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LPa Risk Factor For Heart Disease -
New Antisense Drug for LPa in Studies
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Previous work, in larger samples, has confirmed that Lp(a) >50 mg/dL is a risk factor for cardiovascular disease in blacks,9
Lipoprotein(a) [Lp(a)] is an independent, causal, genetically determined risk factor for cardiovascular disease (CVD).
In FOURIER, the investigators observed a possibly greater relative risk reduction from PCSK9i among patients with Lp(a) above the median (hazard ratio, 0.77; 95% CI, 0.67-0.88) than in those with Lp(a) at or below the median (hazard ratio, 0.93; 95% CI, 0.80-1.08). Using a meta-regression framework, and after adjustment for change in LDL cholesterol, the investigators demonstrate that for each 25-nmol/L reduction in Lp(a) from PCSK9i, there was a concomitant 15% relative risk reduction (95% CI, 2%-26%).....it provides exciting suggestive evidence that Lp(a) lowering might explain some of the benefits of PCSK9i, and it adds to the evidence that Lp(a) could be a modifiable causal risk factor for cardiovascular disease. Indeed, a compelling argument can be made that all individuals should have Lp(a) measured at least once in their lifetime, given that levels remain largely stable throughout life. The most recent version of the US lipid guidelines10 includes a new recommendation for Lp(a) measurement in select individuals, as a risk enhancer, and this should further raise awareness of Lp(a).
Elevated Lp(a) concentration exceeding 50 mg/dL at baseline or on-treatment was associated with an increased HR of MACE independent of other CVD risk factors.
A newer class of lipid-lowering drugs called proprotein convertase subtilisin/kexin 9 (PCSK9) inhibitors has been shown to reduce Lp(a) by ∼25% [68] and this Lp(a)-lowering effect was evident across apo(a) size distributions [69].
- Of interest, it was reported previously that Lp(a) confers CV risk predominantly when LDL-C levels are elevated.3,18,19 However, we found that the relationship between Lp(a) and coronary risk remained similar throughout the entire LDL-C range, thereby suggesting a consistent association of Lp(a) with CV risk in patients with established CV disease independent of concomitant baseline or achieved LDL-C levels. In support, patients who achieved lower levels of both LDL-C and Lp(a) were those who were at lowest risk of subsequent events.-
To date, few therapies are available to reduce the concentration of Lp(a), and it remains unclear whether lowering Lp(a) will translate into improved cardiovascular (CV) outcomes.8-10 PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitors may offer clinical utility because they have been shown in phase 2 trials to reduce Lp(a) concentration by ≈25% to 30%.11-13 However, it remains unknown whether the effect of evolocumab on risk of coronary events may be modified by baseline Lp(a) concentrations. Therefore, as a prespecified analysis of the FOURIER trial (Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk), we assessed the relationship between Lp(a) levels, PCSK9 inhibition with evolocumab, and CV risk reduction.14 Patients with higher baseline concentrations of Lp(a) were more likely to be female and have a history of MI or peripheral artery disease. Conversely, patients with higher baseline Lp(a) concentrations were less likely to be smokers and have a history of ischemic stroke or diabetes mellitus....... In the placebo arm, each doubling of baseline Lp(a) concentration was associated with an 8% higher risk of coronary heart disease (CHD) death, MI, or urgent coronary revascularization (major coronary events: unadjusted HR per doubling of Lp(a), 1.08; 95% CI, 1.04-1.11; P<0.001). Patients with baseline Lp(a) concentration in the highest quartile (>165 nmol/L) had a 33% higher risk of CHD death, MI, or urgent coronary revascularization (HR, 1.33; 95% CI, 1.10-1.60; P=0.003) than those in the first quartile (Table 2).......From baseline to 48 weeks, evolocumab decreased the concentration of Lp(a) by a median of 26.9% (interquartile range, 6.2%-46.7%) or 11 (interquartile range, 1-32) nmol/L (P<0.001). The absolute reduction in Lp(a) was greatest for individuals with higher baseline Lp(a) concentrations (P trend <0.001.......Overall, evolocumab reduced the risk of CHD death, MI, or urgent coronary revascularization by 16% (HR, 0.84; 95% CI, 0.76-0.93). Evolocumab tended to reduce the risk of major coronary events to a greater degree in patients with higher baseline Lp(a) levels, with a reduction of 23% in those with a baseline Lp(a) above the median (HR, 0.77; 0.67-0.88) versus 7% for those at or below the median (HR, 0.93; 0.80-1.08; P interaction=0.07; Figure 1A)......When stratifying patients into deciles by baseline Lp(a) concentration, whereas the LDL-C reduction was virtually the same (59-62 mg/dL) across each decile of baseline Lp(a), the median Lp(a) reductions ranged from 0 to 60.5 mg/dL at 48 weeks. In a weighted least-square linear regression analysis that examined the association between treatment effect on CHD death, MI, or urgent coronary revascularization and per unit decrease in Lp(a) adjusting for differences in LDL-C, there was a significant relationship with a 15% relative risk reduction (95% CI, 2%-26%; P=0.0199) per 25 nmol/L reduction in Lp(a) (Figure 2). In contrast, the relationship between the percent change in Lp(a) and the HR for major coronary events was not significant (P=0.79).....An exploratory analysis examined achieved levels at 12 weeks and subsequent risk of CHD death, MI, or urgent coronary revascularization in a landmark analysis through long-term follow-up. After 12 weeks, there was a significant relationship between achieved Lp(a) level and the adjusted risk of CHD death, MI, or urgent coronary revascularization (Figure 3; HR, 1.04; 95% CI, 1.01-1.06; P=0.01 per doubling of achieved Lp(a) concentration).
