucose and insulin
concentration in his study, however, there was a signicant
increase in insulin resistance found.14 Higher glucose levels in
atorvastatin-treated diabetic mice as compared to control
International Journal of Angiology
Risks and Benefits of Statins Sunjaya et al.
Fig. 4 Mechanisms of statin-induced myopathy.3739
with no change in insulin secretion were, however, reported
by Kanda et al.41
Clinical data: In a study by Newman et al, 2,838 type 2
diabetic patients were treated with atorvastatin 10 mg/day
for 3.9 years, which resulted in a modest change in HbA1c
levels.42 Whereas, Yokote et al also reported no change in
fasting plasma glucose, fasting plasma insulin, and insulin
resistance levels in his study with atorvastatin 10 mg/day,
however, it was reported that there was a tendency for a
higher HbA1c level among the participants.43 These results
were in agreement with that of Mita et al, Szotowska et al,
Huptas et al, Endo et al, Holman et al, Athyros et al, Kryzha-
novski et al, Ogawa et al, and Nakata et al.4452
Other studies found, however, demonstrated unfavorable
effects of atorvastatin as shown by Liu et al, in this study 113
type 2 diabetic patients were treated with atorvastatin 10 mg/
day for 12 weeks, which resulted in signicant negative
outcomes in glucose control, namely, increase in glucose levels,
insulin levels, insulin resistance as well as HbA1c levels.16
Increase in blood glucose levels following atorvastatin therapy
was also reported by Yamakawa et al and Takano et al.53,54
Furthermore, Her et al also reported increase in insulin resis-
tance, fasting insulin with no signicant change in HbA1c levels
and fasting glucose in her study.55 A signicant worsening of
fasting insulin, fasting glucose, HbA1c, and insulin-resistance
levels was also reported by Sasaki et al.56
A dose-dependent effect of atorvastatin on glucose control
was also shown by Koh et al in his study evaluating varying
doses of atorvastatin (10, 20, 40, and 80 mg/day) and their
effects on glucose control. His result shows that there was an
increase in fasting plasma insulin, HbA1c levels and decrease
in insulin sensitivity with increase doses though it was not
linear.57 Simsek et al in his study also showed that while
atorvastatin 20 and 40 mg/day for 6 weeks resulted in no
signicant change in HbA1c levels and fasting plasma glucose,
International Journal of Angiology
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a signicant increase was reported among atorvastatin
80 mg/day users.58 Similarly, Stalenhoef et al also reported
greater increase in fasting glucose and insulin resistance
among atorvastatin 20 mg/day users as compared with
10 mg/day users.59
Furthermore, a study by Gumprecht et al also suggested that
short-term use of atorvastatin will not result in a signicant
increase in blood glucose, whereas long-term use resulted in a
signicant increase in blood glucose levels.60 Owing to the lack of
similar studies this result must be considered with caution
though it may explain the various short-term studies reporting
no effect of atorvastatin on glucose control.
Fluvastatin
Experimental data: Only one study by Aguirre et al that
showed unfavorable effects, namely, increase in serum glucose
concentration, insulin resistance followed by no change in
insulin concentration among 10 obese Zucker rats treated
with uvastatin 0.6 mg/kg/day for 6 weeks was found.14
Clinical data: The effect of uvastatin on glucose control
among diabetic patients has not been extensively studied,
only one study was found that t this criterion. In the study by
Derosa et al, showed that extended release uvastatin 80 mg/
day for 12 months among 48 diabetic patients with dyslipi-
demia and coronary heart disease did not signicantly alter
fasting or postprandial glucose levels. In addition, a trend
toward reduction in HbA1c levels by 7% was shown to occur.61
These possibly favorable effects on glucose control should be
noted by caution and supported by more studies before
conclusions can be made.
Lovastatin
Experimental data: Similar to uvastatin, there exists a lack
of evidence reporting the effects of lovastatin among diabetic
patients. Only one experimental study was found which

