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ORIGINAL RESEARCH ARTICLE
Use of Statins and the Risk of Incident Diabetes: A
Retrospective
Cohort Study
Busuyi S. Olotu1,2,3 • Marvin D. Shepherd2 • Suzanne
Novak2,3 • Kenneth A. Lawson2 •
James P. Wilson2 • Kristin M. Richards2 • Rafia S. Rasu1
� Springer International Publishing Switzerland 2016
Abstract

Introduction Even though several landmark statin trials
have demonstrated the beneficial effects of statin therapy
in both primary and secondary prevention of cardiovas-
cular disease, several studies have suggested that statins
are associated with a moderate increase in risk of new-
onset diabetes. These observations prompted the US
FDA to revise statin labels to include a warning of an
increased risk of incident diabetes mellitus as a result of
increases in glycosylated hemoglobin (HbA1c) and fast-
ing plasma glucose. However, few studies have used US-
based data to investigate this statin-associated increased
risk of diabetes.
Objective The primary objective of our study was to
examine whether the use of statins increases the risk of
incident diabetes mellitus using data from the Thomson
Reuters MarketScan
�
Commercial Claims and Encounters
Database.

Method This study was a retrospective cohort analysis
utilizing data for the period 2003–2004. The study popu-
lation included new statin users aged 20–63 years at index
who did not have a history of diabetes.
Results The proportion (3.4 %) of statin users
(N = 53,212) who had incident diabetes was higher
than the proportion (1.2 %) of non-statin users
(N = 53,212) who had incident diabetes. Compared
with no statin use and controlling for demographic and
clinical covariates, statin use was significantly associ-
ated with increased risk of incident diabetes (hazard
ratio 2.01; 99 % confidence interval 1.74–2.33;
p 0.0001). In addition, risk of diabetes was highest
among users of lovastatin, atorvastatin, simvastatin, and
fluvastatin. Diabetes risk was lowest among pravastatin
and rosuvastatin users.
Discussion Because the potential for diabetogenicity dif-
fers among different statin types, healthcare professionals

should individualize statin therapy by identifying patients
who would benefit more from less diabetogenic statin
types.
& Busuyi S. Olotu
[email protected]
Marvin D. Shepherd
[email protected]
Suzanne Novak
[email protected]
Kenneth A. Lawson
[email protected]
James P. Wilson
[email protected]
Kristin M. Richards
[email protected]
Rafia S. Rasu
[email protected]
1
Department of Pharmacy Practice, University of Kansas
School of Pharmacy, 2010 Becker Dr., Lawrence, KS 66047,
USA
2
Division of Health Outcomes and Pharmacy Practice, College

of Pharmacy, The University of Texas at Austin, 2409
University Avenue A1930, Austin, TX 78712-1120, USA
3
Austin Outcomes Research, 1600 Flintridge Rd,
West Lake Hills, TX 78746, USA
Am J Cardiovasc Drugs
DOI 10.1007/s40256-016-0176-1
http://crossmark.crossref.org/dialog/?doi=10.1007/s40256-016-
0176-1&domain=pdf
http://crossmark.crossref.org/dialog/?doi=10.1007/s40256-016-
0176-1&domain=pdf
Key Points
Statin therapy was significantly associated with
increased risk of new-onset diabetes mellitus.
Risk of diabetes was highest among lovastatin and
atorvastatin users and lowest among pravastatin and
rosuvastatin users.
Statin therapy needs to be individualized by
identifying patients who would benefit more from
less diabetogenic statin types.

1 Introduction
In February 2012, the US FDA approved important safety
labeling changes for statins, including an increased risk of
incident diabetes mellitus as a result of increases in gly-
cosylated hemoglobin (HbA1c) and fasting plasma glucose
(FPG) found to be associated with statin therapy [1]. The
FDA based its decision on a combination of results from
randomized controlled trials (RCTs) [2–5], meta-analyses
of RCTs [6–8], a systematic review [9], and a few obser-
vational studies [10, 11], which indicated an increased risk
of incident diabetes due to statin therapy.
The potential increased risk in diabetes associated with
statin use is significant because patients with dyslipidemia
being treated with statins already have a baseline increased
risk of diabetes due to abnormal lipid levels, combined
with comorbidities such as high blood pressure, increased
weight and body mass index (BMI), metabolic syndrome,
and cardiovascular diseases. Statin-induced diabetes risk is

not a desirable outcome because the already increasing
incidence and prevalence of prediabetes and diagnosed
diabetes contributes significantly to increasing rates of
morbidity and mortality among Americans [12]. Diabetes
is the seventh leading cause of death in the USA, with
attendant complications such as kidney failure, heart
attack, stroke, and amputation [13]. Diabetes also imposes
a substantial economic burden on the US population in the
form of increased direct and indirect medical costs [14].
Several RCTs, meta-analyses of RCTs, and observa-
tional studies have examined the association between statin
use and incidence of diabetes. The JUPITER (Justification
for the Use of Statins in Prevention: an Intervention Trial
Evaluating Rosuvastatin) trial was one of the RCTs the
FDA used in reaching a decision to change the labeling for
all statins [5]. A secondary outcome of the JUPITER study
results showed that rosuvastatin was significantly associ-
ated with a 26 % increased risk of diabetes [5].

Similar to the JUPITER study, the PROSPER (Pravas-
tatin in Elderly Individuals at Risk of Vascular Disease)
study found a 32 % increased risk of diabetes associated
with pravastatin [15]. The results from the JUPITER and
PROSPER studies were consistent with results from other
RCTs [2–4] that showed statins to be associated with
increased risk of diabetes. However, results from other
RCTs showed that statins may be associated with a reduced
risk (or protective effect) of diabetes rather than an
increased risk [16, 17].
Evidence from meta-analyses of RCTs also indicates
that statins may be associated with a moderate increase in
risk of diabetes of about 9 % as found in the 2010 meta-
analysis of 19 RCTs by Sattar et al. [8], the 2011 meta-
analysis of 17 RCTs by Mills et al. [6], and the 2013 meta-
analysis of 55 RCTs by Naci et al. [18].
Evidence from observational studies appears to follow
that observed from RCTs and meta-analyses of RCTs with

respect to the direction and strength of association between
statin therapy and incidence of diabetes. The 2012
prospective cohort study by Culver et al. [11] showed that
statin use was associated with a 47 % increased risk of
new-onset diabetes mellitus among postmenopausal
women participating in the longitudinal WHI (Women’s
Health Initiative) study. The retrospective cohort studies by
Danaei et al. [19], Wang et al. [20], and Zaharan et al. [21]
reported a 14, 15, and 20 % increased risk in diabetes,
respectively. In a more recent retrospective cohort study by
Mansi et al. [22], an 87 % higher odds of incident diabetes
was recorded among statin users compared with non-statin
users.
The main purpose of the present study was to examine
whether the use of statins increases the risk of incident
diabetes mellitus using data from the Thomson Reuters
MarketScan
�

