Impact of Statin Use on Development of New-Onset Diabetes Mellitus in Asian Population

Accepted Manuscript Impact of Statin Use on Development of New-onset Diabetes Mellitus in Asian Population Seung-Woon Rha, MD, PhD, Byoung Geol Choi, BS, Hong Seog Seo, MD, PhD, Sang-Ho Park, MD, PhD, Ji Young Park, MD, PhD, Kang-Yin Chen, MD, PhD, Yoonjee Park, MD, Se Yeon Choi, BS, Min-Suk Shim, BS, Ji Bak Kim, MD, Taeshik Park, MD, Joonhyung Park, MD, Jae Joong Lee, MD, Eun Jin Park, MD, Sung Hun Park, MD, Jah Yeon Choi, Sunki Lee, MD, Jin Oh Na, MD, PhD, Cheol Ung Choi, MD, PhD, Hong Euy Lim, MD, PhD, Jin Won Kim, MD, PhD, Eung Ju Kim, MD, PhD, Chang Gyu Park, MD, PhD, Dong Joo Oh, MD, PhD PII:

S0002-9149(15)02242-0

DOI:

10.1016/j.amjcard.2015.11.009

Reference:

AJC 21518

To appear in:

The American Journal of Cardiology

Received Date: 5 August 2015 Revised Date:

2 November 2015

Accepted Date: 3 November 2015

Please cite this article as: Rha S-W, Choi BG, Seo HS, Park S-H, Park JY, Chen K-Y, Park Y, Choi SY, Shim M-S, Kim JB, Park T, Park J, Lee JJ, Park EJ, Park SH, Choi JY, Lee S, Na JO, Choi CU, Lim HE, Kim JW, Kim EJ, Park CG, Oh DJ, Impact of Statin Use on Development of New-onset Diabetes Mellitus in Asian Population, The American Journal of Cardiology (2015), doi: 10.1016/j.amjcard.2015.11.009. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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Impact of Statin Use on Development of New-onset Diabetes Mellitus in Asian

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Population

Seung-Woon Rha, MD, PhD, Byoung Geol Choi, BS, Hong Seog Seo, MD, PhD, Sang-Ho Park, MD, PhD, Ji Young Park, MD, PhD, Kang-Yin Chen, MD, PhD, Yoonjee Park, MD, Se Yeon Choi, BS, Min-Suk Shim, BS, Ji Bak Kim, MD, Taeshik Park, MD, Joonhyung Park,

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MD, Jae Joong Lee, MD, Eun Jin Park, MD, Sung Hun Park, MD, Jah Yeon Choi, Sunki Lee, MD, Jin Oh Na, MD, PhD, Cheol Ung Choi, MD, PhD, Hong Euy Lim, MD, PhD, Jin Won Kim, MD, PhD, Eung Ju Kim, MD, PhD, Chang Gyu Park, MD, PhD, and Dong Joo Oh, MD,

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PhD

From: Cardiovascular Center, Korea University Guro Hospital, Seoul, Korea (SWR, MSS, YP, JJL,EJP, SHP, JYC, SL, JON, CUC, HEL, JWK, EJK, CGP, DJO); Department of Medicine, Korea University Graduate School, Seoul, Korea (BGC, SYC); KU-KIST Graduate School

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Converging Science and Technology, Seoul, Korea (HSS); Cardiology Department, Soonchunhyang University Cheonan Hospital, Cheonan, Korea (SHP); Cardiovascular Center, Eulji University, Eulji General Hospital, Korea (JYP); Cardiology Department, The Second Hospital of Tianjin Medical University, Tianjin, China (KYC); Division of Cardiology,

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Department of Internal Medicine, Sejong General Hospital, Bucheon, Korea (JBK); Internal Medicine, Weiss Memorial Hospital, Chicago, IL, USA (TP); Department of Internal

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Medicine, Incheon Christian Hospital, Incheon, Korea (JP).