reported that the use of lovastatin 0.6 mg/kg/day for 6 weeks
on obese Zucker rats resulted in a signicant increase in
serum glucose concentration, insulin resistance while subse-
quently showing no change in insulin concentration.14
Clinical data: No clinical data reporting lovastatin use
among diabetic patients was found which followed our
criteria.
Pitavastatin
Experimental data: From 2000 to date, no published experi-
mental studies were found which assess the effect of pita-
vastatin on glucose control among diabetic patients.
Clinical data: Pitavastatin is the newest statin found in the
market to date. However, ample clinical studies have been
found documenting its effects on glucose control among
diabetic patients. A report by Gumprecht et al on 279 patients
aged 18 to 75 years with type 2 diabetes treated with
pitavastatin 4 mg/day for 12 weeks resulted in a signicant
increase in blood glucose levels (7.2%). A further 44-week
extended study was also done, which on the contrary, showed
a less signicant increase in blood glucose (3.5%).60
Studies evaluating the use of pitavastatin 2 mg/day were
reported by Sasaki et al among 103 patients, which reported
increases in fasting insulin, fasting glucose, HbA1c, and insulin
resistance.56 This result was in agreement with that of Liu et al
which evaluated pitavastatin 2 mg/day use among 112
patients with diabetes, which showed signicant increases
in glucose levels, insulin levels, insulin resistance, and
HbA1c.16 Further negative effects were shown by Daido et
al, which reported falling insulin secretion though accompa-
nied by no change in HbA1c levels, fasting plasma glucose
levels, and insulin resistance.62 Similar results were obtained
by Takano et al as well, with regard to blood glucose and
HbA1c levels.54
However, a study by Yamakawa et al reported no signicant
effect of pitavastatin on both blood glucose and HbA1c levels.53 It
was in agreement with the results reported by Kawai et al which
showed the use of pitavastatin 1 to 2 mg/day resulted in no
signicant change in fasting plasma glucose and HbA1c levels.63
On a large-scale 5-year study by Teramoto et al evaluating the
use of pitavastatin 1, 2, or 4 mg/day among 1,843 patients with
diabetes and hypercholesterolemia, improvements in HbA1c
levels were reported. There was a reduction in mean HbA1c
levels from 7.2 (1.5) to 6.8 (1.3).11 A small comparison study
with 28 patients equally divided among atorvastatin and pit-
avastatin conducted by Mita et al also showed that pitavastatin
had a more favorable effect on glucose metabolism, including
HbA1c, glycoalbumin, fasting blood glucose, and insulin resis-
tance as compared with atorvastatin.44
Pravastatin
Experimental data: Prior experimental studies support a
potential favorable effect of pravastatin on glucose control.
Treatment with pravastatin of rats bound to develop diabetes
mellitus reported increase glucose metabolism as well as
reduction in glucose intolerance as compared with untreated
rats following a 20 and 30 week follow-up.64 Similarly favor-
able results were reported by Otani et al, pravastatin therapy
Risks and Benefits of Statins Sunjaya et al.
resulted in a lower fasting glucose serum concentration,
lower insulin serum concentration, and no change in insulin
resistance.15 Different outcomes were, however, reported by
Kanda et al wherein signicantly higher glucose levels and no
change in insulin secretion were found. Aguirre et al reported
a neutral effect of pravastatin on serum glucose concentration
and insulin concentration with a detrimental effect on insulin
resistance.14,41
Clinical data: In agreement with the above experimental
data, several studies on the effect of pravastatin on glucose
control have reported its favorable or otherwise neutral
effects among diabetic patients. Benecial effects of prava-
statin on glucose control include a modest lowering of glucose
levels, insulin levels combined with no change on HbA1c and
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insulin resistance as reported by Koh et al, Yamakawa et al,
and Mita et al.53,65,66
Rosuvastatin
Experimental data: Miller et al reported that 5 weeks of
rosuvastatin therapy on insulin-resistant rats resulted in a
moderate reduction in insulin concentrations though it
remains elevated (did not return to normal). However, no
signicant changes in fasting glucose were reported.67 Unfa-
vorable effects of rosuvastatin were however reported by
Aguirre et al wherein 6 weeks of rosuvastatin therapy in
obese Zucker rats resulted in an increase in serum glucose
concentration, insulin resistance with no change in insulin
concentrations.14
Clinical data: Varying unfavorable effects of rosuvastatin
on glycemic control in varying degrees have been reported by
numerous clinical trials. A study by Stalenhoef et al among
244 patients with metabolic syndrome treated by either
rosuvastatin 10 or 20 mg/day for 6 weeks showed that low-
dose rosuvastatin resulted in an insignicant increase in
fasting glucose while showing a modest increase in insulin
resistance, the higher dose resulted in a modest increase
fasting glucose accompanied by a large increase in insulin
resistance (12.1%).59 Simsek et al also reported that high
doses of rosuvastatin (40 mg/day) for 6 weeks resulted in a
signicant increase in HbA1c levels (7.9  1.2%) and mean
fasting plasma glucose.58
A large increase in fasting insulin (16  53%), insulin resis-
tance (19  56%) with a modest increase in fasting glucose and
HbA1c was also reported by Her et al.55 A modest increase in
fasting serum insulin and serum insulin levels were also
reported Moutzori et al and Koh et al, respectively.34,65 Whereas
Bellia et al in her two studies reported no change in insulin
sensitivity and falling insulin levels. In addition, insulin secretion
was also reported to be markedly reduced (21.9%).10,68 No
signicant change in HbA1c levels were shown in studies by
Moutzori et al, Ogawa et al, Koh et al, and Bellia et al.10,34,51,65
Simvastatin
Experimental data: Few animal studies were found which
reported simvastatins effects on glucose control, further-
more they present conicting results. In one study, Aguirre
et al reported that simvastatin use (0.6mg/kg/day) for 6 weeks
on obese Zucker rats resulted in a signicant decrease in
International Journal of Angiology
Risks and Benefits of Statins Sunjaya et al.
serum glucose concentration with no change reported in
