First Author Research Articles

Characterization of Inclisiran Use in Real World: Prescription Data from Germany

<h3>Lead Author's Financial Disclosures</h3> Raquel Lahoz is an employee of Novartis Pharma AG, Basel, Switzerland, and owns Novartis shares. <h3>Study Funding</h3> None. <h3>Background/Synopsis</h3> Despite the availability of effective low-density lipoprotein cholesterol (LDL-C) lowering drugs, ∼80% of patients with established ASCVD fall short of achieving and maintaining LDL-C levels <70 mg/dL, highlighting the need for innovative new LDL-C lowering therapies. Inclisiran is a novel small-interfering RNA (siRNA) that effectively reduces circulating LDL-C. Administered as a single subcutaneous injection initially, again at 3 months, and then every 6 months, inclisiran has been approved by the European Medicines Agency (EMA) in December 2020 for adult patients with hypercholesterolemia as an adjunct to diet who require additional lowering of LDL-C despite receiving other lipid-lowering therapies and by the Food and Drug Administration (FDA) in December 2021. <h3>Objective/Purpose</h3> This study aimed to assess real-world patient characteristics, adherence and persistence for patients being initiated with inclisiran in Germany. <h3>Methods</h3> This retrospective non-interventional study used the IQVIA LRx prescription database and included adult patients being initiated with inclisiran treatment between February 2021 and October 2021 with a 6-month lookback period. For the adherence and persistence analyses, a subgroup of patients with a first inclisiran prescription recorded between February and June 2021 was selected, allowing for at least 4 months follow-up, up to October 2021. <h3>Results</h3> A total of 697 patients receiving at least one dose of inclisiran between February- October 2021 were included in this study. Mean age of patients was 63 years (50% females) and 81% were ≥ 55 years old. Majority of patients were prescribed inclisiran by their nephrologists (42%) and cardiologists (30%). Of the 334 patients receiving their first inclisiran dose between February-June 2021, the second dose was also recorded for 257 (77%) patients until the time of the analysis; median time between the two doses was 3 months and 91% (233) of patients received the second dose within 4 months of treatment initiation. <h3>Conclusions</h3> This study shows early results from one of the first real-world studies describing the characteristics of patients being initiated with inclisiran with majority returning for their second dose within 4 months. Future real-world studies with longer follow-up are needed to evaluate the long-term adherence and persistence as well as effectiveness of inclisiran.

^Sex Disparities in the Treatment and Outcomes of Familial Hypercholesterolemia

<h3>Lead Author's Financial Disclosures</h3> Nothing to disclose. <h3>Study Funding</h3> Fonds de recherche du Québec - Santé (FRQ-S). <h3>Background/Synopsis</h3> Familial hypercholesterolemia (FH), an inherited condition equally prevalent in males and females, is characterized by elevated low-density lipoprotein cholesterol (LDL-C) in the blood. If left untreated, FH leads to the development of premature atherosclerotic cardiovascular disease (ASCVD) and death. Many barriers to care in FH exist, which can result in low rates of diagnosis and suboptimal treatment and outcomes. Sex disparities have been identified as an important barrier to care in CVD, however their influence on treatment and lipid target achievement in FH remains to be explored. <h3>Objective/Purpose</h3> To determine sex differences in treatment and lipid level achievement in Heterozygous (HeFH) patients at the MUHC. <h3>Methods</h3> Here we performed a longitudinal registry analysis of sex differences in treatment and lipid level achievement in HeFH patients at the MUHC. Patients were included in the study if they were diagnosed as either "definite", "probable", or "possible" FH based on the Simon- Broome criteria, Dutch Lipid Clinic Network criteria, or the new Canadian FH definition. Differences between males and females were calculated using a t-test or chi-squared test. <h3>Results</h3> There were 127 females and 162 males from the McGill FH Registry included in the analysis. The mean age at the initial clinic visit was 49±17 years for females and 45±16 years for males (p=0.04). At the most recent clinic visit, there were more males (89%) than females (76%) taking statins (p=0.7), and only 35% of females were on high-intensity statins, compared to 74% of males (p=0.002). Interestingly, statin intolerance was reported in 40% of females and 22% of males (p=0.02). We then examined guideline-recommended lipid target achievement between both sexes. At baseline, males and females had similar mean LDL-C levels of 6.9±2.2 mmol/L and 6.7±1.6 mmol/L respectively (p=0.7). Despite this, at the most recent visit, 55% of males reached a target LDL-C of 2.5 mmol/L compared to just 32% of females (p=0.02). As well, from baseline to most recent visit, females reduced their LDL-C by 51%, whereas males lowered their LDL-C by 62% (p=0.01). Thus, fewer females are reaching appropriate guideline-based target LDL-C levels compared to males. <h3>Conclusions</h3> Our analysis reveals a sex bias in FH patients in favor of males regarding treatment intensity and lipid level target achievement. Identifying these imbalances will allow us to break down these barriers in care through educational initiatives and additional training, to improve quality of life and life expectancy of individuals with FH.