The first two authors (Drs. SW Rha and BG Choi) contributed equally to this article. Co-corresponding author: Dr. HS Seo. Running title: Impact of Statin Use on Development of Diabetes Address for correspondence: Seung-Woon Rha, MD, PhD; Cardiovascular Center, Korea University Guro Hospital, 80, Guro-dong, Guro-gu, Seoul, 152-703, Korea, Republic of; Tel: +2-2-2626-3020, Fax: +82-2-864-3062, E‐mail: [email protected]

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ABSTRACT There have been several reports showing that statin use is associated with new-onset diabetes mellitus (DM). The aim of the present study was to evaluate the impact of chronic

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statin use on development of new-onset DM in a series of Asian population. The patients were retrospectively enrolled using the electronic database of Korea University Guro Hospital from January 2004 to February 2010. A total of 10,994 patients without history of

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diabetes were analyzed. Baseline lipid profiles, fasting glucose, Hemoglobin (Hb) A1c and

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glucose tolerance tests were measured in all patients before statin treatment. Included patients had HbA1c ≤ 5.7 % and fasting glucose level ≤ 100 (mg/dL). The patients were divided into 2 groups according to the use of statins (the statin group, n=2,324 patients; the non-statin group, n=8,670 patients). To adjust baseline potential confounders, a propensity score

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matched analysis was performed using logistic regression model. After propensity score matching (PSM), 2 propensity-matched groups (1,699 pairs, n = 3,398, C-statistic=0.859) were generated and analyzed. After PSM, baseline characteristics of both groups were

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balanced, except that the statin group was older and had higher rate of coronary artery disease compared to the non-statin group. During 3-year follow up, the statin group had higher

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incidence of new-onset DM compared to the non-statin group (HR 1.99, 95% CI 1.36-2.92, p<0.001), but the statin group showed lower incidence of major adverse cerebralcardiovascular events compared to the non-statin group (HR 0.40, 95% CI 0.19-0.85, p<0.001). In the present study, although the use of statins was associated with higher rate of new-onset DM, it markedly improved 3-year cardiovascular outcomes in Asian population.

Key words: statins, new-onset diabetes mellitus, clinical outcomes

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The statins are widely used for cardiovascular disease prevention, and which are clearly supported by clinical evidences. However, there have been several debates,1-3 and there have been several reports showing that the statin use is associated with a slightly higher However, there are limited data

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incidence of new-onset diabetes mellitus (DM).4-12

regarding the impact of chronic statin use on the development of new-onset DM in Asian population, especially in patients without DM.10,13 Therefore, the aim of the present study

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was to evaluate the impact of chronic statin use on the development of new-onset DM in

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patients without DM and impaired glucose tolerance (IGT) in a series of Asian population.

METHODS

A total of 65,686 consecutive patients who visited cardiovascular center of Korea

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University Guro Hospital (KUGH) from January 2004 to February 2010 were retrospectively enrolled using the electronic database of KUGH. All patients did lipid profiles, fasting glucose, Hemoglobin (Hb) A1c level and glucose tolerance tests before statin treatment.

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Inclusion criteria included both Hb A1c ≤ 5.7 % and fasting glucose level ≤ 100 (mg/dL).

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Finally, a total of 10,994 patients without DM and IGT were analyzed. The study protocol was approved by the Institutional Review Board at Korea University Guro Hospital. New-onset DM was defined as fasting blood glucose ≥ 126 (mg/dL), HbA1c ≥

6.5 %, or current use of hypoglycemic agents depending on the physician’s discretion.14 Major adverse cardiac and cerebral events (MACCE) was defined as the composite of total death, non-fatal myocardial infarction (MI), and cerebrovascular accidents (CVA). New-onset DM related MACCE was defined as both new-onset DM and MACCE occurring at the same

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follow-up period. The primary study end-point was the cumulative incidence of new-onset DM during 3-year clinical follow-up. For continuous variables, differences between two groups were evaluated by

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unpaired t-test or Mann-Whitney rank test. Data were expressed as mean ± standard deviations. For discrete variables, differences were expressed as counts and percentages and analyzed with χ2 or Fisher’s exact test between the groups as appropriate. To adjust for

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potential confounders, propensity score matched analysis was performed using the logistic regression model. We tested all available variables that could be of potential relevance: age,

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male, cardiovascular risk factors (hypertension, diabetes, heart failure, chronic kidney disease, coronary artery disease, cerebrovascular accidents), co-medication treatment (Angiotensin II receptor blockers, angiotensin-converting enzyme inhibitors, calcium channel blockers, beta blockers, diuretics, warfarin), and laboratory findings (total cholesterol, low density

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lipoprotein cholesterol, high density lipoprotein cholesterol, triglyceride). The logistic model by which the propensity scores were estimated showed good predictive value (C statistic=0.859). Patients in the statin group were then 1-to-1 matched to those in the non-

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statin group according to propensity scores with the nearest available pair matching method.

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Subjects were matched with a caliper width equal to 0.05. The procedure yielded 1,699 wellmatched pairs. A two-tailed p-value of <0.05 was considered to be statistically significant. Various 3-year clinical outcomes were estimated with Kaplan-Meier method, and differences between groups were compared with log-rank test. All the statistical analyses were performed using SPSS 20.0 (SPSS Inc., Chicago, IL, USA).

