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

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- total or approximately one out of four are consuming statins
tase inhibitors or better known as statins are a class of in the United States.5
medications widely known for decreasing low-density lipo- There are currently seven types of statins available in the
protein cholesterol (LDL-C) and reducing the risk for coronary market: atorvastatin, uvastatin, lovastatin, pitavastatin,
heart disease and are considered the rst-line pharmacologi- pravastatin, rosuvastatin, and simvastatin. All statins are
cal treatment and have become the cornerstone for the cholesterol-lowering agents with the primary effect of reduc-
management of dyslipidemia today.1,2 A total of 96.4% of ing cardiovascular risks.6 However, adverse effects such as
Europes and 96.1% of Americas population, 6.6% of them myopathy, rhabdomyolysis, increased activity shown by liver
diabetic, are currently eligible for statins following the 2013 tests, acute renal failure, and incidence of type 2 diabetes
American College of Cardiology/American Heart Association mellitus have been reported.7
(ACC/AHA) cholesterol guidelines lowered threshold rate of Furthermore, the U.S. Food and Drug Administration
atherosclerotic cardiovascular disease 10-year risk (7.5%) recently revised statin drug labels to include information
required to start statin therapy.3,4 They are considered to that increases in fasting serum glucose and glycated hemo-
be the number one prescribed class of drugs and ranks third in globin levels have been reported with the use of statins which
terms of sales worldwide. In 2013, the Centre for Disease was supported by a recent study showing that statin use is
Control and Prevention reported that 32 million people in 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 diabetes complications and overall effect on mortality as well
a cost or a benet to glucose control. 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
Materials and Methods
India.13
Participants It must be noted that the studies included were based on
Studies that had patients diagnosed with type 2 diabetes published reports and take into account that studies report-
mellitus and using statins were included. Ideally, diabetes in ing positive effects are more readily accepted to be published
the studies should be dened following guidelines provided as compared with studies reporting negative effects.
either by the International Diabetic Federation, American
Diabetes Association, or PERKENI (Perkumpulan Endokrino-
Discussion
logi Indonesia).
It is widely known that insulin resistance in muscle as well as
Data Source liver and -cell failure represent the core pathophysiologic