The NLRP3 inhibitor and Nrf2 Agonist, RRx-001, Ameliorates Non-alcoholic Fatty Liver Disease in Rats

Lead Author's Financial Disclosures EpicentRx. Study Funding EpicentRx Inc. Background/Synopsis The development and progression of non-alcoholic steatohepatitis (NASH), an increasingly prevalent disease for which no pharmacological therapy has been approved, is linked to oxidative stress, inflammation, and fibrosis of the liver. Here, we investigated the novel mechanism of RRx-001, an NLRP3 inhibitor and Nrf2 agonist, which is in Phase 3 clinical trials for the treatment of cancer, as a therapeutic option for ameliorating NASH in a diet-induced mice model. Objective/Purpose To investigate whether intraperitoneal administration of RRx-001 improved high-fat diet-induced NASH in rats. Methods Sprague-Dawley rats (6-weeks-old male; about 180g weight) were randomly divided into three groups, one subjected to normal diet (ND) and two groups in high-fat, atherogenic diet (HFD, 40 kcal % fat, 1.25% cholesterol, 0.5% sodium cholate) for 12 weeks. One of HFD groups was treated IP with (5 mg/kg of RRx-001 every other week) for the last 8 weeks before characterization. Several markers of inflammation and steatosis were evaluated. Results Every other week administrations of RRx-001 reduced hepatic steatosis scores, serum ALT and AST levels, and hepatic levels of cholesterol and triglycerides in rats fed a high-fat diet. These were correlated with the suppression of NLRP3 inflammasome activation by RRx-001 as evidenced by decreased levels of NLRP3, caspase-1, and IL-1β levels on ELISA. Conclusions The findings of this study demonstrate that RRx-001 reduced inflammation with an anti-lipidemic and anti-NASH effect mediated at least in part by inhibition of the NLRP3 pathway. Thus, targeting the NLRP3 inflammasome with RRx-001 may contribute to the prevention and treatment of NASH. EpicentRx.

Association Between Dietary Fat Content and Serum Lipoprotein(a) Level

<h3>Lead Author's Financial Disclosures</h3> Nothing to disclose. <h3>Study Funding</h3> None. <h3>Background/Synopsis</h3> Lipoprotein(a) (Lp(a)) is an established causal risk factor of atherosclerotic cardiovascular disease. The association between dietary fat intake and Lp(a) has only been partially explored. <h3>Objective/Purpose</h3> To further investigate the association between intake of dietary fat, including specific individual fatty acids, and its effect on overall serum Lp(a) level. <h3>Methods</h3> We used the NHANES III cohort's 24-hour dietary recall and laboratory data. Multivariable regression was implemented to determine the association between dietary fat content (total, saturated, monounsaturated, and polyunsaturated) and serum Lp(a) level. Additional analyses explored the association between individual fatty acids by carbon chain length and Lp(a). Results were adjusted for sample weights, age, sex, race/ethnicity, statin use, and total caloric intake. <h3>Results</h3> The sample (n=8,722) was mostly female (56.3%) and most commonly non-Hispanic white (38.5%). Associations (mg/dL change in Lp(a) per gram of fat intake per day) were found between intake of total fat (-0.05 p=0.01) and total monosaturated fat (-0.10 p=0.02), but not saturated or polyunsaturated fats. Among individual fatty acids, only myristoleic (C14:1), oleic (C18:1), and alpha-linolenic acid (C18:3) were associated with Lp(a). <h3>Conclusions</h3> Lp(a) levels, albeit with a small effect size, were negatively correlated with increased total and monounsaturated fat consumption. The impact of fatty acids on Lp(a) may differ based on fatty acid chain length. The lack of significant association of saturated fat content with Lp(a) conflicts with the prior literature.