RESULTS

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In the present study, a total of 10,994 patients were finally enrolled. The patients were divided into two groups according to the use of statins (the statin group, n=2,324; the non-statin group, n=8,670). After propensity score matching (PSM), baseline characteristics

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of 2 propensity-matched groups (1,699 pairs, n = 3,398, C-statistic=0.859) were balanced except that the statin group were older and had a higher rate of coronary artery disease compared to the non-statin group. The mean treatment days were 1,456 ± 791 days in the

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statin group (after PSM, 1,402 ± 782 days) [Table 1].

After PSM, during 3-year follow up period, the incidence of new-onset DM was

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higher in the statin group compared to that in the non-statin group (4.7 % vs. 2.4%, p-value <0.001). However, the rates of total death and MACCE were lower in the statin group as compared with those in the non-statin group [Table 2, 3].

In the present study, we compared the incidence of new-onset DM related MACCEs

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between the two groups during 3-year follow up period. In the statin group, new-onset DM related MACCEs occurred 3 case (0.18 %), accounting for 20% of the total MACCE (HR;

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4.42, 95% CI; 1.16-16.7, p=0.029). In the non-statin group, new-onset DM related MACCE occurred 1 case (0.06 %), accounting for 3.2 % of the total MACCE (HR; 0.85, 95% C.I;

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0.10-6.95, p=0.882). The incidence of MACCE between the statin group and the non-statin group was similar, suggesting the risk of MACCE occurred from chronic statin use is not different with that of patients without statin (Figure). After PSM, multivariate Cox-regression analysis showed that elderly, male gender and drug intake (diuretics, overall statins and subtype statins) were the independent risk factors for new-onset DM. However, when we analyze the impact of individual statin on the incidence of new-onset DM, the use of simvastatin was not a significant risk factor for newonset DM [Table 4].

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DISCUSSION

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The main findings of the present study is as follows; 1) the chronic statin use was associated with higher incidence of new-onset DM, 2) the chronic statin use was associated with reduced incidence of total death and MACCE. Also, 3) we carefully suggested that the

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impact of statin related DM on long-term clinical outcomes were not different with those of abiogenesis DM.

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Interestingly, the relation between the glucose intolerance and the statin use has been argued since 1990s.15-17 Several studies proposed the possible mechanisms of statins-related DM.2,3,18-20

In summarized by Brault et al.2 1) Statins inhibited glucose induced calcium

(Ca2+) signaling in pancreatic islet β-cells by directly blocking L-type Ca2+ channels, result in

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impaired insulin secretion. In pancreatic β-cells, insulin secretion is initiated by an increase in intracellular Ca2+ concentration, which is principally controlled by the opening of voltagegated calcium channels. Changes in the function or levels of these channels may significantly

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affect glucose homeostasis. 2) Within the cell, insulin signaling and via glucose transporter 4

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(GLUT4) transport can be altered by changes in IRS-1, Akt, Rab4, Ras, phosphorylation of the IR β-subunit, or membrane fraction of RhoA, all of which have been shown to be inhibited by statin therapy. It is suggested that statins contribute to new-onset DM by reducing insulin signal transduction via inhibition of necessary phosphorylation events and altering cellular distribution of small G proteins. Insulin receptor substrate (IRS-1) is critical for insulin signaling and is phosphorylated in response to insulin or insulin like growth factor (IGF) binding to the insulin receptor (IR). Through the phosphatidylinositol 3-kinase (PI3K) pathway, Akt becomes phosphorylated and mediates glucose uptake by controlling GLUT4

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translocation to the plasma membrane. Also, the proteins RhoA and Rab4 are small G proteins involved in the insulin signal transduction via modification of IRS-1 and Akt phosphorylation. 3) Koh et al.18,19 summarized that the lipophilic statins inhibit the synthesis

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of isoprenoid and suppressing ubiquinone (CoQ10) biosynthesis and thus delaying formation of ATP by pancreatic β-cells leading to impaired insulin secretion, inhibiting glucose-induced insulin secretion from pancreatic islets, reducing sensitivity to insulin, altering glycemic

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control by decreasing various isoprenoids that enhance glucose uptake via GLUT4 in adipocytes. Isoprenoids are known to enhance glucose uptake via up regulation of GLUT4 in