Qualitatively consistent with these findings, we observed that a 34 nmol/L (95% CI, 18.5-97 nmol/L) absolute reduction in Lp(a) may be required to translate into a 20% relative risk reduction in CV events, which approximates the median reduction in Lp(a) that was seen in patients in the top quartile of Lp(a) concentration. These findings suggest that the benefit of Lp(a)-lowering therapies might be largely restricted to patients with elevated levels at baseline, therapies that produce large reductions in Lp(a), or both. These observations may also help to explain why higher baseline Lp(a) concentration was useful for helping to identify individuals with greater clinical efficacy with evolocumab.
Of note, first-line management of dyslipidemia is a healthy lifestyle including a healthy diet [8]. However, the effect of dietary modification on Lp(a) remains unclear.
New Antisense Drug - APO(a)-LRx reduced lipoprotein(a) levels in a dose-dependent manner in patients who had elevated lipoprotein(a) levels and established cardiovascular disease.
An investigational antisense drug targeting LPA gene expression successfully reduced levels of lipoprotein(a), or Lp(a), in a dose-ranging study aimed at informing a future outcomes trial. People randomized to one of five dosing regimens of APO(a)-LRx had large drops in Lp(a) by the sixth month, the reduction ranging from 35% from baseline (at a dose of 20 mg every 4 weeks) to 80% (at 20 mg every week) compared with a 6% drop in the saline placebo arm (P=0.003 and P<0.001, respectively).
Moving beyond the role of Lp(a) in CVD risk in the general population, a recent meta-analysis attempted to clarify Lp(a)-attributable residual CVD risk in patients with established CVD or on statin therapy [62]. This study using patient-level data from seven placebo-controlled statin trials encompassing 29,069 patients analyzed the relation of baseline and on-treatment Lp(a) concentration to risk of major adverse cardiovascular events (MACE). Statin therapy, as expected, reduced LDL-C level; after accounting for the contribution of Lp(a) the degree of reduction was 39%. However, the statin effect on Lp(a) was heterogeneous with three trials showing an increase (2% to 15%) and four trials showing a decrease (-1% to -13%) [62]. Elevated Lp(a) concentration exceeding 50 mg/dL at baseline or on-treatment was associated with an increased HR of MACE independent of other CVD risk factors. Interestingly, this association was stronger in patients receiving statins than those on placebo, suggesting that residual risk is present in patients with elevated Lp(a) that is not addressed by statins [62]. In patients with elevated Lp(a) levels who managed their LDL-C-attributable risk with statin therapy, specific therapies to lower Lp(a) may alleviate Lp(a)-induced CVD risk.
A newer class of lipid-lowering drugs called proprotein convertase subtilisin/kexin 9 (PCSK9) inhibitors has been shown to reduce Lp(a) by ∼25% [68] and this Lp(a)-lowering effect was evident across apo(a) size distributions [69].
Lp(a), Lipid-Lowering Therapeutics and Cardiovascular Benefit
Apart from lipid apheresis that induces a consistent large reduction (>65%) in Lp(a) concentration with a subsequent improvement in CVD outcomes (e.g., 86% reduction in MACE) [63,64], other lipid-lowering therapeutics have produced heterogeneous effects on Lp(a) and their cardiovascular benefits are mostly absent or remain to be proven. The effect of lipid-lowering therapeutics on Lp(a) range from no response to opposing directions of change (i.e., increases vs. lowering). As noted earlier, statins have generated a highly variable response in Lp(a) in clinical trials [62]. Randomized placebo-controlled clinical trials of anacetrapib, a cholesterol ester transfer protein (CETP) inhibitor, reported a 37% reduction in Lp(a) concentration, but no significant cardiovascular benefit in statin-treated high-risk patients [65]. Another CETP-inhibitor (TA-8995) dose dependently reduced Lp(a) (range: ∼27% to 37%) in patients with mild dyslipidemia [66], but its effect on CVD risk is yet to be established. The AIM-HIGH (Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglyceride and Impact on Global Health Outcomes) trial using a combination of extended-release niacin and statin showed a modest decrease (19%) in Lp(a) compared with the placebo without significant reductions in cardiovascular events [67].
