Low Lipoprotein(a) Levels Linked to Higher Diabetes Risk in the FOURIER Trial
USA: An analysis of the FOURIER trial found that lower levels of lipoprotein(a) [Lp(a)] were associated with an increased risk of developing diabetes. The findings suggest a potential inverse relationship between Lp(a) concentrations and incident diabetes, indicating that while elevated Lp(a) is a recognized cardiovascular risk factor, very low Lp(a) levels may be linked to a higher likelihood of diabetes onset. These results provide further insight into the complex metabolic and cardiovascular effects of Lp(a).
Published in the European Heart Journal, the study by Baris Gencer and colleagues from Geneva University Hospitals, Switzerland, examined whether low lipoprotein(a) [Lp(a)] levels are associated with adverse safety outcomes, a key consideration as novel Lp(a)-lowering therapies advance through clinical development.
Lp(a) is a well-established risk factor for atherosclerotic cardiovascular disease (ASCVD), with elevated levels linked to an increased risk of heart attack, stroke, and other cardiovascular events. However, concerns have emerged that very low Lp(a) levels may be associated with a higher risk of conditions such as diabetes.
To explore this relationship, the researchers analyzed data from the FOURIER trial, which enrolled 27,564 patients with stable ASCVD who received either evolocumab or placebo alongside statin therapy. Baseline Lp(a) measurements were available for 25,090 participants, with a median concentration of 37 nmol/L. The investigators assessed the association between Lp(a) levels and multiple safety outcomes, including hemorrhagic stroke, major bleeding, neurocognitive events, cancer, atrial fibrillation, and diabetes.
The trial revealed the following findings:
- Low lipoprotein(a) [Lp(a)] levels were not associated with an increased risk of hemorrhagic stroke, serious bleeding, neurocognitive events, cancer, or atrial fibrillation.
- The absence of increased risk for these adverse outcomes remained consistent even among participants with very low Lp(a) concentrations (≤13 nmol/L).
- Lower baseline Lp(a) levels were associated with a higher prevalence of diabetes at study entry.
- For every 50 nmol/L reduction in Lp(a), the risk of developing diabetes during follow-up increased by 5%.
- The association between lower Lp(a) levels and diabetes risk was consistent across treatment groups.
- Evolocumab therapy did not increase the risk of new-onset diabetes regardless of baseline Lp(a) concentration.
- Participants with the highest baseline Lp(a) levels experienced substantial reductions in Lp(a) with evolocumab, yet did not show an increased risk of diabetes.
The findings suggest that naturally low Lp(a) concentrations may be linked to a greater likelihood of diabetes, while therapeutic lowering of Lp(a) with evolocumab does not appear to adversely affect diabetes risk. The researchers concluded that low Lp(a) levels were not associated with most major safety concerns, although the observed relationship with prevalent and incident diabetes warrants further investigation as dedicated Lp(a)-lowering therapies continue to advance through clinical trials.
Reference:
Gencer, B., Giugliano, R. P., Ran, X., Mach, F., Stroes, E. S., Gouni-Berthold, I., Češka, R., Ezhov, M. V., Jukema, J. W., Jensen, H. K., Tokgözoğlu, S. L., Huber, K., Im, K., Sabatine, M. S., & L, M. Safety of low lipoprotein(a) levels: The FOURIER trial. European Heart Journal. https://doi.org/10.1093/eurheartj/ehag398
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