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The databases searched to obtain the articles included MED- defects in type 2 diabetes (triumvirate). However, other mech-
LINE full text, PubMed, Science Direct, Pro Quest, SAGE, Taylor anisms have been identied as metabolic defects present in type
and Francis Online, Google Scholar, High Wire, and Elsevier 2 diabetes representing various roles in the development of
Clinical Key. The search strategies used included availability glucose intolerance in type 2 diabetic individuals. Together,
of full text written in English from January 1, 2000 to till date. these eight players consisting of the fat cell (accelerated lipolysis),
Keywords used were glucose control or synonyms OR gastrointestinal tract (incretin deciency/resistance), -cell
diabetes or synonyms AND statins. When multiple articles (hyperglucagonemia), kidney (increased glucose reabsorption),
for a single study was found, the most recent publication was brain (insulin resistance) in addition to the triumvirate comprise
used. Relevance of studies was assessed by using an approach to form the ominous octet.17
based on title, abstract, and full text. An ongoing discussion has opened up on whether statins
exert any inuence on glucose metabolism and the patho-
Study Selection physiology of type 2 diabetes (ominous octet).17 On this part,
Studies were included if they were original studies and if they numerous health institutions have created clinical guidelines
have a randomized controlled trial (RCT) and cohort study on statin use for patients suffering from type 2 diabetes which
design. In addition, studies were included if (1) they were are still used today. In Indonesia, PERKENI 2011 clinical
done on patients or animals with continuous statin treatment guidelines recommend diabetic patients over the age of
of any dose, (2) parameters related to glucose control were 40 years the use of statin therapy to reduce levels of LDL-C
reported, (3) studies compare patients/animals treated with as much as 30 to 40% of its initial measurement. Patients of
statins versus placebo, or (4) studies comparing patients/ less than 40 years of age with acute coronary syndrome or in
animals treated with one type of statin versus another type higher risks of cardiovascular disease which cannot be
with placebo as control. The rest were excluded from this improved by lifestyle changes are also included in this
review. category provided an observation of the risks of side effects
are done.18
In 2015, the American Diabetes Association revised its
Results
guidelines in statin use for diabetic patients to align with the
Our initial search resulted in 5,069 articles found, of which ACC/AHA 2013 guidelines resulting in patients over the age of
4,968 were excluded on the basis of title and abstract. Of the 40 and beyond, regardless of whether CVD risks or overt CVD
remaining 101, 57 were excluded because they did not meet are present will be required to take moderate-to-high statin
the inclusion criteria or were duplicated publications. Finally, therapy in addition to lifestyle therapy.19
44 articles were found that fullled all of our inclusion
criteria, 7 of which were experimental studies and the
Potential Mechanisms of Action
remaining 37 were clinical studies.
Sample sizes vary in between studies ranging from 10 to Effect of Statins on Insulin Production and Secretion by -
6,770 with a follow-up duration in between 4 weeks10 and Pancreatic Cells
5 years.11 Majority of them were RCTs with two cohort Statins are responsible for the inhibition of de novo synthesis
studies9,12 included. A total of 27,966 subjects were found of cholesterol, which caused the LDL-C receptors present in
in the clinical studies. the pancreatic cells to increase their uptake of LDL-C which
The animal studies included had a sample size ranging resulted in the increased production of plasma-derived LDL-C
from 6 to 60 with a follow-up time between 3 and which held several key differences as compared with de novo
52 weeks.1315 A total of 138 subjects were found in the synthesized cholesterol. The oxidation of plasma-derived
animal studies. LDL-C is known to induce the intracellular response system
The outcomes of interest were changes in blood glucose of the body, leading to inammatory consequences which can
and HbA1c level, reported impacts on diabetes either improv- lead to impaired insulin secretion. In this case, statins instead
ing, worsening or no change, the adverse effects reported, provide a benecial effect by improving insulin resistance

International Journal of Angiology


Risks and Benefits of Statins Sunjaya et al.

through their anti-inammatory effects. It is believed that the on the cellular physiology of the adipocyte in multiple
usage of statins increase the amounts of nitric oxides in an levels.26 White adipose tissue is responsible for the secretion
effort to improve endothelial function which in turn activates of an array of signaling molecules termed as adipokines,
calpain (a calcium-dependent protease) leading to cellular which include leptin, adiponectin, resistin, and visfatin.
apoptosis.20,21 Adipokines could lead to an inammatory response in the
The mevalonate pathway or HMG-CoA reductase pathway adipose tissue which could play a role in the development of
is an important cellular metabolic pathway which plays a key insulin resistance. A dysfunction of adipokines can be impli-
role in synthesizing sterol isoprenoids, such as cholesterol cated with obesity, type 2 diabetes, and the increased risk of
and nonsterol isoprenoids.22 Statins are able to reduce gly- cardiovascular disease27,28 (Table 1).
cemic control as they block the production of several metab-
olites usually produced during cholesterol synthesis in the Effect of Statins on Adipose Tissue
mevalonate pathway, such as isoprenoids, geranylgeranyl The plasma membrane of the adipose tissue contains distinct
pyrophosphate (GGPP), farnesyl pyrophosphate (FPP), and regions of lipid storage known as lipid rafts and caveolae.
ubiquinone (coenzyme Q10, CoQ10) which are determining Caveolae are unique forms of lipid rafts due to their expres-

