Safety and Effectiveness of Pravastatin in Korean Patients with Dyslipidemia Based on the Cardiovascular Risk Classification: Pooled Analysis of Four Observational Studies
Article information
Abstract
Background
Despite their efficacy, statin-related adverse events (AEs) may interfere with statin treatment and contribute to negative outcomes in patients with cardiovascular diseases. In this study, we evaluated the safety and effectiveness of pravastatin in Korea.
Methods
Pooled data were collected from four multicenter prospective observational studies conducted in Korea between 2011 and 2020. Finally, 7,334 and 2,022 participants were included in the safety and effectiveness analyses, respectively. Overall safety, particularly muscle-related, incidence of new-onset diabetes mellitus (DM), changes in fasting plasma glucose and hemoglobin A1c level, achievement of target low-density lipoprotein cholesterol (LDL-C) level, and changes in LDL-C level were analyzed.
Results
At week 24, after 20 or 40 mg pravastatin treatment, safety results showed that AEs and adverse drug reactions (ADRs) were 8.7% and 1.3%, respectively, and that muscle-related AEs and ADRs were 0.5% and 0.3%, respectively, with no statistically significant difference in risk factors for statin-associated muscle symptoms. No patients developed DM during the study period. Additionally, at week 24, the achievement rates of target LDL-C levels were 87.9%, 78.4%, 57.8%, and 11.6% in low-, moderate-, high-, and very high-risk groups, respectively.
Conclusion
This study found that 20 or 40 mg pravastatin had minimal side effects and was safe for use in real-world clinical settings in Korea. Specifically, these doses effectively achieved the target LDL-C levels in patients with dyslipidemia in low-, moderate-, and high-risk groups for atherosclerotic cardiovascular disease (ASCVD). These results demonstrate that pravastatin can be safely administered continuously to patients with low-, moderate-, and high-risk ASCVD in a real-world clinical setting.
INTRODUCTION
Low-density lipoprotein cholesterol (LDL-C) is implicated as a causative factor in the pathogenesis of cardiovascular diseases (CVDs), wherein the accumulation of cholesterol-rich LDL, especially oxidized LDL, within the vascular walls triggers the formation and progression of atherosclerotic lesions and vascular diseases [1]. Consequently, most guidelines recommend the management of dyslipidemia in Korea, emphasize LDL-C reduction as pivotal for primary CVD prevention [2], with statins serving as the primary therapeutic modality for lipid-lowering interventions [3].
Statins, a pharmacotherapeutic class aimed at lowering lipid levels, have been pivotal in mitigating the risk of CVD and adverse CVD outcomes owing to their robust efficacy and favorable tolerability profile [4]. Despite their efficacy, statins are associated with adverse events (AEs), including myalgia or myopathy, renal impairment, hepatic dysfunction, and new-onset diabetes mellitus (NODM) [5]. Although various definitions and terms have been used to define the muscle-related symptoms of statins treatment and often vary according to the guidelines, the term statin-associated muscle symptoms (SAMS) have garnered preference [6].
The SAMS encompasses a spectrum of muscular discomfort or pain associated with statin therapy. Notwithstanding their established benefits, a substantial proportion of patients discontinue or opt against commencing statin therapy because of SAMS [7], with discontinuation or poor adherence linked to the recurrence of elevated lipids to pretreatment levels and subsequent increased CVD mortality [8]. Hence, for healthcare providers to adeptly manage patients with SAMS reconciling symptom alleviation with the continuity of preventive therapy is imperative. An enhanced understanding through further investigation into SAMS is warranted to provide healthcare providers with comprehensive insights.
Also, there are various conflicting reports regarding the effects of pravastatin treatment on the incidence of NODM and insulin sensitivity. Some reports suggest that pravastatin significantly increases insulin sensitivity, while other studies indicate that pravastatin may increase the incidence of NODM [9-12].
While current guidelines typically rely on evidence from clinical trials and meta-analyses for decision-making, the relevance of real-world data in clinical practice appears paramount. Thus, future guidelines should be of greater importance to real-world data [13]. A few studies in Korea have evaluated the safety and effectiveness of pravastatin in real-world clinical settings. Therefore, in this study, we evaluated the safety, specifically muscle-related, and effectiveness of pravastatin. Additionally, it explored the potential impact of pravastatin treatment on the development of NODM.