Commercial Claims and Encounters Data-
base. This is warranted because the findings linking statin
therapy to the development of incident diabetes are
inconsistent. While some studies indicate a moderate, sta-
tistically significant increase in risk of diabetes with statin
therapy [2–4, 6–8, 10, 11, 18–21, 23, 24], others indicate
that statins are protective or reduce the risk of diabetes
[16, 17], while still others suggest the increase in risk is not
statistically significant [25–27].
In addition, a majority of the observational studies that
examined the association between statin use and the
development of diabetes were conducted using non-US
population data. Thus, further examination of this topic
among the US population was required. The US population
may differ from other populations in terms of the preva-
lence of risk factors such as overweight, obesity, and car-
diovascular diseases that may put people at an increased
risk of diabetes, independent of the effects of statin therapy

[28]. For example, the USA has the highest rate of obesity
(defined as BMI of C30, an independent risk factor for
diabetes and cardiovascular disease) among all high-
B. S. Olotu et al.
income populations such as those found in North America,
Canada, and Europe [29]. This is in contrast to people from
East Asia (e.g., Taiwan, China, and Japan), the BMIs for
whom are known to be among the lowest in the world [29].
2 Methods
The study protocol submission was granted an institution
review board waiver by the Office of Research Support of
The University of Texas at Austin’s Institution Review
Board because a secondary analysis of de-identified data
does not meet the criteria for human subjects research.
2.1 Study Design
The study utilized a retrospective cohort design using an
administrative claims database containing patients’ phar-

macy and medical claims (i.e., the MarketScan
�
Com-
mercial Claims and Encounters Database) for the period of
1 January 2003 to 31 December 2004. The study popula-
tion consisted of patients in the MarketScan database who
(1) were aged 20–63 years at the index date (defined as
date of the first prescription claim for a statin or a non-
statin drug during the index period 1 July 2003 to 1 January
2004); (2) did not have a diagnosis of diabetes (Interna-
tional Classification of Diseases, Ninth revision, Clinical
Modification [ICD-9-CM] codes 250.xx) in the pre-index
period (defined as a period of at least 6 months before the
first index medication was received) to ensure measure-
ment of incident rather than prevalent diabetes cases; and
(3) were continuously enrolled in their health plan during
the pre-index period and for at least 1 year after the index
date. To further strengthen the association between expo-
sure and outcome, subjects were required to have a mini-

mum drug exposure period of at least 6 months, after
which the outcome (i.e., diabetes occurrence) can be con-
sidered valid. Thus, we excluded diabetes cases that
occurred within 6 months of initial drug exposure.
2.2 Cohort Formation
In the retrospective cohort design, we formed two cohorts of
patients from the retrospective data. The first cohort, called
statin users (or the exposed group) were (1) patients who
received at least one statin prescription for atorvastatin,
fluvastatin, lovastatin, pravastatin, rosuvastatin, or simvas-
tatin during the index period ranging from 1 July 2003 to 1
January 2004; (2) new statin users (i.e., new statin use was
established if a subject had no prescription for a statin
medication in the 6 months before their first statin use; to
establish a history of drug use of at least 6 months, the ear-
liest first use of any statin drug was set at 1 July 2003); and (3)
those who did not fill a statin drug that was in a combined
dosage form with any other drug or agent.

The second cohort, called non-statin users (or the
unexposed group) were patients who did not receive statin
medication. These two cohorts were then ‘‘followed-up’’
until (1) manifestation of diabetes; or (2) end of the follow-
up period (31 December 2004) without manifestation of
diabetes. We based drug exposure on the intention-to-treat
principle (i.e., subjects were assumed to be treated with the
medication to which they were exposed at the index date).
2.3 Outcome Measures and Statistical Analysis
We analyzed the retrospective cohort design using two dif-
ferent statistical methods. This was to assess whether the
magnitude and significance of the risk ratios associating
statin use with diabetes would differ depending on the nature
of the dependent variable. We used the Cox proportional
hazards regression when survival time (defined as the time
from receipt of index medication to manifestation of diabetes
or end of the study period if no diabetes occurred) was the
dependent variable of interest. In contrast, we used the binary

logistic regression analysis when the dependent variable of
interest was presence or no presence of incident diabetes.
Several demographic and clinical covariates were con-
trolled for in each of the regression models, including age,
sex, hyperlipidemia (ICD-9-CM codes 272.0, 272.1, 272.2,
and 272.4), obesity (278.00 and 278.01), hypertension
(401.0, 401.1, and 401.9), number of prescriptions for all
diabetogenic medications used (i.e., thiazide diuretics,
beta-blockers, antipsychotics, antidepressants, immuno-
suppressants, and glucocorticoids), and the Charlson
Comorbidity Index (CCI) score. We estimated this score
using the Dartmouth–Manitoba method [30]. We used
SAS
�
for Windows
�
version 9.3 (SAS Institute, Cary, NC,
USA) and IBM SPSS Statistics version 21 (SPSS Inc.,
Chicago, IL, USA) to perform data manipulation and

analyses and evaluated statistical significance at p 0.01.
2.4 Sensitivity Analysis
Sensitivity analyses were conducted to examine how the risk
ratios were influenced by (1) using two types of statistical
analysis (i.e., Cox and logistic regression models) to estimate
the measures of risk; (2) controlling for significant time-
dependent covariates (i.e., independent variables that vio-
lated the proportionality of hazards assumption) in the Cox
models; and (3) using a regression-based propensity score
covariate adjustment rather than traditionally controlling for
all covariates in both the Cox and the logistic regression
models. Though susceptible to the effects of unmeasured
covariates, propensity score analysis helps reduce the effects
of confounding when using observational data [31].
Statins and Risk of Incident Diabetes
3 Results
3.1 Patient Selection Criteria and Sample Size

Figures 1 and 2 describe the inclusion/exclusion criteria
used in selecting both the statin user and the non-statin
user cohort, respectively. The study sample consisted of
106,424 subjects aged 20–63 years at index date and who
had no evidence of diabetes both in the pre-index period
and 6 months after the index date. The mean length of the
pre-index period used to exclude prevalent diabetes cases
did not significantly differ between statin users
(8.86 months, standard deviation [SD] 1.74) and non-
statin users (8.74 months, SD 1.76). Both the statin and
non-statin user cohorts were followed from the earliest
index date of 1 July 2003 until they had a diagnosis of
diabetes or reached the end of the study period (31
December 2004) without a diabetes diagnosis. The study
sample (N = 106,424) comprised equal proportions of
statin users (N = 53,212) and non-statin users
(N = 53,212).
3.2 Demographic and Clinical Characteristics

Table 1 shows the differences in demographic and clinical
characteristics between statin users and non-statin users.
An independent samples t test showed that mean age was
Unique number of patients using lipid-lowering agents
(N=1,223,169): aged 20-63 at index
Excluded (N=220,032): users of non-statin drugs
Statin users (N=1,003,137)
Excluded (N=902,962): index statin drug cases did not fall
within the index period of July 1, 2003 and January 1, 2004
New statin users (N=100,175)
Excluded (N=3,638): had diabetes during six months of post-
index period
Excluded (N=30,664): had diabetes during the pre-index
period
New statin users without pre-index diabetes (N=69,511)
New statin users without pre-index diabetes and six-months
post-index diabetes (N=65,873)
Statin user cohort (N=53,212)
Excluded (N=12,661): not continuously enrolled during the
pre-index period and for at least a year after the index date
Fig. 1 Inclusion/exclusion
criteria for the statin cohort