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factors in glucose uptake as well as insulin levels.23,24 sion of Cav proteins (Cav-1 and Cav-2), a family of integral
Statins also block other products formed in the process of membrane proteins that are the principal components of the
the biosynthetic pathway of cholesterol with the greater caveolae forming small, bulb-shaped invaginations of the
impact falling upon dolichol, FPP, GGPP, and CoQ10 (ubiqui- plasma membrane. Caveolae plays a role in fatty acid trans-
none). Dolichol is a cofactor necessary for intracellular mem- port and is linked to the transduction of lipid-linked signaling
brane-bound receptor processing. Isoprenoids (FPP and proteins present in adipocytes. Statins have been proven to
GGPP) are known to improve glucose uptake through glucose provide an inhibitory effect on the caveolae formation
transporter 4 (GLUT 4). A downregulation of GLUT4 would through low Cav-1 levels. Although statins increased the
impair insulin action and will cause insulin resistance.25 number of caveolae present, there is a reduced number of
Under statin, CoQ10 (ubiquinone), which is responsible in the typical bulb-like caveolar structures and instead a buildup
the electron-transfer system in the mitochondria was associ- of caveolar vesicles thus affecting adiponectin levels. As
ated with a decrease in nutrient-related insulin secretion by adiponectin levels and Cav-1 positively correlate each other,
the cells due to reduced adenosine triphosphate. In addition when statins inhibit the Cav-1 expression and proper forma-
to these effects, statins are known to decrease insulin secre- tion of caveolar structure, the mechanism on the secretion of
tion due to its consequences on systolic Ca2 which has been adiponectin is disrupted thus reducing its circulation levels
linked to the endogenous cholesterol functions in cells by though studies show that total adiponectin levels (intracellu-
the functional activity of Ca2 channels and thus was able to lar and in circulation) remain mostly unchanged.26
reduce Ca2-dependent insulin secretion by blocking this Adipocyte maturation/differentiation is a process all
signaling (Fig. 1).24 preadipocytes must undergo before they can secrete insulin-
sensitizing hormones along with GLUT4 translocation and
Effect of Statins on Tissue Insulin Sensitivity (Adipocytes therefore directly affects insulin resistance. An accumulation of
and Adipokines) undifferentiated adipocyte may lead to an increased insulin
The exact role of statins on adipose has been a highly resistance and the risk of the development of statin-induced
debatable issue, but has mostly demonstrated a major effect diabetes. Not many studies have been performed on the

Fig. 1 Statin and its possible effects on the mevalonate pathway.21

International Journal of Angiology


Risks and Benefits of Statins Sunjaya et al.

Table 1 Statins effects on various adipocytes affecting molecules

Molecule Physiological effects Statins effects


Adiponectin Hepatic glucose production Decreased by atorvastatin, simvastatin
" Insulin secretion26,29 Neutral or increase by atorvastatin, pravastatin,
simvastatin, uvastatin24,25
Visfatin Mimics the effects of insulin binding the insulin Downregulation by rosuvastatin, atorvastatin
receptor providing hypoglycemic effects30 Neutral effect by simvastatin24,31
Resistin " Blood glucose Little or no effect by statins
" Glycogenolysis (mostly atorvastatin studies)24,29
" Gluconeogenesis
Leptin Effects on insulin signaling and hepatic glucose production29 Suppression by rosuvastatin, simvastatin,
Performs a similar function as compared with insulin32 and atorvastatin
Neutral effect by pravastatin, atorvastatin,
simvastatin24,25