METHODS
Study design
Pooled data were collected from four multicenter prospective observational studies conducted in Korea between 2011 and 2020: CJ-MVT-P01, MVT-OS-13-01 (OS-2), MVT-OS-15-01 (OS-3), and MVT-OS-17-01 (Supplemental Table S1). The results of these observational studies have not been published in any other journal. All the studies were conducted in accordance with the ethical principles of the Declaration of Helsinki and Good Clinical Practice. The protocols for these observational studies were reviewed and approved by the Institutional Review Board (IRB) of each study site. Written informed consent was obtained from all participants before any study-related procedures were performed. This study was approved by the IRB of Korea University Anam Hospital in Seoul, Republic of Korea (IRB no. 2024AN0106).
Participants
A total of 15,475 participants with hyperlipidemia or dyslipidemia, who were prescribed pravastatin at a dose of 5–40 mg for at least 12–48 weeks at the physician’s discretion in routine clinical practice, were enrolled in all four observational studies. In Korea, the starting doses of pravastatin are 10, 20, and 40 mg, which can be increased to 40 mg depending on the patient’s response. Previous systematic reviews examining the effectiveness and safety of statins for CVD prevention confirmed that most doses of pravastatin used for CVD prevention were 20 or 40 mg because the LDL-C-lowering rate of pravastatin is proportional to its dose [14-16]. Therefore, only participants who were prescribed 20 or 40 mg pravastatin were included in this study. In addition, only statin-naïve participants were included to exclude any influence on the effectiveness and safety of previously used statins. A total of 8,141 participants who had (1) not taken pravastatin; (2) no lipid profiles after baseline; (3) violated the inclusion/exclusion criteria; (4) previously taken other statins; or (5) been prescribed 5 or 10 mg of pravastatin were excluded from the study. Consequently, 7,334 participants were included in the safety set. Subsequently, within the safety set, participants who had (1) no LDL-C values at week 24; (2) already achieved their target LDL-C goal according to baseline atherosclerotic cardiovascular disease (ASCVD) risk classification; (3) no high-density lipoprotein cholesterol (HDL-C) values at baseline; and (4) outlier LDL-C values were excluded, and, consequently, 2,022 participants were included in the effectiveness set (Fig. 1). Participants in the effectiveness set were classified into four groups according to ASCVD risk levels of the 2018 Korean Guidelines for the Management of Dyslipidemia: low-, moderate-, high-, and very high-risk groups [17].
Participants included in pooled analysis. OS, observational study; OS 1, CJ-MVT-P01; OS 2, MVT-OS-13-01; OS 3, MVT-OS-15-01; OS 4, MVT-OS-17-01; LDL-C, low-density lipoprotein cholesterol; ASCVD, atherosclerotic cardiovascular disease; HDL-C, high-density lipoprotein cholesterol.
To evaluate the impact of pravastatin on glycemic parameters, two separate ‘NODM’ cohort, and ‘diabetes cohort’ were established using data from two prior observational studies, OS-2 and OS-3, where fasting plasma glucose (FPG) and glycated hemoglobin (HbA1c) were available for analysis. The ‘NODM cohort’ consisted of 80 individuals without baseline diabetes, selected from 382 participants in the OS-2 group who had FBS and HbA1c measurements available at 12 or 24 weeks. Since OS-3 was conducted in patients with dyslipidemia and diabetes, the NODM cohort was limited to participants from the OS-2 group only. Meanwhile, the ‘diabetes mellitus (DM) cohort’ was established to evaluate changes in blood glucose and HbA1c levels following pravastatin use. This cohort included 883 participants, all of whom had FPG and HbA1c results at 12 or 24 weeks from both two previous observational studies.