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adipocytes. CoQ10 is an essential part of the mitochondrial respiratory chain, hence is necessary for ATP production. Mitochondrial ATP inhibits ATP-dependent potassium channels on β-cells, thereby stimulating insulin secretion by Ca2+ influx. 4) Activation of the NOD-like receptor family, pyrin domain containing (NLRP)3/caspase-1 inflammasome

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promotes insulin resistance, and statins activate the NLRP3 inflammasome in various immune and metabolic cells of adipose tissue, independently of potency or lipophilic properties.20

5) Other mechanisms exists for decreased adipocyte differentiation, dolichol

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reductions, adiponectin and leptin decreases, as well as new avenues, such as UCP3 changes and miRNA inhibition. However, the mechanisms of statins-related DM is not definitely

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unclear yet.

The main purpose of statin use is primary or secondary prevention for cardiovascular

disease, and which are clearly supported by clinical evidences. Also, this study showed that the chronic statin use was associated with reduced risk of total death (0.4% vs. 1.3%, p-value = 0.007) and MACCE (HR 0.47, 95% CI 0.25-0.89, p=0.020) at 3 years. However, one of the main argues in the use of statin is whether there is higher incidence of new-onset insulin resistance and subsequent new-onset DM in association with chronic statin use. This study,

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despite of a retrospective, single center, population-based study, the analysis results from larger study population in real world clinical practice implies that the chronic statins use was associated with higher risk of new-onset DM (HR 1.99, 95% CI 1.36-2.92, p<0.001). It is

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added to the evidence of the debate. Wang et al.13 has published similar outcomes, statin therapy in pre-diabetic patients was associated with a greater risk of new-onset DM (hazard ratio 1.20, 95% confidence interval 1.08 to 1.32) and less risk of MACE (HR 0.70, 95% CI

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0.61-0.80).

In the previous studies, there has no data reporting the impact of new-onset DM on

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long-term clinical outcomes in statin users. Kang et al. supports that diabetic or statin-using percutaneous coronary intervention patients experiencing a higher absolute change in fasting plasma glucose have statistically significant cardiovascular event risk.21 Therefore, in the present study, we evaluated not only the impact of chronic statin use

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on the development of new-onset DM but also the impact of new-onset DM on the incidence of MACCE. The statin group showed that the new-onset DM related MACCE occurred in 3

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cases (0.18 %), counting for 20 % of the total MACCE (HR 4.42, 95% CI 1.16-16.7, p=0.029). In the non-statin group, the new-onset DM related MACCE occurred in 1 case

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(0.06 %), accounting for 3.2 % of the total MACCE (HR 0.85, 95% CI 0.10-6.95, p=0.882). Based on these results, we assumed that the risk of new-onset DM related MACCE may be higher in the statin group compared to that of the non-statin group. However, there was no statistically significant differences in the rates of new-onset DM related MACCE between the two groups (0.18% vs. 0.06%, p=0.625) [Figure]. There are several reasons for the lower incidence of new-onset DM related MACCE than we expected. In the present study, most patients received all-round optimal medical management to control the risk of cardiovascular disease. Moreover, IGT-related events were excluded from new-onset DM related events. In

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addition, 3-year follow-up is relatively shorter observation period to analyze the risk of newonset DM related MACCE because DM is a chronic disease and duration of DM is an important determinant of MACCE. According to Twito et al.,22 an HbA1c level >7.5 % is

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associated with increased risk for all-cause mortality in elderly patients with new-onset DM. In the present study, except for simvastatin, the other statins were associated with a markedly increased risk of new-onset DM. Also, several reports showed that the prevalence

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of new-onset DM varies according to different statin types, (Table 4, 5) each statin seems to have a specific pro-diabetic risk profile. Clearly, more evidence from other studies with larger

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study population will be needed in the future to investigate the impact of individual statin on the development of new-onset DM. The present study is retrospectively analyzed and we performed propensity score matched analysis to minimize the effects of baseline confounding factors which might influence the results. Also, we excluded IGT patients to minimize errors.

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Therefore, we defined new-onset DM as fasting blood glucose ≥126 mg/dl, HbA1c ≥ 6.

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5 %, or current use of hypoglycemic agents depending on the physician’s discretion.

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ACKNOWLEDGEMENTS

This study was partially supported by a grant from the KIST Institutional Program

(Project No. 2E24080), and a grant of the Korea University-Korea Institute of Science and Technology (KU-KIST) Graduate School Converging Science and Technology (R1307921).

DISCLOSURE The authors have no financial conflicts of interest.

