Accepted Manuscript

Title: Balancing Primary Prevention and Statin Induced Diabetes Mellitus

Prevention

Author: Yogita Rochlani, Ajoe John Kattoor, Naga Venkata Pothineni, Raga
Deepak Reddy Palagiri, Francesco Romeo, Jawahar L Mehta

PII: S0002-9149(17)31116-5
DOI: http://dx.doi.org/doi: 10.1016/j.amjcard.2017.06.054
Reference: AJC 22729

To appear in: The American Journal of Cardiology

Received date: 5-4-2017

Revised date: 11-6-2017

Please cite this article as: Yogita Rochlani, Ajoe John Kattoor, Naga Venkata Pothineni, Raga
Deepak Reddy Palagiri, Francesco Romeo, Jawahar L Mehta, Balancing Primary Prevention and
Statin Induced Diabetes Mellitus Prevention, The American Journal of Cardiology (2017),
http://dx.doi.org/doi: 10.1016/j.amjcard.2017.06.054.

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 1

Balancing Primary Prevention and Statin Induced Diabetes Mellitus

Prevention

*Yogita Rochlani MD1, *Ajoe John Kattoor MD1, Naga Venkata Pothineni MD1, Raga Deepak
Reddy Palagiri MD1, Francesco Romeo MD2, Jawahar L Mehta MD, PhD1

*both authors contributed equally

Institutions
1
Division of Cardiology, University of Arkansas for Medical Sciences, Little Rock, AR, USA
2
Division of Cardiology, University of Rome TorVergata, Rome, Italy

Corresponding Author:

JL Mehta, MD, PhD

Cardiovascular Division, UAMS

Little Rock, AR 72212

Tel: 501-296-1426

MehtaJL@uams.edu

Word Count: 3079(including references, table and figure legends)

Conflicts of Interest: None

Funding / Declarations Self / None

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Abstract

DM, a modern day epidemic, is a significant risk factor for cardiovascular disease. Statins are

thought to elevate the risk for incident DM. Multiple trials were suggestive of the hyperglycemic

effect of long term statin use. This has prompted the Food and Drug Administration to include

risk of DM in the product label of statins. New onset DM with statin use is biologically plausible

and can be explained based on the multiple pathways in glucose metabolism affected by statins.

Most pivotal clinical trials of statins were not powered to adequately assess the risk for incident

DM with statin use and the results from multiple meta-analysis are mixed. Current US

Preventive Services Task Force (USPSTF) recommend the use of statins for primary prevention

in patients with at least one cardiovascular risk factor and a 10 year risk of >7.5%. With the new

ACC /AHA guidelines, the number of patients eligible for statin therapy has risen exponentially,

which also calls for caution and increased vigilance among the prescribing physicians regarding

the controversies surrounding it. This article aims to highlight the existing data on statin use for

primary prevention in diabetics and non-diabetics and association of statins use with new onset

DM and its postulated mechanisms.

Keywords

Statin and DM, statin and primary prevention, statin induced DM

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Introduction

HMG CoA reductase inhibitors (statins) are the mainstay of pharmacologic management

for dyslipidemia. However, long term use of statins has been thought to be associated with an

increase in hyperglycemia and overt DM.1 We aim to review existing data on use of statins for

primary prevention in patients with DM and in non- DM patients, implications of statin use on

glucose control in diabetics, and association of statins with new onset DM. The article also aims

to shed light on the effects of dose, different drugs within the statin family, and the postulated

mechanisms for worsening glycemic control associated with statin therapy.