B. S. Olotu et al.
significantly higher (p 0.0001) among statin users
(52.1 years) than among non-statin users (40.5 years).
Similarly, the mean CCI score was significantly higher
among statin users (0.24) than among non-statin users
(0.04). In addition, the results showed that the proportion
of statin users with a diagnosis of hyperlipidemia (50.8
vs. 6.1 %), obesity (0.9 vs. 0.3 %), and hypertension (30.6
vs. 4.1 %) was significantly higher than that of non-statin
users. Furthermore, the proportion of statin users who
received at least one diabetogenic medication prescription
(45.6 %) or who had a CCI score of C1 (12.4 %) was
higher than the proportion of non-statin users who
received at least one diabetogenic medication prescription
(12.2 %) or who had a CCI score of C1 (2.3 %). Given
these significant differences, we controlled for all demo-
graphic and clinical variables in the Cox and logistic

regression models.
3.3 Incidence of Diabetes
Table 2 shows a breakdown of the weighted and
unweighted incidence density and cumulative incidence of
diabetes by statin use. A total of 106,424 subjects were
followed for 1,608,088.77 months, and 2478 new cases of
diabetes were found, resulting in an unweighted diabetes
incidence density rate of 1.54 per 1000 person-months or
*A simple random sampling (without replacement) of exactly
N=53,112 from N=395,339. Baseline
characteristics of enrolled (N=53,212) and unenrolled controls
(N=342,127) were not statistically different.
Unique, non-statin index drug cases (N=716,049)
Excluded (N=14,607): aged <20 or >63 at index
Non-statin users aged 20 – 63 years at index (N=701,442)
Excluded (N=1,197): had diabetes during six months of
post-index period
Excluded (N=16,085): had pre-index diabetes
Non-statin users without pre-index diabetes (N=685,357)
Non-statin users without pre-index diabetes and six-months
post-index diabetes

(N=684,160)
Final non-statin user cohort (N=53,212)*
Excluded (N=288,821): not continuously enrolled during
the pre-index period and for at least a year after the index
date
Non-statin user cohort (N=395,339)
Fig. 2 Inclusion/exclusion
criteria for the non-statin cohort
an unweighted diabetes cumulative incidence of 23.2 per
1000 population.
In addition, statin users (N = 53,212) were followed-up
for an average of 15.01 months (SD 1.86, median 15.04)
while non-statin users (N = 53,212) were followed-up for
an average of 15.21 months (SD 1.81, median 15.31). The
unweighted diabetes incidence density rate for statin users
(2.29 per 1000 person-months) was higher than that for
non-statin users (0.8 per 1000 person-months). This means
that, if 1000 statin users were followed-up for 1 month,

2.29 new cases of diabetes would be recorded. This rate is
higher than the 0.8 new cases of diabetes that would be
recorded if 1000 non-statin users were followed-up for
1 month.
Among the statin types, the unweighted diabetes inci-
dence density rate was highest for lovastatin (2.97 per 1000
person-months) and decreased, consecutively, for fluvas-
tatin (2.61 per 1000 person-months), rosuvastatin (2.38 per
1000 person-months), simvastatin (2.29 per 1000 person-
months), and atorvastatin (2.24 per 1000 person-months).
The diabetes incidence density rate was lowest for
pravastatin (2.01 per 1000 person-months).
Table 1 Differences in demographic and clinical characteristics
between statin users and non-statin users
Covariates Statin users (N = 53,212) Non-statin users (N =
53,212) Significance
Age 52.1 ± 7.8 40.5 ± 11.9 p 0.0001
Categorized p 0.0001
20–34 1633 (3.1) 17,327 (32.6)
35–44 7224 (13.6) 14,572 (27.4)

45–54 20,186 (37.9) 13,820 (26.0)
55–63 24,169 (45.4) 7493 (14.1)
Sex p 0.0001
Male 26,704 (50.2) 27,694 (52.0)
Female 26,508 (49.8) 25,518 (48.0)
Hyperlipidemia
a
27,007 (50.8) 3245 (6.1) p 0.0001
Obesity
a
498 (0.9) 165 (0.3) p 0.0001
Hypertension
a
16,278 (30.6) 2175 (4.1) p 0.0001
Diabetogenic medications 5.9 ± 9.1 0.8 ± 3.1 p 0.0001
Categorized
b
p 0.0001
0 28,917 (54.3) 46,696 (87.8)
1–5 5400 (10.1) 3579 (6.7)
6–10 5413 (10.2) 1515 (2.8)
[10 13,482 (25.3) 1422 (2.7)

Type
c
Thiazides 4797 (9.0) 1006 (1.9) p 0.0001
Beta-blockers 11,928 (22.4) 1698 (3.2) p 0.0001
Antipsychotics 740 (1.4) 181 (0.3) p 0.0001
Antidepressants 13,617 (25.6) 4497 (8.5) p 0.0001
Immunosuppressants 203 (0.4) 33 (0.1) p 0.0001
Glucocorticoids 52 (0.1) 32 (0.1) p = 0.029
Charlson comorbidity index score 0.24 ± 0.92 0.04 ± 0.39 p
0.0001
Categorized p 0.0001
0 46,599 (87.6) 52,021 (97.8)
1–5 6009 (11.3) 1093 (2.1)
6–10 596 (1.1) 97 (0.2)
[10 8 (0.02) 1 (0.002)
Data are presented as N (%) or mean ± standard deviation
a
Proportion of statin users and non-statin users who had a
diagnosis of the indicated condition
b
Categorized number of prescriptions for all diabetogenic
medications
c
Proportion of statin users and non-statin users who used each
type of diabetogenic medication
B. S. Olotu et al.

3.4 Kaplan–Meier Survival Analysis by Exposure
Type
Study results showed that the estimated mean survival time
(i.e., time to a diabetes diagnosis in months) for statin users
(17.8, standard error [SE] 0.006) was shorter than that for
non-statin users (18.0, SE 0.003).
In addition, Fig. 3 shows two Kaplan–Meier survival
curves comparing the survival probabilities against time
for statin users and non-statin users. The log-rank test
comparing the distribution of the two survival curves
showed that statin users had a significantly shorter sur-
vival probability over time than non-statin users
(v2 = 604; df = 1; p 0.0001). From Fig. 3, the
12-month survival probability for statin users (98.6 %)
was lower than that for non-statin users (99.3 %). At
18 months, the survival probability for statin users fell to
0.963 (i.e., 96.3 % of statin users survived past 18 months

without having diabetes) compared with 98.2 % of non-
statin users who survived past 18 months without having
diabetes. Thus, statin users had a shorter survival time
(and shorter survival probabilities over time) than non-
statin users.
3.5 Kaplan–Meier Survival Analysis by Statin Type
Study results showed that the estimated mean survival time
(in months) was shortest among rosuvastatin users (16.15,
SE 0.03) and increased, consecutively, among lovastatin
(17.74, SE 0.02), fluvastatin (17.77, SE 0.03), simvastatin
(17.80, SE 0.01), and atorvastatin (17.81, SE 0.01) users.
Pravastatin (17.83, SE 0.02) users had the longest esti-
mated mean survival time.
In addition, Fig. 4 shows six Kaplan–Meier survival
curves comparing the survival probabilities against time
among users of different statin types. The log-rank test
comparing the distributions of the six survival curves
showed that at least one of the survival curves significantly

differed from another (v2 = 20.5; df = 5; p = 0.001).
3.6 Cox Proportional Hazards Regression Models
Table 3 shows the results of the Cox proportional hazards
regression model comparing the hazard of diabetes
between statin users and non-statin users and between users
of each statin type and non-statin users while controlling
for demographic and clinical covariates. Sensitivity
Table 2 Weighted
a
and unweighted incidence density and cumulative incidence of
diabetes by statin use
Subjects (N)
[a]
Sum of follow-up
months (person-months)
[b]
Number of new
cases of diabetes
[c]
Incidence density rate