Endpoints
Safety endpoints included the overall incidence of AEs, adverse drug reactions (ADRs), serious adverse events (SAEs), and serious adverse drug reactions (SADRs). An AE was considered an ADR if its causality was deemed to be certainly related, probably/likely related, possibly related, conditional/unclassified, or unassessable/unclassifiable to pravastatin. To evaluate the safety of pravastatin in muscle, muscle-related AEs and ADRs were measured; specifically, the incidence of muscle-related ADRs was analyzed according to SAMS risk factors defined as (1) an individual aged 65 years or older; (2) female sex; (3) body mass index (BMI) <18.5 kg/m2; or (4) estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2 [18]. Muscle-related AEs and ADRs in this study included myalgia, myopathy, muscle spasms, muscular weakness, musculoskeletal discomfort, musculoskeletal chest pain, musculoskeletal pain, musculoskeletal stiffness, and blood creatine phosphokinase (CPK) increased [7]. The percentages (%) of participants with abnormal aspartate aminotransferase (AST), alanine aminotransferase (ALT), and CPK levels were analyzed if they could be collected from participants with laboratory test results. Abnormalities were defined as >3 times the upper limit of normal (ULN) for AST and ALT and >5 times the ULN for CPK.
For the evaluation of NODM, patients were classified as ‘without DM at baseline’ if they did not meet any of the following criteria at baseline: HbA1c ≥6.5%, FPG ≥126 mg/dL, a prior diagnosis of diabetes, or current use of antidiabetic medications, including oral agents or insulin. NODM was defined as HbA1c ≥6.5% and FPG ≥126 mg/dL at either the 12- or 24-week time point. Additionally, changes in HbA1c and FPG from baseline to weeks 12 and 24, as well as differences between the pravastatin 20 and 40 mg dosage groups, are presented.
Regarding the effectiveness of pravastatin, the achievement rate of the LDL-C target level and the change in LDL-C level at week 24 compared to baseline are presented in each ASCVD risk group.
Pooled data and statistical analysis
The pooled data included demographic information, visit date, medical history, inclusion/exclusion criteria, study drug use status, laboratory test results, vital signs, preceding/concomitant medications, and AEs.
Continuous variables were summarized using descriptive statistics, including mean and standard deviation (SD), whereas categorical variables were presented as the number of participants and percentages. AEs were coded and summarized using the Medical Dictionary for Regulatory Activities (MedDRA) version 24.1. In instances where the original AEs data were coded using a MedDRA version other than 24.1, the terms were recoded using MedDRA version 24.1. Participant-reported AEs were presented according to the system organ class (SOC) and preferred term of MedDRA.
When subgroup comparisons were warranted for categorical data, the chi-squared test or Fisher’s exact test was used. Among the laboratory test results, the proportions of participants above the ULN in AST, ALT, and CPK at baseline and week 24 were analyzed, and their changes above the ULN from baseline to week 24 were analyzed using McNemar’s test.
To identify the incidence of NODM during study period in patients without DM at baseline, the incidence of NODM and its 95% confidence interval (CI) were reported. To assess glycemic changes in patients with and without diabetes, changes in HbA1c and FPG from baseline to 12 and 24 weeks for each pravastatin 20 and 40 mg group were analyzed using Wilcoxon signed rank test. Furthermore, a subgroup analysis was performed to evaluate the risk of glucose metabolism deterioration between the 20 and 40 mg treatment groups using either an independent t test or a Wilcoxon rank sum test.
Differences in the achievement rate of the target LDL-C level at week 24 in the ASCVD risk group were analyzed using the chi-square test. The significance of absolute change (mg/dL) and change rate (%) in LDL-C from baseline to week 24 in the pravastatin dose and ASCVD risk groups was determined using the paired t test or Wilcoxon signed rank test, and one-sample t test or sign test, respectively. Furthermore, depending on the normality of the data distribution, the differences in absolute change (mg/dL) and change rate (%) in LDL-C were analyzed using different statistical tests: (1) between pravastatin doses for each ASCVD risk group were analyzed using either the t test or Wilcoxon rank sum test; and (2) by ASCVD risk group were analyzed using either analysis of variance (ANOVA) or the Kruskal-Wallis test. All statistical analyses were performed using SAS version 9.4 (SAS Institute Inc., Cary, NC, USA).
RESULTS
Baseline characteristics
The baseline characteristics of the 7,334 participants included in the pooled analysis are shown in Table 1. Briefly, the mean age of participants was 60.8 years, with 40.0% aged ≥65 years, of which 47.7% were male. The mean BMI of participants was 24.8±3.3 kg/m2, and the mean duration of dyslipidemia was 1.5±3.3 years. Regarding pravastatin dose, 20 and 40 mg was administered to 30.1% and 69.9%, respectively.
