Pretreatment Low-density Lipoprotein Cholesterol Research Articles

Abstract 60: Cost-Effectiveness of Intensive Lipid-Lowering in Young Adulthood

Introduction: Cumulative exposure to elevated low-density lipoprotein cholesterol (LDL-C) in young adulthood (ages 18-39) increases later life atherosclerotic cardiovascular disease risk. Statins are cost-effective in young adults with LDL-C ≥130 mg/dL. However, current guidelines only recommend statins for LDL-C ≥190 mg/dL. Some young adults may not achieve treatment goals with statin monotherapy and additional lipid-lowering therapy may be cost-effective, especially given the advent of generic pricing for ezetimibe and reduced pricing for PCSK9 inhibitors (PCSK9-Is). Objective: We aimed to estimate the cost-effectiveness of statins with supplemental ezetimibe and supplemental PCSK9-Is in US young adults with LDL-C ≥130 mg/dL. Methods: The CVD Policy Model, an established computer simulation model, calculated the lifetime costs and quality-adjusted life years (QALYs) of lipid-lowering therapy. Analyses were stratified by pretreatment LDL-C and sex and the model accounted for cumulative LDL-C exposure in young adulthood. Treatment costs and effects were derived from published literature and publicly available data. Results were presented as incremental cost-effectiveness ratios (ICERs) and categorized as highly cost-effective (<$50,000/QALY), intermediately cost-effective ($50,000-$150,000/QALY), and not cost-effective (>$150,000/QALY). Results: Compared with no treatment, statin plus ezetimibe therapy was highly cost-effective for young adult men with LDL-C ≥160 mg/dL (ICER: $38,400/QALY; Table) and young adult women with LDL-C ≥190 mg/dL (ICER: $26,600/QALY). Statin plus PCSK9-I therapy substantially increased QALYs but was not cost-effective in any subgroup. To be highly cost-effective for young adults with LDL-C ≥190 mg/dL, PCSK9-I prices would need to be reduced by 61%. Conclusion: With generic pricing, statin plus ezetimibe therapy is highly cost-effective for young adults with elevated LDL-C. Large price reductions are required for statins plus PCSK9-Is to be cost-effective.

Effect of Statin Therapy on Cardiovascular Outcome in Stroke Patients with Low Baseline Low-Density Lipoprotein Cholesterol.

To investigate whether post-stroke statin therapy reduces subsequent major vascular events in statin-naïve patients with pretreatment low-density lipoprotein cholesterol (LDL-C) below the recommended target (≤70 mg/dL for atherosclerotic stroke and ≤100 mg/dL for non-atherosclerotic stroke) at stroke onset. Patients from an ongoing stroke registry who had an ischemic stroke between 2011 and 2020 were screened. Statin naïve patients with baseline LDL-C below the target were assessed. The effect of post-stroke statin therapy on major vascular events (composite of recurrent stroke, myocardial infarction, and death) was investigated using weighted Cox regression analyses using stabilized inverse probability treatment weighting. The baseline LDL-C level of the 1,858 patients (mean age 67.9 ± 15.3 years, 61.4% men, 13.2% atherosclerotic stroke) included in the study was 75.7 ± 17.0 mg/dL. Statins were prescribed to 1,256 (67.7%) patients (low-to-moderate intensity, 23.5%; high intensity, 44.1%). Post-stroke statin therapy was associated with a lower risk of major vascular events during 1-year follow-up (weighted hazard ratio 0.55, 95% confidence interval 0.42-0.71). In a subgroup of patients who were at very high risk of atherosclerotic cardiovascular disease with LDL-C <55 mg/dL or patients who were not at very high risk of atherosclerotic cardiovascular disease with LDL-C <70 mg/dL, post-stroke statin therapy was also associated with a reduction in major vascular events (weighted hazard ratio 0.45, 95% confidence interval 0.29-0.70). The intensity of the most beneficial statin varied by subtype of stroke. Statin therapy may improve vascular outcomes after ischemic stroke, even in cases of LDL-C below the target without pre-stroke lipid-lowering therapy. ANN NEUROL 2024;95:876-885.

Genetic Spectrum and Cascade Screening of Familial Hypercholesterolemia in Routine Clinical Setting in Hong Kong.

