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9th January 2023
Higher lipoprotein A levels among patients with hypertension, increase their risk of an adverse cardiovascular event according to the findings of a study by US researchers.
Lipoprotein A is a form of low-density lipoprotein (LDL) and an established, genetically determined risk factor for atherosclerosis, coronary artery disease, stroke, thrombosis, and aortic stenosis. It is synthesised in the liver and its plasma concentration ranges from < 1 mg to > 1,000 mg/dL although concentrations above 50 mg/dL are associated with an increased risk for cardiovascular disease including myocardial infarction, stroke, aortic valve stenosis, heart failure, peripheral arterial disease, and all-cause mortality. Levels are largely determined by genetics with up to 90% of the concentration explained by a single gene, the LPA gene. Moreover, concentrations above 50 mg/dL are observed in roughly 20% of the Caucasian population and in an even higher proportion of African-American and Asian-Indian people. It can therefore be assumed that Lp(a) is one of the most important genetically determined risk factors for cardiovascular disease.
Given this relationship with cardiovascular disease risk, in the current study, US researchers used data from the Multi-Ethnic Study of Atherosclerosis (MESA) trial, to examine the longitudinal relationship of Lipoprotein A and hypertension to cardiovascular outcomes in a large multi-ethnic cohort, who were initially free of cardiovascular disease. MESA was designed to include patients from different ethnicities and aimed to include approximately 38% White, 28% African-American, 23% Hispanic and 11% Asian (of Chinese descent) individuals.
Among risk factors for cardiovascular disease, hypertension is associated with the strongest evidence for causation. As a result, in the current study, researchers categorised participants into four groups based on both lipoprotein A (Lp(a)) and the presence/absence of hypertension, which was defined by a systolic pressure of 140 mmHg or higher and a diastolic of 90 mmHg or the use of antihypertensive medicines. Group 1 had Lp(a) levels below <50 mg/dL and no hypertension; group 2 had Lp(a) levels ≥50 mg/dL but no hypertension; group 3 had Lp(a) <50 mg/dL and hypertension, whereas participants in group 4 had both an elevated Lp(a) (≥50 mg/dL) and hypertension. Individuals were then followed up until an adverse cardiovascular event.
Lipoprotein A levels, hypertension and adverse cardiovascular events
A total of 6,674 individuals with mean age of 62.1 years (52.8% female) and of whom, 38.6% were White, 27.5% Black, 22.1% Hispanic and 11.9% Chinese American, were followed for a mean of 13.9 years. During this time 809 participants experienced a cardiovascular disease event.
Using group 1 as the reference, those with Lp (a) ≥50 mg/dL and no hypertension (group 2) had no significant increased risk for cardiovascular disease events (Hazard ratio, HR = 1.09, 95% CI 0.79 – 1.50). In contrast, participants in group 3 (i.e., Lp(a) <50 mg/dL and hypertension) had a statistically significant increase in risk (HR = 1.66, 95% CI 1.39 – 1.98). The risk was also significantly elevated for those in group 4 (HR = 2.07, 95% CI 1.63 – 2.62).
In further analysis, the researchers identified that those with an elevated Lp(a) and with hypertension had an increased risk of cardiovascular disease events (HR = 1.24, 95% CI 1.01 – 1.53) relative to those with hypertension but lower Lp(a).
The authors concluded that while hypertension was a major contributor to cardiovascular risk, elevated Lp(a) significantly modified the association of hypertension with cardiovascular disease.
Citation
Rikhi R et al. Association of Lp(a) (Lipoprotein[a]) and Hypertension in Primary Prevention of Cardiovascular Disease: The MESA. Hypertension 2022
17th November 2022
The small interfering RNA olpasiran has been found to virtually eliminate lipoprotein A in patients with atherosclerotic cardiovascular disease according to the findings of a randomised, placebo-controlled trial by US researchers.
Lipoprotein A (LPA) is a large glycoprotein attached to a low-density lipoprotein-like particle, that is associated with a risk of coronary heart disease and stroke. Lipoprotein A is produced by the apo(a) gene and levels are genetically determined with higher levels increasing the risk of atherosclerotic disease via mechanisms associated with increased atherogenesis, inflammation, and thrombosis. Despite this known link and therefore risk of cardiovascular disease, there are currently no pharmacological therapies available to reduce its levels. Olpasiran is a small interfering molecule that interrupts the expression of the LPA gene by degrading the messenger RNA that encodes the apo(a) protein. In a preclinical study with mice, olpasiran reduced LPA concentrations by 80% from baseline for 5 – 8 weeks after administration of a single dose. Based on these findings, the US researchers undertook the Olpasiran Trials of Cardiovascular Events and Lipoprotein[a] Reduction–Dose Finding Study to assess the efficacy and safety of repeated administration of the product.