Baseline Characteristics
Among the participants, 16.1% had ASCVD with specific conditions including coronary artery disease, stroke, peripheral vascular disease, and carotid artery disease in 10.1%, 3.2%, 2.5%, and 1.3%, respectively. Additionally, 50.1% and 45.7% had hypertension and diabetes, respectively.
The means of baseline levels of total cholesterol, LDL-C, HDL-C, non-HDL-C, and triglycerides were 215.8±44.5, 133.7±38.9, 50.9±16.0, 203.1±44.9, and 153.2±71.1 mg/dL, respectively. In addition, 24.2% had an eGFR <60 mL/min/1.73 m2, and the means of baseline levels±SD of ALT, AST, and CPK were 26.4±19.6, 25.6±14.3, and 120.1±123.6 IU/L, respectively.
Overall safety of pravastatin
Fig. 2 shows the incidence of ADRs and SADRs among the 7,334 participants, whereas Supplemental Fig. S1 shows the incidence of AEs and SAEs reported in the same cohort. A total of 637 participants (8.7%) reported AEs, with 97 participants (1.3%) experiencing pravastatin-related ADRs. According to SOC of MedDRA, ‘gastrointestinal disorders’ were the most frequently reported AEs, affecting 1.6% (116 participants), followed by ‘nervous system disorders’ reported in 1.4% (103 participants), and ‘infections and infestations’ in 1.3% (97 participants). Among them, ‘nervous system disorders’ were the most commonly reported SAE, affecting 0.3% (19 participants), followed by ‘infections and infestations’ in 0.3% (18 participants) and ‘cardiac disorders’ in 0.2% (16 participants) (Supplemental Fig. S1).
Overall summary of adverse drug reaction and serious adverse drug reaction. Incidence rate (%): (no. of subjects with adverse drug reaction in each category)/(no. of subjects of safety set)×100. The preferred terms for the system organ class term ‘investigations’ in the category of adverse drug reactions include ‘blood creatine phosphokinase increased,’ ‘alanine aminotransferase increased,’ ‘aspartate aminotransferase increased,’ ‘blood triglycerides increased,’ ‘blood cholesterol increased,’ and ‘hepatic enzyme increased.’
Regarding ADRs, ‘investigations’ such as ‘blood CPK increased, ALT, increased and AST increased,’ was the most common, affecting 0.3% (25 participants), followed by ‘gastrointestinal disorders’ with 0.3% (21 participants) and ‘musculoskeletal and connective tissue disorders’ with 0.2% (12 participants). A total of 109 participants (1.5%) reported SAEs, of whom six participants (0.1%) experienced pravastatin-related SADRs. SADRs included ‘nervous system disorders’ in three participants; ‘metabolism and nutrition disorders,’ ‘injury, poisoning, and procedural complications,’ and ‘reproductive system and breast disorders’ in one participant each (Fig. 2). When classified by ASCVD risk group, the incidence rates of ADRs were 1.5%, 1.0%, 1.5%, and 1.9% in low-, moderate-, high-, and very high-risk groups, respectively. However, no statistically significant difference in the incidence of ADRs between the groups was observed (Supplemental Table S2).
Regarding liver-related safety data, no statistically significant change from baseline to week 24 in the proportion of participants with ALT and AST >3 times ULN was observed, when analyzing participants with ALT and AST data at baseline and 24 weeks (Supplemental Tables S3, S4).
Muscle-related safety of pravastatin
Table 2, Supplemental Table S5 show the muscle-related safety results for 20 and 40 mg pravastatin in 7,334 participants. In this study, a total of 33 participants (0.5%) reported 36 muscle-related AEs, of whom 19 participants (0.3%) experienced muscle-related ADRs. Specifically, ‘myalgia,’ ‘blood CPK increased,’ and ‘musculoskeletal discomfort’ were reported as AEs in 15 (0.2%, 15 events), 12 (0.2%, 12 events), and three participants (0.0%, three events), respectively. ‘Muscle spasm,’ ‘muscular weakness,’ and ‘musculoskeletal stiffness’ were each reported as AEs in two participants (0.0%, two events). ‘Myalgia,’ ‘blood CPK increased,’ and ‘muscle spasm’ have been reported as ADRs (Supplemental Table S5). Although ‘blood CPK increased’ was reported as an ADR in this study, no participant had CPK >5 times the ULN at baseline and 24 weeks when analyzing participants with CPK data available at both baseline and 24 weeks (Supplemental Table S6).