*Ketogenic Diets Exacerbating Hypercholesterolemia in APOE Variants and APOB Mutations-Potential Role for Measuring Intestinal Absorption of Lipids

Lead Author's Financial Disclosures Nothing to disclose. Study Funding None. Background/Synopsis Familial Hypercholesterolemia (FH) is caused primarily by mutations in either LDL receptor, APOB, or PCSK9 genes. There are other genetic causes of LDL elevation including APOE4 variants. Objective/Purpose We present two patients with markedly elevated LDL suspicious for FH who were subsequently diagnosed with APOE3/4 variants while on ketogenic diets. We also present a patient with a known APOB mutation who had a marked elevation of LDL on a ketogenic diet. Methods Case 1: 58-year-old male with no prior medical history was found to have elevated cholesterol of 600mg/dL and LDL>455mg/dL while on a ketogenic diet. Prior to initiating the diet, his cholesterol was 206mg/dL and LDL was 132mg/dL. Genetic testing revealed a ApoE3/4 variant. His most recent cholesterol increased to 706mg/dL and LDL to >500mg/dL. Case 2: 53-year-old male with hypertension cholesterol of 282mg/dL and LDL of 212mg/dL went on a ketogenic diet and lost 100lbs. Follow up lipid panel demonstrated a cholesterol of 400mg/dL and LDL of 317mg/dL. Genetic testing revealed a APOE3/4 variant. Case 3: 45-year-old female with FH and known APOB missense mutation went on a ketogenic diet for weight loss. Prior to initiating the diet, her total cholesterol was 311 mg/dL and LDL was 211 mg/dL. While on the ketogenic diet, her total cholesterol was 550 mg/dL and LDL was 454 mg/dL. Her LDL decreased to 276mg/dl on a less strict ketogenic diet. Results All three patients had a normal exercise stress test, normal carotid duplex ultrasound, and coronary calcium score of zero. They refused the initiation of a statin. All 3 patients had the Boston Heart Cholesterol Balance Test performed that directly measures the absorption markers (beta-sitosterol, campesterol and cholestanol) for circulating plasma cholesterol. Only the patient with the APOB mutation had increased intestinal absorption of cholesterol, suggesting a response to ezetimibe. She agreed to initiate ezetimibe, her LDL subsequently decreased by 52% to 132mg/dl. Conclusions We hypothesize patients with APOE variants and APOB mutations could have an exaggerated elevation of their LDL levels while on ketogenic diets. Although these 3 patients did not demonstrate progressive atherosclerosis, the long-term effect of this diet is unknown. We recommend that all patients on a ketogenic diet have their LDL monitored and if there is a significant increase, undergo genetic testing for FH, APOE and other genetic variants. Since this patient group is often reluctant to start statins, the Cholesterol Balance Test may be useful to identify patients who may respond well to ezetimibe. Nothing to disclose.

†Safety and Efficacy of Bempedoic Acid in Patients with Hypertension

<h3>Lead Author's Financial Disclosures</h3> KCF has received honorarium for consultancy from Amgen, Boehringer Ingelheim, Medtronic, Novartis, and Quantum Genomics. <h3>Study Funding</h3> Esperion Therapeutics, Inc. <h3>Background/Synopsis</h3> Patients with hypercholesterolemia often have hypertension (HTN), further increasing cardiovascular disease risk. Statins may affect blood pressure (BP) due to vascular effects. Bempedoic acid (BA) is an ATP citrate lyase inhibitor that lowers LDL-C. <h3>Objective/Purpose</h3> To investigate the safety and lipid-lowering effect of BA in patients with hypercholesterolemia and comorbid HTN. <h3>Methods</h3> Data were pooled from 4 phase 3 studies; patients were randomized 2:1 to BA or placebo (PBO) for 12-52 weeks. In 2 studies, patients also received moderate- to high-intensity statin, and in 2 studies, patients with statin intolerance received low-dose or no statin. Patients were grouped based on history of HTN, which was treated pharmacologically. Percent change from baseline to week 12 of LDL-C and other lipid parameters, and vital signs and adverse events were assessed. Moreover, in a 6 week 1:1 randomized phase 2 study (NCT02178098), the safety and efficacy of BA were assessed in patients with uncontrolled HTN (BP ≥140/90 and ≤180/110 mmHg) not receiving statins or other lipid-lowering therapies. <h3>Results</h3> Of the 3,623 (2,425 BA, 1,198 PBO) patients included, 78% had a history of HTN. At week 12, the PBO-corrected least squares mean (95% CI) percent change in LDL-C was −19.2% (−20.9, −17.5; P<.0001) in patients with HTN and −20.9% (−24.2, −17.5; P<.0001) in patients without HTN (interaction P=.3697). Results were similar for ApoB levels (−13.0% [−14.5, −11.5; P<.0001] for patients with HTN and −15.3% [−18.0, −12.6; P<.0001] for patients without HTN [interaction P=.1586]). Overall, through 12-52 weeks, the BA safety profile was similar in patients with or without HTN with no clinically meaningful changes in BP. In the phase 2 study (n=143; mean baseline [SD] BP 155/96 [12/6] mmHg), the PBO-corrected LS mean (95% CI) percent change in LDL C was −24.2% (−30.3, −18.1; P<.0001) at week 6. Through 6 weeks of BA treatment, 24-hour ambulatory BP monitoring showed no change from baseline in BP; BA was generally well-tolerated with a consistent safety profile across treatment groups. <h3>Conclusions</h3> Regardless of HTN status, BA was generally well-tolerated and significantly lowered LDL-C with no clinically meaningful BP changes.