Familial hypercholesterolemia (FH) is a prevalent but often underdiagnosed monogenic disorder affecting lipoprotein metabolism, and genetic testing for FH has not been widely conducted in Asia in the past. In this cross-sectional study of 31 probands (19 adults and 12 children) and an addition of 15 individuals (12 adults and 3 children), who underwent genetic testing and cascade screening for FH, respectively, during the period between February 2015 and July 2023, we identified a total of 25 distinct LDLR variants in 71.0% unrelated probands. Among the adult proband cohort, a higher proportion of genetically confirmed cases exhibited a positive family history of premature cardiovascular disease. Treatment intensity required to achieve an approximate 50% reduction in pretreatment low-density lipoprotein cholesterol (LDL-C) exhibited potentially better diagnostic performance compared to pretreatment LDL-C levels, Dutch Lipid Clinic Network Diagnostic Criteria (DLCNC) score, and modified DLCNC score. Adult individuals identified through cascade screening demonstrated less severe phenotypes, and fewer of them met previously proposed local criteria for FH genetic testing compared to the probands, indicating that cascade screening played a crucial role in the early detection of new cases that might otherwise have gone undiagnosed. These findings underscore the significance of genetic testing and cascade screening in the accurate identification and management of FH cases.

The German CaRe high registry for familial hypercholesterolemia – Sex differences, treatment strategies, and target value attainment

Background and aimsFamilial hypercholesterolemia (FH) is among the most common genetic disorders in primary care. However, only 15% or less of patients are diagnosed, and few achieve the goals for low-density lipoprotein cholesterol (LDL-C). In this analysis of the German Cascade Screening and Registry for High Cholesterol (CaRe High), we examined the status of lipid management, treatment strategies, and LDL-C goal attainment according to the ESC/EAS dyslipidemia guidelines. MethodsWe evaluated consolidated datasets from 1501 FH patients diagnosed clinically and seen either by lipid specialists or general practitioners and internists. We conducted a questionnaire survey of both the recruiting physicians and patients. ResultsAmong the 1501 patients, 86% regularly received lipid-lowering drugs. LDL-C goals were achieved by 26% and 10% of patients with atherosclerotic cardiovascular disease (ASCVD) according to the 2016 and 2019 ESC/EAS dyslipidemia guidelines, respectively. High intensity lipid-lowering was administered more often in men than in women, in patients with ASCVD, at higher LDL-C and in patients with a genetic diagnosis of FH. ConclusionsFH is under-treated in Germany compared to guideline recommendations. Male gender, genetic proof of FH, treatment by a specialist, and presence of ASCVD appear to be associated with increased treatment intensity. Achieving the LDL-C goals of the 2019 ESC/EAS dyslipidemia guidelines remains challenging if pre-treatment LDL-C is very high.

Lipoprotein(a) Genotype Influences the Clinical Diagnosis of Familial Hypercholesterolemia.

Background Evidence suggests that LPA risk genotypes are a possible contributor to the clinical diagnosis of familial hypercholesterolemia (FH). This study aimed at determining the prevalence of LPA risk variants in adult individuals with FH enrolled in the Italian LIPIGEN (Lipid Transport Disorders Italian Genetic Network) study, with (FH/M+) or without (FH/M-) a causative genetic variant. Methods and Results An lp(a) [lipoprotein(a)] genetic score was calculated by summing the number risk-increasing alleles inherited at rs3798220 and rs10455872 variants. Overall, in the 4.6% of 1695 patients with clinically diagnosed FH, the phenotype was not explained by a monogenic or polygenic cause but by genotype associated with high lp(a) levels. Among 765 subjects with FH/M- and 930 subjects with FH/M+, 133 (17.4%) and 95 (10.2%) were characterized by 1 copy of either rs10455872 or rs3798220 or 2 copies of either rs10455872 or rs3798220 (lp(a) score ≥1). Subjects with FH/M- also had lower mean levels of pretreatment low-density lipoprotein cholesterol than individuals with FH/M+ (t test for difference in means between FH/M- and FH/M+ groups <0.0001); however, subjects with FH/M- and lp(a) score ≥1 had higher mean (SD) pretreatment low-density lipoprotein cholesterol levels (223.47 [50.40] mg/dL) compared with subjects with FH/M- and lp(a) score=0 (219.38 [54.54] mg/dL for), although not statistically significant. The adjustment of low-density lipoprotein cholesterol levels based on lp(a) concentration reduced from 68% to 42% the proportion of subjects with low-density lipoprotein cholesterol level ≥190 mg/dL (or from 68% to 50%, considering a more conservative formula). Conclusions Our study supports the importance of measuring lp(a) to perform the diagnosis of FH appropriately and to exclude that the observed phenotype is driven by elevated levels of lp(a) before performing the genetic test for FH.