(per 1000 person-months)
[c/b 9 1000]
Cumulative incidence
(per 1000 population)
[c/a 9 1000]
Study population 106,424 1,608,088.77 2478 1.54 23.2
4,554,802 68,836,394.87 115,720 1.68 25.4
Statin users 53,212 798,909.73 1833 2.29 34.4
2,454,285 36,851,101.44 88,208 2.39 35.9
Non-statin users 53,212 809,179.03 645 0.80 12.1
2,100,517 31,985,293.44 27,512 0.86 13.1
Atorvastatin users 27,155 408,534.83 917 2.24 33.8
1,245,296 18,730,198.34 44,408 2.37 35.7
Fluvastatin users 1638 24,883.32 65 2.61 39.7
76,533 1,163,607.06 3013 2.59 39.4
Lovastatin users 3570 53,448.25 159 2.97 44.5
178,617 2,673,568.39 8359 3.13 46.8
Pravastatin users 5870 89,767.29 180 2.01 30.7

275,824 4,215,723.83 8945 2.12 32.4
Rosuvastatin users 2766 37,341.83 89 2.38 32.2
124,383 1,678,244.14 4249 2.53 34.2
Simvastatin users 12,213 184,934.21 423 2.29 34.6
553,632 8,389,759.67 19,234 2.29 34.7
a
Weighted values are in italics. MarketScan person-level
national weights (available as a weight variable in the data)
were constructed utilizing
weight estimates from the Household Component of the Medical
Expenditure Panel Survey (MEPS). MEPS weights account for
demographic
variables that include region (northeast, north central, south,
west); age (0–17, 18–44, 45–64 years); and sex (male, female).
The MarketScan
weight is the ratio of MEPS-based estimates in the different
age/sex/region categories and the MarketScan number in the
same category
Fig. 3 Comparison of the
survival probability curves of
statin users and non-statin users

Fig. 4 Graph comparing the
survival probability curves of
different statin types
B. S. Olotu et al.
analysis of the hazard ratios (HRs) adjusting for significant
time-dependent covariates and utilizing propensity score
adjustment is also presented.
Compared with no statin use, and controlling for
covariates, statin use (as a class) was significantly associ-
ated with increased risk of incident diabetes mellitus (HR
2.01; 99 % confidence interval [CI] 1.74–2.33;
p 0.0001). In other words, the hazard of incident dia-
betes for statin users was two times that for non-statin
users.
Except for pravastatin use, which was associated with a
non-significant increase in diabetes risk, the use of ator-
vastatin, fluvastatin, lovastatin, rosuvastatin, or simvastatin
was significantly associated with an increased risk of

incident diabetes. The risk of diabetes was highest among
lovastatin users (HR 2.07) and lowest among pravastatin
users (HR 1.29).
3.7 Logistic Regression Models
Table 4 shows the results of the logistic regression model
comparing the odds of incident diabetes between statin
users and non-statin users and between users of each statin
type and non-statin users while controlling for demo-
graphic and clinical covariates. Sensitivity analysis of the
odds ratios (ORs) utilizing propensity score adjustment is
also presented. Except for the non-significance of the OR
for the rosuvastatin group, the results of the logistic
regression did not differ significantly from the results
obtained for the Cox regression in terms of the magnitude
and significance of the HRs and ORs.
The results obtained for the logistic regression model
also suggest that statin use was significantly associated
with increased risk of diabetes. Except for pravastatin and

rosuvastatin users, who had non-significant increases in
risk, diabetes risk was significantly associated with the
use of atorvastatin, fluvastatin, lovastatin, or simvastatin.
The risk of diabetes was highest among lovastatin users
(OR 2.05) and lowest among rosuvastatin users (OR
1.21).
3.8 Sensitivity Analysis
As presented above, the results obtained for the Cox and
logistic regression analyses were similar in terms of the
magnitude and significance of the HRs and ORs. In addi-
tion, compared with the original Cox regression models,
where only demographic and clinical covariates were
adjusted for, further adjusting for significant time-depen-
dent covariates did not change the magnitude and signifi-
cance of the HRs (Table 3). However, the use of propensity
score adjustment in lieu of including all covariates in the
original Cox model was associated with (1) an increase in
the magnitude of the HRs for all statin users and users of

Table 3 Cox proportional hazards regression showing the
association between statin use and incidence of diabetes
Total Incident
diabetes cases
Cox regression
a
Cox regression adjusting for significant
time-dependent covariates
a,b
Cox regression with
propensity score adjustment
Statin users 53,212 (100.0) 1833 (3.4) 2.01 (1.74–2.33)* 2.01
(1.74–2.33)* 2.07 (1.77–2.42)*
Atorvastatin 27,155 (51.0) 917 (3.4) 1.88 (1.59–2.24)* 1.89
(1.59–2.24)* 1.95 (1.62–2.35)*
Fluvastatin 1638 (3.1) 65 (4.0) 1.60 (1.08–2.38)
[p = 0.002]
1.60 (1.08–2.38) [p = 0.002] 1.95 (1.28–2.96)*
Lovastatin 3570 (6.7) 159 (4.5) 2.07 (1.57–2.74)* 2.09 (1.58–
2.76)* 2.45 (1.82–3.25)*
Pravastatin 5870 (11.0) 180 (3.1) 1.29 (0.97–1.70)

[p = 0.019]
1.29 (0.98–1.70) [p = 0.019] 1.40 (1.04–1.87) [p = 0.003]
Rosuvastatin 2766 (5.2) 89 (3.2) 1.58 (1.10–2.27)
[p = 0.001]
1.59 (1.10–2.28) [p = 0.001] 1.75 (1.19–2.56)*
Simvastatin 12,213 (23.0) 423 (3.5) 1.71 (1.38–2.12)* 1.72
(1.39–2.13)* 1.79 (1.43–2.24)*
Non-statin
users
c
53,212 (100.0) 645 (1.2) Reference Reference Reference
Data are presented as N (%) or hazard ratio (99 % confidence
interval) [p value]
* Significant at p 0.0001 (the significance of each parameter
estimate was evaluated at p 0.01)
a
Demographic and clinical covariates controlled for in each
model include age, sex, hyperlipidemia, obesity, hypertension,
use of diabetogenic
medications, and Charlson Comorbidity Index score
b
Significant time-dependent covariates controlled for in the
models included statin model (sex, hyperlipidemia,
hypertension, and diabetogenic

