Interpreting the role of lipoprotein(a) in metabolic disorders: current evidence and future perspectives

Lipoprotein(a) [Lp(a)] consists of an LDL-like particle that is covalently linked to apolipoprotein(a) [Apo(a)] through a disulfide bond. An elevated Lp(a) level is causally implicated in atherosclerotic cardiovascular disease (ASCVD). However, its clinical interpretation becomes more complex in metabolic disorders, including dyslipidemia, obesity, type 2 diabetes mellitus (T2DM), and metabolic dysfunction-associated steatotic liver disease (MASLD). When elevated Lp(a) levels coexist with elevated LDL-C levels, obesity, or T2DM, the risk of ASCVD may be further increased. Accordingly, Lp(a) should be incorporated into the overall cardiovascular risk profile rather than assessed using a stand-alone cutoff. Conversely, emerging evidence has described a “low Lp(a) paradox,” in which very low Lp(a) levels have been reported in individuals with T2DM, MASLD, and advanced liver disease. These associations remain noncausal and may partly reflect insulin resistance, hyperinsulinemia, or impaired hepatic synthesis function. In addition, marked hypertriglyceridemia, hyperinsulinemia, and impaired liver function may transiently lower the measured Lp(a) concentrations, thereby masking the genetically determined Lp(a) burden and supporting the consideration of a reassessment after metabolic stabilization or an improvement in hepatic function in selected patients. This review summarizes the evidence linking Lp(a), metabolic disease, and ASCVD and, based on this integrated evidence, proposes an illustrative framework for interpreting the clinical significance of Lp(a) levels in patients with varying metabolic backgrounds within specific clinical contexts.