Statins in primary prevention

The Collaborative Atorvastatin DM Study (CARDS) was an initial study on the use of

statins in patients with type 2 DM. Results from this trial showed that in adults aged 40 - 75

years with DM and >1 risk factor for cardiovascular disease (CVD), fixed moderate-dose statin

therapy with atorvastatin 10 mg, which achieved a mean low density lipoprotein-cholesterol

(LDLC) of 72 mg/dL (mean 39% reduction), reduced the risk for CVD event by 37%. In

addition, statin therapy resulted in a 31% reduction in coronary revascularizations and 48%

reduction in stroke, making statins an important consideration in patients with DM.2 Multiple

meta-analyses reported a decrease in CVD with statin use in DM. Cholesterol Treatment Trialists

(CTT) collaboration analyzed data from 14 randomized controlled trials (RCTs), which included

18,686 patients with DM. The investigators reported that for every 1 mmol/ L reduction in LDL-

c, there was a 21% reduction in mortality in patients with DM (RR 0.79, 99% CI 0.72 - 0.86,

p<0.0001) and without DM (RR 0.79, 99% CI 0.76 - 0.82; p<0.0001).3In a meta-analysis by

Vijan et al, that included data from 5 RCTs of statin vs. placebo (and one RCT of fibrate vs.

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placebo) in patients with type 2 DM, the relative risk for CVD events in statin users was 0.78 (CI

0.67 - 0.89), and the absolute risk reduction was 0.03 (CI 0.01 - 0.04). This, meta-analysis

showed that 34.5 patients with type 2 DM would need to be treated for a period of 4.3 years to

prevent a single CVD event.4Vries et al. analyzed data from four trials, which included a total of

10,187 participants, to determine if statins were useful for primary prevention of

cardiovascular/cerebrovascular events in patients with DM. This analysis showed that statin

therapy resulted in a significant relative risk reduction in the occurrence of first major

cardiovascular or cerebrovascular events (RR 0.75, 95% CI 0.670.85), fatal/ non-fatal stroke

(RR 0.69, 95% CI 0.510.92) and fatal/ non-fatal myocardial infarction (RR 0.70, 95% CI 0.54

0.90), but a non-significant RR reduction in all-cause mortality (RR 0.84, 95% CI 0.65

1.09).5Earlier, it was recommended that statins be used in diabetics over 40 years with one or

more CVD risk factors;6 however, in view of the evidence presented thus far, the American

College of Cardiology/American Heart Association (ACC/AHA) recommend using statins in all

diabetics between 40 75 years of age (level A recommendation). The decision between

intensive vs. moderate dose therapy is to be made based on the risk as calculated by the pooled

cohort risk equation.7 Use of statins in primary prevention in the general population has been

long debated. The 2001 Adult Treatment Panel III (ATP III) recommended statin therapy in

adults over 20 years of age with markedly elevated LDL-c (>190 mg/dl) or moderately elevated

LDL-c (>130 mg /dl), 2 risk factors, and a Framingham risk score >10% over the next 10 years.8

However, recent studies support the use of statins for primary prevention even in subjects with

low risk for CVD event (Framingham risk score 5-10% or < 5%).9 In 2012, a meta-analysis of

data from 27 trials that included 174,149 participants showed a reduction in the risk of major

CVD events (non-fatal MI, coronary death, coronary revascularization or stroke) with statin use,

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even in subjects with an estimated 5-year risk of <10%. Every 1 mmol/L reduction in LDL-c led

to a reduction of 11/1000 CVD events over a 5-year treatment period.9 A Cochrane database

systematic review that included over 56,000 participants showed that statins caused a reduction

in all-cause mortality (OR 0.86, 95% CI 0.79 - 0.94), combined fatal and non-fatal

cardiovascular events as well as fatal and non-fatal stroke. In this analysis, use of statins was

beneficial even in low risk groups, and was estimated to prevent 6 events per 1000 people treated

for 5 years in the < 5% five-year risk category, and to prevent 15 events per 1000 people treated

for 5 years in the 5-10% five-year risk category. There was also a reduction in LDL-c levels as

well as coronary revascularizations.10 Importantly, there was also an elevated risk of developing