insulin concentration and insulin resistance.14 Its result
was in disagreement with a study by Wang et al among 16
diabetic Wistar rats treated with simvastatin (10 mg/kg/day)
for 12 weeks which resulted in a signicant increase in fasting
plasma glucose.69
Clinical data: Differing results showing either a detrimen-
tal or neutral effect were shown among the several studies
included. Results from a large-scale study done by the Heart
Protection Study Collaborative Group to nd out the various
long-term effects of simvastatin, which included 5,963 adults
with diabetes and were given simvastatin 40 mg/day therapy
for a period of 5 years showed a nonsignicant trend toward a
worsening development of diabetes.70 No signicant increase
in fasting serum insulin and HbA1c was also reported by
Moutzori et al.34 Furthermore, a study by Krysiak et al among
patients with impaired glucose tolerance treated by simva-
statin 20 mg/day for 12 weeks showed no signicant changes
in fasting glucose, HbA1c, and insulin resistance, in addition
the study reported a modest reduction in 2-hour postglucose
load plasma.71
In another study, Bellia et al reported in her study using
simvastatin 20 mg/day a modest increase in insulin levels
accompanied by no signicant change in glucose levels.10
Further longer term study made by her with simvastatin
20 mg/day, however, reported a signicant increase in fasting
glucose (8.32  0.28 mmol/L) accompanied by a modest
increase in HbA1c levels (0.8  0.2%) as well as a 21.9% decrease
in insulin secretion. No change in insulin sensitivity was found.68
The use of high doses of simvastatin (80 mg/day) in a study
by Szendroedi et al among type 2 diabetic patients with a
known duration of disease between 3 and 10 years reported a
signicant increase in HbA1c levels (6.7  0.6%) followed by a
modest increase in insulin resistance (2.7  0.6%).72 The
modest increase in insulin resistance was also reported by
Kater et al among patients treated by simvastatin 20 mg/day
though to a much lesser degree.73 Taking into account the
varying doses used in the above studies and their effects, it
may be possible to infer that simvastatin shows a dose-
dependent effect on glucose control (Table 2).
Concerns and Practical Implications to Type 2 Diabetes
Mellitus
The worsening glucose control among diabetic patients during
the use of statin is clinically concerning due to the large number
of diabetic patients using statins and the possibility of increasing
mortality, morbidity, and complications among diabetic patients
following statins use. Thus, it is of great concern to evaluate the
various effects of the different types of statins among diabetic
patients as their use has become a regular regiment for diabetic
patients to prevent cardiovascular diseases.
Statins have been associated with unfavorable effects on
glucose control as shown by the cohort retrospective study by
Liew et al evaluating the use of various statins on glucose
control, which reported signicantly higher change in HbA1c
levels among diabetic statin users as compared with nondia-
betic statin users.9 In a recent study by Mansi et al, similar
results were obtained in which diabetic statin users have
International Journal of Angiology
more than double the odds of developing diabetic complica-
tions as compared with nonstatin users.12 Increase in fasting
plasma glucose levels were also reported in a RCT by Sukhija
et al among 6,770 diabetic statins users treated with a variety
of statins for 2 years.74 However, it is important to evaluate
whether all statins confer an unfavorable effect on glucose
control among diabetic patients or only some of them do.
Our review shows that rosuvastatin has shown a tendency
for unfavorable effects on glucose control. Conicting results
exists for atorvastatin use though the use of high doses of
atorvastatin has been shown to negatively impact glucose
control. Similarly, a dose-dependent effect was also observed
regarding simvastatin use. Pitavastatin was also reported to
be related to worsening in glucose control though to a lesser
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degree as compared with atorvastatin. Lovastatin was also
shown to result in unfavorable effects in experimental
studies, however, further studies are required to conrm it.
On the other side, pravastatin was shown to give neutral or
possibly favorable results on glucose control. Fluvastatin was
also shown to benecially effect glucose control nevertheless
the lack of evidence meant further studies are required to
ascertain it surely.
Limitations of the Review
This review article suffers limitations in only being able to
synthesize journal articles and trials previously published
which are accessible to the authors.
Conclusions
Current evidence available shows that most of the statins give
unfavorable side effects with regard to glucose control among
diabetic patients. A dose-dependent effect was also observed
in some statins wherein higher doses are associated with
greater worsening side effect to glucose control. Furthermore,
a time-dependent effect was also observed with regards to
atorvastatin use which may be present among other statins.
However, given the overwhelming life-saving benets of
statin use on cardiovascular health further concrete eviden-
ces from large-scale long-term studies evaluating the side
effects of statins use on glucose control as well as complica-
tions among diabetic patients are still required to further
conrm these ndings. Future research should also aim on
not only evaluating statins effect on cardiovascular morbidity
but also on the patients overall morbidity as well. Only then
should the current guidelines be reviewed to accommodate
those ndings.
With regard to these ndings, it is important to evaluate
the widespread use of statins for primary prevention and use
them only when clear and strict indications for their use are
met. It is also important to inform patients of the possible
risks and motivate them to adhere to lifestyle changes, such as
losing weight, exercising, stop smoking, etc., to avoid taking
statins. For now, it may be best to be prudent and encourage
greater caution in prescribing statins especially with elderly
patients suffering from chronic diabetes with low-cardiovas-
cular risk category.
 Table 2 Effects of different statins on glucose metabolism, insulin signaling, and specic tissues

