Comparative Effects Between High-intensity Atorvastatin and Rosuvastatin on New Onset Diabetes Mellitus and Cardiovascular Outcome

Background: High-intensity statin is typically used in patients with acute myocardial infarction (AMI) for secondary prevention; however, concern regarding its association with diabetes mellitus has been consistent. We investigated and compared the impact of high-intensity atorvastatin on new-onset diabetes mellitus (NODM) and cardiovascular outcomes with that of high-intensity rosuvastatin for a 3-year follow-up period. Methods: Data from the Korea Acute Myocardial Infarction Registry were collected from November 2011 to October 2015, and 13,104 AMI patients were enrolled from major cardiovascular centers. Among them, 2,221 patients without diabetes who had been administered with high-intensity atorvastatin (40–80 mg) and rosuvastatin (20 mg) were investigated. The atorvastatin and rosuvastatin groups were compared and evaluated for the incidence of NODM and major adverse cardiac event (MACE) including total death, myocardial infarction, and revascularization cases in the following 3 years. Results: Baseline characteristics were comparable between two groups. Event-free survival rate of NODM and MACE was not signicantly different between the atorvastatin and rosuvastatin groups (92.5% vs. 90.8%, respectively; Log-rank P-value = 0.550). The event-free survival rate of MACE was also not signicantly different between atorvastatin and rosuvastatin groups (89.0% vs. 89.6%, respectively; Log rank p-value = 0.662). Multivariable Cox analysis revealed that the statin type was not a prognostic factor in the development of NODM and MACE. atorvastatin and rosuvastatin comparable NODM suggesting their in secondary prevention.


Background
Statins typically prevent cardiovascular events by lowering total and low-density lipoprotein (LDL) cholesterol levels in the serum. Considering their rapid and sustained clinical advantages, the current guideline recommends administration of high-intensity statin in AMI patients for secondary prevention.
However, there has been consistent concern regarding its association with new-onset diabetes mellitus (NODM) [1]. Clinical trials, meta-analyses of randomized controlled trials (RCT), and observational studies have demonstrated a 10-12% increase in NODM among patients receiving statins [2,3]. Meta-analysis of 5 large-scale trials comparing intensive and moderate doses of statin have demonstrated that the risk of NODM further increases in intensive therapy group [4]. However, it is unclear if the diabetogenic effect of statins is a class effect. Considering their mandatory role for secondary prevention in acute myocardial infarction (AMI) patients, it would be important to identify the speci c statin that can provide protective cardiovascular effects without deteriorating the glycemic status. In Korea, atorvastatin 40-80 mg and rosuvastatin 20 mg are currently available as high-intensity statins for clinical use. Here, we investigated and compared the impact of high-intensity atorvastatin and rosuvastatin on cardiovascular outcome and NODM in AMI patients for a 3-year follow-up period.

Data collection and study population
The Korea Acute Myocardial Infarction Registry (KAMIR), a Korean prospective, multicenter, nationwide database supported by the Korean Society of Cardiology, re ects real-world treatment practices and outcomes in Asian patients diagnosed with AMI. Twenty university or community hospitals have participated in the registry. Data collection at the institution level is performed by a well-trained study coordinator using a standardized case report form. The collected data is managed using web-based systems. All participants provided written informed consent, and the study was approved by the ethics committee at each participating institution.
A total of 13,104 AMI patients were enrolled in the KAMIR registry between November 2011 and October 2015. A total of 6,728 patients without a history of diabetes mellitus (DM) with successful percutaneous coronary intervention (PCI) with drug-eluting stent implantation and high-intensity statin treatment were eligible for our study. Patients were selected considering the following exclusion criteria: history of DM or initial HbA1c level ≥ 6.5%, bare metal stent implantation, plain old balloon angioplasty, or failed PCI. Additionally, we did not include patients with in-hospital major adverse cardiac events (MACE) to speci cally include AMI survivors. Finally, 2,221 patients with AMI and high-intensity atorvastatin or rosuvastatin, treatment, according to 2014 ACC/AHA Release Updated Guideline, were enrolled in this study. Of them, 60.7% (1,349/2,221) of patients had received 40-80 mg atorvastatin and 39.3% (872/2,221) had received 20 mg rosuvastatin (Fig. 1).

Clinical Outcome And De nition
The primary endpoint was the incidence of NODM and the incidence of MACE during the 3 years of clinical follow-up. Secondary endpoints were each component of MACE, reasons for mortality, MI, and revascularization. Diagnosis of NODM was de ned as a HbA1c level ≥ 6.5% or newly administration of oral hypoglycemic agents. Clinical data of the enrolled patients were obtained through face-to-face interviews during regular outpatient visits, medical chart reviews, and telephonic interviews.