medication); atorvastatin model (sex, hyperlipidemia, and
diabetogenic medication); fluvastatin model (age and
diabetogenic medication);
lovastatin model (sex and diabetogenic medication); pravastatin
model (sex, hyperlipidemia, and diabetogenic medication);
rosuvastatin model
(sex and diabetogenic medication); simvastatin model
(hyperlipidemia and diabetogenic medication)
c
Reference category for statin users and users of atorvastatin,
fluvastatin, lovastatin, pravastatin, rosuvastatin, and simvastatin
each statin type, and (2) the HR for pravastatin becoming
significant (p = 0.019 vs. p = 0.003).
Similar to above, using a propensity score adjustment in
lieu of including all covariates in the original logistic
regression model resulted in an increase in the magnitude
of the OR for all statin users and users of each statin type.
In addition, the HR for pravastatin became significant
(p = 0.01 vs. p = 0.001). However, the association of
rosuvastatin therapy and risk of diabetes remained non-

statistically significant even with propensity score adjust-
ment (p = 0.19 vs. p = 0.05) (see Table 4).
Furthermore, because of the potential problem of
immortal time bias, we analyzed the data without requiring
subjects to have a treatment duration of at least 6 months
before a diagnosis of diabetes could be considered valid.
Results of this sensitivity analyses revealed that the magni-
tude of the HRs increased for statin users and users of each
statin type, since more cases of incident diabetes would be
included. In this sensitivity analysis, the HR comparing the
risk of diabetes among statin users with that of non-statin
users are as follows: all statin users (HR 2.75), atorvastatin
(HR 2.43), fluvastatin (HR 2.06), lovastatin (HR 3.41),
pravastatin (HR 1.89), rosuvastatin (HR 1.62), and simvas-
tatin (HR 1.53). All associations were significant atp 0.01.
4 Discussion
4.1 Incidence of Diabetes
The unadjusted cumulative incidence of diabetes (over

2003–2004) among this study sample aged 20–63 years was
23.2 per 1000 population. This rate is higher than the unad-
justed incidence of diabetes of 7.8 per 1000 population of US
adults aged C20 years [12]. This discrepancy may be
because statin users constituted half the study population at
risk in this study, and statin users may be more likely than the
average population to have several risk factors for diabetes.
Thus, it might be reasonable that the rate of incident diabetes
for the current study population would be higher than that of
the US population that does not have half its population at
risk composed essentially of statin users.
However, the unadjusted diabetes incident density rate
obtained among this study population (1.54 per 1000 per-
son-months) was comparable to rates (unadjusted) obtained
in similar population-based observational studies of statin
use and incidence of diabetes as reported by Culver et al.
[11] (0.85 per 1000 person-months), Danaei et al. [19]
(0.96 per 1000 person-months), and Wang et al. [20] (1.75

per 1000 person-months).
Furthermore, only one observational study has com-
pared diabetes incident density rates between statin users
and non-statin users [19]. The unadjusted diabetes incident
density rates reported among statin users (2.29 per 1000
person-months) and non-statin users (0.8 per 1000 person-
months) in this study were comparable to those reported in
the Danaei et al. [19] study, which examined the risk of
type 2 diabetes mellitus among 285,864 men and women
aged 50–84 years. In that study, the unadjusted diabetes
incidence density rates for statin users (or statin ‘‘initia-
tors’’) and non-statin users (or statin ‘‘non-initiators’’) were
1.30 per 1000 person-months and 0.94 per 1000 person-
months, respectively [19].
4.2 Statin Use and Risk of Diabetes
The results of the Cox and logistic regression analyses
showed that the risk of incident diabetes was higher among
Table 4 Binary logistic regression analysis showing the

association between statin use and incidence of diabetes
Total Incident diabetes
cases
Logistic regression
a
Logistic regression with propensity
score adjustment
Statin users 53,212 (100.0) 1833 (3.4) 2.01 (1.74–2.33)* 2.07
(1.76–2.43)*
Atorvastatin 27,155 (51.0) 917 (3.4) 1.89 (1.59–2.25)* 1.96
(1.63–2.36)*
Fluvastatin 1638 (3.1) 65 (4.0) 1.64 (1.10–2.46) [p = 0.001]
1.99 (1.30–3.05)*
Lovastatin 3570 (6.7) 159 (4.5) 2.05 (1.54–2.72)* 2.40 (1.79–
3.21)*
Pravastatin 5870 (11.0) 180 (3.1) 1.33 (1.00–1.76) [p = 0.01]
1.44 (1.07–1.94) [p = 0.001]
Rosuvastatin 2766 (5.2) 89 (3.2) 1.21 (0.84–1.74) [p = 0.19]
1.33 (0.91–1.96) [p = 0.05]
Simvastatin 12,213 (23.0) 423 (3.5) 1.74 (1.40–2.15)* 1.81
(1.44–2.27)*
Non-statin users
b

53,212 (100.0) 645 (1.2) Reference Reference
Data are presented as N (%) or odds ratio (99 % confidence
interval) [p value]
* Significant at p 0.0001 (the significance of each parameter
estimate was evaluated at p 0.01)
a
Demographic and clinical covariates controlled for in each
model include age, sex, hyperlipidemia, obesity, hypertension,
use of diabetogenic
medications, and Charlson Comorbidity Index score
b
Reference category for statin users and users of atorvastatin,
fluvastatin, lovastatin, pravastatin, rosuvastatin, and simvastatin
B. S. Olotu et al.
statin users than among non-statin users. Even though the
strength of association (or magnitude of the risk ratios) of
statin use and incidence of diabetes was higher in this study
(HR 2.01 and OR 2.01), the increase in the risk of diabetes
that was associated with statin therapy, compared with no
statin therapy, is consistent with increases reported in
several observational studies. Statin therapy was signifi-

cantly associated with a 14, 15, 20, and 48 % increase in
risk of incident diabetes, respectively, in the retrospective
cohort studies by Danaei et al. [19] (HR 1.14, 95 % CI
1.10–1.19), Wang et al. [20] (HR 1.15, 95 % CI
1.08–1.22), and Zaharan et al. [21] (HR 1.20, 95 % CI
1.17–1.23), and the prospective cohort study by Culver
et al. [11] (HR 1.48, 95 % CI 1.38–1.59). Our study results
were more consistent with a 2015 retrospective cohort
study of statin use among healthy US adults by Mansi et al.
[22], which reported an 87 % increase in the odds of dia-
betes with statin use (OR 1.87, 95 % CI 1.67–2.01).
Meanwhile, the 2013 prospective cohort study by Izzo
et al. [27] (HR 1.03, 95 % CI 0.79–1.35) and the 2004
case–control study by Jick and Bradbury [26] (OR 1.1,
95 % CI 0.8–1.4) found that statin therapy was not sig-
nificantly associated with increased risk of diabetes
mellitus.
4.3 Comparison of the Risk of Diabetes Among

