Atherosclerotic cardiovascular disease (ASCVD) remains the leading cause of mortality worldwide despite tremendous advancements in diagnostic and therapeutic modalities. The pathophysiological mechanisms behind atherosclerosis are complex, with vascular inflammation playing a key role in its initiation, progression, and clinical manifestations.¹ Although the benefits of achieving low low-density lipoprotein cholesterol (LDL-C) values as a fundamental approach in treating ASCVD are unequivocal, the role of adjuvant strategies targeting residual inflammatory risk compared with further lowering of cholesterol levels has remained a topic of particular interest.

To address this question, Ridker et al. performed a collaborative analysis of three contemporary randomized trials that included patients with or at high risk of ASCVD²: PROMINENT (Pemafibrate to Reduce Cardiovascular Outcomes by Reducing Triglycerides in Patients With Diabetes), REDUCE-IT (Reduction of Cardiovascular Events With Icosapent Ethyl–Intervention Trial), and STRENGTH (Long-Term Outcomes Study to Assess Statin Residual Risk With Epanova in High Cardiovascular Risk Patients With Hypertriglyceridemia). A total of 31,245 patients of predominantly white ethnicity with mean age 64 years, 31% of whom were women, were evaluated. A high proportion of participants had concomitant type 2 diabetes mellitus and obesity.

Notably, most participants had ASCVD and almost 100% were taking a statin. The median baseline LDL-C value was approximately 75 mg/dL and high-sensitivity C-reactive protein (hs-CRP) value was approximately 2.2 mg/L. The baseline level of hs-CRP was significantly associated with incident major adverse cardiovascular (CV) events, CV mortality, and all-cause mortality. In contrast, the relationship of residual cholesterol risk was neutral for major adverse CV events and of low magnitude for CV death and all-cause death.

These results indicate that knowledge of residual inflammatory risk is crucial beyond foundational statin therapy in treating people with ASCVD. Furthermore, among patients with improved LDL-C levels with statins, further lowering of cholesterol levels may be associated with only modest gains. Ultimately, it is important to remember that this is not a competition between cholesterol and inflammation; both of these are dominant risk factors, and the best outcomes are likely going to be achieved by dual-targeting complementary approaches. The best way to reduce inflammation remains weight loss, increased brisk daily exercise, and better glycemic control.

References

1. Lawler PR, Bhatt DL, Godoy LC, et al. Targeting cardiovascular inflammation: next steps in clinical translation. Eur Heart J 2021;42:113-31.
2. Ridker PM, Bhatt DL, Pradhan AD, Glynn RJ, MacFadyen JG, Nissen SE; PROMINENT, REDUCE-IT, and STRENGTH Investigators. Inflammation and cholesterol as predictors of cardiovascular events among patients receiving statin therapy: a collaborative analysis of three randomised trials. Lancet 2023;401:1293-301.