How does cholesterol burden change the case for investing in familial hypercholesterolaemia? A cost-effectiveness analysis

Background and aimsThis study aimed to ascertain how the long-term benefits and costs of diagnosis and treatment of familial hypercholesterolaemia (FH) vary by prognostic factors and ‘cholesterol burden’, which is the effect of long-term exposure to low-density lipoprotein cholesterol (LDL-C) on cardiovascular disease (CVD) risk. MethodsA new cost-effectiveness model was developed from the perspective of the UK National Health Service (NHS), informed by routine data from individuals with FH. The primary outcome was net health gain (i.e., health benefits net of the losses due to costs), expressed in quality-adjusted life years (QALYs) at the £15,000/QALY threshold. Prognostic factors included pre-treatment LDL-C, age, gender, and CVD history. ResultsIf cholesterol burden is considered, diagnosis resulted in positive net health gain (i.e., it is cost-effective) in all individuals with pre-treatment LDL-C ≥ 4 mmol/L, and in those with pre-treatment LDL-C ≥ 2 mmol/L aged ≥50 years or who have CVD history. If cholesterol burden is not considered, diagnosis resulted in lower net health gain, but still positive in children aged 10 years with pre-treatment LDL-C ≥ 6 mmol/L and adults aged 30 years with pre-treatment LDL-C ≥ 4 mmol/L. ConclusionsDiagnosis and treatment of most people with FH results in large net health gains, particularly in those with higher pre-treatment LDL-C. Economic evaluations of FH interventions should consider the sensitivity of the study conclusions to cholesterol burden, particularly where interventions target younger patients, and explicitly consider prognostic factors such as pre-treatment LDL-C, age, and CVD history.

Effect of Lipoprotein Apheresis on Progression of Carotid Intima-Media Thickness in Patients with Severe Hypercholesterolemia

The extent of intervention effects on carotid intima-media thickness (CIMT) can predict the degree of atherosclerotic cardiovascular risk-reduction. We hypothesized that regular lipoprotein apheresis over the course of 10 years might slow down progression of CIMT in patients with severe hypercholesterolemia. This case series describes 10 Caucasian patients (mean age 60 ± 9 years, 70% female, 80% statin intolerant) with a severe hypercholesterolemia phenotype treated with lipoprotein apheresis between 2005 and 2020 (mean duration, 10 ± 4 years). The median pretreatment low-density lipoprotein cholesterol (LDL-C) level was 214 mg/100 ml (95% confidence interval, 145 to 248), lipoprotein(a) (Lp[a]), 26 mg/100 ml (15 to 109; 40% with Lp(a)>60 mg/100 ml). Three patients were diagnosed with a monogenic cause. The baseline mean CIMT was 850 ± 170 µm, and maximum CIMT was 1,040 ± 220 µm across the age range of 46 to 70 years. Acute effects of lipoprotein apheresis determined as a difference before and immediately after the procedure were estimated as a median of 72 ± 8% and 75 ± 7% reduction in the LDL-C and Lp(a) levels, respectively. Using the imputed trajectories, period-specific on-treatment time-weighted averages for LDL-C and Lp(a) were 141 mg/100 ml (interquartile range, 89 to 152; 38% reduction from the baseline) and 24 mg/100 ml (interquartile range, 12 to 119; 19% reduction from baseline), respectively. The number of patients with CIMT above their "vascular age" decreased from 80% to 30% over the treatment course. In conclusion, an increase in CIMT seen with advanced age and severe hypercholesterolemia was halted with lipoprotein apheresis with an estimated annual rate of change in mean common CIMT of -4 µm/y and maximum CIMT of -3 µm/y.

Predictors of Efavirenz Plasma Exposure, Auto-Induction Profile, and Effect of Pharmacogenetic Variations among HIV-Infected Children in Ethiopia: A Prospective Cohort Study

