Study patients
Patients aged 30 to 79 years were eligible for the original trial of this study if they were (1) diagnosed with acute coronary syndrome (ACS) that was successfully treated with coronary stent implantation (TIMI flow grade 3 after the procedure). A total of 2463 consecutive patients were screened for inclusion at the Korea University Anam Hospital Cardiovascular Center between March 2013 and April 2015. Exclusion criteria were: (1) hypersensitivity to pitavastatin; (2) serum creatinine > 2.0 mg/dL; (3) hemoglobin A1c > 9%; (4) type 1 DM; (5) serum platelet level < 100,000/μL; (6) left main coronary artery lesion; (7) left ventricular ejection fraction < 40%; (8) hepatic dysfunction (aspartate aminotransferase or alanine aminotransferase > twice the upper limit); (9) gastrointestinal disorders, such as Crohn’s disease; (10) alcohol abuse; (11) steroid or hormone replacement therapy; (12) life expectancy less than 1 year; (13) those with a known pregnancy, breast feeding, or having an intention to become pregnant during the study period; (14) any condition that would make participation in this study unsafe or unsuitable in the opinion of the investigator or (15) a lack of follow-up data.
Among these patients, we enrolled the patients who fulfilled at least 1 of following criteria for a high risk of developing type 2 DM: FBG ≥ 100 mg/dL, fasting triglycerides ≥ 150 mg/dL, BMI ≥ 25 kg/m2 according to the Korean guidelines of obesity, or presence of HTN (Fig. 1) [19]. To investigate the impacts on NOD, we excluded the patients with an existing diagnosis of DM.
Study design
This study was a post hoc analysis of the prospective, open-label, single-blinded, randomized trial. A total of 1044 patients received lowest-dose pitavastatin (1 mg) or highest-dose pitavastatin (4 mg) for 3 years in the original study. Among them, 667 patients were at high risk of developing type 2 DM in the subanalysis (Fig. 1). Patients received randomization numbers sequentially from a secret randomization list that was computer generated in blocks of 3 by individuals who had no contact with the persons who assigned the patients to study groups or performed any of the assessments. Participants were unaware of the randomization assignments until the final data were obtained. The study was approved by the Korea University Hospital Institutional Review Board, and written informed consent was obtained from all participants or their legal guardians before their inclusion in the study. All clinical investigations were conducted according to the principles of the Declaration of Helsinki.
Endpoints
The primary endpoint was a comparison of the differences in the cumulative incidence of NOD in the pitavastatin 1 mg and pitavastatin 4 mg groups during a 3-year follow-up. NOD was defined as ≥ HbA1c 6.5% or the current use of hypoglycemic agents according to the physician’s discretion. The secondary endpoints were the predictors of NOD and comparison of the changes in vascular function. Vascular function was evaluated by brachial-ankle pulse wave velocity (PWV), central blood pressure (BP), and augmentation index (AI). A patient was defined as an alcoholic when an average of ≥ 7 units of alcohol among men and ≥ 5 units among women were consumed for 2 days per week.
Pulse wave velocity
All patients were evaluated for PWV at baseline and at the 36-month follow-up. After 5 min of rest in the supine position, PWV was measured using a volume plethysmographic apparatus (BP-203 RPE II; Colin, Komaki, Japan), which simultaneously recorded the PWV and the brachial and ankle BP on the left and right sides.
Measurements of central BP and AI
Central BP recordings were obtained using the Omron HEM-9000AI cSBP device (Omron Healthcare, Kyoto, Japan) according to the manufacturer’s and user’s manuals. BP measurement was obtained via the digital oscillometric method using a BP cuff. The accompanying AI calculation was based on the patient’s pressure waveforms calibrated using the brachial systolic and diastolic BP. AI was determined by the change in pressure between the first and second peaks divided by the pulse pressure (AI = ΔP/PP). The first peak was obtained when the blood was ejected from the aorta. The second pressure peak occurred when the blood reflected at the aortic bifurcation. The pulse pressure was the overall peak pressure. All data were stored and analyzed off-line after the completion of testing.
Laboratory analysis
Venous blood samples were drawn from each patient after fasting for 8 h or overnight. Blood samples were centrifuged to obtain plasma that was stored at − 80 °C. Plasma glucose was measured using the glucose oxidase method, and serum insulin levels were measured using an immunoradiometric assay (Biosource, Nivelles, Belgium). Total cholesterol, triglyceride, high-density lipoprotein (HDL) cholesterol, and low-density lipoprotein (LDL) cholesterol levels were determined using enzymatic methods with standard biochemical procedures on a BM Hitachi automated clinical chemistry analyzer (Hitachi, Tokyo, Japan).
Statistical analysis
Data were expressed as mean ± standard deviation for the continuous variables, and as number and percentage of patients for the categorical variables. Fisher’s exact test or Chi-square test was used for categorical variables. The change from baseline was calculated as the value obtained at the end of treatment subtracted from the pre-treatment value. The results of the 2 groups were compared using the unpaired Student’s t test, and the comparisons of the results obtained before and after the treatment were analyzed using the paired t test. To balance the distribution of baseline characteristics, we used propensity score matching. We estimated a propensity score for each study participant using the multivariable logistic regression model. In the model, potential confounders and variables, such as age, sex, alcohol intake and smoking status, BMI, HTN, DM, and medication history were included. We then created an exchangeable comparison group of patients receiving pitavastatin 1 mg by matching each with a patient in the pitavastatin 4 mg group. The model was fit to the data during all steps of the regression analyses (Hosmer and Lemeshow goodness-of-fit test χ2 = 6.30, p = 0.85, and relative multivariate imbalance L1 after matching = 0.96). Using the propensity scores, we matched 251 of those patients receiving pitavastatin 1 mg to another 251 patients receiving pitavastatin 4 mg who had a similar propensity score. Our assessment of the covariate balance after matching focused on these standardized differences. p value < 0.05 was considered statistically significant. SAS software (version 9.3; SAS Institute, Cary, NC, USA) was used for the statistical analyses.