Incidence of Muscle-Related ADRs by SAMS Risk Factors
The incidence of muscle-related ADRs according to SAMS risk factors was 0.2% (17/6,967) and 0.5% (2/367) in participants with and without risk factors, respectively, with no statistically significant difference in the incidence of muscle-related ADRs based on SAMS risk factors. Furthermore, when examining the incidence of muscle-related ADRs by each SAMS risk factor, no statistically significant effect on the incidence of muscle-related ADRs was observed by age 65 years or older; female sex; BMI <18.5 kg/m2; or eGFR <60 mL/min/1.73 m2 (Table 2).
Exploring the incidence of NODM with statin therapy
Among the 80 patients without DM at baseline from OS-2 (NODM cohort), none developed NODM following pravastatin treatment (0.00%; 95% CI, 0.00 to 4.51) (Supplemental Table S7).
In the DM cohort, both FPG and HbA1c levels were lower compared to baseline at most of the time points. Specifically, in patients without diabetes who received pravastatin 20 mg, the median FPG levels were 103.50 mg/dL (interquartile range [IQR], 101.00 to 105.00) at baseline, 103.00 mg/dL (IQR, 101.00 to 105.00) at 12 weeks, and 103.00 mg/dL (IQR, 100.00 to 105.00) at 24 weeks. Median HbA1c levels were 5.80% (IQR, 5.70 to 5.90) at baseline, 5.80% (IQR, 5.70 to 5.90) at 12 weeks, and 5.79% (IQR, 5.60 to 5.80) at 24 weeks. In patients with diabetes receiving pravastatin 20 mg, median FPG levels were 138.00 mg/dL (IQR, 118.00 to 163.50) at baseline, 131.00 mg/dL (IQR, 112.00 to 148.00) at 12 weeks, and 134.00 mg/dL (IQR, 116.00 to 155.00) at 24 weeks. Median HbA1c levels were 7.00% (IQR, 6.50 to 7.60) at baseline, 6.80% (IQR, 6.30 to 7.50) at 12 weeks, and 6.70% (IQR, 6.20 to 7.50) at 24 weeks. For patients without diabetes who received pravastatin 40 mg, the median FPG levels were 99.95 mg/dL (IQR, 94.00 to 109.00) at baseline, 98.00 mg/dL (IQR, 92.00 to 106.00) at 12 weeks, and 100.50 mg/dL (IQR, 97.50 to 105.00) at 24 weeks. Although FPG levels were slightly higher at 24 weeks, the change was not statistically significant. Median HbA1c levels were 5.68% (IQR, 5.50 to 5.90) at baseline, 5.70% (IQR, 5.50 to 6.00) at 12 weeks, and 5.70% (IQR, 5.60 to 5.80) at 24 weeks, with no statistically significant changes. In patients with diabetes receiving pravastatin 40 mg, median FPG levels were 131.00 mg/dL (IQR, 112.00 to 150.00) at baseline, 126.00 mg/dL (IQR, 111.00 to 146.00) at 12 weeks, and 127.00 mg/dL (IQR, 112.00 to 147.00) at 24 weeks. Median HbA1c levels were 6.80% (IQR, 6.40 to 7.50) at baseline, 6.60% (IQR, 6.20 to 7.20) at 12 weeks, and 6.70% (IQR, 6.20 to 7.30) at 24 weeks. Additionally, there were no significant differences in glycemic changes between the two pravastatin dosage groups during the study period (Supplemental Table S8).
Effect of pravastatin on LDL-C target achievement and LDL-C reduction
At week 24 after administration of either 20 or 40 mg pravastatin, the achievement rates of target LDL-C levels were 87.9%, 78.4%, 57.8%, and 11.6% in low-, moderate-, high-, and very high-risk groups, respectively, with statistically significant differences in ASCVD risk group (P<0.001). Regardless of ASCVD risk, the achievement rate of target LDL-C level in 2,022 participants at week 24 by pravastatin was 53.9% (Fig. 3).