Statistical analysis
For continuous variables, differences between the two groups were evaluated by Student's t-test. Data were expressed as mean ± standard deviation (SD). For discrete variables, differences were expressed as counts and percentages and analyzed using the Chi-square test or Fisher's exact test. The cumulative incidence of NODM and MACE was estimated using the Kaplan-Meier method, and the intergroup differences were determined using the log-rank test. Cox-proportional hazard models were used to identify potential prognostic factors for NODM and MACE, and assess the hazard ratio (HR) of the atorvastatin group compared with the rosuvastatin group. Multivariable analysis was performed by including variables with signi cant P-values in the univariate analysis (P < 0.05). For all analyses, a Pvalue of < 0.05 was considered statistically signi cant. The data were processed using SPSS (version 22.0, Inc Chicago, IL).

Baseline characteristics
Baseline clinical, laboratory, and angiographic characteristics are shown in Table 1. We did not observe any signi cant intergroup differences with regard to age, gender, LV systolic function, incidence of STEMI, and underlying disease such as hypertension, cerebrovascular accidents. Patients in the rosuvastatin group had higher levels of LDL cholesterol and peak CK-MB and a longer total stent length than those in the atorvastatin group. Dual antiplatelet therapy rate was above 99% in both groups.

Clinical outcomes
Kaplan-Meier curves for the cumulative incidence of NODM up to 3 years are presented in Fig. 2A and Table 2. There was no signi cant difference in the event-free survival rate of NODM between the atorvastatin and rosuvastatin groups (92.5% vs. 90.8%, respectively; Log-rank P-value = 0.550). Kaplan-Meier curves for the cumulative incidence of MACE up to a period of 3 years are presented in Fig. 2B and Table 2. There was no signi cant difference between atorvastatin and rosuvastatin groups regarding the event free survival rate of MACE (89.0% vs. 89.6%, respectively; Log rank p-value = 0.662), reasons for mortality, myocardial infarction, and revascularizations. Comparing 40 mg and 80 mg of atorvastatin with 20 mg of rosuvastatin revealed no signi cant differences in the event-free survival rate of NODM and MACE (see Additional le 1: Fig. S1A and B).  Table 3). Conventional risk factor including older age, lower left ventricular ejection fraction (LVEF), and higher creatinine levels were associated with a higher incidence of MACE. The type of high-intensity statin, atorvastatin or rosuvastatin, was not a potential prognostic factor for MACE (HR = 0.944% con dence interval [CI]: 0.727-1.225, P = 0.662, Table 3).

Discussion
To the best of our knowledge, this is the rst study to compare the impact of high-intensity statin treatment on the development of NODM and MACE in AMI patients. Our results indicated that highintensity atorvastatin and rosuvastatin therapies showed no signi cant difference with regard to the incidence of NODM and cardiovascular events. Statins reduce serum LDL cholesterol level and the risk of cardiovascular events. As numerous studies revealed that the degree of cardiovascular risk reduction is proportional to the statin intensity [5,6], the current guideline strongly recommended high-intensity or maximally tolerated intensity statin therapy in AMI patients in the absence of contraindications [7,8]. Several studies have that suggested that statin may increase the incidence of NODM [3,9]. The issue has started attracting attention since the Justi cation for the Use of Statin in Prevention: An Intervention Trial Evaluating Rosuvastatin (JUPITER) trial reported a higher incidence of NODM in patients treated with rosuvastatin for primary prevention [10]. Numerous observational studies [11,12] and meta-analyses of major RCT [3,13] have consistently reported an increased incidence of NODM in patients receiving statin treatment. In Korea, a populationbased cohort study using the Korean National Health Insurance claims database has shown an increased incidence of NODM in statin-treated groups [2].
Whether the diabetogenic effect of statin is a class effect has been a controversial subject. Typically, atorvastatin and rosuvastatin are thought to unfavorably in uence glycemic parameters, while pitavastatin and pravastatin have relatively neutral effects on glycemic control regardless of the presence or absence of DM [1]. Our group recently published a report regarding the favorable glycemic effects of moderate intensity pitavastatin in comparison to those of moderate intensity atorvastatin and rosuvastatin in AMI patients [14]. However, the current guideline recommends high-intensity or maximally tolerated statin for secondary prevention to achieve cardiovascular improvements in AMI patients [7,8], and to the best of our knowledge, there is no study that has compared the diabetogenic and cardiovascular effects of different high-intensity statins.
Several studies were conducted regarding the cardiovascular outcome after high-intensity statin therapy.
In patients with acute coronary syndrome, both the atorvastatin and rosuvastatin groups had comparable effects on lipid parameters [15,16], although patients with familial hypercholesterolemia in the rosuvastatin group demonstrated a greater reduction in LDL cholesterol levels than those in the atorvastatin group [17]. Some studies has reported more favorable effects of rosuvastatin on reducing atherosclerotic plaque volume [15,18] and plaque stabilization [15] than atorvastatin, however, there has been no signi cant difference with regard to the cardiovascular outcome in both groups [17,19]. In line with previous studies, we could not identify the differences between the effects of high-intensity atorvastatin and rosuvastatin administration on major cardiovascular events.