Users of Different Statin Types
The results of the Cox and logistic regression analyses
showed that lovastatin users (HR 2.07, OR 2.05) had the
highest risk of new-onset diabetes; this was followed,
consecutively, by users of atorvastatin (HR 1.88, OR 1.89),
simvastatin (HR 1.71, OR 1.74), and fluvastatin (HR 1.60,
OR 1.64). Rosuvastatin (HR 1.58, OR 1.21) and pravastatin
(HR 1.29, OR 1.33) users had the least risk of new-onset
diabetes among all statin users.
The potency hypothesis [32]—which correlates higher
statin potencies with more side effects—does not seem to
explain why the risks of diabetes were highest among users
of lovastatin, atorvastatin, simvastatin, or fluvastatin since
higher potency statins such as atorvastatin, rosuvastatin,
and simvastatin would be expected to have consistently
higher risk ratios than lower potency statins such as
lovastatin, pravastatin, and fluvastatin.
Evaluation of current observational studies of statin use

and incidence of diabetes [11, 19–21, 26, 27, 33–37]
appears to suggest that simvastatin and atorvastatin had the
greatest potential to be significantly associated with
increased risk of incident diabetes, while fluvastatin and
lovastatin had the least potential to be significantly asso-
ciated with an increase in risk. Pravastatin and rosuvastatin
appear to have moderate potential to be significantly
associated with increased risk of diabetes. This observation
is partly consistent with our results, which showed that
lovastatin, atorvastatin, simvastatin, and fluvastatin had the
strongest association with risk of diabetes, while pravas-
tatin and rosuvastatin had moderate associations with dia-
betes risk.
4.4 Study Strengths and Limitations
This study confirmed the hypothesis that statin therapy is
associated with an increase in risk of diabetes and helped
fill some gaps in the literature because there are few
observational studies examining this phenomenon using

US population data. This is significant because the US
population may differ from other populations in terms of
the risk factors for diabetes mellitus. The results of this
study further confirm the findings of other studies con-
ducted among US adult populations, where a higher dia-
betes risk was associated with statin therapy [10, 11, 22].
The current study has some limitations; however, it is
worthwhile to acknowledge some of its merits. First, the
study was adequately powered to detect significant asso-
ciations between statin use and incidence of diabetes if they
truly existed. Second, the study utilized two different sta-
tistical approaches, including the use of propensity score
covariate adjustment, to estimate the risk of diabetes
associated with statin use. To our knowledge, this is the
first observational study of statin use and incidence of
diabetes to conduct several sensitivity analyses utilizing a
combination of robust statistical methodologies.
Despite these study strengths, it is important that the

study results be interpreted in light of its limitations. One
of the main study limitations was the possibility of disease
misclassification. Because the data were limited to 2 years
in length, a short pre-index period (ranging between
6 months and 1 year) was used to identify and exclude
prevalent diabetes cases. This has the potential to increase
diabetes incidence among the study population, as some
prevalent diabetes cases may be misclassified as incident
diabetes cases. However, this limitation might be attenu-
ated by both statin users and non-statin users being equally
exposed to the same sets of study inclusion and exclusion
criteria and by further excluding diabetes cases that
occurred within 6 months of subjects starting their medi-
cations. In addition, the length of the pre-index period used
to exclude prevalent diabetes cases did not significantly
differ between statin users and non-statin users. However,
utilizing a longer pre-index period to exclude prevalent
diabetes cases would have strengthened the argument for

the associations observed.
Second, we were not able to control for some variables
that may increase diabetes risk in one group compared with
another, independent of statin use. These variables include
race/ethnicity, family history of diabetes, cholesterol level,
body mass index, and presence or absence of prediabetes.
We attempted to attenuate these limitations by (1) adjusting
for disease comorbidities (using the CCI score, which
accounted for baseline diseases such as myocardial
infarction, congestive heart failure, peripheral vascular
disease, cerebrovascular disease, dementia, chronic pul-
monary disease, rheumatologic disease, peptic ulcer dis-
ease, mild or severe liver disease, hemiplegia, renal
disease, any malignancy, and AIDS) and accounting for the
use of diabetogenic medications, (2) controlling for obesity
(though under-reported in the data), hypertension, and

hyperlipidemia diagnoses, and (3) utilizing a regression-
based propensity score covariate adjustment. In particular,
obesity was under-reported in our data and may not be
adequately controlled for. Since obesity and metabolic
syndrome are important risk factors for diabetes and may
be more prevalent among statin users, it is possible that the
increased risk of diabetes observed among statin users is
partly explained by these inadequately controlled-for
variables. Future observational studies should fully adjust
for these important variables that could account for the
increased risk of diabetes, irrespective of statin therapy.
Finally, the MarketScan Database that was used for this
study used data collected in 2003–2004 and did not include
people aged C65 years. Changes in statin prescribing and
utilization patterns means there is a possibility that study
results might be different if current data were applied. In
addition, bias could be introduced because older people
may have more comorbidities and risk factors for diabetes.

Furthermore, the dataset was sourced mainly from large
employers with private insurance and, therefore, may not
generalize well to the entire US population or to other US
populations such as Medicaid, Medicare, and uninsured
populations.
4.5 Study Implications
Although the benefit of statins in primary and secondary
prevention of cardiovascular disease is well-documented,
this study and several other studies have suggested that
statins are associated with a moderate increase in risk of
new-onset diabetes. These previous observations
prompted the FDA to revise statin labels to include a
warning of an increased risk of incident diabetes mellitus
[1]. Even though the precise pathway by which statins
induce incident diabetes is still unclear, statins are
thought to worsen glycemic control and increase FPG
and insulin resistance, thereby possibly leading to dia-
betes mellitus [10].

Because types and doses of statin differ in their ability
to reduce low-density lipoprotein cholesterol (i.e., the
‘‘bad’’ cholesterol) as well as in their diabetogenic
potential, Navarese et al. [32] suggested there might be a
need for physicians to individualize statin therapy, espe-
cially among people with low cardiovascular risk. This
tailored therapy should be based on sound clinical judg-
ment, the patient’s overall cardiovascular risk and meta-
bolic profile, and the type and dose of statin used [32].
According to Navarese et al. [32], pravastatin seems to be
the least diabetogenic statin currently available on the
market, and it could be ideal for patients with hyperlipi-
demia who have a low risk of cardiovascular disease but
who have a high predisposition for diabetes. The results
of this study also support this argument, as the risk of
diabetes was lowest among pravastatin and rosuvastatin
users. However, it should be noted that even though study
results indicate that statin therapy may be associated with

increased diabetes risk, there is evidence that the car-
diovascular benefits offered by statin therapy may out-
weigh the potential for increased risk in diabetes. The
meta-analysis of 13 statin trials with 91,140 participants
by Sattar et al. [8] indicated that statin therapy was
associated with 5.4 fewer deaths from coronary heart
disease and non-fatal myocardial infarction per 255
patients treated over 4 years. This is in contrast to only
one additional case of new-onset diabetes recorded per
255 patients treated with statins over 4 years [8].
5 Conclusion
The results of the study lend support to the hypothesis that
statin therapy is significantly associated with increased risk
of new-onset diabetes. This increased risk was found not
only in the use of statins as a class, but each statin type was
also significantly associated with an increased risk of
incident diabetes mellitus. Nevertheless, healthcare pro-
fessionals can use a targeted approach to optimize the

management of their patients by identifying those who
would benefit more from less diabetogenic statin types.
Acknowledgments The authors acknowledge Thomson Reuters
for
providing us with the 2003–2004 MarketScan data as part of the
Thomson Reuter’s MarketScan Dissertation Support Program.
Compliance with Ethical Standards
This study complied with standards required for observational
study
of de-identified data. The study did not involve human subjects.
Funding No external funding was used in the preparation of this
manuscript.
Conflict of interest All authors, Busuyi Olotu, Marvin
Shepherd,
Suzanne Novak, Kenneth Lawson, James Wilson, Kristin
Richards,
and Rafia Rasu, declare they have no conflicts of interest that
might
be relevant to the contents of this manuscript.
B. S. Olotu et al.
References