Achievement rate of target low-density lipoprotein cholesterol (LDL-C) level at week 24 by Korean Guidelines (4th edition of the 2018 Dyslipidemia Management Guidelines) for the management of dyslipidemia. ASCVD, atherosclerotic cardiovascular disease.
The absolute change (mg/dL) and change rate (%) in LDL-C from baseline to week 24 in the pravastatin- and ASCVD risk groups were analyzed. At week 24 after administering either 20 mg or 40 mg pravastatin, the mean decrease in LDL-C was −58.4± 29.7, −46.5±25.3, −40.2±30.8, and −25.3±35.5 mg/dL in low-, moderate-, high-, and very high-risk groups, respectively, with statistically significant decreases from baseline (all P<0.001). Similarly, the mean change rate (%) of LDL-C in low-, moderate-, high-, and very high-risk groups was −32.3±16.0, −29.4±15.5, −28.0±20.6, and −15.9±27.9, respectively, after 24 weeks of treatment, with statistically significant change observed (all P<0.001) (Supplemental Table S9).
DISCUSSION
In this study, the incidences of AEs and ADRs were 8.7% and 1.3%, respectively, and the incidences of muscle-related AEs and ADRs were 0.5% and 0.3%, respectively, showing no statistically significant difference based on the SAMS risk factors. In addition, 20 or 40 mg pravastatin effectively achieved the target LDL-C levels in patients with dyslipidemia at low- and moderate-risk for ASCVD in a real-world clinical settings in Korea. At week 24, the achievement rates of target LDL-C levels were 87.9%, 78.4%, 57.8%, and 11.6% in low-, moderate-, high-, and very high-risk groups, respectively. This is the first large observational study to pool data from four observational studies and to demonstrate the safety and effectiveness of pravastatin across different levels of ASCVD risk in a diverse population, including 40% who were 65 or older, 52% females, and 24% with kidney problems.
Although clinical trials are powerful tools for generating scientific evidence regarding the safety and efficacy of medicinal products, statin therapy between clinical trials and real-world settings is contrasting [13,19]. Large scale observational studies and registry reviews have shown an incidence of SAMS ranging from 10% to 29% [20,21], while systemic reviews from randomized controlled trials have reported an incidence of SAMS with 12.7% and 12.4% in statin therapy and placebo group, respectively [22].
In the present study analyzing the pooled data from four observational studies conducted in real-world clinical settings in Korea, among 7,334 participants taking pravastatin for 24 weeks, 0.5% reported muscle-related AEs, including myalgia, blood CPK increased, musculoskeletal discomfort, muscle spasm, muscular weakness, and musculoskeletal stiffness (Supplemental Table S5). Previous clinical trials on pravastatin have reported a low incidence of muscle-related AEs in the pravastatin group, similar to that in the placebo group. For instance, in the Pravastatin or Atorvastatin Evaluation and Infection Therapy trial for patients with an acute coronary syndrome within the preceding 10 days, statin discontinuation due to myalgias or muscle aches or creatine kinase elevations occurred in 2.7% of the pravastatin-treated patients and 3.3% of the atorvastatin-treated patients [23]. In prospective study of pravastatin in the elderly at risk (PROSPER) study, 40 mg of pravastatin was associated with only 2.7% of myalgia compared to 2.5% in the placebo group [24]. In the study by Shepherd et al. [25], 0.6% and 2.9% in pravastatin group reported myalgia and muscle aches, respectively, and 0.5% and 3.0% in placebo group reported myalgia and muscle aches, respectively. In the Cholesterol and Recurrent Events trial, 0.5% of the pravastatin group reported elevated serum creatine kinase levels compared to 0.3% of the placebo group. Furthermore, myositis was reported in 0.1% in the placebo group, whereas none was observed in the pravastatin group [26]. Regarding on 10–20 mg of pravastatin, in the primary prevention of CVD with pravastatin in Japan (MEGA) study, the incidence of creatine kinase elevation was 2.8% in the diet plus pravastatin group compared to 2.4% in diet group [27].