A newer class of lipid-lowering drugs called proprotein convertase subtilisin/kexin 9 (PCSK9) inhibitors has been shown to reduce Lp(a) by ∼25% [68] and this Lp(a)-lowering effect was evident across apo(a) size distributions [69]. A post hoc analysis of the FOURIER (Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk) trial demonstrated that evolocumab, a PCSK9 inhibitor, reduced Lp(a) in patients with established CVD by ∼27% [70]. As expected, elevated Lp(a) concentrations were associated with an increased risk of cardiovascular events irrespective of LDL-C. Notably, patients with higher baseline Lp(a) concentrations experienced greater absolute reductions in their Lp(a) and tended to derive greater coronary benefit (CHD deaths, MI, or urgent revascularization) compared in those with lower baseline concentrations [70]. Evidence from a recent meta-analysis of two PCSK9 inhibitor trials—the FOURIER and ODYSSEY OUTCOMES (Evaluation of Cardiovascular Outcomes after an Acute Coronary Syndrome during Treatment with Alirocumab)—supports Lp(a) as a risk mediator of venous thromboembolism (VTE) as PCSK9 inhibition significantly reduced VTE, which was associated with the degree of Lp(a) lowering, but not LDL-C lowering [71]. The ODYSSEY OUTCOMES trial also reports a similar role for Lp(a) in PAD risk as PCSK9 inhibition with alirocumab reduced the risk of major PAD events by 31%, which was associated with baseline Lp(a), but not LDL-C levels [72]. Furthermore, in the ORION 1 trial (Trial to Evaluate the Effect of ALN-PCSSC Treatment on Low Density Lipoprotein Cholesterol), another PCSK9-modulating agent—inclisiran (a small interference RNA)—resulted in a large interindividual variability in Lp(a) response (-14% to -18% in the single-dose groups and -15% to -26% in the 2-dose groups), which contributed to a non-significant effect of the agent on Lp(a) [73].
Other emerging therapeutics such as those based on antisense oligonucleotide (ASO) targeting apoB-100 or apo(a) appear promising. Addition of mipomersen, an ASO to apoB-100, to a maximal medical therapy in patients with FH reduced Lp(a) by ∼26% [74]. An ASO-based approach targeting apo(a) synthesis in the liver reduced Lp(a) concentration by ∼35% to 80%, depending on dose and injection frequency, in individuals with established CVD and Lp(a) levels of at least 60 mg/dL [75].
These large reductions in Lp(a) may be the key to testing the Lp(a) hypothesis; the required degree of Lp(a) lowering to meaningfully reduce CHD outcomes has been a subject of debate. A 2018 Mendelian randomization analysis suggested that the clinical benefit of reducing Lp(a) may be proportional to the absolute reduction in Lp(a) concentration and a reduction in Lp(a) of 101.5 mg/dL may be required to produce a clinically relevant reduction in the risk of CHD similar in magnitude to what can be achieved by lowering LDL-C level by 38.67 mg/dL (i.e., 1 mmol/L) [76]. A subsequent 2019 Mendelian randomization analysis estimated that a much lower reduction in Lp(a) (65.7 mg/dL) would be equivalent to a 38.67 mg/dL reduction in LDL-C [77]. The authors noted that the influence of SNPs on Lp(a) concentration and standardization of the Lp(a) assay used may have led to an overestimation (101.5 mg/dL) in the past [77]. More recently, a population-based study concluded that high concentrations of Lp(a) are associated with high risk of recurrent CVD in individuals from the general population and to achieve 20% and 40% MACE risk reduction in secondary prevention, Lp(a) should be lowered by 50 mg/dL and 99 mg/dL for 5 years, respectively [78].
As described, there has been significant investigation of pharmacological intervention for lowering Lp(a) and reducing residual risk conferred by high Lp(a). Heterogeneity is observed in the effect of current lipid-lowering drugs on Lp(a) and the clinical significance is still being investigated. Of note, first-line management of dyslipidemia is a healthy lifestyle including a healthy diet [8]. However, the effect of dietary modification on Lp(a) remains unclear. There is a prevailing perception that dietary modification has no significant effect on Lp(a) (2), which has likely hampered research efforts in this area. There have been several human clinical trials conducted, however that have measured Lp(a) in response to dietary interventions.
