Utility of Genetically Predicted Lp(a) (Lipoprotein [a]) and ApoB Levels for Cardiovascular Risk Assessment

Background: Current lipid guidelines suggest measurement of Lp(a) (lipoprotein[a]) and ApoB (apolipoprotein B) for atherosclerotic cardiovascular disease risk assessment. Polygenic risk scores (PRSs) for Lp(a) and ApoB may identify individuals unlikely to have elevated Lp(a) or ApoB and thus reduce such suggested testing. Methods: PRSs were developed using LASSO regression among 273 222 and 356 958 UK Biobank participants of white British ancestry for Lp(a) and ApoB, respectively, and validated in separate sets of 60 771 UK Biobank and 15 050 European Prospective Investigation into Cancer and Nutrition-Norfolk participants. We then assessed the proportion of participants who, based on these PRSs, were unlikely to benefit from Lp(a) or ApoB measurements, according to current lipid guidelines. Results: In the UK Biobank and European Prospective Investigation into Cancer and Nutrition-Norfolk cohorts, the area under the receiver operating curve for the PRS-predicted Lp(a) and ApoB to identify individuals with elevated Lp(a) and ApoB was at least 0.91 (95% CI, 0.90–0.92) and 0.74 (95% CI, 0.73–0.75), respectively. The Lp(a) PRS and measured Lp(a) showed comparable association with atherosclerotic cardiovascular disease incidence, whereas the ApoB PRS was in general less predictive of atherosclerotic cardiovascular disease risk than measured ApoB. In the context of the ESC/EAS lipid guidelines, at a 95% sensitivity to identify individuals with elevated Lp(a) and ApoB levels, at least 54% of Lp(a) and 24% of ApoB testing could be reduced by prescreening with a PRS while maintaining a low false-negative rate. Conclusions: A substantial proportion of suggested testing for elevated Lp(a) and a modest proportion of testing for elevated ApoB could potentially be reduced by prescreening individuals with PRSs.

Lipid-Lowering Therapy in Patients with Coronary Heart Disease and Prior Stroke: Mission Impossible?

Hyperlipidemia is a powerful risk factor for coronary heart disease (CHD). It has been known for a long time that lipid-lowering drugs significantly reduce morbidity from CHD, thus proving a causal role for cholesterol in coronary events. Conversely, the relationship between low-density lipoprotein cholesterol (LDL-C) levels and stroke has been less clear and debated for many years. Recent data conclusively demonstrate not only the inverse epidemiological relationship of blood LDL-C with stroke, but also the efficacy of different strategies to attain cholesterol-lowering on stroke. They also dissipate lingering doubts about the possibility that lipid-lowering is linked to an increase in hemorrhagic stroke. However, despite current international lipid guidelines now strongly recommend aggressive lipid-lowering therapy in patients with atherosclerotic cardiovascular disease, including CHD and cerebrovascular disease (CeVD), secondary prevention patients are often undertreated with lipid-lowering therapies in routine clinical practice. This review highlights that patients with CHD and concomitant CeVD do not receive aggressive lipid-lowering therapy despite being at very high risk and with clear evidence of benefit from lowering LDL-C levels below current targets.

Does Evolocumab use in Europe match 2019 ESC/EAS lipid guidelines? Results from the HEYMANS study

Background 2019 ESC/EAS dyslipidaemia guidelines recommend a 50% lowering in untreated LDL-C and use of PCSK9 inhibitors (PCSK9i) for patients at very-high cardiovascular (CV) risk when LDL-C target goals of <1.4 mmol/L or <1.0 mmol/L (for those with 2 CV events within two-years) are not met despite maximally tolerated statins and ezetimibe. Purpose This observational study describes a cohort of patients initiating evolocumab across 10 EU countries. Methods Patients are followed from evolocumab initiation (baseline). Demographic/clinical characteristics, lipid modifying therapy (LLT) and lipid values were collected from medical records (6 months prior to evolocumab initiation through 30 months post initiation). We report interim data from patients initiating evolocumab from August 2015 with follow-up through October 2019. Results 1896 patients initiated on evolocumab as per local reimbursement criteria were included in this interim analysis (planned sample size: N=2,000). Most (1663 [88%]) had 12 months follow-up, 665 (35%) had 18 months follow-up; mean follow-up, 16.3 months. Mean (SD) age was 60.0 (10.8) years; 85% of patients had a history of CV disease (CVD), 44% had a diagnosis of familial hypercholesterolemia (FH), 19% had type 2 diabetes, 66% were hypertensive, 7% had renal impairment and half (51%) were prior or current smokers. The majority (60%) reported statin intolerance and 42% were not receiving any LLT at evolocumab initiation. Fewer than half (805 [43%]) were receiving a statin (±ezetimibe) at evolocumab initiation; of these, most were on a high/moderate intensity (68%/22%). 12% of patients were receiving statin monotherapy. Median (Q1, Q3) baseline LDL-C was 3.98 (3.16, 5.06) mmol/L. Within 3 months of evolocumab initiation median LDL-C fell by 58% to 1.62 mmol/L. This reduction was maintained over time (Figure). Overall, 58% of patients achieved at least one LDL-C <1.4 mmol/L during follow-up. Among patients receiving background statins and/or ezetimibe at evolocumab initiation, 67% (667/990) achieved at least one LDL-C <1.4 mmol/L, compared with 43% (295/679) of patients not receiving background statins/ezetimibe. During follow-up, 39–46% patients received no background LLT, 40–44% received statin ±ezetimibe, 11–14% received statin monotherapy. Conclusion In Europe, patients initiated on evolocumab had baseline LDL-C levels almost 3 times higher than the present threshold for PCSK9i use, reflecting local reimbursement criteria. Evolocumab resulted in a more than 50% reduction in LDL-C; however, only approximately half of all patients achieved an LDL-C <1.4 mmol/L. LDL-C goal attainment was higher among patients receiving evolocumab with background LLT, suggesting that achievement of EAS/ESC LDL-C goals requires multiple LLTs and a lower threshold for PCSK9i initiation. LDL-C levels after evolocumab initiation Funding Acknowledgement Type of funding source: Private company. Main funding source(s): Amgen