Individuals aged 18 to 80 with serum LPA levels higher than 150nmol/L and a history of atherosclerotic cardiovascular disease were included. These participants were randomised 1:1:1: 1:1 to receive four doses of olpasiran administered subcutaneously (10 mg, 75 mg, 225 mg every 12 weeks) and 225 mg every 24 weeks or matching placebo, for a period of 48 weeks. The primary endpoint was the percentage change in the LPA concentration from baseline to week 36 whereas the secondary outcome was the change at the end of the trial.
Olpasiran and Lipoprotein A levels
A total of 281 participants with a mean age of 61.9 years (32% female) were enrolled and randomised to one of the five arms (between 54 and 58 per arm). The overall median baseline LPA level was 260.3 nmol/L and 88% of participants were taking a statin and 23% a proprotein convertase subtilisinkexin type 9 (PCSK9) inhibitor.
At week 36, the LPA level increased by 3.6% in the placebo group but was significantly reduced in each of the active treatment arms. For example, the placebo-adjusted change in the 10 mg group was -70.5%, -97.4% in the 75 mg group and -101.1% in the 225 mg group and -100.5% in the 225 mg arm when administered every 24 weeks (p < 0.001 for all comparisons with the baseline value).
In addition, LDL cholesterol levels were also reduced with placebo-adjusted reductions ranging from -22.6% to -24.8%.
Adverse effects were generally similar across the groups.
The authors concluded that olpasiran significantly reduced lipoprotein(a) concentrations in patients with established atherosclerotic cardiovascular disease and called for future trials to assess the impact of treatment on cardiovascular disease.
Citation
O’Donoghue ML et al. Small Interfering RNA to Reduce Lipoprotein(a) in Cardiovascular Disease. N Eng J Med 2022
3rd November 2022
Elevated levels of both C-reactive protein (CRP) levels and lipoprotein A (LpA) in those with coronary heart disease undergoing a percutaneous coronary intervention (PCI) result in a greater risk of major adverse cardiovascular and cerebrovascular events according to the results of a study by Chinese researchers.
The risk of a recurrent vascular event in patients with established cardiovascular disease remains even in those with optimal treatment. For example, one study has found that when risk factors are modified to achieve guideline recommended targets, the residual 10-year risk while < 10% in 47% of patients is >30% in 9%. One factor associated with this residual risk is inflammation and it has been found that patients who have low CRP levels after statin therapy, had better clinical outcomes than those with higher CRP levels, regardless of the resultant level of LDL cholesterol. Furthermore, clinical and genetic research studies have also shown that lipoprotein A has a crucial role in the pathogenesis of cardiovascular disease. In fact, it has been found that elevated LpA levels during treatment of cardiovascular disease are related to cardiovascular-related death when CRP levels are > 2 mg/L. Nevertheless, much less is known about the relationship between CRP and LpA levels in patients undergoing PCI.
For the present study, the Chinese team set out to examine the joint and independent association between LpA and CRP levels among patients with coronary artery disease who underwent a PCI. The researchers used data from a prospective, observational cohort at a national tertiary care centre and identified patients undergoing PCI and where LpA and CRP levels had been measured. Patients were followed-up for 5 years after discharge and the team set the primary endpoint as major adverse cardiac and cerebrovascular events (MACCE), which was a composite of all-cause mortality, myocardial infarction, unplanned revascularisation and ischaemic stroke.
C-reactive protein and lipoprotein A levels and MACCE
A total of 10,424 patients with a mean age of 58.4 years (77.2% male) were included in the analysis. The median level of LpA was 18.53 mg/dL and CRP 1.62 mg/L. After 5 years of follow-up, the primary endpoint (MACCE) occurred in 20.5% of participants.