DM (RR 1.18, 95% CI 1.01 - 1.39). Recently, another systematic review was conducted by Chou

et al for the US Preventive Services Task Force (USPSTF). This review pooled data from 19

trials to assess the benefit of statins in 71,344 adults with increased CVD risk. This meta-analysis

showed a reduced risk of all-cause mortality (RR 0.86, 95% CI 0.80-0.93), cardiovascular

mortality (RR 0.69, 95% CI 0.54-0.88). The absolute benefit was most pronounced in patients

with the highest risk. The pooled analysis, however, failed to show increased risk of new onset

DM (RR 1.05, 95% CI, 0.91 to 1.20).11 Based on this study, USPSTF recommends low to

moderate dose statins in patients with one or more CVD risk factors and calculated 10 year event

risk of >7.5% a)10% or greater (level B recommendation); b) 7.5% to 10% (level C

recommendation).12 As the debate is now lopsided in favor of benefit, a pertinent counter

argument for harm remains, especially with the reported increase in the incidence of new onset

DM.

Statin use and incidence of new onset DM

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The relationship between statins and development of DM was first reported in the West of

Scotland Coronary Prevention Study (WOSCOPS) in 2001. The study was a randomized placebo

controlled trial of 40 mg pravastatin in 5974 participants, and revealed a 30% reduction in the

incidence of new onset DM.13 However, this trial did not use standard diagnostic criteria for the

diagnosis of DM. In addition, the sample population in the WOSCOPS was also thought to be

non-representative as patients were younger males and the population in general had a low risk

of developing DM. After WOSCOPS, several other trials tried to assess the protective effects of

atorvastatin and simvastatin, and these studies instead reported an increase in the incidence of

new onset DM.14 Justification for the Use of Statins in Prevention: an Intervention Trial

Evaluating Rosuvastatin (JUPITER), a randomized double blind placebo control trial of

rosuvastatin 20 mg in patients with elevated C-reactive protein levels, also contradicted the

findings in WOSCOPS, and showed an increased incidence of new onset DM in the statin group

(3% in statin users vs. 2.4% in placebo, p=0.01).15 Several investigators have since analyzed data

from different RCTs to test the association of statins with increased incidence of new onset DM

(Table 1). Rajpathak et al., in a meta-analysis of 6 RCTs reported a modest increase in new onset

DM with statin use but results were not consistent.16 Sattar et al. in a meta-analysis of 13 RCTs

found a 9% increase in the risk for new onset DM in statin users over a 4 year period. One new

case of new onset DM was detected for every 255 (95% CI 150 852) patients treated with

statins for 4 years.1 Mills et al. in a large meta-analysis of 17 RCTs found a significantly

increased risk of new onset DM with statin use, 3.8 % in statin users vs. 3.5 % in controls.17

Izzo et al., performed an observational study in an outpatient setting in 4,750 hypertensive and

non-diabetic patients, age group 58.579 years, followed for 55 42 months, with each patient

receiving at least 12 months of statin therapy. The prevalence of DM was 18.1 % in statin users

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compared with 7.2% in the non-statin users, while the rates of incident new DM were not

significantly higher in statin users, 10.2%, and 8.8 % in patients not on statins (RR =1.02,

p=0.92).18 The study done by waters et al. showed that 80 mg of atorvastatin daily did not

increase the risk of new onset DM in patients with 0-1 risk baseline risk factors, but increased the

risk by 24% in patients with 3 to 4 baseline risk factors (Table 2).19Significant reduction in CVD

events was noted in both subgroups. JUPITER also showed a high incidence of new onset DM in

those with one more major risk factors for DM. For every 54 new cases of DM, 134 vascular

events were avoided when statins were used for primary prevention.20 Studies have also

indicated that older age could be a significant risk factor for new onset DM with statin use. For

example, an increased incidence of new onset DM was seen with pravastatin use in PROSPER

(PROspective Study of Pravastatin in the Elderly at Risk) trial. Culver et al investigated the

association between new onset DM and statin use in postmenopausal women by gathering data

from the Womens Health Initiative which recruited 161,808 postmenopausal women aged 50 to

