Residual cardiovascular risk beyond LDL-cholesterol control: what remains unaddressed?

Statins, ezetimibe, and PCSK9 inhibitors have enabled LDL-cholesterol to be lowered to levels previously thought very hard to achieve. However, even after achieving low levels, some patients continued to have cardiovascular events, a phenomenon known as residual cardiovascular risk. This phenomenon indicates the complexity of atherosclerosis, not limited to a simple LDL-driven process. Vascular inflammation persists even in the presence of well-controlled lipids and is largely mediated by the NLRP3-interleukin-1β-interleukin-6 signaling pathway, which has been shown to be a viable therapeutic target in the CANTOS, COLCOT, and LoDoCo2 trials. Triglyceride-rich lipoproteins and remnant cholesterol accumulate in the arterial intima and drive atherogenesis independent of LDL-C, with icosapent ethyl showing meaningful cardiovascular benefit in the REDUCE-IT trial. Apolipoprotein B reflects the true number of circulating atherogenic particles that LDL-C alone fails to identify, especially in patients with metabolic disease. Lipoprotein(a) is an inherited risk factor that statins barely affect, and it carries a well-established association with myocardial infarction, stroke, and aortic stenosis; RNA-based therapies targeting it are now in late-stage trials. The 2026 ACC/AHA Dyslipidemia Guideline now carries a Class I recommendation for universal Lp(a) measurement at least once in all adults. Impaired HDL function, insulin resistance, and a prothrombotic environment provide further risk. GLP-1 receptor agonists and SGLT2 inhibitors have emerged as important contributors to residual cardiovascular risk reduction in patients with metabolic dysfunction, showing consistent cardiovascular benefit on top of their background of statin therapy, with mechanisms that extend far beyond glycemic control. Coronary imaging, such as coronary calcium scoring and coronary CT angiography, can identify high-risk plaque features that persist despite aggressive lipid-lowering. Taken together, these findings make the case that LDL-C treatment is important but incomplete. A more comprehensive approach is required to meaningfully reduce the residual risk, one that considers apoB, remnant cholesterol, inflammation, lipoprotein(a), and metabolic risk.