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potential mechanism and the implications of statins toward it. tance is often associated with the progression of atherosclerosis
Peroxisome proliferator activated receptor gamma and CCAAT/ and coronary heart disease. Although, a high majority of studies
enhancer-binding protein(C/EBPs) are the two main transcrip- have shown that statins provide an increment in HOMA-IR,
tion factors associated with adipocyte differentiation, both others (rosuvastatin, simvastatin) have also demonstrated a
which decreased in levels following statin treatment. C/EBP- decrease or no change in insulin resistance. The mechanisms
decient cells are linked to increase to normal levels of GLUT4 by which statins affect insulin resistance are multifactorial. One
but reduced expression of insulin receptor (IR) and insulin possibility is the decrease of several important metabolites
receptor substrate (IRS-1) which increased upon statin therapy. produced in the mevalonate pathway which has been linked
However, some studies also showed no effect on adipocyte to the protein, GLUT4 in 3T3L1 adipocytes, thus augmenting
differentiation occurring upon consuming statins.25 glucose uptake. Lipophilic statins have also been argued to
Obesity has been known to give rise to a state of chronic, penetrate the cell membrane more than its hydrophilic counter-
low-grade inammation that contributes to insulin resistance part and are likely to possess more extrahepatic effects.34
and type 2 diabetes. Macrophages present in the adipose A study has also shown that statins could induce insulin
tissue possess several proinammatory cytokines such as resistance through inammasome activation. This works by
tumor necrosis factor (TNF)- that inhibit insulin action along activating NLRP3 inammasome in the presence of a priming
with adiponectin production in adipocyte thus leading to agent lipopolysaccharide, which induces the secretion of
risks of inammation. Statins, with their anti-inammatory interleukin (IL)-1 (catabolin) leading to caspase-1 activation
properties, is able to reduce macrophage accumulation in and the subsequent insulin resistance in fat. NLRP3 inam-
atherosclerotic plaque and lower levels of proinammatory masome is a protein present in the macrophages as well as the
cytokines such as TNF- mostly through a direct effect adipose tissue in humans, which plays a role in inammation
through the liver (Fig. 2).26,33 and apoptosis. However, it was later proven that caspase-1
activation without the appearance of IL-1 is sufcient to
Effect of Statins on Insulin Resistance (HOMA-IR Levels) impair insulin signaling in adipocyte causing insulin resis-
The homeostatic model assessment (HOMA)-IR is a method used tance.35 However, statins could also reduce insulin resistance
to quantify insulin resistance and cell function. Insulin resis- through the lowering of triglyceride levels. Triglycerides have

Fig. 2 Statins other effects on adipose tissue. 26,33

International Journal of Angiology


Risks and Benefits of Statins Sunjaya et al.

been known to impair insulin action during its infusion Other than the mevalonate pathway, the ubiquitin-pro-
(activity of the Randle cycle) after 3 to 4 hours. An improve- teasome pathway (UPP), a principal mechanism for protein
ment in insulin sensitivity was detected on the usage of catabolism in the mammalian cytosol and nucleus is also
statins due to its hypotriglyceridemic effect.24 adversely affected. The UPP plays an important role in the
On the other hand, the effect of statin can also be shown to structural integrity of the skeletal muscle and is responsible
be inhibitory. GLUT4 is an insulin-regulated glucose trans- for the degradation and repair of many skeletal muscle
porter that moves from its intracellular storage to the plasma proteins. One of the enzymes produced in the atrophy process
membrane through the initiation of insulin-receptor tyrosine is an ubiquitin protein ligase known as atrogin-1 which
kinase phosphorylation. IRS-1 undergoes phosphorylation to increased and is often associated with muscle wasting other
insulin or insulin growth factor which binds to the IR which than disease or fasting. Statin-induced apoptosis could also
creates a chain reaction through the PI3K/AKT pathway occur via calpain (stimulates programmed cell death), the
resulting in GLUT4 translocation to the plasma membrane. repression of the antiapoptosis gene (Birc4) and the activa-
Studies have shown that statins downregulate the activation tion of proapoptosis gene (Car). Finally, statins alter Ca2
of small GTPases, which are involved in GLUT4 expression in homeostasis increasing systolic Ca2 which might impair

