The present study is a retrospective national cohort study that compared the efficacy of secondary prevention for CCVD among different types of statins using claim data from the NHIS in Korea. This study shows that there was no significant difference to prevent the recurrence of CCVD and/or death among five different types of statin in CCVD patients.
Statins were classified into three groups according to their reported LDL-cholesterol lowering intensity. Its intensity will depend on the individual dose, but in general, atorvastatin, and rosuvastatin belong to moderate to high intensity groups, and the remaining statins are classified as low or moderate intensity groups . The 2018 American College of Cardiology/American Heart Association (ACC/AHA) guidelines recommend that patients with clinical atherosclerotic CCVD should reduce their LDL-cholesterol with either a high-intensity statin therapy or via a maximum tolerated statin therapy . Due to their efficacy and safety, statins are widely administered for primary and secondary prevention treatment of ASCVD in individuals with dyslipidaemia [3–6].
Different types of statins have different pharmacokinetics, as well as, varied clinical efficacies to improve patient lipid profiles and to prevent ASCVD . In particular, the degree of LDL-cholesterol reduction achieved with statins appears different among Asian and Western patients. Asian CCVD patients often have an increased response to statins. As a result, recommended drug dosages often tend to be lower in Asian countries than in Western countries . However, there is insufficient evidence to directly compare the efficacy of different statins in the secondary prevention of CCVD events . Moreover, the efficacy of reducing LDL-cholesterol and increasing HDL-cholesterol varies from statin to statin. Pitavastatin is classified as a moderate- to low-intensity statin , but its effect on HDL-cholesterol elevation is reported to be superior to those of atorvastatin, rosuvastatin, and simvastatin [13–15].
The results of this study show that there is no difference in secondary prevention effect between different types statins. This may be due to a more complex mechanism in which statins reduce recurrence of CCVD events in apparently healthy individuals beyond LDL-cholesterol reduction and HDL-cholesterol elevation [16, 17]. Statins inhibit HMG-CoA reductase activity in the mevalonate pathway. The mevalonate pathway produces mevalonic acids, which are precursors of cholesterol and some non-sterol isoprenoid derivatives. Isoprenoid derivatives play an important role in the regulation of various cellular functions including proliferation, differentiation, and survival [18, 19]. As a result, statins inhibit the production of isoprenoid intermediates in the cholesterol biosynthetic pathway. Therefore, statins are known to be pluripotent in their ability to modulate cell signalling and to reduce oxidative stress and pro-inflammation . In addition, since the data used in this study was obtained in a real-world setting, it is necessary to interpret the results in consideration of the respective conditions of the participants included in this study. For example, high-intensity statins may be prescribed to participants with a higher risk of CCVD, while low-intensity statins may be prescribed to participants with relatively low risk of CCVD. Lastly, information about the participants’ detailed lifestyle behaviours, such as dietary patterns, were not considered because they were not available in the NHIS-HEALS database. These factors can affect the efficacy of statins, and for this reason, there may be an confounding effect in secondary prevention between different types of statin that was not accounted for – future studies should consider dietary patterns in their analysis.
There are other limitations when interpreting the results of this study. First, several potentially confounding factors have been adjusted, but some residual confounding effects could not be completely controlled for in this study, and include lifestyle factors and/or underlying genetic or familial conditions. We also could not include the non-statin lipid-lowering agents as confounders due to the limited availability of data. Instead of non-statin lipid-lowering agents, we adopted total cholesterol as the second-best option. Second, since the operational definition of CCVD was determined based on ICD-10th codes, the participants in the study might not match actual CCVD patients in a real-world scenario. Third, because the number of participants in each statin group in this study is relatively small, large-scale clinical trials are needed to compare the main preventive effects of each statin type on CCVD. Fourth, we could not check that statin users took their medications as prescribed. Finally, a selection bias possibly exists because several participants of NHIS-HEALS were excluded according to the inclusion and exclusion criteria.
Nevertheless, there are several strengths that distinguish this study from previous studies. Of utmost importance, we used data from a large population provided by the NHIS-HEALS, which represents the entire Korean population based on real-world measurements in the clinical setting. In addition, since this study analysed claim data that included disease diagnosis, health and lifestyle questionnaires, some blood tests, such as lipid profiling, and prescriptions, recall bias is minimized. Finally, regarding the effort to evaluate the differences in efficacy between different types of statins, all participants in this study took only one type of statin during a relatively long study period (median follow-up duration: 12.4 years). Thus, one type of statin's long-term effect of secondary prevention was confirmed.