Inflammation
The Lp(a) paradox: high levels drive atherosclerosis but very low levels may raise type 2 diabetes risk, review argues for a risk-benefit reckoning (Diabetes Res Clin Pract 2025)
Original title: Between Scylla and Charybdis - Enigmatic role of lipoprotein(a) in atherosclerotic cardiovascular disease and type 2 diabetes mellitus
This review, titled for the mythological strait between two dangers, addresses lipoprotein(a)'s dual, seemingly contradictory relationship with cardiometabolic disease. Epidemiological and Mendelian randomisation studies support elevated Lp(a) as a causal risk factor for atherosclerotic cardiovascular disease through pro-inflammatory, pro-atherogenic and pro-thrombotic mechanisms, while separate genomic and population studies show very low Lp(a) is associated with increased risk of type 2 diabetes mellitus, a paradox recent guidelines have flagged as a potential concern for potent Lp(a)-lowering therapies. The review details the evidence for Lp(a)-induced inflammation and thrombosis, the mechanisms linking Lp(a) to ASCVD, and the more complicated and less-established links between Lp(a) and diabetes development. The authors conclude current evidence favours the anti-atherogenic benefit of lowering Lp(a) outweighing its paradoxical association with new-onset diabetes, but call for explicit risk-benefit assessment as potent Lp(a)-lowering therapies advance.
Original abstract
Lipoprotein(a) [Lp(a)], one of the major residual cardiovascular risks, is a highly polymorphic low-density lipoprotein (LDL)-like particle. Epidemiological and Mendelian randomization studies have suggested that elevated Lp(a) is a causal risk factor for atherosclerotic cardiovascular disease (ASCVD) due to its pro-inflammatory, pro-atherogenic and pro-thrombotic properties. However, metabolic and pathological mechanisms of Lp(a) remain under-investigated. Recent genomic and population studies show that very low Lp(a) levels are associated with increased risk of type 2 diabetes mellitus (T2DM). Thus, whether potent Lp(a)-lowering therapies might increase the risk of T2DM incident has been raised as a potential issue from recent guidelines. This review details Lp(a)-induced inflammation and thrombosis evidences, the underlying mechanisms of Lp(a) in ASCVD, and the complicated associations and potential mechanistic effects of Lp(a) on the development of T2DM. Current evidences tend to favor that the anti-atherogenic benefits of lowering Lp(a) shall override the paradoxical negative impact on the new-onset T2DM. The risk-benefit assessments for potent Lp(a)-lowering therapies are warranted.
diabetesinflammationmechanisms
Summary written by lp-a.org from the published abstract; figures as published. Page updated 17 August 2026. Methods.