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the plasma membrane through the altered intracellular insu- sarcoplasmic reticulum calcium cycling.38,39
lin signal transduction (Fig. 3).24,25 The mechanism of statin-induced myopathy has still been
much theorized but it is widely agreed that multiple factors
Effect of Statins on Skeletal Muscle contribute to this as shown in the gure below (Fig. 4).
The most complication in the usage of statins is some degree
of skeletal myopathy though the degree of complications can Effects of Various Statins on Glucose Control
range from myositis (inammation of the muscles) to rhab- The effect of statins on glucose control among diabetic patients
domyolysis (breakdown of muscle tissue that releases the has been extensively evaluated by numerous clinical trials.
muscle ber content into the blood).36
The mechanism of statin-induced myopathy has still been Atorvastatin
much theorized but it is widely agreed that multiple factors Experimental data: Several studies which evaluate the effect
contribute to this. Statins reduce LDL-C by altering the of atorvastatin treatment on glucose control in experimental
mevalonate pathway at the cost of the formation of several animal model were found. Both Suzuki et al and Ahmed et al
important products, the mitochondrial cofactor and CoQ10 reported that atorvastatin improved glucose control, decreas-
(ubiquinone) being associated the most with muscle ing plasma glucose levels, plasma insulin levels as well as a
symptoms. The ubiquinone, a metabolite produced in the reduction in insulin resistance index among diabetic mice
mevalonate pathway is involved in electron transport during models treated with atorvastatin.13,40 Whereas, Aguirre et al
oxidative phosphorylation in the mitochondria (OXPHOS). reported no signicant change in serum glucose and insulin
Statin treatment may result in the impaired mitochondrial concentration in his study, however, there was a signicant
oxidative metabolism as well as energy production. A lower increase in insulin resistance found.14 Higher glucose levels in
capacity of OXPHOS has been linked with the usage of statins atorvastatin-treated diabetic mice as compared to control
in several studies.37

Fig. 3 Statins effects on insulin resistance. 24,25,34,35

International Journal of Angiology


Risks and Benefits of Statins Sunjaya et al.

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Fig. 4 Mechanisms of statin-induced myopathy.3739

with no change in insulin secretion were, however, reported a signicant increase was reported among atorvastatin
by Kanda et al.41 80 mg/day users.58 Similarly, Stalenhoef et al also reported
Clinical data: In a study by Newman et al, 2,838 type 2 greater increase in fasting glucose and insulin resistance
diabetic patients were treated with atorvastatin 10 mg/day among atorvastatin 20 mg/day users as compared with
for 3.9 years, which resulted in a modest change in HbA1c 10 mg/day users.59
levels.42 Whereas, Yokote et al also reported no change in Furthermore, a study by Gumprecht et al also suggested that
fasting plasma glucose, fasting plasma insulin, and insulin short-term use of atorvastatin will not result in a signicant
resistance levels in his study with atorvastatin 10 mg/day, increase in blood glucose, whereas long-term use resulted in a
however, it was reported that there was a tendency for a signicant increase in blood glucose levels.60 Owing to the lack of
higher HbA1c level among the participants.43 These results similar studies this result must be considered with caution
were in agreement with that of Mita et al, Szotowska et al, though it may explain the various short-term studies reporting
Huptas et al, Endo et al, Holman et al, Athyros et al, Kryzha- no effect of atorvastatin on glucose control.
novski et al, Ogawa et al, and Nakata et al.4452
Other studies found, however, demonstrated unfavorable Fluvastatin
effects of atorvastatin as shown by Liu et al, in this study 113 Experimental data: Only one study by Aguirre et al that
type 2 diabetic patients were treated with atorvastatin 10 mg/ showed unfavorable effects, namely, increase in serum glucose
day for 12 weeks, which resulted in signicant negative concentration, insulin resistance followed by no change in
outcomes in glucose control, namely, increase in glucose levels, insulin concentration among 10 obese Zucker rats treated
insulin levels, insulin resistance as well as HbA1c levels.16 with uvastatin 0.6 mg/kg/day for 6 weeks was found.14
Increase in blood glucose levels following atorvastatin therapy Clinical data: The effect of uvastatin on glucose control
was also reported by Yamakawa et al and Takano et al.53,54 among diabetic patients has not been extensively studied,
Furthermore, Her et al also reported increase in insulin resis- only one study was found that t this criterion. In the study by
tance, fasting insulin with no signicant change in HbA1c levels Derosa et al, showed that extended release uvastatin 80 mg/
and fasting glucose in her study.55 A signicant worsening of day for 12 months among 48 diabetic patients with dyslipi-
fasting insulin, fasting glucose, HbA1c, and insulin-resistance demia and coronary heart disease did not signicantly alter
levels was also reported by Sasaki et al.56 fasting or postprandial glucose levels. In addition, a trend
A dose-dependent effect of atorvastatin on glucose control toward reduction in HbA1c levels by 7% was shown to occur.61
was also shown by Koh et al in his study evaluating varying These possibly favorable effects on glucose control should be
doses of atorvastatin (10, 20, 40, and 80 mg/day) and their noted by caution and supported by more studies before
effects on glucose control. His result shows that there was an conclusions can be made.
increase in fasting plasma insulin, HbA1c levels and decrease
in insulin sensitivity with increase doses though it was not Lovastatin
linear.57 Simsek et al in his study also showed that while Experimental data: Similar to uvastatin, there exists a lack
atorvastatin 20 and 40 mg/day for 6 weeks resulted in no of evidence reporting the effects of lovastatin among diabetic
signicant change in HbA1c levels and fasting plasma glucose, patients. Only one experimental study was found which