79 years of which 7.04% were taking statins. There were 10,242 incident cases of self-reported

DM over 1,004,466 person-years of follow-up. The authors concluded that statin therapy was

associated with a 48% increase in the risk of self-reported DM after 3 years among

postmenopausal women.21 Most of the earlier studies on the association of new onset DM and

statins were performed on high CVD risk patients; this high CVD risk per se can affect the risk

of incident DM. Importantly, often the criteria for diagnosing DM did not conform to the current

diagnostic criteria. A recent population based prospective cohort study in non-diabetic men using

the current diagnostic criteria for diagnosis of DM, including fasting blood glucose, oral glucose

tolerance test and HbA1c, showed a significant 46% increase in the risk of new onset DM (HR

1.46, 95% CI 1.22 - 1.74), after adjusting for confounding factors, among the 2,142 statin

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users.32 The study also showed a decrease in insulin secretion and insulin sensitivity, 12% and

24% respectively, among statin users. The decrease in insulin secretion and insulin sensitivity

was dose-dependent in patients receiving simvastatin or atorvastatin.22 Chou et al looked

specifically into the randomized controlled trials which had <10% of patients with a history of

prior CVD events so as to analyze the risk vs. benefit of use of statins in primary prevention.

This meta-analysis however failed to show an increased incidence of DM (RR 1.05, CI 0.91-

1.20; I2=52%).11 However as mentioned earlier, WOSCOPS trial which was included in this

analysis, used non-standard methods for defining patients with DM and hence may have

underestimated the real incidence of DM. We performed a summary analysis excluding the

WOSCOPS study, since it was the hypothesis generating study (chronologically first) to avoid

any regression to mean effect.16, 23 When we excluded the WOSCOPS trial, there is statistically

significant incident DM in statin group (RR 1.11, CI 1.01-1.22; I2=0%) (Fig A). However, when

data from the reanalysis of WOSCOPS using less stringent diagnostic criteria, as calculated by

Sattar et al. was added into the analysis, the incidence of incident DM became non-significant.1

In addition WOSCOPS trial only included men, which could in turn have contributed to the

heterogeneity. It should be noted that most of the major RCTs are powered to estimate the

primary outcome which is CVD risk reduction. P values of risk for incident DM which are

obtained through exploratory analysis are far less interpretable compared to p-values for primary

end points.23

Mechanisms of statin induced hyperglycemia

The precise mechanism by which statins may induce DM is not clear. Some of the major

proposed mechanism are shown in figure B. Insulin after binding to insulin receptors in the cells

produces a cascade of intracellular changes that result in the activation of systems that transport

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glucose into the cells. Insulin receptor substrate-1 (IRS-1) plays a key role in these signal

transmission from insulin receptors. Phosphorylation of IRS by protein kinase C (PKC) mediated

pathways leads to suppression of this signal transmission and hence decreases glucose uptake by

cells. Statins, due to the inhibition of HMG CoA reductase enzyme activity lead to accumulation

of the HMG CoA precursor acetyl CoA which is diverted to the fatty acid synthesis pathway

thereby causing accumulation of free fatty acids. Statins independently induce genes that are

involved in fatty acid synthesis.24 Free fatty acids are known to cause modulation of PKC

pathways leading to IRS phosphorylation and blocking signal transduction by insulin. Thus

statins cause inhibition to insulin-stimulated glucose uptake.25 Further, statins as a class inhibit

cholesterol synthesis which is important in the functioning of membrane proteins associated with

glucose transport such as GLUT1.26 Statins also alter immune function; which alters

inflammatory milieu and contributes to cardiovascular risk reduction. However, studies have

shown that statins increase the production of IL-1 which is a pro-inflammatory cytokine. This

inflammatory action might increase insulin resistance and in turn cause hyperglycemia.27 Wang

et al in in vitro experiments showed that statins upregulate the expression of G6PC (glucose-6-

phosphatase) and PCK1 (phosphoenolpyruvate carboxykinase 1) both of which are

gluconeogenic enzymes through induction of autophagy. Thus, chronic statin use may activate

gluconeogenesis axis leading to increased hepatic glucose output.28 Adipocytes secretes

adiponectin which lowers insulin resistance. Adiponectin receptors on pancreatic cells suppress

fatty acid induced -cell apoptosis and is considered to be the most likely pathogenesis by which