(1) Background: Efavirenz plasma concentration displays wide between-patient variability partly due to pharmacogenetic variation and autoinduction. Pediatric data on efavirenz pharmacokinetics and the relevance of pharmacogenetic variation are scarce, particularly from sub-Saharan Africa, where >90% of HIV-infected children live and population genetic diversity is extensive. We prospectively investigated the short- and long-term effects of efavirenz auto-induction on plasma drug exposure and the influence of pharmacogenetics among HIV-infected Ethiopian children. (2) Method: Treatment-naïve HIV-infected children aged 3–16 years old (n = 111) were enrolled prospectively to initiate efavirenz-based combination antiretroviral therapy (cART). Plasma efavirenz concentrations were quantified at 4, 8, 12, 24, and 48 weeks of cART. Genotyping for CYP2B6, CYP3A5, UGT2B7, ABCB1, and SLCO1B1 common functional variant alleles was performed. (3) Results: The efavirenz plasma concentration reached a peak at two months, declined by the 3rd month, and stabilized thereafter, with no significant difference in geometric mean over time. On average, one-fourth of the children had plasma efavirenz concentrations ≥4 µg/mL. On multivariate analysis, CYP2B6*6 and ABCB1c.3435 C > T genotypes and low pre-treatment low-density lipoprotein (LDL) were significantly associated with higher plasma efavirenz concentration regardless of treatment duration. Duration of cART, sex, age, nutritional status, weight, and SLCO1B, CYP3A5, UGT2B7, and ABCB1 rs3842 genotypes were not significant predictors of efavirenz plasma exposure. (4) Conclusion: Pre-treatment LDL cholesterol and CYP2B6*6 and ABCB1c.3435 C > T genotypes predict efavirenz plasma exposure among HIV-infected children, but treatment-duration-dependent changes in plasma efavirenz exposure due to auto-induction are not statistically significant.

Association of Contemporary Statin Pretreatment Intensity and LDL-C Levels on the Incidence of STEMI Presentation

Constituting hypolipidemic and pleiotropic effects, statins stabilize coronary artery plaque and may prevent STEMI events. This study investigated the association between contemporary statin pretreatment intensity, low-density lipoprotein cholesterol (LDL-C) levels, and the type of acute coronary syndrome (ACS) presentation: STEMI vs. NSTE-ACS. Data were drawn from the ACS Israeli Survey (ACSIS), a biennial prospective national survey that took place in 2008–2018. The rate of STEMI vs. NSTE-ACS was calculated by statin use, including statin intensity (high-intensity statin therapy (HIST) and low-intensity statin therapy (LIST) prior to the index ACS event. Among 5103 patients, 2839 (56%) were statin-naive, 1389 (27%) used LIST and 875 (17%) used HIST. Statin pretreated patients were older and had a higher rates of co-morbidities, cardiovascular disease history and pretreatment with evidence-based medications. STEMI vs. NSTE-ACS was lower among HIST vs. LIST vs. statin-naive patients (31.0%, 37.8%, and 54.0%, respectively, p for trend < 0.001). Multivariate analysis revealed that HIST was independently associated with lower STEMI presentation (ORadj 0.70; 95% CI 0.57–0.86), while LIST (ORadj 0.92; 95% CI 0.77–1.10) and LDL-C < 70 mg/dL (ORadj 0.96; 95% CI 0.82–1.14) were not. In conclusion, among patients admitted with ACS, pretreatment with HIST was independently associated with a lower probability of STEMI presentation, while LIST and LDL-C < 70 mg/dL were not.

Progression of carotid intima-media thickness in patients treated with lipoprotein apheresis: real-world evidence over 12 years

Abstract Background The extent of intervention effects on carotid intima-media thickness (CIMT) can predict the degree of atherosclerotic cardiovascular disease (ASCVD) risk reduction. There is limited evidence of long-term effects of lipoprotein apheresis on the CIMT progression. Purpose We hypothesized that regular lipoprotein apheresis over the course of 10 years may slow down progression of CIMT in patients with severe hypercholesterolemia. Methods This case series describes ten Caucasian patients (mean age 60±9 years, 70% female, 80% statin intolerant) with familial hypercholesterolemia and/or hyperlipoproteinemia(a) treated with lipoprotein apheresis at a single academic center between 2005 and 2020. The mean and maximum diastolic CIMT of the distal 1 cm of the far wall of the right and left common carotid arteries was measured by the same, trained sonographer utilizing an automated border-detection algorithm. Results The median pre-treatment low-density lipoprotein cholesterol (LDL-C) level was 214 mg/dL (95% confidence interval, 145 to 248), lipoprotein(a), 26 mg/dL (15 to 109; 40% with lipoprotein(a) &amp;gt;60 mg/dL). Using the imputed trajectories, period-specific on-treatment time-weighted averages for LDL-C and lipoprotein(a) were 141 mg/dL (IQR, 89 to 152) and 24 mg/dL (IQR, 12 to 119), respectively. The baseline mean CIMT was 850±170μm and maximum CIMT was 1040±220μm across the age range of 46 to 70 years. Over a median duration of 12 years, regular treatment with lipoprotein apheresis resulted in an average reduction in the mean CIMT of −40μm (IQR, −50 to 20) and maximum CIMT −30μm (IQR, −60 to −10). Among tested lipid and lipoprotein fractions in this sample, the follow-up mean CIMT values strongly correlated only with the baseline lipoprotein(a) levels. Median CIMT progression rates were as follows: mean common carotid, −4μm/y (IQR, −9 to 1), mean common carotid, −12μm/3y (IQR, −26 to 4), maximal common carotid, −3μm/y (IQR, −8 to −1). This translated into 70% (7/10) of cases demonstrating composite mean CIMT below their expected chronologic age, gender and race-stratified vascular age. There was a strong direct correlation between the mean CIMT value at the end of the treatment period and the age of treatment initiation. In this cohort of primary and secondary prevention of patients with severe hypercholesterolemia, the overall rate of ASCVD was 37.5 per 1000 person-years while on lipoprotein apheresis. Conclusions Our observation performed in the clinical setting, demonstrated a real-world effectiveness of lipoprotein apheresis. This analysis supports implementation of aggressive lipid-modifying strategies across all ages. Surveillance with CIMT allows for continued monitoring of atherosclerosis progression and increases compliance with the lipid-modifying therapies in the high-risk patients with poor statin tolerance in the clinical setting. Funding Acknowledgement Type of funding sources: Public Institution(s). Main funding source(s): KUMC