International Journal of Angiology


Risks and Benefits of Statins Sunjaya et al.

reported that the use of lovastatin 0.6 mg/kg/day for 6 weeks resulted in a lower fasting glucose serum concentration,
on obese Zucker rats resulted in a signicant increase in lower insulin serum concentration, and no change in insulin
serum glucose concentration, insulin resistance while subse- resistance.15 Different outcomes were, however, reported by
quently showing no change in insulin concentration.14 Kanda et al wherein signicantly higher glucose levels and no
Clinical data: No clinical data reporting lovastatin use change in insulin secretion were found. Aguirre et al reported
among diabetic patients was found which followed our a neutral effect of pravastatin on serum glucose concentration
criteria. and insulin concentration with a detrimental effect on insulin
resistance.14,41
Pitavastatin Clinical data: In agreement with the above experimental
Experimental data: From 2000 to date, no published experi- data, several studies on the effect of pravastatin on glucose
mental studies were found which assess the effect of pita- control have reported its favorable or otherwise neutral
vastatin on glucose control among diabetic patients. effects among diabetic patients. Benecial effects of prava-
Clinical data: Pitavastatin is the newest statin found in the statin on glucose control include a modest lowering of glucose
market to date. However, ample clinical studies have been levels, insulin levels combined with no change on HbA1c and