-cell dysfunction occurs in type 2 DM. Adiponectin theory suggest that statins decreases

adiponectin and hence promote -cell apoptosis. But this theory remains controversial.14

Lipophilic statins cause a decrease in GLUT4 protein levels in adipocytes leading to decreased

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glucose uptake and hence hyperglycemia.29 Statins have been shown to cause inhibition of

adipocyte differentiation. Immature adipocytes do not secrete insulin sensitizing hormone, and

may lead to insulin resistance. Statins also affect Ca2+ channel signaling in islet beta cells by

chronic cholesterol depletion. No clear mechanism is proposed for this relationship, but it is

believed that cholesterol depletion leads to conformational changes in Ca2+ channel subunits and

other membrane bound proteins30. By inhibiting early steps in cholesterol synthesis pathway,

statins induce a decline in some of the key molecules like geranylgeranyl pyrophosphate (GGPP)

dolichol, farnesyl pyrophosphate (FPP), coenzyme q10 (ubiquinone), etc. Some of these

molecules are known to upregulate GLUT 4. Decrease in these isoprenoids leads to a reduction

in insulin medicated glucose uptake. Cholesterol depletion downregulates GLUT 4 and this

impairs insulin action and causes insulin resistance. Lastly, chronic cholesterol depletion results

in caveolin-1 depletion which is necessary for normal insulin uptake by endothelial cells.

Based on the results of in vitro and in vivo studies cited here it is safe to conclude that multiple

mechanisms are involved in statin induced DM. 31

Effect of type and dose of statin on the incidence of DM

The new cholesterol treatment guidelines allude to the use of moderate to intensive dose

statins in all subjects between 40- 75 years of age with LDL-c levels of 70 -189 mg/dl based on

risk stratification with the pooled cohort equations.7 The effect of statins on the development of DM

appears to correspond with the dose of the drug used, and this class effect also varies in between different

drugs based on their potency and lipophilic vs. hydrophilic nature. Multiple meta-analysis and several

retrospective studies suggest an increased risk of incident DM with the higher dose and potency of statin

(Table 2). However, the meta-analysis by Navarese et al, involving 17 RCTs failed to demonstrate

statistically significant increased risk in incident DM among various statins.32 . Pitavastatin is a newer

statin, shown to be as effective as potent statins like atorvastatin in reducing LDL-c levels, and

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has added benefits of improvement in HDL-c levels, and lack of deleterious effects on glycemic

control. In some studies, it has in fact been shown to improve HbA1c levels in patients with

DM.33 However, in a meta-analysis based on 15 studies (comprising ~1600 subjects),

pitavastatin use did not affect fasting blood glucose, HbA1c or incidence of new onset DM when

compared with the control group. The control group, in most of the studies, consisted of another

statin drug.34 In a recent study, by Wang et al, >30% reduction in LDL-c was associated with a

proportionately increased risk of developing DM. Hence that larger the reduction of LDL-c with

statin therapy, higher the risk of developing DM.35 Thus, a universal recommendation of using a

high potency statin to achieve maximal reduction on LDL-c levels has to be received with

caution. Risk of incident DM appears to be proportional to the dose and potency of statin therapy.

Glycemic control with statins in patients with pre-existing DM

With studies showing increase in incident DM with statin use, it is important to assess

influence of different statins on glycemic control in patients with pre-existing DM (Table 2).