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2. Brault M, Ray J, Gomez YH, Mantzoros CS, Daskalopoulou SS. Statin treatment and newonset diabetes: a review of proposed mechanisms. Metabolism 2014;63:735-745.

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6. Preiss D, Seshasai SR, Welsh P, Murphy SA, Ho JE, Waters DD, DeMicco DA, Barter P, Cannon CP, Sabatine MS, Braunwald E, Kastelein JJ, de Lemos JA, Blazing MA, Pedersen TR, Tikkanen MJ, Sattar N, Ray KK. Risk of incident diabetes with intensive-dose compared with moderate-dose statin therapy: a meta-analysis. J Am Med Assoc 2011;305(24):25562564. 7. Culver AL, Ockene IS, Balasubramanian R, Olendzki BC, Sepavich DM, Wactawski-

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Wende J, Manson JE, Qiao Y, Liu S, Merriam PA, Rahilly-Tierny C, Thomas F, Berger JS, Ockene JK, Curb JD, Ma Y. Statin use and risk of diabetes mellitus in postmenopausal women in the Women's Health Initiative. Arch Intern Med 2012;172:144-152.

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8. Ridker PM, Pradhan A, MacFadyen JG, Libby P, Glynn RJ. Cardiovascular benefits and diabetes risks of statin therapy in primary prevention: an analysis from the JUPITER trial. Lancet 2012;380:565-571.

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9. Carter AA, Gomes T, Camacho X, Juurlink DN, Shah BR, Mamdani MM. Risk of incident diabetes among patients treated with statins: population based study. Brit Med J

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11. Danaei G, Garcia Rodriguez LA, Fernandez Cantero O, Hernan MA. Statins and risk of diabetes: an analysis of electronic medical records to evaluate possible bias due to differential survival. Diabetes Care 2013;36:1236-1240.

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12. Park JY, Rha SW, Choi B, Choi JW, Ryu SK, Kim S, Noh YK, Choi SY, Akkala RG, Li H, Ali J, Xu S, Ngow HA, Lee JJ, Lee GN, Kim J, Lee S, Na JO, Choi CU, Lim HE, Kim JW,

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Kim E, Park CG, SeogSeo H, Oh DJ. Impact of low dose atorvastatin on development of new-onset diabetes mellitus in Asian population: Three-year clinical outcomes. Int J Cardiol 2015;184:502-506.

13. Wang KL, Liu CJ, Chao TF, Chen SJ, Wu CH, Huang CM, Chang CC, Wang KF, Chen TJ, Lin SJ, Chiang CE. Risk of new-onset diabetes mellitus versus reduction in cardiovascular events with statin therapy. Am J Cardiol 2014;113:631-636. 14. American Diabetes A. Diagnosis and classification of diabetes mellitus. Diabetes Care

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2013;36 Suppl 1:S67-74. 15. Metz SA, Rabaglia ME, Stock JB, Kowluru A. Modulation of insulin secretion from normal rat islets by inhibitors of the post-translational modifications of GTP-binding proteins.

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Biochem J 1993;295 ( Pt 1):31-40. 16. McGuire TF, Xu XQ, Corey SJ, Romero GG, Sebti SM. Lovastatin disrupts early events in insulin signaling: a potential mechanism of lovastatin's anti-mitogenic activity. Biochem

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17. Öhrvall M, Lithell H, Johansson J, Vessby B. A comparison between the effects of

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gemfibrozil and simvastatin on insulin sensitivity in patients with non—Insulin-dependent diabetes mellitus and hyperlipoproteinemia. Metabolism 1995;44:212-217. 18. Koh KK. Letter by Koh regarding article, "Statins and risk of new-onset diabetes mellitus". Circulation 2013;127:e837.

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19. Lim S, Sakuma I, Quon MJ, Koh KK. Potentially important considerations in choosing specific statin treatments to reduce overall morbidity and mortality. Int J Cardiol 2013;167:1696-1702.

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20. Henriksbo BD, Lau TC, Cavallari JF, Denou E, Chi W, Lally JS, Crane JD, Duggan BM, Foley KP, Fullerton MD, Tarnopolsky MA, Steinberg GR, Schertzer JD. Fluvastatin causes

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NLRP3 inflammasome-mediated adipose insulin resistance. Diabetes 2014;63:3742-3747. 21. Kang DO, Seo HS, Choi BG, Lee E, Kim JP, Lee SK, Im SI, Na JO, Choi CU, Lim HE, Kim JW, Kim EJ, Rha SW, Park CG, Oh DJ. Absolute change in fasting plasma glucose over 12 months is associated with 2-year and 5-year major adverse cardiovascular events in patients with drug-eluting stent implants. Int J Cardiol 2015;179:146-152. 22. Twito O, Ahron E, Jaffe A, Afek S, Cohen E, Granek-Catarivas M, Klein P, Hermoni D. New-onset diabetes in elderly subjects: association between HbA1c levels, mortality, and

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coronary revascularization. Diabetes Care 2013;36:3425-3429.