Other emerging therapeutics such as those based on antisense oligonucleotide (ASO) targeting apoB-100 or apo(a) appear promising. Addition of mipomersen, an ASO to apoB-100, to a maximal medical therapy in patients with FH reduced Lp(a) by ∼26% [74]. An ASO-based approach targeting apo(a) synthesis in the liver reduced Lp(a) concentration by ∼35% to 80%, depending on dose and injection frequency, in individuals with established CVD and Lp(a) levels of at least 60 mg/dL [75].
These large reductions in Lp(a) may be the key to testing the Lp(a) hypothesis; the required degree of Lp(a) lowering to meaningfully reduce CHD outcomes has been a subject of debate. A 2018 Mendelian randomization analysis suggested that the clinical benefit of reducing Lp(a) may be proportional to the absolute reduction in Lp(a) concentration and a reduction in Lp(a) of 101.5 mg/dL may be required to produce a clinically relevant reduction in the risk of CHD similar in magnitude to what can be achieved by lowering LDL-C level by 38.67 mg/dL (i.e., 1 mmol/L) [76]. A subsequent 2019 Mendelian randomization analysis estimated that a much lower reduction in Lp(a) (65.7 mg/dL) would be equivalent to a 38.67 mg/dL reduction in LDL-C [77]. The authors noted that the influence of SNPs on Lp(a) concentration and standardization of the Lp(a) assay used may have led to an overestimation (101.5 mg/dL) in the past [77]. More recently, a population-based study concluded that high concentrations of Lp(a) are associated with high risk of recurrent CVD in individuals from the general population and to achieve 20% and 40% MACE risk reduction in secondary prevention, Lp(a) should be lowered by 50 mg/dL and 99 mg/dL for 5 years, respectively [78].
As described, there has been significant investigation of pharmacological intervention for lowering Lp(a) and reducing residual risk conferred by high Lp(a). Heterogeneity is observed in the effect of current lipid-lowering drugs on Lp(a) and the clinical significance is still being investigated. Of note, first-line management of dyslipidemia is a healthy lifestyle including a healthy diet [8]. However, the effect of dietary modification on Lp(a) remains unclear. There is a prevailing perception that dietary modification has no significant effect on Lp(a) (2), which has likely hampered research efforts in this area. There have been several human clinical trials conducted, however that have measured Lp(a) in response to dietary interventions.
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There are currently no approved pharmacologic therapies that specifically target lipoprotein(a). Antisense oligonucleotides (ASOs) inhibit the production of apolipoprotein(a) in the hepatocyte, the source of approximately 99% of plasma lipoprotein(a).6
Antisense Oligonucleotide (ASO) Drug - Lipoprotein(a) Reduction in Persons with Cardiovascular Disease
https://www.nejm.org/doi/full/10.1056/NEJMoa1905239?query=featured_home
Abstract
Background
Lipoprotein(a) levels are genetically determined and, when elevated, are a risk factor for cardiovascular disease and aortic stenosis. There are no approved pharmacologic therapies to lower lipoprotein(a) levels.
Methods
We conducted a randomized, double-blind, placebo-controlled, dose-ranging trial involving 286 patients with established cardiovascular disease and screening lipoprotein(a) levels of at least 60 mg per deciliter (150 nmol per liter). Patients received the hepatocyte-directed antisense oligonucleotide AKCEA-APO(a)-LRx, referred to here as APO(a)-LRx (20, 40, or 60 mg every 4 weeks; 20 mg every 2 weeks; or 20 mg every week), or saline placebo subcutaneously for 6 to 12 months. The lipoprotein(a) level was measured with an isoform-independent assay. The primary end point was the percent change in lipoprotein(a) level from baseline to month 6 of exposure (week 25 in the groups that received monthly doses and week 27 in the groups that received more frequent doses).
Results
The median baseline lipoprotein(a) levels in the six groups ranged from 204.5 to 246.6 nmol per liter. Administration of APO(a)-LRx resulted in dose-dependent decreases in lipoprotein(a) levels, with mean percent decreases of 35% at a dose of 20 mg every 4 weeks, 56% at 40 mg every 4 weeks, 58% at 20 mg every 2 weeks, 72% at 60 mg every 4 weeks, and 80% at 20 mg every week, as compared with 6% with placebo (P values for the comparison with placebo ranged from 0.003 to <0.001). There were no significant differences between any APO(a)-LRx dose and placebo with respect to platelet counts, liver and renal measures, or influenza-like symptoms. The most common adverse events were injection-site reactions.
Conclusions
APO(a)-LRx reduced lipoprotein(a) levels in a dose-dependent manner in patients who had elevated lipoprotein(a) levels and established cardiovascular disease. (Funded by Akcea Therapeutics;
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