Yamakava et. al. studied the effect of three statins (pravastatin, pitavastatin and atorvastatin) on

blood glucose levels and HbA1c levels in patients with DM over 3 months, and reported that the

blood glucose levels were significantly higher in atorvastatin users but there was no difference in

HbA1c between the groups.36 Simsek et al. found a significant increase in HbA1c levels in

patients with pre-existing DM; however, fasting blood glucose levels did not increase

significantly.37 The LIVES extension study reported a significant decrease in the HbA1c levels in

patients with DM and hyperlipidemia treated with pitavastatin, indicating a potentially beneficial

effect.33 But as described earlier, a recent meta-analysis of 15 trials suggested absence of any

beneficial effects of this statin. A observational study by Sukhija et al. showed a statistically

significant increase in fasting glucose levels in both diabetic and non-diabetic statin users (table

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2).38 Thus, though multiple studies show worsening glycemic control with statin use in diabetic

patients. Further studies are necessary to determine whether this leads to a clinically significant

adverse outcome.

Statins and complications of DM

While statins are known to improve cardiovascular outcomes by effectively reducing

macro-vascular disease risk with control of dyslipidemia, their effect on the micro-vascular

complications of DM is unclear. Since, theoretically, these micro-vascular complications are

thought to result from a hyperosmolar state that causes cellular damage, these complications

may be expected to continue to develop at a similar rate as seen in type 2 DM. Whether or not,

statins have any additional effects that can retard the development of these micro-vascular

complications remains to be an area of study. Sukhija et al., in an observational study assessing

the effect of statins on renal dysfunction, analyzed data from 197,551 patients that included

58,332 statin users and showed a beneficial effect of statins (OR 0.87, CI 0.82 - 0.92) in

preventing renal dysfunction, independent of their lipid lowering effect.39 In another hospital

chart review (based on ICD codes), an increase in microvascular complications of DM was found to be

associated with statin use (OR 2.50, 95% CI 1.88-3.32). But this study was retrospective and the authors

did not report the type of complication.40 Hence, whether worsening in glycemic control associated

with statin use has any implications relative to development of micro-vascular complications like

nephropathy, retinopathy or neuropathy remains unknown.

Risk versus benefit of statin use in primary prevention

Statins haven been shown to have undisputed benefit in CVD prevention in high risk

groups. A recent large meta-analysis showed a reduction in fatal and non-fatal CVD events,

coronary revascularizations and all-cause mortality in low risk groups, such that stain use will

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prevent 6 -15 vascular events per 1000 low risk subjects. The number needed to treat (NNT) for

the <5% 5 year-risk group is 167 while that for 5-10% 5 year-risk group is 67.41 None of the

adverse events related with statin use were noted to be statistically significant except new onset

DM. Data from the CTT meta-analysis showed that for every 255 patients treated for 4 years,

there was one case of new onset DM while 9 vascular catastrophic CVD events (death, MI,

revascularization, stroke) were prevented.1 Priess et al. reported that the number NTH per year

with statin use is 498 while the NNT per year is 155.42 Recent meta-analysis performed for the

USPSTF showed a decrease in cardiovascular and all-cause mortality in the statin group, but

failed to show significant elevated risk for incident DM. Most of the trials in this meta-analysis

used lower doses of statins which might have contributed to the non-significant risk for new

onset DM. Recent studies suggest that >30% reduction in LDL-c and use of high intensity statins

may be related to higher risk of incident DM. In summary, a signal towards increased risk of

incident DM with long-term statin use is evident. Most of the published data support that

patients with a higher number of traditional cardiovascular risk factors at baseline tend to have a

higher incidence of DM with statin use, as compared to patients with lower number of

cardiovascular risk factors at baseline. Does this represent a natural progression of the underlying

metabolic syndrome or does it represent lead time bias where we identify patients at risk for DM

earlier with statin therapy? It is also not clear if statin induced DM is different from naturally

occurring DM at a pathophysiological level. We also do not know: a) does statin-induced DM

leads to macro- and micro-vascular complications as naturally occurring DM? b) how to best

treat statin induced DM? c) does stain-induced DM disappear or regress with lowering the dose

of or discontinuing statin therapy?. Unravelling this would help understand the optimal

treatment of statin induced DM. However, these questions are extremely difficult to answer at a