FIGURE LEGEND

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FIGURE: Cumulative Incidence of New-onset Diabetes (DM), Major Adverse Cardiac and

Cerebral Events (MACCE) and new-onset DM related MACCE up to 3-year. Figures are the

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cumulative incidences of New-onset Diabetes (new-onset DM, Right), the composite of death, myocardial infarction, or stroke (MACCE, Mid), and the incidences of MACCE even or after newonset DM (Left) after propensity score matching. The incidence of MACCE between the statin group and the non-statin group was similar, suggesting the risk of MACCE occurred from chronic statin use

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was not different with that of patients without statin.

Table 1: Baseline Clinical Characteristics and Medication Treatments.

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Overall Patients

Matched Patients

Variables,

Statin Use

No Use

N (%) or mean ± SD

(n=2324)

(n=8670)

P Value

Statin Use

No Use

(n=1699)

(n=1699)

P Value

1318 (56.7 %)

4033 (46.5 %)

< 0.001

883 (51.9 %)

879 (51.7 %)

0.891

60.6 ± 10.8

51.1 ± 14.9

< 0.001

59.8 ± 10.8

60.7 ± 12.4

0.027

Body mass index, kg/m2

24.4 ± 3.0

24.3 ± 3.4

0.091

24.5 ± 3.1

24.4 ± 3.6

0.576

Hypertension

1273 (54.7 %)

3149 (36.3 %)

< 0.001

888 (52.2 %)

904 (53.2 %)

0.582

Dyslipidemia

597 (25.6 %)

1125 (12.9 %)

< 0.001

388 (22.8 %)

408 (24 %)

0.418

Coronary artery disease

693 (29.8 %)

386 (4.4 %)

< 0.001

253 (14.8 %)

178 (10.4 %)

< 0.001

Myocardial infarction

208 (8.9 %)

40 (0.4 %)

< 0.001

44 (2.5 %)

31 (1.8 %)

0.129

Coronary revascularizations

436 (18.7 %)

63 (0.7 %)

< 0.001

73 (4.2 %)

53 (3.1 %)

0.069

Coronary spasm

101 (4.3 %)

280 (3.2 %)

0.009

79 (4.6 %)

92 (5.4 %)

0.308

Cerebrovascular accidents

438 (18.8 %)

670 (7.7 %)

< 0.001

Heart failure

93 (4.0 %)

259 (2.9 %)

0.014

Angina pectoris

634 (27.2 %)

1877 (21.6 %)

< 0.001

Chest pain

131 (5.6 %)

729 (8.4 %)

< 0.001

Arrhythmia

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Gender (men) Age, (years)

311 (18.3 %)

329 (19.3 %)

0.430

68 (4.0 %)

69 (4.0 %)

0.931

412 (24.2 %)

0.605

84 (4.9 %)

0.358

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425 (25 %)

96 (5.6 %)

178 (7.6 %)

520 (5.9 %)

0.004

122 (7.1 %)

122 (7.1 %)

ns

Atrial fibrillation

119 (5.1 %)

267 (3.0 %)

< 0.001

82 (4.8 %)

81 (4.7 %)

0.936

340 (3.9 %)

95 (4.0 %) 94.1 ± 8.1

Hemoglobin A1c, (%)

5.5 ± 0.2

Insulin, (ng/ml)

7.5 ± 4.9

Total cholesterol, (mg/dL)

179 ± 45

Triglyceride, (mg/dL)

135 ± 93

High-density lipoprotein cholesterol, (mg/dL)

50 ± 13

Low-density lipoprotein cholesterol, (mg/dL)

113 ± 41

Angiotensin receptor blockers

Nitrates Type of Statins Atorvastatin Fluvavastatin Pitavastatin Pravastatin Rosuvastatin Simvastatin Fibrates

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Diuretics

0.785 0.900

5.4 ± 0.2

< 0.001

5.5 ± 0.2

5.5 ± 0.2

0.464

7.1 ± 5.3

0.072

7.6 ± 5.0

7.6 ± 5.4

0.945

178 ± 33

0.100

181 ± 44

182 ± 34

0.664

122 ± 88

< 0.001

135 ± 97

136 ± 118

0.866

< 0.001

52 ± 13

51 ± 14

0.508

110 ± 29

0.008

114 ± 41

114 ± 30

0.733

641 (27.5 %)