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found documenting its effects on glucose control among insulin resistance as reported by Koh et al, Yamakawa et al,
diabetic patients. A report by Gumprecht et al on 279 patients and Mita et al.53,65,66
aged 18 to 75 years with type 2 diabetes treated with
pitavastatin 4 mg/day for 12 weeks resulted in a signicant Rosuvastatin
increase in blood glucose levels (7.2%). A further 44-week Experimental data: Miller et al reported that 5 weeks of
extended study was also done, which on the contrary, showed rosuvastatin therapy on insulin-resistant rats resulted in a
a less signicant increase in blood glucose (3.5%).60 moderate reduction in insulin concentrations though it
Studies evaluating the use of pitavastatin 2 mg/day were remains elevated (did not return to normal). However, no
reported by Sasaki et al among 103 patients, which reported signicant changes in fasting glucose were reported.67 Unfa-
increases in fasting insulin, fasting glucose, HbA1c, and insulin vorable effects of rosuvastatin were however reported by
resistance.56 This result was in agreement with that of Liu et al Aguirre et al wherein 6 weeks of rosuvastatin therapy in
which evaluated pitavastatin 2 mg/day use among 112 obese Zucker rats resulted in an increase in serum glucose
patients with diabetes, which showed signicant increases concentration, insulin resistance with no change in insulin
in glucose levels, insulin levels, insulin resistance, and concentrations.14
HbA1c.16 Further negative effects were shown by Daido et Clinical data: Varying unfavorable effects of rosuvastatin
al, which reported falling insulin secretion though accompa- on glycemic control in varying degrees have been reported by
nied by no change in HbA1c levels, fasting plasma glucose numerous clinical trials. A study by Stalenhoef et al among
levels, and insulin resistance.62 Similar results were obtained 244 patients with metabolic syndrome treated by either
by Takano et al as well, with regard to blood glucose and rosuvastatin 10 or 20 mg/day for 6 weeks showed that low-
HbA1c levels.54 dose rosuvastatin resulted in an insignicant increase in
However, a study by Yamakawa et al reported no signicant fasting glucose while showing a modest increase in insulin
effect of pitavastatin on both blood glucose and HbA1c levels.53 It resistance, the higher dose resulted in a modest increase
was in agreement with the results reported by Kawai et al which fasting glucose accompanied by a large increase in insulin
showed the use of pitavastatin 1 to 2 mg/day resulted in no resistance (12.1%).59 Simsek et al also reported that high
signicant change in fasting plasma glucose and HbA1c levels.63 doses of rosuvastatin (40 mg/day) for 6 weeks resulted in a
On a large-scale 5-year study by Teramoto et al evaluating the signicant increase in HbA1c levels (7.9  1.2%) and mean
use of pitavastatin 1, 2, or 4 mg/day among 1,843 patients with fasting plasma glucose.58
diabetes and hypercholesterolemia, improvements in HbA1c A large increase in fasting insulin (16  53%), insulin resis-
levels were reported. There was a reduction in mean HbA1c tance (19  56%) with a modest increase in fasting glucose and
levels from 7.2 (1.5) to 6.8 (1.3).11 A small comparison study HbA1c was also reported by Her et al.55 A modest increase in
with 28 patients equally divided among atorvastatin and pit- fasting serum insulin and serum insulin levels were also
avastatin conducted by Mita et al also showed that pitavastatin reported Moutzori et al and Koh et al, respectively.34,65 Whereas
had a more favorable effect on glucose metabolism, including Bellia et al in her two studies reported no change in insulin
HbA1c, glycoalbumin, fasting blood glucose, and insulin resis- sensitivity and falling insulin levels. In addition, insulin secretion
tance as compared with atorvastatin.44 was also reported to be markedly reduced (21.9%).10,68 No
signicant change in HbA1c levels were shown in studies by
Pravastatin Moutzori et al, Ogawa et al, Koh et al, and Bellia et al.10,34,51,65
Experimental data: Prior experimental studies support a
potential favorable effect of pravastatin on glucose control. Simvastatin
Treatment with pravastatin of rats bound to develop diabetes Experimental data: Few animal studies were found which
mellitus reported increase glucose metabolism as well as reported simvastatins effects on glucose control, further-
reduction in glucose intolerance as compared with untreated more they present conicting results. In one study, Aguirre
rats following a 20 and 30 week follow-up.64 Similarly favor- et al reported that simvastatin use (0.6mg/kg/day) for 6 weeks
able results were reported by Otani et al, pravastatin therapy 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 more than double the odds of developing diabetic complica-
insulin concentration and insulin resistance.14 Its result tions as compared with nonstatin users.12 Increase in fasting
was in disagreement with a study by Wang et al among 16 plasma glucose levels were also reported in a RCT by Sukhija
diabetic Wistar rats treated with simvastatin (10 mg/kg/day) et al among 6,770 diabetic statins users treated with a variety
for 12 weeks which resulted in a signicant increase in fasting of statins for 2 years.74 However, it is important to evaluate
plasma glucose.69 whether all statins confer an unfavorable effect on glucose
Clinical data: Differing results showing either a detrimen- control among diabetic patients or only some of them do.
tal or neutral effect were shown among the several studies Our review shows that rosuvastatin has shown a tendency
included. Results from a large-scale study done by the Heart for unfavorable effects on glucose control. Conicting results
Protection Study Collaborative Group to nd out the various exists for atorvastatin use though the use of high doses of
long-term effects of simvastatin, which included 5,963 adults atorvastatin has been shown to negatively impact glucose
with diabetes and were given simvastatin 40 mg/day therapy control. Similarly, a dose-dependent effect was also observed
for a period of 5 years showed a nonsignicant trend toward a regarding simvastatin use. Pitavastatin was also reported to
worsening development of diabetes.70 No signicant increase be related to worsening in glucose control though to a lesser