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population level and call for clinical decision making. With the new pooled cohort risk equation,

the number of patients who are candidates for statin therapy has grown exponentially (upto an

additional 12.8 millon). This may be an overestimation, as the guidelines recommends a

clinician-patient risk discussion prior to initiation of statin.43 Clinicians caring for patients who

come for primary prevention need to remain vigilant of these unanswered controversies. A one

size fits all approach may not work well and a risk-benefit discussion with the patient should

guide initiation of statins especially in low risk groups.

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Figure A: Meta-analysis on risk of Incident diabetes with and without WOSCOPS in studies with
<10% population with prior cardiovascular event (Data adapted from Chou et al11 and Sattar et
al1)
1. Excluding WOSCOPS trial
2. Including reanalyzed data from WOSCOPS trial

Figure B. Proposed mechanisms of statins induced DM

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Table 1: Meta-analyses that support the increase in the risk of incident DM with statins

Meta-analysis RCT Trials Sample size Conclusion

RR = 1.13 [95% CI = 1.03- 1.23] *

Rajpathak et al.20 6 57,593
RR = 1.06 [95% CI = 0.93-1.25] **

Sattar et al.4 13 91,140 OR = 109 [95% CI = 102117]

Mills et al.21 17 111,003 OR = 1.09 [95% CI = 1.021.16]

*WOSCOPS excluded, ** WOSCOPS included

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Table 2: Studies comparing risk of incident diabetes with various statins groups and doses
Number
Study Study design
of trials,
(First author, Type of study Comparison of Risk of incident diabetes
sample
year, Ref) glycemic control
size

Studies On Non-Diabetic Population

Intensive Vs.
Meta-analysis 5, incident diabetes in intensive dose statin [OR = 1.12,
Preiss, 2011,45 Moderate dose
(5RCT) 32752 1.04-1.22, I2=0%]
statin

Navarese, 2013,36 Meta-analysis 17, Different statin Rosuvastatin Vs. placebo [OR = 1.25, 0.82 1.90]
* (17RCT) 113,394 doses Vs. placebo Pravastatin Vs. placebo [OR = 1.07, 0.86-1.30]

Atorvastatin 80mg
Meta-analysis 2,
Waters, 2014,24 Vs. low dose DM in atorvastatin group [HR = 1.16, 1.03-1.30]
(2 RCT) 15,056
statin

Atorvastatin [HR = 1.22, 1.15- 1.29]; Rosuvastatin [HR

Retrospective Statin Vs
Carter, 2013,46 471,250 = 1.18, 1.10-1.26]; Simvastatin [HR = 1.10, 1.04-1.17];
Cohort Pravastatin
Lovastatin and fluvastatin - NS

DM among
Retrospective in DM [HR = 1.18, 1.15-1.22] with Rosuvastatin,
Zaharen, 2013,47 197,138 various statin
Cohort Atorvastatin and Simvastatin
users

Studies On Pre-existing Diabetic Population

High dose statin

41 Randomized, therapy Vs. HbA1c levels in both atorvastatin (p-0.003) and
Simsek, 2012, 263
Parallel-Group, baseline glycemic rosuvastatin groups (p<0.001)
levels
Efficacy and
LIVES extension Prospective
~ 20,000 safety of HbA1c by 0.4, p<0.001.
study, 2011,37 Post Marketing
Pitavastatin
FPG in non-diabetic statin users = 7mg/dL
Statin Vs. No
Sukhija, 2009,5 Observational 345,417 (p<0.0001)
statin
FPG in Diabetic statin users = 39mg/dL (p<0.0001)
*4 out of 17 studies in this trial included data from patients with preexisting diabetes mellitus; FPG- Fasting Plasma Glucose; NS
non significant

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