Management of Atherogenic Dyslipidemia in a Patient with LDL Discordance

<h3>Lead Author's Financial Disclosures</h3> Nothing to disclose. <h3>Study Funding</h3> None. <h3>Background/Synopsis</h3> We review a case of a 43-year-old male referred for optimal management of dyslipidemia and cardiovascular risk reduction. This is intended to highlight key features in diagnosis and management of atherogenic dyslipidemia in the setting of metabolic syndrome. <h3>Objective/Purpose</h3> To review a clinical scenario involving LDL discordance in a patient with atherogenic dyslipidemia and its impact on management. <h3>Methods</h3> Clinical management done at tertiary care lipid program. Advanced lipid testing including LDL particle number and size is ordered through Quest Diagnostics. <h3>Results</h3> A 43-year-old nonsmoker male with metabolic syndrome and recently diagnosed insulin dependent type 2 diabetes mellitus was referred to the lipid clinic for further evaluation. With subclinical atherosclerosis noted with calcium score of 6.6 at age 43 (50-75th percentile) and above-average carotid intimal medial thickness, he was treated with rosuvastatin 20 mg daily. Subsequently, he had a good response of ∼50% LDL reduction with LDL-c of 75 mg/dL. At this point, while most clinicians as well as guideline directed approach may suggest a sufficient management of his dyslipidemia, the advent of advanced lipid testing contrasts this dogma otherwise. LDL discordance noted based on higher-than-expected particle number strongly warrants further aggressive LDL lowering for optimal cardiovascular risk reduction in the setting of metabolic syndrome. <h3>Conclusions</h3> While calculated LDL cholesterol has been well established as a primary target of treatment to reduce cardiovascular risk, in patients with hypertriglyceridemia or metabolic syndrome, this may underestimate the true burden of atherogenic, cholesterol-carrying lipoproteins. Measurements of apoB or LDL particle number by NMR may more closely quantify the atherogenic lipoprotein load and thus prove to be better indices of cardiovascular disease risk than calculated LDL cholesterol or non-HDL cholesterol in such a population. In our clinical case, the patient may not be adequately treated based on a calculated LDL of 75 mg/dL on high intensity statin, however, an advanced lipid panel revealing LDL discordance suggests intensification and more aggressive LDL lowering for optimal cardiovascular risk reduction.

Coronary Computed Tomography Angiography Evaluation of Plaque Morphology and Its Relationship to HDL and Total Cholesterol to HDL Ratio

