Genetic evidence demonstrates that combined targeting of lipoprotein(a) and LDL cholesterol provides additive reductions in coronary artery disease risk beyond either alone, without adverse effects.
Key Findings
Results
Carriers of loss-of-function variants in both LPA and PCSK9 have lower CAD risk than carriers of either variant alone.
Among 408,039 individuals from the UK Biobank, LPA loss-of-function carriers had an odds ratio (OR) of 0.91 for CAD compared to noncarriers
PCSK9 loss-of-function carriers had an OR of 0.81 for CAD compared to noncarriers
Carriers of both LPA and PCSK9 loss-of-function variants had an OR of 0.73 for CAD, lower than either variant alone
These findings were replicated in 65,171 individuals from the Mass General Brigham Biobank
Results
Combined genetic lowering of both Lp(a) and LDL-C reduced CAD risk more than lowering either trait individually.
In a two-factor genetic score analysis, combined genetic lowering of Lp(a) and LDL-C was associated with an OR of 0.70 for CAD
Genetic lowering of Lp(a) alone was associated with an OR of 0.85 for CAD
Genetic lowering of LDL-C alone was associated with an OR of 0.81 for CAD
The combined effect (OR 0.70) was stronger than either individual effect, supporting an additive benefit
Results
Among statin users, Lp(a) reduction was linearly associated with CAD risk reduction.
This linear association was observed specifically within the subgroup of statin users
This finding suggests that individuals already on LDL-C-lowering therapy (statins) can still derive additional CAD risk reduction from Lp(a) lowering
The analysis was conducted in the UK Biobank cohort of 408,039 individuals
Results
A phenome-wide association study (PheWAS) revealed cardiometabolic benefits of combined Lp(a) and LDL-C lowering without adverse effects.
The PheWAS examined associations across a broad range of phenotypes for the combined therapy genetic profile
Combined therapy was associated with cardiometabolic benefits beyond CAD risk reduction
No adverse effects were identified in the phenome-wide scan
The safety profile supports the potential for combined therapeutic targeting of both Lp(a) and LDL-C
Results
The additive CAD risk reduction from combined Lp(a) and LDL-C lowering was replicated in an independent biobank cohort.
Replication was performed in 65,171 individuals from the Mass General Brigham Biobank
The additive benefits of combined targeting observed in the UK Biobank were confirmed in this independent sample
Distinct genetic mechanisms govern how Lp(a) and LDL-C promote atherosclerosis, providing a biological rationale for additive effects
Methods
The study used coding loss-of-function variants in LPA and PCSK9 as well as multi-variant genetic scores to evaluate Lp(a) and LDL-C effects on CAD.
Primary analysis used coding loss-of-function variants in LPA (affecting Lp(a) levels) and PCSK9 (affecting LDL-C levels)
A complementary two-factor genetic score analysis used genetic scores associated with Lp(a) and LDL-C levels respectively
The primary discovery cohort comprised 408,039 individuals from the UK Biobank
Both analytical approaches (single loss-of-function variants and polygenic scores) yielded consistent findings supporting additive benefits
What This Means
This research used large genetic datasets to investigate whether lowering two different types of blood fats — lipoprotein(a), or Lp(a), and LDL cholesterol (often called 'bad' cholesterol) — at the same time provides greater protection against coronary artery disease (CAD) than lowering just one of them. The researchers studied over 408,000 people in the UK Biobank and confirmed their findings in another 65,000 people from a US hospital system. They identified people who naturally carry gene variants that reduce either Lp(a) or LDL cholesterol levels, and found that people with gene variants affecting both had the lowest risk of coronary artery disease compared to those with variants affecting only one or neither.
Using genetic scoring methods that mimic the effects of drugs that lower Lp(a) or LDL cholesterol, the study found that reducing both together was associated with an approximately 30% lower odds of CAD, compared to about 15–19% reductions when targeting each individually. This suggests the benefits are additive — meaning combining both treatments works better than either alone. Importantly, among people already taking statins (a common LDL-lowering medication), further reducing Lp(a) was still associated with additional CAD risk reduction, suggesting statin users could benefit from Lp(a)-lowering therapy as well.
A broad scan across hundreds of health outcomes found that the genetic profile mimicking combined Lp(a) and LDL lowering was linked to additional cardiovascular and metabolic benefits, with no harmful side effects detected. This research suggests that new Lp(a)-lowering drugs currently in clinical development could be particularly valuable when used alongside existing LDL-lowering treatments like statins or PCSK9 inhibitors, potentially offering greater cardiovascular protection than current single-target approaches.
Wang S, Tang Y, Sui Y, Zhao H, Khan A, Yin W, et al.. (2026). Genetic evidence supports the combined targeting of lipoprotein(a) and LDL cholesterol to reduce coronary artery disease risk.. Nature cardiovascular research. https://doi.org/10.1038/s44161-026-00865-9