Multivariable analysis showed that when LpA levels were > 30 mg/dL there was a higher risk of MACCE (Hazard ratio, HR = 1.14, 95% CI 1.05 – 1.25, p < 0.05) compared to levels below 30 mg/dL. Similarly, CRP levels above 2 mg/L were also significantly associated with a greater risk of MACCE (HR = 1.10, 95% CI 1.01 – 1.20, p < 0.05).
But when both LpA and CRP were higher than 30 mg/dL and 2 mg/L respectively, in fully adjusted models, there was a 22% higher risk of MACCE (HR = 1.22, 95% CI 1.07 – 1.39, p < 0.05).
The authors concluded that elevated LpA levels were associated with a higher risk of adverse cardiovascular events and that this risk was even higher when C-reactive protein levels were above 2 mg/L. They suggested that measuring levels of both could help identify high-risk individuals and who might benefit from further therapeutic interventions.
Citation
Yuan D et al. Lipoprotein(a), high-sensitivity C-reactive protein, and cardiovascular risk in patients undergoing percutaneous coronary intervention Atherosclerosis 2022
4th February 2022
A study by researchers from the Department of Epidemiology and Biostatistics, Imperial College, London has revealed a positive association between lipoprotein A concentrations and the risk of total, advanced and early age onset prostate cancer.
Prostate cancer is the second most common cancer diagnosis in men and the fifth leading cause of death worldwide. The GLOBOCAN 2018 data revealed how prostate cancer accounted for 7.1% of all incident cancers and 3.8% of all deaths. Moreover, there is some degree of biological heterogeneity with prostate cancer such that while there are several traditional risk factors including, age, ethnicity, family history, smoking, alcohol consumption, vasectomy and diet, the risk are different for more advanced disease. For instance, with more aggressive prostate cancer, the risk factors have mirrored those associated with cardiovascular disease such as obesity, dyslipidaemia, glucose intolerance, metabolic syndrome, unhealthy dietary habits or caloric excess, lack of physical activity and inflammation. Nevertheless, there remains much uncertainty over the precise relationship between cardiovascular risk factors and prostate cancer. For instance, though dyslipidaemia, as characterised for example, by elevated cholesterol levels, is a potential risk factor, a meta-analysis of 14 studies concluded that blood total cholesterol, HDL and LDL levels were not associated with the risk of either overall prostate cancer or high-grade prostate cancer. Furthermore, treatment for hyperlipidaemia, especially with the use of statins found that although there was no evidence that cholesterol lowering is beneficial for the prevention of low-grade or localised prostate cancer, there did appear to be an association between statin use and a reduced risk of advanced or high-grade prostate cancer. Much of the evidence for the relationship between prostate cancer and lipids comes from observational studies and one approach to control for the various confounders present in such analyses, is the use of Mendelian randomisation. In fact, one such Mendelian randomisation study assessing whether circulating lipids causally influence prostate cancer risk, concluded that there was some weak evidence to suggest that higher LDL and triglyceride levels increase aggressive prostate cancer risk.
For the present study, the UK researchers sought to determine whether genetically predicted lipid traits were associated with the overall risk of prostate cancer. They used data from the UK Biobank and looked for associations between not only cholesterol, HDL and LDL levels and prostate cancer but also with other lipid sub-fractions including lipoprotein A, apolipoprotein A and B.
Lipoprotein A and prostate cancer
Univariate analysis revealed that HLD and LDL cholesterol levels, triglycerides and apolipoprotein A and B concentrations were not associated with total prostate cancer risk. There was also no significant association between these sub-fractions and advanced prostate cancer. However, the analysis did reveal that elevated lipoprotein A levels were associated with advanced prostate cancer (odds ratio, OR = 1.03, 95% CI 1.0 – 1.06, p = 0.046) and with an increased risk of early onset prostate cancer (OR = 1.25, 95% CI 1.107 – 1.42, p < 0.001). Using multivariate analysis, the authors found that lipoprotein A levels were associated with total (OR = 1.068, p = 0.034), advanced (OR = 1.07, p = 0.055) and early onset prostate cancer (OR = 1.15, p = 0.028).
The authors concluded that their data indicated a positive association between lipoprotein A levels and the risk of total, advanced and early onset prostate cancer. In addition, they suggested that screening for high lipoprotein A levels, could be used to identify high-risk groups for prostate cancer.
Citation
Ioannidou A et al. The relationship between lipoprotein A and other lipids with prostate cancer risk: A multivariable Mendelian randomisation study PLoS Med 2022
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