807 (9.3 %)

< 0.001

356 (20.9 %)

350 (20.6 %)

0.800

1160 (49.9 %)

1816 (20.9 %)

< 0.001

794 (46.7 %)

814 (47.9 %)

0.492

756 (32.5 %)

1218 (14.0 %)

< 0.001

516 (30.3 %)

511 (30.0 %)

0.852

335 (14.4 %)

279 (3.2 %)

< 0.001

137 (8.0 %)

145 (8.5 %)

0.619

534 (22.9 %)

1039 (11.9 %)

< 0.001

383 (22.5 %)

385 (22.6 %)

0.935

974 (41.9 %)

798 (9.2 %)

< 0.001

490 (28.8 %)

450 (26.4 %)

0.125

811 (34.8 %)

-

-

605 (35.6 %)

-

-

133 (5.7 %)

-

-

106 (6.2 %)

-

-

241 (10.3 %)

-

-

161 (9.4 %)

-

-

252 (10.8 %)

-

-

196 (11.5 %)

-

-

344 (14.8 %)

-

-

220 (12.9 %)

-

-

543 (23.3 %)

-

-

411 (24.1 %)

-

-

29 (1.2 %)

98 (1.1 %)

0.638

25 (1.4 %)

34 (2.0 %)

0.237

EP

Angiotensin converting enzyme inhibitors

61 (3.5 %) 94.2 ± 7.9

< 0.001

TE D

Calcium channel blockers

64 (3.7 %)

94.2 ± 7.8

93.1 ± 8.0

53 ± 13

Medication treatment Beta blockers

0.715

M AN U

Cardiac arrhythmia Fasting glucose, mg/dl

Data are presented as N (%) or mean ± SD unless otherwise indicated.

Table 2: Cumulative Clinical Outcomes up to 3-year.

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Overall Patients

Matched Patients

No Use

Statin Use

No Use

(n=2324)

(n=8670)

(n=1699)

(n=1699)

New-onset diabetes

116 (4.9 %)

111 (1.2 %)

< 0.001

80 (4.7 %)

41 (2.4 %)

< 0.001

Mortality

18 (0.7 %)

48 (0.5 %)

0.221

8 (0.4 %)

23 (1.3 %)

0.007

10 (0.4 %)

11 (0.1 %)

0.006

3 (0.1 %)

7 (0.4 %)

0.205

Myocardial infarction

14 (1.0 %)

8 (0.1 %)

< 0.001

4 (0.4 %)

6 (0.6 %)

0.755

Cerebrovascular accidents

11 (0.4 %)

26 (0.2 %)

0.200

6 (0.3 %)

15 (0.8 %)

0.049

MACCE

34 (1.4 %)

64 (0.7 %)

0.001

15 (0.8 %)

Cardiac death

AC C

EP

TE D

M AN U

SC

MACCE indicates major adverse cardiac and cerebral events.

P Value

RI PT

Statin Use

Variable, N (%)

31 (1.8 %)

P Value

0.018

Table 3: Risk of New-onset Diabetes Mellitus (new-onset DM) and Major Adverse Cardiac and Cerebral Events

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(MACCE) by Statin Use

New-onset DM

MACCE

Description

Patients. No.

HR (95% CI)

P Value

HR (95% CI)

P Value

Unadjusted HR

10 994

4.05 (3.10-5.27)

< 0.001

1.99 (1.31-3.03)

0.001

Multivariate

10 994

2.70 (1.99-3.67)

< 0.001

0.70 (0.42-1.18)

0.191

Propensity score

10 994

2.71 (1.94-3.79)

< 0.001

0.50 (0.29-0.87)

0.015

Propensity score matched

3 398

1.99 (1.36-2.92)

< 0.001

0.47 (0.25-0.89)

0.020

RI PT

Adjusted HR (95% CI)

The hazard ratio (HR) along with its corresponding 95% confidence interval (CI) and p values are based on Cox

AC C

EP

TE D

M AN U

SC

proportional hazard analysis.

Table 4: A Predictors of New-onset Diabetes Mellitus after Propensity Score Matched analysis.