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in fasting serum insulin and HbA1c was also reported by degree as compared with atorvastatin. Lovastatin was also
Moutzori et al.34 Furthermore, a study by Krysiak et al among shown to result in unfavorable effects in experimental
patients with impaired glucose tolerance treated by simva- studies, however, further studies are required to conrm it.
statin 20 mg/day for 12 weeks showed no signicant changes On the other side, pravastatin was shown to give neutral or
in fasting glucose, HbA1c, and insulin resistance, in addition possibly favorable results on glucose control. Fluvastatin was
the study reported a modest reduction in 2-hour postglucose also shown to benecially effect glucose control nevertheless
load plasma.71 the lack of evidence meant further studies are required to
In another study, Bellia et al reported in her study using ascertain it surely.
simvastatin 20 mg/day a modest increase in insulin levels
accompanied by no signicant change in glucose levels.10
Limitations of the Review
Further longer term study made by her with simvastatin
20 mg/day, however, reported a signicant increase in fasting This review article suffers limitations in only being able to
glucose (8.32  0.28 mmol/L) accompanied by a modest synthesize journal articles and trials previously published
increase in HbA1c levels (0.8  0.2%) as well as a 21.9% decrease which are accessible to the authors.
in insulin secretion. No change in insulin sensitivity was found.68
The use of high doses of simvastatin (80 mg/day) in a study
Conclusions
by Szendroedi et al among type 2 diabetic patients with a
known duration of disease between 3 and 10 years reported a Current evidence available shows that most of the statins give
signicant increase in HbA1c levels (6.7  0.6%) followed by a unfavorable side effects with regard to glucose control among
modest increase in insulin resistance (2.7  0.6%).72 The diabetic patients. A dose-dependent effect was also observed
modest increase in insulin resistance was also reported by in some statins wherein higher doses are associated with
Kater et al among patients treated by simvastatin 20 mg/day greater worsening side effect to glucose control. Furthermore,
though to a much lesser degree.73 Taking into account the a time-dependent effect was also observed with regards to
varying doses used in the above studies and their effects, it atorvastatin use which may be present among other statins.
may be possible to infer that simvastatin shows a dose- However, given the overwhelming life-saving benets of
dependent effect on glucose control (Table 2). statin use on cardiovascular health further concrete eviden-
ces from large-scale long-term studies evaluating the side
Concerns and Practical Implications to Type 2 Diabetes effects of statins use on glucose control as well as complica-
Mellitus tions among diabetic patients are still required to further
The worsening glucose control among diabetic patients during conrm these ndings. Future research should also aim on
the use of statin is clinically concerning due to the large number not only evaluating statins effect on cardiovascular morbidity
of diabetic patients using statins and the possibility of increasing but also on the patients overall morbidity as well. Only then
mortality, morbidity, and complications among diabetic patients should the current guidelines be reviewed to accommodate
following statins use. Thus, it is of great concern to evaluate the those ndings.
various effects of the different types of statins among diabetic With regard to these ndings, it is important to evaluate
patients as their use has become a regular regiment for diabetic the widespread use of statins for primary prevention and use
patients to prevent cardiovascular diseases. them only when clear and strict indications for their use are
Statins have been associated with unfavorable effects on met. It is also important to inform patients of the possible
glucose control as shown by the cohort retrospective study by risks and motivate them to adhere to lifestyle changes, such as
Liew et al evaluating the use of various statins on glucose losing weight, exercising, stop smoking, etc., to avoid taking
control, which reported signicantly higher change in HbA1c statins. For now, it may be best to be prudent and encourage
levels among diabetic statin users as compared with nondia- greater caution in prescribing statins especially with elderly
betic statin users.9 In a recent study by Mansi et al, similar patients suffering from chronic diabetes with low-cardiovas-
results were obtained in which diabetic statin users have cular risk category.

International Journal of Angiology


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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