A real-world analysis of characteristics and lipid-lowering therapy use in patients initiating treatment with evolocumab in Sweden

Abstract Background/Introduction Proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitors reduce low-density lipoprotein cholesterol (LDL-C) levels and the risk of cardiovascular events in patients with atherosclerotic cardiovascular disease (ASCVD) in clinical trials. In January 2019, evolocumab reimbursement recommendation in Sweden was broadened to include patients on maximally tolerated oral lipid-lowering therapy (LLT) and either ASCVD and LDL-C ≥2.5 mmol/L, or familial hypercholesterolemia (FH) with no ASCVD and LDL-C ≥3.0 mmol/L. Purpose Describe characteristics and LLT use in patients initiating treatment with evolocumab in the context of the 2019 reimbursement recommendation in Sweden. Methods Cross-sectional, population-based, retrospective, observational study of patients initiating treatment with evolocumab between January 2019 and June 2020. Data were obtained from national healthcare registers and electronic medical records, covering more than half of the Swedish population. Results Out of 1560 patients included, 41% had LDL-C available ≤3 months prior to treatment initiation with evolocumab. Among those with LDL-C available, 79% had ASCVD and 19% had definite, probable or possible FH with no ASCVD. Mean pre-treatment LDL-C levels were 3.7 and 5.0 mmol/L for patients with ASCVD, and FH with no ASCVD, respectively. Most of the patients, 84.6% and 80.0%, respectively, had been ever treated with both statins and ezetimibe. However, 28.0% and 38.3% of them, respectively, were not on oral LLT at the time of treatment initiation with evolocumab. Patient characteristics and LLT use are presented in Table 1. Conclusions Patients initiating treatment with evolocumab in Sweden had pre-treatment LDL-C levels far from treatment targets, despite being at very high risk for cardiovascular events. Most of the patients had been treated with both statins and ezetimibe in the past. However, almost a third of them were not using oral LLT at the time of treatment initiation with evolocumab. The conditions in the 2019 evolocumab reimbursement recommendation in Sweden were generally met. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): Amgen

Statin treatment and LDL-cholesterol treatment goal attainment among individuals with familial hypercholesterolaemia in primary care

ObjectivesGuidance recommends statin treatment in familial hypercholesterolaemia (FH) to achieve at least a 50% reduction in low-density lipoprotein cholesterol (LDL-C). We assessed statin prescribing rates and LDL-C treatment goal attainment...

Carotid intima-media thickness (IMT) in patients with severe familial and non-familial hypercholesterolemia: The effect of measurement site on the IMT correlation with traditional cardiovascular risk factors and calcium scores.