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Patients, N (%)

New-onset DM, N (%)

(n=3,398)

(n=121)

Gender (men)

1762 (51.8 %)

Age, [mean ± SD]

P Value

-

1.76 (1.19-2.59)

0.004

60.2 ± 11.6

-

1.01 (1.00-1.03)

0.025

Hypertension

1792 (52.7 %)

-

1.38 (0.94-2.02)

0.097

Cardiovascular disease

431 (12.6 %)

-

0.96 (0.56-1.65)

0.891

Coronary spasm

171 (5.0 %)

-

1.64 (0.80-3.35)

0.169

Dyslipidemia

796 (23.4 %)

-

1.00 (0.63-1.58)

0.973

Angiotensin receptor blockers

1027 (30.2 %)

-

1.34 (0.87-2.05)

0.173

Angiotensin converting enzyme inhibitors

282 (8.2 %)

-

0.80 (0.38-1.67)

0.559

Calcium channel blockers

1608 (47.3 %)

-

0.72 (0.49-1.05)

0.090

Beta blockers

706 (20.7 %)

-

1.30 (0.85-2.01)

0.218

Diuretics

768 (22.6 %)

-

1.61 (1.03-2.52)

0.035

Nitrates

940 (27.6 %)

-

1.07 (0.70-1.64)

0.735

Statins (overall)

1699 (50.0 %)

80/1699 (4.7 %)

2.06 (1.40-3.04)

< 0.001

Atorvastatin*

605 (35.6 %)

28/605 (4.6 %)

2.09 (1.27-3.44)

0.003

Simvastatin*

411 (24.1 %)

10/411 (2.4 %)

0.99 (0.49-2.02)

0.998

Rosuvastatin*

220 (12.9 %)

10/220 (4.5 %)

2.13 (1.04-4.38)

0.038

Pravastatin*

196 (11.5 %)

13/196 (6.6 %)

2.88 (1.50-5.55)

0.001

Pitavastatin*

161 (9.4 %)

13/161 (8.0 %)

3.46 (1.79-6.68)

< 0.001

Fluvastatin*

106 (6.2 %)

6/106 (5.6 %)

2.53 (1.03-6.21)

0.041

SC

RI PT

HR (95% CI)

M AN U

Description

Adjusted by male gender, age, history of risk (hypertension, coronary artery disease, coronary spasm, dyslipidemia,

diuretics, nitrates and statins.

TE D

angiotensin-receptor blockers, angiotensin-converting enzyme inhibitors, calcium channel blockers, beta blockers,

*Adjusted by male gender, age, history of risk (hypertension, coronary artery disease, coronary spasm, dyslipidemia,

EP

angiotensin receptor blockers, angiotensin converting enzyme inhibitors, calcium channel blockers, beta blockers, diuretics, nitrates and subtype statins (atorvastatin, simvastatin, rosuvastatin, pravastatin, pitavastatin, fluvastatin).

AC C

The hazard ratio (HR) along with its corresponding 95% confidence interval (CI) and p values are based on Cox proportional hazard analysis.

ACCEPTED MANUSCRIPT Table 5: Previous reports; Summary in Risk of New-onset Diabetes Mellitus according Statins type. Subjects

Authors

condition

Atorvastatin

Simvastatin

Rosuvastatin

Pravastatin

Fluvastatin

Lovastatin

Overall South Korea

2.06 (1.40-3.04)

ns

2.13 (1.04-4.38)

2.88 (1.50-5.55)

2.53 (1.03-6.21)

-

Wang et al.12

Prediabetes, Taiwan

1.28 (1.12-1.47)

1.22 (1.07-1.39)

ns

ns

ns

1.14 (1.01-1.30)

Chen et al.6

Women, Taiwan

2.80 (1.74-4-46)

4.09 (2.25-6.64)

4.69 (2.78-7-92)

3.41 (1.66-7-04)

-

-

Navarese et al.18

High dose, Meta

1.13 (1.00-1.27)

1.27 (1.13-1.41)

1.25 (1.00-1.54)

ns

-

ns

Culver et al.8

Postmenopausal Women, USA

1.61 (1.26-2.06)

1.41 (1.25-1.61)

-

1.63 (1.43-1.87)

1.61 (1.35-1.92)

1.35 (1.19-1.55)

Carter et al.5

Age≥66 (year), Canada

1.22 (1.15-1.29)

1.10 (1.04-1.17)

1.18 (1.10-1.26)

reference

ns

ns

SC

RI PT

Rha et al.

Data are presented as HR (95% CI); the hazard ratio (HR) along with its corresponding 95% confidence interval

AC C

EP

TE D

M AN U

(CI). Not significant indicates with 'ns'.

AC C

EP

TE D

M AN U

SC

RI PT

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