1. US Food and Drug Administration. FDA Drug Safety
Commu-
nication: Important safety label changes to cholesterol-lowering
statin drugs. 2012. http://www.fda.gov/Drugs/DrugSafety/
ucm293101.htm. Accessed 12 May 2012.
2. Koh KK, Quon MJ, Han SH, Lee Y, Kim SJ, Shin EK. Ator-
vastatin causes insulin resistance and increases ambient
glycemia
in hypercholesterolemic patients. J Am Coll Cardiol.
2010;55(12):1209–16. doi:10.1016/j.jacc.2009.10.053.
3. Sabatine MS, Wiviott SD, Morrow DA, McCabe CH, Cannon
CP.
High-dose atorvastatin associated with worse glycemic control:
a
PROVE-IT TIMI 22 substudy. Circ J. 2004;110(Suppl I):S834.
4. Thongtang N, Ai M, Otokozawa S, Himbergen TV, Asztalos
BF,
Nakajima K, et al. Effects of maximal atorvastatin and rosuvas-
tatin treatment on markers of glucose homeostasis and inflam-
mation. Am J Cardiol. 2011;107(3):387–92. doi:10.1016/j.
amjcard.2010.09.031.

5. Ridker PM, Danielson E, Fonseca FA, Genest J, Gotto AM Jr,
Kastelein JJ, et al. Rosuvastatin to prevent vascular events in
men
and women with elevated C-reactive protein. N Engl J Med.
2008;359(21):2195–207. doi:10.1056/NEJMoa0807646.
6. Mills EJ, Wu P, Chong G, Ghement I, Singh S, Akl EA, et al.
Efficacy and safety of statin treatment for cardiovascular
disease:
a network meta-analysis of 170,255 patients from 76
randomized
trials. QJM. 2011;104(2):109–24. doi:10.1093/qjmed/hcq165.
7. Rajpathak SN, Kumbhani DJ, Crandall J, Barzilai N,
Alderman
M, Ridker PM. Statin therapy and risk of developing type 2
diabetes: a meta-analysis. Diabetes Care. 2009;32(10):1924–9.
doi:10.2337/dc09-0738.
8. Sattar N, Preiss D, Murray HM, Welsh P, Buckley BM, de
Craen
AJM, et al. Statins and risk of incident diabetes: a collaborative
meta-analysis of randomised statin trials. Lancet.

2010;375(9716):735–42. doi:10.1016/s0140-6736(09)61965-6.
9. Kostapanos MS, Liamis GL, Milionis HJ, Elisaf MS. Do
statins
beneficially or adversely affect glucose homeostasis? Curr Vasc
Pharmacol. 2010;8(5):612–31.
10. Sukhija R, Prayaga S, Marashdeh M, Bursac Z, Kakar P,
Bansal
D, et al. Effect of statins on fasting plasma glucose in diabetic
and
nondiabetic patients. J Investig Med. 2009;57(3):495–9. doi:10.
231/JIM.0b013e318197ec8b.
11. Culver AL, Ockene IS, Balasubramanian R, Olendzki BC,
Sepavich DM, Wactawski-Wende J, et al. Statin use and risk of
diabetes mellitus in postmenopausal women in the Women’s
Health Initiative. Arch Intern Med. 2012;172(2):144–52. doi:10.
1001/archinternmed.2011.625.
12. US Centers for Disease Control and Prevention. National
diabetes
statistics report: estimates of diabetes and its burden in the
United
States, 2014. Atlanta: US Department of Health and Human

Services;
2014.
13. Centers for Disease Control and Prevention. Leading causes
of
death. 2015. http://www.cdc.gov/nchs/fastats/leading-causes-of-
death.htm. Accessed 28 Nov 2015.
14. American Diabetes Association. Economic costs of diabetes
in
the US in 2012. Diabetes Care. 2013;36(4):1033–46. doi:10.
2337/dc12-2625.
15. Shepherd J, Blauw GJ, Murphy MB, Bollen EL, Buckley
BM,
Cobbe SM, et al. Pravastatin in elderly individuals at risk of
vascular disease (PROSPER): a randomised controlled trial.
Lancet. 2002;360(9346):1623–30. doi:10.1016/S0140-
6736(02)11600-X.
16. Downs JR, Clearfield M, Weis S, Whitney E, Shapiro DR,
Beere
PA, et al. Primary prevention of acute coronary events with
lovastatin in men and women with average cholesterol levels:

results of AFCAPS/TexCAPS. Air Force/Texas Coronary
Atherosclerosis Prevention Study. JAMA.
1998;279(20):1615–22. doi:10.1001/jama.279.20.1615.
17. Shepherd J, Cobbe SM, Ford I, Isles CG, Lorimer AR,
MacFar-
lane PW, et al. Prevention of coronary heart disease with
pravastatin in men with hypercholesterolemia. West of Scotland
Coronary Prevention Study Group. N Engl J Med.
1995;333(20):1301–7. doi:10.1056/NEJM199511163332001.
18. Naci H, Brugts J, Ades T. Comparative tolerability and
harms of
individual statins: a study-level network meta-analysis of 246
955
participants from 135 randomized, controlled trials. Circ
Cardiovasc
Qual Outcomes.2013;6(4):390–9.
doi:10.1161/CIRCOUTCOMES.
111.000071.
19. Danaei G, Garcı́a Rodrı́guez LA, Fernandez Cantero O,
Hernán
MA. Statins and risk of diabetes: an analysis of electronic med-

ical records to evaluate possible bias due to differential
survival.
Diabetes Care. 2013;36(5):1236.
20. Wang KL, Liu CJ, Chao TF, Huang CM, Wu CH, Chen SJ,
et al.
Statins, risk of diabetes, and implications on outcomes in the
general population. J Am Coll Cardiol. 2012;60(14):1231–8.
doi:10.1016/j.jacc.2012.05.019.
21. Zaharan NL, Williams D, Bennett K. Statins and risk of
treated
incident diabetes in a primary care population. Br J Clin Phar-
macol. 2013;75(4):1118–24. doi:10.1111/j.1365-2125.2012.
04403.x.
22. Mansi I, Frei CR, Wang CP, Mortensen EM. Statins and
new-
onset diabetes mellitus and diabetic complications: a retrospec-
tive cohort study of US healthy adults. J Gen Intern Med.
2015;30(11):1599–610. doi:10.1007/s11606-015-3335-1.
23. Coleman CI, Reinhart K, Kluger J, White CM. The effect of
statins on the development of new-onset type 2 diabetes: a
meta-

analysis of randomized controlled trials. Curr Med Res Opin.
2008;24(5):1359–62. doi:10.1185/030079908x292029.
24. Navarese EP, Buffon A, Andreotti F, Kozinski M, Welton N,
Fabiszak T, et al. Meta-analysis of impact of different types and
doses of statins on new-onset diabetes mellitus. Am J Cardiol.
2013;111(8):1123–30. doi:10.1016/j.amjcard.2012.12.037.
25. Nakamura H, Arakawa K, Itakura H, Kitabatake A, Goto Y,
Toyota T, et al. Primary prevention of cardiovascular disease
with pravastatin in Japan (MEGA Study): a prospective ran-
domised controlled trial. Lancet. 2006;368(9542):1155–63.
doi:10.1016/s0140-6736(06)69472-5.
26. Jick SS, Bradbury BD. Statins and newly diagnosed
diabetes. Br J
Clin Pharmacol. 2004;58(3):303–9. doi:10.1111/j.1365-2125.
2004.02142.x.
27. IzzoR,deSimoneG,TrimarcoV,GiudiceR,DeMarcoM,DiRenzo
G, et al. Primary prevention with statins and incident diabetes
in
hypertensive patients at high cardiovascular risk. Nutr Metab