The carotid intima-media thickness (IMT) measurement may be carried out proximally (pIMT) or distally (dIMT) in relation to the bulb of the common carotid artery which has significant implications on the results and correlation with risk factors. The aim of the study was to compare the pIMT and dIMT in patients with familial hypercholesterolemia confirmed by genetic testing (FH group) and patients with severe non-familial hypercholesterolemia, with negative results of genetic testing (NFH group) and to determine the correlation of results with traditional atherosclerotic risk factors and calcium scores. A total of 86 FH and 50 NFH patients underwent pIMT and dIMT measurements of both carotid arteries as well as computed tomography (CT) with coronary and thoracic aorta calcium scoring. The meanpIMT of both right and left common carotid artery were significantly higher in patients with FH compared to the NFH group (meanpRIMT 0.721 ± 0.152 vs. 0.644 ± 0.156, p < 0.01, meanpLIMT 0.758 ± 0.173 vs. 0.670 ± 0.110, p < 0.01). Patient age, pre-treatment lowdensity lipoprotein (LDL) cholesterol levels (LDLmax) at baseline and systolic blood pressure were independent predictors of pIMT increases in both carotid arteries. Smoking history, age and LDLmax were independent predictors of dIMT increase. There was a significant correlation between the calcium scores of the ascending aorta, coronary artery and aortic valve and all IMT parameters. The IMT measured proximally better between patients with familial and non-familial hypercholesterolemia. The association between IMT and traditional cardiovascular risk factors varies between measurement sites. IMT values correlate CT calcium scores in all patients with hypercholesterolaemia regardless of genetic etiology.

Long term follow-up of children with familial hypercholesterolemia and relatively normal LDL-cholesterol at diagnosis

Familial hypercholesterolemia (FH) is a genetic disorder with high low-density lipoprotein cholesterol (LDL-C) levels and high risk of cardiovascular disease. The long-term importance of carrying an FH mutation despite having relatively normal LDL-C levels in childhood is not known. We investigated the development of LDL-C levels and need of statin therapy in children with an FH mutation, with pretreatment LDL-C ≤ 4.1 mmol/L (~160 mg/dL), followed-up at lipid clinics in Oslo, Norway and Rotterdam, The Netherlands. Of 742 FH children, 109 (15%) had pretreatment LDL-C ≤ 4.1 mmol/L (~160 mg/dL) [mean (SD) 3.5 (0.5) mmol/L; (~130 (19) mg/dL)] measured at 11.8 (3.9) years of age [mean age (SD)]. After 8.2 (5.2) years [mean (SD)] of follow-up, 71.6% had started statin treatment. Therefore, all children carrying an FH mutation, independent of cholesterol levels, should receive follow-up at specialized lipid clinics for optimal and individualized treatment.

Treatment of Hepatitis C Virus Infection with Direct-acting Antiviral Agents Elevates the Serum Small-dense Low-density Lipoprotein Cholesterol Level.

Objective The low-density lipoprotein cholesterol (LDL) level is known to increase following the treatment of hepatitis C virus (HCV) infection using direct-acting antiviral agents (DAAs). This study aimed to investigate the changes in the lipid profiles, including small-dense LDL cholesterol (sdLDL), in HCV patients treated with DAAs. Patients We retrospectively assessed 67 HCV patients who achieved sustained virological response with DAA administration and were observed for more than 2 years, of whom 32 were on daclatasvir/asunaprevir, 14 were on sofosbuvir/ledipasvir, and 21 were on sofosbuvir/ribavirin. Methods We evaluated the lipid profiles, including sdLDL, every 6 months until 2 years after the start of treatment and analyzed the factors related to changes in the sdLDL level. Results The median sdLDL value at baseline was 12.8 mg/dL, which increased to 19.5 mg/dL at 6 months (p<0.001) and remained elevated at 25.4 mg/dL at 2 years later (p<0.001). The Kaplan-Meier curve indicated that patients with high values of LDL, albumin, muscle attenuation and visceral to subcutaneous adipose tissue area ratio were at increased risk for elevation of sdLDL over 35 mg/dL (log-rank test: p<0.001; p=0.008, p=0.002 and p=0.042, respectively). A multivariate analysis performed on the factors contributing to elevation of sdLDL 2 years after DAA treatment (≥35.0 mg/dL) revealed pretreatment LDL (≥91.0 mg/dL) and muscle attenuation (≥33.7 HU) as significant factors (p=0.007 and p=0.032, respectively). Conclusion SdLDL increased continuously after DAA treatment, and high LDL levels and low intramuscular fat deposition before treatment contributed to elevated sdLDL levels after treatment.