Statin Dose Glucose metabolism Insulin signaling Tissue-specific effects/toxicity

(mg)
Glucose FPG 2-h OGTT HbA1c Insulin level IS FPI HOMA-IR
Atorvastatin 10 "53,54 "56,59 46 "16,42,43,5254,56 "16 57 "56,57 "16,56,59 Conicting effects on hepatic glucose
Neutral16,45,66 Neutral43,52 Neutral46,47,51,57,66 Neutral66 Neutral43 Neutral 43,66 production24,25
75 46 75 46 46 Causes insulin resistance among peripheral
tissues especially adipocytes24,25,31
20 "50,55,60 "55,58,59 "55,57,75 57 "55,57 "55,59
75 Neutral48,58,59
75
40 "60 Neutral58 "57 57 "57
Neutral58
80 "58 "57,58 57 "57,58
61 61
Fluvastatin 80 Neutral Reduces or neutral effect on hepatic glucose
production 24,25
Lovastatin No clinical studies were found
Pitavastatin 1 Neutral63 Neutral63 No reports were found
11
2 "16,56 "56 "16,62 "16 "56 "16,56
Neutral53 Neutral62,63 Neutral43,53,63 62 43 43,62
43 11
4 Neutral50,60 11
53,54,66
Pravastatin 10 Neutral Neutral53,54,66 Neutral66 Neutral66 Reduces or neutral effect on hepatic glucose
production 24,25
20 Neutral65 Neutral47,65 Neutral65
Does not cause insulin resistance among
peripheral tissues 24,25
Rosuvastatin 5 Neutral51 Causes insulin resistance among peripheral
55,65 55,59 tissues especially adipocytes24,31
10 Neutral " "55 Neutral65 "34,55 "55,59
58 Neutral34,58,65
20 Neutral10 "59,68 "68 Neutral10 Neutral68 "59
Neutral58 Neutral58 68
40 "58 "58
Simvastatin 20 Neutral10 71 71 "68 "10 Neutral68 "73 Conicting effects on hepatic glucose
"68 71 68 71 production 24,25
Causes insulin resistance among peripheral
40 Neutral34 "34
tissues especially adipocytes 24,25
72 Inhibits caveolae and adiponectin formation on
80 " "72
adipocytes 26
Reduces OXPHOS among myocytes and
Risks and Benefits of Statins

myotubules leading to myopathy37

Abbreviations: 2-h OGTT, 2 hours post-oral glucose load tolerance test; FPG, fasting plasma glucose; FPI, fasting plasma insulin; HbA1c, glycated hemoglobin; HOMA-IR, homeostasis model assessment insulin
resistance; IS, insulin sensitivity; OXPHOS, oxidative phosphorylation.

International Journal of Angiology

Sunjaya et al.

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Risks and Benefits of Statins Sunjaya et al.
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