Elevated Lipoprotein(a) Increases Cardiovascular Risk Independently of SMuRFs

How lipoprotein(a) (Lp[a]) affects cardiovascular (CV) risk, particularly in the context of major adverse CV events (MACE) among patients based on the baseline atherosclerotic CV disease (ASCVD) status, was recently presented as, “The Association of Lipoprotein(a) With MACE Among Individuals With and Without Baseline ASCVD: the Mass General Brigham Lp(a) Registry” during the American Heart Association Scientific Sessions 2023, which ran from November 11 to 13, 2023, in Philadelphia, Pennsylvania.^1,2

Lp(a) has been recognized as an independent and causal risk factor for coronary heart disease (CHD).³ In a retrospective study of the Mass General Brigham Lp(a) Registry, Shiyovach and colleagues examined the relationship between elevated Lp(a) and standard modifiable risk factors (SMuRFs) in the context of MACE.¹ Identified risk factors included diabetes mellitus, hyperlipidemia, hypertension, and smoking. MACE was defined as nonfatal myocardial infarction (MI), nonfatal stroke, coronary revascularization, or CV mortality.²

The investigators used a large dataset provided by the MGB Lp(a) Registry, a repository of Lp(a) measurements covering approximately 2 decades (2000-2019).^1,3 The cohort, consisting of more than 16,000 patients aged at least 18 years, offered a diverse representation of individuals who underwent Lp(a) testing between 2000 and 2019.^1,2 Among the total patient cohort (N = 16,419), 10,181 patients (62%) had baseline ASCVD, whereas 6238 patients (38%) did not have baseline ASCVD.2 Compared with patients without baseline ASCVD, patients with baseline ASCVD were older (54 vs 64 years), more likely to be male (55% vs 62%), and showed a higher prevalence of traditional CV risk factors.

The 4 pillars of SMuRFs—diabetes, hyperlipidemia, hypertension, and smoking—were used to evaluate the impact of elevated Lp(a).¹ These factors may influence CV risk and can be evaluated to understand the relationship between Lp(a) levels and MACE.⁴

Analysis of the distribution of SMuRFs within the cohort showed that 23.7% of patients had no SMuRFs, revealing the inherent diversity in CV risk profiles. In contrast, 17.8% of patients had 3 or more SMuRFs and presented a heightened risk of MACE. Patients with severe kidney dysfunction and malignant neoplasm were excluded from the study to avoid the influence of complicating variables.¹

The median follow-up of 11.9 years enabled comprehensive examination of the incidence of MACE with respect to the number of SMuRFs and Lp(a) levels.¹ A larger number of SMuRFs led to an increased risk of MACE among patients with Lp(a) levels that were high (log-rank P = .031) and low (log-rank P = .001). High Lp(a) emerged as an independent predictor of the primary outcome of fatal or nonfatal MI, challenging the conventional hierarchy of risk factors.^1,5

This finding is supported by those of Nordestgaard and colleagues, who observed a strong association between elevated Lp(a) and an increased risk of CV events.⁶ They described that Lp(a) was established as a potent and independent predictor of ASCVD in meta-analyses of large cohorts. Furthermore, Berman described that in the registry study, patients with baseline ASCVD showed a relatively stable rate of MACE regardless of Lp(a) levels.² In contrast, patients without baseline ASCVD showed an increased rate of MACE with increasing Lp(a) levels.

The Framingham Risk Score, a standard metric in CV risk estimation, primarily factors in age, sex, total cholesterol, high-density lipoprotein cholesterol, blood pressure, and smoking status.⁷ However, the unique contribution of Lp(a) to CV risk, as highlighted by Shiyovach and colleagues, challenges the reliance on traditional risk factors.

The risk imposed by Lp(a) surpasses that associated with individual SMuRFs and approximates the risk conferred by having 2 SMuRFs.¹ These findings echo those of a meta-analysis performed through the Emerging Risk Factors Collaboration, which demonstrated the incremental predictive value of Lp(a) in assessing CV risk beyond traditional risk factors.⁸ The independence of Lp(a) as a predictor of MACE supports its contribution to CV risk.¹

The investigators demonstrated that Lp(a) affects CV risk, particularly in the context of MACE among patients regardless of baseline ASCVD status independently of the number of SMuRFs.¹ Baseline ASCVD increases the absolute risk of MACE, with the association between Lp(a) levels and CV events plateauing at Lp(a) levels of 150 to 200 nmol/L.² Patients without baseline ASCVD show a decreased absolute risk of MACE, with a linear association between Lp(a) levels and CV events. Integration of Lp(a) into risk assessment models may change how CV risk is considered and managed.

References

1. Shiyovich A, Berman AN, Besser SA, et al. Abstract 16773. The association of Lp(a) and standard modifiable cardiovascular risk factors (SMuRFs) with incident myocardial infarction: the Mass General Brigham Lp(a) Registry. Circulation. 2023;148(suppl 1):A16773. doi:10.1161/circ.148.suppl_1.16773
2. Berman AN, Biery DW, Besser SA, Singh A, et al. The association of lipoprotein(a) with MACE among individuals with and without baseline ASCVD: the Mass General Brigham Lp(a) Registry. Moderated digital poster presented at: American Heart Association Scientific Sessions 2023; November 11-13, 2023; Philadelphia, PA. PR.MDP.43
3. Berman AN, Biery DW, Ginder C, et al. Study of lipoprotein(a) and its impact on atherosclerotic cardiovascular disease: design and rationale of the Mass General Brigham Lp(a) Registry. Clin Cardiol. 2020;43(11):1209-1215. doi:10.1002/clc.23456
4. Figtree GA, Vernon ST, Harmer JA, et al. Clinical pathway for coronary atherosclerosis in patients without conventional modifiable risk factors: JACC state-of-the-art review. J Am Coll Cardiol. 2023;82(13):1343-1359. doi:10.1016/j.jacc.2023.06.045
5. Dawber TR, Moore FE, Mann GV. Coronary heart disease in the Framingham study. Am J Public Health Nations Health. 1957;47(4 pt 2):4-24. doi:10.2105/ajph.47.4_pt_2.4
6. Nordestgaard BG, Chapman MJ, Ray K, et al. Lipoprotein(a) as a cardiovascular risk factor: current status. Eur Heart J. 2010;31(23):2844-2853. doi:10.1093/eurheartj/ehq386
7. D’Agostino RB Sr, Vasan RS, Pencina MJ, et al. General cardiovascular risk profile for use in primary care: the Framingham Heart Study. Circulation. 2008;117(6):743-753. doi:10.1161/CIRCULATIONAHA.107.699579
8. Emerging Risk Factors Collaboration, Erqou S, Kaptoge S, et al. Lipoprotein(a) concentration and the risk of coronary heart disease, stroke, and nonvascular mortality. JAMA. 2009;302(4):412-423. doi:10.1001/jama.2009.1063