Comparison of the mutation spectrum and association with pre and post treatment lipid measures of children with heterozygous familial hypercholesterolaemia (FH) from eight European countries

Background and aimsFamilial hypercholesterolaemia (FH) is commonly caused by mutations in the LDLR, APOB or PCSK9 genes, with untreated mean low density lipoprotein-cholesterol (LDL-C) concentrations being elevated in APOB mutation carriers, even higher in LDLR mutation and highest in those with a PCSK9 mutation. Here we examine this in children with FH from Norway, UK, The Netherlands, Belgium, Czech Republic, Austria, Portugal and Greece. MethodsDifferences in characteristics and pre- and post-treatment lipid concentrations in those with different molecular causes were compared by standard statistical tests. ResultsData were obtained from 2866 children, of whom 2531 (88%) carried a reported LDLR/APOB/PCSK9 variant. In all countries, the most common cause of FH was an LDLR mutation (79% of children, 297 different), but the prevalence of the APOB p.(Arg3527Gln) mutation varied significantly (ranging from 0% in Greece to 39% in Czech Republic, p < 2.2 × 10−16). The prevalence of a family history of premature CHD was significantly higher in children with an LDLR vs APOB mutation (16% vs 7% p=0.0005). Compared to the LDLR mutation group, mean (±SD) concentrations of pre-treatment LDL-C were significantly lower in those with an APOB mutation (n = 2260 vs n = 264, 4.96 (1.08)mmol/l vs 5.88 (1.41)mmol/l, p < 2.2 × 10−16) and lowest in those with a PCSK9 mutation (n = 7, 4.71 (1.22)mmol/l). ConclusionsThe most common cause of FH in children from eight European countries was an LDLR mutation, with the prevalence of the APOB p.(Arg3527Gln) mutation varying significantly across countries. In children, LDLR-FH is associated with higher concentrations of LDL-C and family history of CHD compared to those with APOB-FH.

Characteristics and Outcomes of Patients Treated With Proprotein Convertase Subtilisin/Kexin Type 9 Inhibitors (The Mayo Clinic Experience)

Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) inhibitors represent a novel addition to the lipid-lowering armamentarium. We attempted to characterize a real-world group of patients with a clinical indication for PCSK9 inhibitors and describe their clinical outcomes and adverse effect profile. A retrospective chart review was conducted, evaluating all patients referred to preventive cardiology at the Mayo Clinic (Minnesota) between September, 2015 and December, 2018 for management of severe dyslipidemia. A total of 222 patients were referred and a recommendation to start a PCSK9 inhibitor was given to 164 patients (73.9%). Of these, 28 patients (17.1%) declined the use of a PCSK9 inhibitor. A total of 136 previous authorizations were submitted. Of these applications, 96 (70.6%) were approved and 17 (12.5%) were rejected. The cohort's mean age was 64.1 years (range 39 to 91). High-intensity statins and ezetimibe were used in 50 (52.1%) and 80 (83.3%) of the treated patients. Mean pretreatment low-density lipoprotein cholesterol was 167.9 mg/dl. At a median follow-up of 19.0 months, the mean low-density lipoprotein reduction was 60.9% (range 0 to 90.3%). Higher low-density lipoprotein cholesterol percent reductions were seen in younger patients (p value 0.048), patients on high-intensity statins (p value 0.027), those with statin intolerance (p value 0.046), and individuals with a higher baseline triglycerides (p value 0.047). Two (2.1%) patients underwent coronary revascularization, and 1 (1.0%) patient was hospitalized for unstable angina. No cardiovascular deaths occurred. Adverse events were reported in 12 (12.5%) patients, and were all minor (injection site reactions, myalgias, and flu-like illness). In conclusion, our study shows an efficacy and safety profile that is concordant with previous investigations. The use of a standardized application form was associated with a high insurance approval rate.

Percentage low-density lipoprotein-cholesterol response to a given statin dose is not fixed across the pre-treatment range: Real world evidence from clinical practice: Data from the ESC-EORP EUROASPIRE V Study.

Recent European guidelines recommend in patients with atherosclerotic cardiovascular disease to achieve a reduction of low-density lipoprotein-cholesterol of at least 50% if the baseline low-density lipoprotein-cholesterol level is between 1.8 and 3.5 mmol/L. Systematic reviews have associated a given statin/dose combination with a fixed percentage low-density lipoprotein-cholesterol response. Algorithms for detecting cases and estimating the prevalence of familial hypercholesterolaemia often rely on such fixed percentage reductions. We used data from 915 coronary patients participating in the EUROASPIRE V study in whom atorvastatin or rosuvastatin therapy was initiated at hospital discharge and who were still using these drugs at the same dose at a follow-up visit 6 or more months later. Pre and on-treatment low-density lipoprotein-cholesterol levels were compared across the full low-density lipoprotein-cholesterol range. The prevalence of FH was estimated using the Dutch Lipid Clinic Network criteria, once using observed pre-treatment low-density lipoprotein-cholesterol and once using imputed pre-treatment low-density lipoprotein-cholesterol by following the common strategy of applying fixed correction factors to on-treatment low-density lipoprotein-cholesterol. Inter-individual variation in the low-density lipoprotein-cholesterol response to a fixed statin and dose was considerable, with a strong inverse relation of percentage reductions to pre-treatment low-density lipoprotein-cholesterol. The percentage low-density lipoprotein-cholesterol response was markedly lower at the left end of the pre-treatment low-density lipoprotein-cholesterol range especially for levels less than 3 mmol/L. The estimated prevalence of familial hypercholesterolaemia was 2% if using observed pre-treatment low-density lipoprotein-cholesterol and 10% when using imputed low-density lipoprotein-cholesterol. The inter-individual variation in the percentage low-density lipoprotein-cholesterol response to a given dose of a statin is largely dependent on the pre-treatment level: the lower the pre-treatment low-density lipoprotein-cholesterol level the smaller the percentage low-density lipoprotein-cholesterol reduction. The use of uniform correction factors to estimate pre-treatment low-density lipoprotein-cholesterol is not justified.