Before initiating statin therapy, a comprehensive evaluation is recommended to identify predisposing factors for SAMS, including demographics, comorbid conditions, and the use of medications that can adversely affect statin metabolism [18]. Therefore, according to SAMS risk factors (Table 2), we assessed the incidence of muscle-related ADRs across the different subgroups defined by age (<65 years vs. ≥65 years), sex (male vs. female), BMI (<18.5 kg/m2 vs. ≥18.5 kg/m2), and baseline eGFR (<60 mL/min/1.73 m2 vs. ≥60 mL/min/1.73 m2); no statistically significant differences in the incidence of muscle-related ADRs was found.
Statin-interacting drugs that affect statin metabolism may also contribute to SAMS [6]. Most statins are primarily metabolized by cytochrome P450 (CYP) enzymes, particularly CYP3A4 and CYP2C9, which are involved in the metabolism of several drugs used to treat chronic diseases. However, pravastatin differs in its metabolism and it primarily undergoes sulfonation rather than being metabolized by CYPs [6,28]. This distinction in the metabolic pathways may influence the potential for drug interactions with statins. Medications such as azole antifungals, macrolide or mycin antibiotics, protease inhibitors, Ca2+ channel blockers, and warfarin can increase the serum concentration of statins [29]. Pravastatin is also much more hydrophilic than other statins, owing to differences in its chemical structure [30]. An increase in SAMS could be responsible for the non-selective diffusion of lipophilic statins into extrahepatic tissues, albeit without differences between hydrophilic and lipophilic statins with respect to other AEs [31].
In addition to SAMS, statin use is associated with a risk of elevated hepatic transaminase levels and DM. Statins are thought to potentially induce hepatotoxicity due to their metabolism in the liver and their interactions with the CYP pathway [6]. Most liver abnormalities associated with statin use tend to occur within the first 3 months of statin therapy [28]. In the present study, consisting of statin-naïve patients with dyslipidemia, no statistically significant change was observed at week 24 after pravastatin treatment in the proportion of participants with ALT and AST >3 times the ULN (Supplemental Tables S3, S4).
An exploratory investigation of the impact of pravastatin on DM was conducted using data from two prior observational studies, where FPG and HbA1c levels were measured. Among 80 patients without DM at baseline, no cases of NODM were observed during the study period. Additionally, in patients without diabetes who received pravastatin at doses of 20 and 40 mg, both FPG and HbA1c levels were lower than baseline at follow-up. Overall, no glycemic deterioration was noted, suggesting that the impact of pravastatin on blood glucose levels is minimal. These findings are consistent with results from the Korean National Health and Nutrition Examination Survey, which reported a non-statistically significant trend of increased fasting blood glucose associated with pravastatin use [32].
In addition to its favorable safety profile, the present study demonstrated the effectiveness of treatment with 20 or 40 mg pravastatin, classified as low- and moderate-intensity statins, respectively, over a 24-week period. Treatment with 20 or 40 mg pravastatin was effective in achieving the target LDL-C level and lowering LDL-C levels, particularly in participants categorized into low-, moderate-, and high-risk groups (Fig. 3, Supplemental Table S9). Achieving LDL-C targets is important for the treatment of dyslipidemia. This is because treatment decisions are guided by whether the LDL-C target is successfully reached with statin therapy, as outlined in evidence-guided approach algorithms, such as those provided in the Korean Guidelines for the Management of Dyslipidemia, 4th edition.
This study had some limitations, primarily stemming from its observational nature. To obtain valid results and minimize bias, controlling several factors is necessary, including treatment group assignment, compliance, baseline characteristics, and laboratory test results. However, these factors were not adequately controlled for in this study. Moreover, the incidence of AEs and ADRs, including SAMS, was low in this study compared to that reported in previous clinical trials of pravastatin, indicating AEs and ADRs were underreported in this study. A good approach to increasing reporting, such as providing education on how to recognize and report ADRs, feedback mechanisms, and removing barriers, including fear or lack of time, to reporting errors or ADRs, is needed because such underreporting can lead to delays in identifying drug safety problems and could potentially harm the patients [33]. The most recent clinical guidelines for the management of dyslipidemia emphasize more intensive control of patients with DM, taking into account the disease duration, presence of target organ damage, and concurrent diseases. Therefore, achieving LDL-C targets in patients with DM should ideally be evaluated considering these factors. To evaluate the effect of pravastatin on diabetes, we established a separate cohort and conducted an analysis using data obtained from previous observational studies. However, since the primary outcome of these studies was not the incidence of NODM, the number of subjects with available HbA1c and FPG measurements was limited. Moreover, due to the observational design, a thorough investigation of potential risk factors for NODM may not be feasible. Additionally, the study duration—restricted to pravastatin use for only 12 or 24 weeks—was insufficient to comprehensively assess the risk of NODM. Lastly, this study was conducted by building an integrated database based on data collected from previous studies. In doing so, we aimed to minimize potential biases that could arise from prior research. But we cannot exclude effect from the previous studies completely.