Car-
diovasc Dis. 2013;. doi:10.1016/j.numecd.2012.11.002.
28. Graham I, Cooney MT, Bradley D, Dudina A, Reiner Z.
Dys-
lipidemias in the prevention of cardiovascular disease: risks and
causality. Curr Cardiol Rep. 2012;14(6):709–20. doi:10.1007/
s11886-012-0313-7.
29. Finucane MM, Stevens GA, Cowan MJ, Danaei G, Lin JK,
Paciorek CJ, et al. National, regional, and global trends in
body-
mass index since 1980: systematic analysis of health
examination
surveys and epidemiological studies with 960 country-years and
9.1 million participants. Lancet. 2011;377(9765):557–67.
doi:10.
1016/s0140-6736(10)62037-5.
30. Romano PS, Roos LL, Jollis JG. Adapting a clinical
comorbidity
index for use with ICD-9-CM administrative data: differing
perspectives. J Clin Epidemiol. 1993;46(10):1075–9. doi:10.
1016/0895-4356(93)90103-8 (discussion 81–90).

31. Austin PC. An introduction to propensity score methods for
reducing the effects of confounding in observational studies.
Multivariate Behav Res. 2011;46(3):399–424. doi:10.1080/
00273171.2011.568786.
http://www.fda.gov/Drugs/DrugSafety/ucm293101.htm
http://www.fda.gov/Drugs/DrugSafety/ucm293101.htm
http://dx.doi.org/10.1016/j.jacc.2009.10.053
http://dx.doi.org/10.1016/j.amjcard.2010.09.031
http://dx.doi.org/10.1056/NEJMoa0807646
http://dx.doi.org/10.1093/qjmed/hcq165
http://dx.doi.org/10.2337/dc09-0738
http://dx.doi.org/10.1016/s0140-6736(09)61965-6
http://dx.doi.org/10.231/JIM.0b013e318197ec8b
http://dx.doi.org/10.231/JIM.0b013e318197ec8b
http://dx.doi.org/10.1001/archinternmed.2011.625
http://dx.doi.org/10.1001/archinternmed.2011.625
http://www.cdc.gov/nchs/fastats/leading-causes-of-death.htm
http://www.cdc.gov/nchs/fastats/leading-causes-of-death.htm
http://dx.doi.org/10.1016/S0140-6736(02)11600-X
http://dx.doi.org/10.1016/S0140-6736(02)11600-X
http://dx.doi.org/10.1001/jama.279.20.1615
http://dx.doi.org/10.1056/NEJM199511163332001
http://dx.doi.org/10.1161/CIRCOUTCOMES.111.000071
http://dx.doi.org/10.1161/CIRCOUTCOMES.111.000071
http://dx.doi.org/10.1016/j.jacc.2012.05.019
http://dx.doi.org/10.1111/j.1365-2125.2012.04403.x

http://dx.doi.org/10.1007/s11606-015-3335-1
http://dx.doi.org/10.1185/030079908x292029
http://dx.doi.org/10.1016/j.numecd.2012.11.002
http://dx.doi.org/10.1016/0895-4356(93)90103-8
http://dx.doi.org/10.1016/0895-4356(93)90103-8
http://dx.doi.org/10.1080/00273171.2011.568786
http://dx.doi.org/10.1080/00273171.2011.568786
32. Navarese EP, Szczesniak A, Kolodziejczak M, Gorny B,
Kubica
J, Suryapranata H. Statins and risk of new-onset diabetes melli-
tus: is there a rationale for individualized statin therapy? Am J
Cardiovasc Drugs. 2014;14(2):79–87. doi:10.1007/s40256-013-
0053-0.
33. Chen CW, Chen TC, Huang KY, Chou P, Chen PF, Lee CC.
Differential impact of statin on new-onset diabetes in different
age groups: a population-based case–control study in women
from an Asian country. PLoS One. 2013;8(8):e71817. doi:10.

1371/journal.pone.0071817.
34. Carter AA, Gomes T, Camacho X, Juurlink DN, Shah BR,
Mamdani MM. Risk of incident diabetes among patients treated
with statins: population based study. BMJ. 2013;346:f2610.
doi:10.1136/bmj.f2610.
35. Ko DT, Wijeysundera HC, Jackevicius CA, Yousef A, Wang
J,
Tu JV. Diabetes mellitus and cardiovascular events in older
patients with myocardial infarction prescribed intensive-dose
and
moderate-dose statins. Circ Cardiovasc Qual Outcomes.
2013;6(3):315–22. doi:10.1161/circoutcomes.111.000015.
36. Ma T, Chang MH, Tien L, Liou YS, Jong GP. The long-term
effect of statins on the risk of new-onset diabetes mellitus in
elderly Taiwanese patients with hypertension and
dyslipidaemia:
a retrospective longitudinal cohort study. Drugs Aging.
2012;29(1):45–51. doi:10.2165/11597250-000000000-00000.
37. Ma T, Tien L, Fang C-L, Liou Y-S, Jong G-P. Statins and
new-

onset diabetes: a retrospective longitudinal cohort study. Clin
Ther. 2012;34(9):1977–83. doi:10.1016/j.clinthera.2012.08.004.
B. S. Olotu et al.
http://dx.doi.org/10.1371/journal.pone.0071817
http://dx.doi.org/10.1371/journal.pone.0071817
http://dx.doi.org/10.1136/bmj.f2610
http://dx.doi.org/10.1161/circoutcomes.111.000015
http://dx.doi.org/10.2165/11597250-000000000-00000
http://dx.doi.org/10.1016/j.clinthera.2012.08.004Use of Statins
and the Risk of Incident Diabetes: A Retrospective Cohort
StudyAbstractIntroductionObjectiveMethodResultsDiscussionIn
troductionMethodsStudy DesignCohort FormationOutcome
Measures and Statistical AnalysisSensitivity
AnalysisResultsPatient Selection Criteria and Sample
SizeDemographic and Clinical CharacteristicsIncidence of
DiabetesKaplan--Meier Survival Analysis by Exposure
TypeKaplan--Meier Survival Analysis by Statin TypeCox
Proportional Hazards Regression ModelsLogistic Regression
ModelsSensitivity AnalysisDiscussionIncidence of
DiabetesStatin Use and Risk of DiabetesComparison of the Risk
of Diabetes Among Users of Different Statin TypesStudy
Strengths and LimitationsStudy
ImplicationsConclusionAcknowledgmentsReferences

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