Longitudinal low density lipoprotein cholesterol goal achievement and cardiovascular outcomes among adult patients with familial hypercholesterolemia: The CASCADE FH registry

Background and aimsThere are limited data from the US on outcomes of patients in specialty care for familial hypercholesterolemia (FH). MethodsCASCADE FH Registry data were analyzed to assess longitudinal changes in medication usage, in low density lipoprotein cholesterol (LDL-C) levels, and the rate of major adverse cardiovascular events (MACE (myocardial infarction, coronary revascularization, stroke or transient ischemic attack) in adults with FH followed in US specialty clinics. ResultsThe cohort consisted of 1900 individuals (61% women, 87% Caucasian), with mean age of 56 ± 15 years, 37% prevalence of ASCVD at enrollment, mean pretreatment LDL-C 249 ± 68 mg/dl, mean enrollment LDL-C 145 mg/dl and 93% taking lipid lowering therapy. Over follow up of 20 ± 11 months, lipid lowering therapy use increased (mean decrease in LDL-C of 32 mg/dl (p < 0.001)). Only 48% of participants achieved LDL-C < 100 mg/dl and 22% achieved LDL-C < 70 mg/dl; ASCVD at enrollment was associated with greater likelihood of goal achievement. MACE event rates were almost 6 times higher among patients with prior ASCVD compared to those without (4.6 vs 0.8/100 patient years). Also associated with incident MACE were markers of FH severity and conventional ASCVD risk factors. ConclusionsWith care in FH specialized clinics, LDL-C decreased, but LDL-C persisted >100 mg/dl in 52% of patients. High ASCVD event rates suggest that adults with FH warrant designation as having an ASCVD risk equivalent. Earlier and more aggressive therapy of FH is needed to prevent ASCVD events.

Optimising treatment of hyperlipidaemia: Quantitative evaluation of UK, USA and European guidelines taking account of both LDL cholesterol levels and cardiovascular disease risk

Background and aimsGuidelines for cholesterol-lowering medication either advocate fixed dose statin treatment without low density lipoprotein (LDL) cholesterol targets or treatment aimed at LDL cholesterol goals. The decrease in LDL cholesterol concentration determines the reduction in atherosclerotic cardiovascular disease (CVD) risk. MethodsAs indices of the effectiveness of reductions in LDL cholesterol concentration achieved by the various guidelines, the number of CVD events prevented in 100 people during 10 years of treatment (N100) and the number of people, who must be treated for 10 years to prevent one CVD event (NNT), were calculated taking into account both CVD risk and pretreatment LDL cholesterol concentration. That our method of calculating NNT and N100, could be extended to statin regimens of different intensity or of statin combined with adjunctive cholesterol-lowering medication was demonstrated by meta-analysis. ResultsReductions in LDL-cholesterol concentration are determined by the choice and dose of medication and by the pre-treatment LDL-cholesterol concentration. At similar CVD risk, whatever cholesterol-lowering strategy is adopted, people with higher pre-treatment LDL cholesterol benefit more than those with lower levels. Fixed dose statin regimens are less effective than target LDL cholesterol levels of 1.8 or 1.4 mmol/l when pre-treatment LDL-cholesterol levels exceed 4 mmol/l. However, fixed dose statin is more effective in people with lower initial LDL cholesterol. The predicted NNT and N100 were closely related to the observed reduction in CVD risk in our meta-analysis. ConclusionsIn hypercholesterolaemia, aiming for LDL cholesterol targets with statin dose titration (and when necessary adjunctive medication) is essential to optimise benefit.