Some guidelines recommend initiating high-intensity statin therapy to achieve a minimum reduction of 50% in LDL-C levels in individuals at very high risk, with higher-intensity statin regimens demonstrating notable benefits for cardiovascular outcomes [18,23,34]. However, each statin has a distinct risk-benefit profile [5]. Additionally, the rules of ‘the lower the better,’ ‘the earlier the better,’ and ‘the longer the better’ highlight the importance of reducing LDL-C for preventing CVD using statin therapy [35]. Recently, a population-based study proposed the concept of ‘longer is better’ for statin therapy, rather than ‘lower is better’ for target LDL-C levels. This assumes that the statin therapy duration or adherence is an important factor in the cardioprotective effects of statins in clinical practice [36]. Therefore, achieving the LDL-C targets in a sustainable and safe manner is important.
In conclusion, this study demonstrated that 20 or 40 mg pravastatin effectively achieved the target LDL-C levels in patients with dyslipidemia, especially in those at low-, moderate-, and high-risk ASCVD, in real-world clinical settings in Korea. Importantly, the incidence of AEs and ADRs in this study was low, especially muscle-related AEs, a common side effect of statins that contributes to the discontinuation of statin therapy. These findings suggest that pravastatin can be safely administered in patients with low- and moderate-, and high-risk ASCVD. By evaluating the safety and effectiveness of pravastatin in real-world clinical settings rather than relying solely on clinical trial data, these findings provide comprehensive and valuable information to healthcare providers who should continuously manage patients experiencing SAMS in real-world clinical settings.
Supplementary Material
Supplemental Table S1.
Characteristics of Four Observational Studies
Supplemental Table S2.
ADR Incidence according to Atherosclerotic Cardiovascular Disease Risk
Supplemental Table S3.
ALT Abnormalities at Baseline and Week 24
Supplemental Table S4.
AST Abnormalities at Baseline and Week 24
Supplemental Table S5.
Muscle-Related AEs-ADRs by Preferred Terms
Supplemental Table S6.
CPK Abnormalities at the Baseline and Week 24
Supplemental Table S7.
Incidence of New-Onset Diabetes Mellitus in Patients without Diabetes Mellitus at Baseline
Supplemental Table S8.
Subgroup Analysis of Glycemic Changes during Treatment in Patients with and without Baseline Diabetes Mellitus Variable Total Pravastatin 20 mg Pravastatin 40 mg
Supplemental Table S9.
Change in LDL-C from Baseline to Week 24 according to the ASCVD Risk
Supplemental Fig. S1.
Overall summary of adverse events and serious adverse events. Incidence rate (%): (no. of subjects with ADR in each category)/(no. of subjects of safety set)×100. The preferred terms for the system organ class term ‘investigations’ in the category of adverse drug reactions include ‘blood creatine phosphokinase increased,’ ‘alanine aminotransferase increased,’ ‘aspartate aminotransferase increased,’ ‘blood triglycerides increased,’ ‘blood cholesterol increased,’ and ‘hepatic enzyme increased.’
Notes
CONFLICTS OF INTEREST
This research was funded by Daiichi Sankyo Korea Co., Ltd.
AUTHOR CONTRIBUTIONS
Conception or design: I.K.J., H.S.K., D.J.K., S.G.K. Acquisition, analysis, or interpretation of data: I.K.J., H.S.K., D.J.K., S.G.K. Drafting the work or revising: I.K.J., H.S.K. Final approval of the manuscript: I.K.J., H.S.K., D.J.K., S.G.K.