Editorial
Residual Cardiovascular Risk Determined through Posthoc Analysis of the REAL-CAD Trial
2024 Volume 31 Issue 1 Pages 21-22
Details
2024 Volume 31 Issue 1 Pages 21-22
See article vol. 31: 61-80
Statins are widely used in the prevention and treatment of cardiovascular diseases, including hypercholesterolemia and coronary artery disease (CAD).
A meta-analysis by the Cholesterol Treatment Trialist collaborators established that statins significantly reduce the occurrence of cardiovascular diseases by approximately 20%–30% by lowering low-density lipoprotein cholesterol (LDL-C) levels1).
However, recent interest shifted to risks reminded after undergoing statin (about 70%), namely, residual risk. This risk is presumably composed of remnants2), Lp(a)3), small dense LDL4), and HDL-C5).
Beyond lipid-related risk factors, inflammation has been identified as a nonlipid-related risk factor. In the CANTOS trial, the use of the IL-1β inhibitor canakinumab reduced the incidence of cardiovascular diseases by improving inflammation without affecting lipid parameters6).
However, residual risk factors unrelated to lipids remain a relatively unexplored area. The REAL-CAD trial, a randomized controlled study, compared high-dose pitavastatin therapy with low-dose therapy in approximately 13,000 Japanese patients with stable CAD, demonstrating that high-dose statin therapy effectively and safely reduced major adverse cardiovascular events (MACEs).
In this study, Kamiya et al. performed a posthoc analysis of the REAL-CAD trial by selecting the cases of patients with stable CAD from the trial who had achieved LDL-C levels below the JAS guideline-recommended threshold of 100 mg/dL and identified eGFR and HbA1c as integral lipid-independent residual risk factors7).
This investigation, which explored residual risk among over 8,000 Japanese patients with stable CAD, is academically significant and has the potential to profoundly influence clinical practice.
Interpreting the study’s outcomes requires the consideration of several limitations. First, triglycerides (TGs) may be a residual risk factor. Indeed, nonfasting and fasting-TG are predictors of cardiovascular disease in the general population8).
Moreover, in the 2022 Japanese Atherosclerosis Society guidelines, cutoff values for nonfasting TGs ≥ 175 mg/dl were established. However, this trial did not exclude patients with high TG levels. This inclusion of cases with elevated TG levels may lead to a potential for bias with the potential to impact the results.
Second, the novel lipid-lowering therapy drug, PCSK9 inhibitor, plays a pivotal role in addressing residual risk factors. This is based on clinical findings that have demonstrated the effectiveness of the PCSK9 inhibitor after statin therapy in reducing MACEs9) and causing changes in plaque composition, as observed by optical coherence tomography10). This study primarily focuses on research related to pitavastatin. Therefore, the use of PCSK9 inhibitors has not been specifically discussed. There is hope for future clinical research to determine whether PCSK9 inhibitors can mitigate the residual risk identified in this study.
Third, concerning the analysis of renal function, CKD was solely defined based on GFR ＜60 mL/min per 1.73 m2, but lacking information of urinary albuminuria was also a study limitation. Consequently, the relationship between CKD stage and residual risk remains unclear, thereby requiring future research.
Moreover, in this study, cases with elevated levels of high-sensitivity C-reactive protein (hs-CRP) were also included, indicating a potential association between inflammation and residual risk. Although eGFR and HbA1c, identified as residual risk factors, seem to be completely different biomarkers, they share a common aspect when considered from an inflammation perspective. For instance, CKD incorporates inflammation as a residual risk factor, contributing to the recurrence of cardiovascular diseases11). Additionally, hs-CRP is a positive predictor of CVD and mortality in type 2 DM, suggesting that inflammation contributes to atherosclerosis progression in DM.
Therefore, CKD and DM share common aspects in inducing atherosclerosis through inflammation. eGFR and HbA1c may help identify high-risk patients for cardiovascular events by integrating aspects of inflammation. Furthermore, novel treatment strategies aimed at alleviating inflammation in patients with CKD and DM may be effective means of controlling the residual risk identified in this study.
In conclusion, this study identified eGFR and HbA1c as novel residual risk factors in Japanese patients with CAD. The shared inflammatory aspect present in CKD and DM holds a potential avenue for addressing the residual risk following statin administration. This suggests a promising direction for addressing the residual risk observed after statin therapy. We anticipate future research aimed at further exploring this connection.
All authors declared no conflicts of interest.