<h3>Lead Author's Financial Disclosures</h3> Nothing to disclose. <h3>Study Funding</h3> None. <h3>Background/Synopsis</h3> Traditionally non-high-density lipoprotein (non-HDL) indicators have been utilized to stratify cardiovascular risk. Population studies have demonstrated an inverse relationship between HDL cholesterol levels and cardiovascular risk, however, the mechanism by which HDL exhibits its protective effect on the cardiovascular system remains unclear. <h3>Objective/Purpose</h3> To investigate the relationship between the HDL-C level and the total cholesterol to HDL (TC/HDL) ratio with coronary artery plaque burden as determined by coronary computed tomography angiography (CCTA). <h3>Methods</h3> This is a cross-sectional study evaluating the association of HDL-C and TC/HDL ratio with coronary artery plaque volumes. We identified 190 subjects who had undergone quantitative plaque analysis and had lipoprotein values available at our institution. Plaque was analyzed quantitatively utilizing semi-automated plaque analysis software (QAngio version 2.0.5). The plaque volumes are presented as total atheroma volume normalized (TAVnorm). The HDL-C level and TC/HDL ratio were analyzed as continuous variables and categorized at clinically relevant levels. Multivariate regression models adjusted for cardiovascular risk factors were used to evaluate the association of HDL-C and TC/HDL ratio with coronary plaque volumes. <h3>Results</h3> The mean (SD) age of the 190 subjects was 58.9 (+/-9.8) years, and 63% were male. After adjustment for cardiovascular risk factors, HDL- C (>40mg/dL) is inversely associated with fibrous (p=0.003), fibrous fatty (p=0.009), low attenuation plaque (LAP) (p=0.014), total non- calcified plaque (TNCP)(p=0.003), and total plaque (TP)(p=0.005) volume but not associated with dense calcified plaque (p=0.229). TC/HDL ratio (>4.0) is directly associated with LAP (p=0.024) and not associated with fibrous, fibrofatty, TNCP, dense calcified plaque and TP volume. Notably, when examined as continuous variables, increasing HDL- C level is inversely associated with fibrous plaque, TNCP and TP volume and increasing TC/HDL ratio is directly associated with increasing fibrous plaque, and fibrous fatty plaque, LAP, TNCP and TP volume, independent of other risk factors. <h3>Conclusions</h3> There is a strong association between low HDL-C and increasing TC/HDL ratio with increasing coronary plaque volumes, independent of traditional risk factors of atherosclerosis. The findings of this study suggest mechanistic evidence supporting the protective role of HDL-C in coronary artery disease. Additionally, TC/HDL ratio offers value as a secondary treatment target beyond LDL-C, which is especially beneficial in individuals with prevalent lipid discordance, such as those with diabetes and metabolic syndrome.

*Effects of Icosapent Ethyl on Plasma Ceramides and Coronary Plaque Progression in EVAPORATE trial

Lead Author's Financial Disclosures Nothing to disclose. Study Funding None. Background/Synops Despite the beneficial effects of statins on progression of coronary atherosclerosis, significant cardiovascular (CV) risk persists in patients with residual hypertriglyceridemia. REDUCE-IT demonstrated that Icosapent ethyl (IPE) added to statins significantly reduced adverse CV outcomes in these patients. The EVAPORATE trial showed a significant reduction in coronary plaque progression in the IPE arm, offering mechanistic insights to the CV benefits of IPE. Circulating ceramide (CER) levels and CER ratios are important predictors of coronary plaque instability, progression, and adverse CV risk. Objective/Purpose We sought to compare the effect of IPE vs placebo on ceramide scores and ratios in participants enrolled in EVAPORATE trial. We further assessed correlations between CER levels and changes in coronary plaque burden and characteristics. Methods EVAPORATE is a randomized, placebo-controlled trial, using CCTA to evaluate the effects of IPE as an adjunct to statins on coronary plaque progression in a cohort with elevated triglycerides, over 18 months. A total of 63 participants from the EVAPORATE trial were included. Changes in serum levels of CER species, ratios, and scores were compared between patients receiving IPE vs placebo. Spearman's correlation was used to examine association of ceramide scores and changes in coronary plaque volumes. Results CER ratios and scores were similar between the groups at baseline. In the IPE group, the CER score was 4.27 (SD 3.02) at baseline and was 4.00 (SD 3.05) at follow-up (p=0.55). At 18 month follow-up, there was a significant increase in CER ratios, CER 16:0/24:0 and CER 18:0/24:0, in the placebo group (p=0.0018; p=0.0076, respectively), compared to no significant change in the IPE group (p=0.85; p=0.37, respectively). Changes in CER score did not correlate with changes in total plaque volumes in either group (IPE (r=0.326), placebo (r=-0.295) (p>0.05). Conclusions There were significant differences in the CER ratios in the IPE arm vs placebo arm in the EVAPORATE trial, as well as a trend to lowered CER score in the IPE group. Future studies are warranted to further characterize correlations of IPE and CER. Nothing to disclose.

Mysterious Case of Reduction in HDL Cholesterol in a Patient with B-cell Monocytosis

<h3>Lead Author's Financial Disclosures</h3> Nothing to disclose. <h3>Study Funding</h3> None. <h3>Background/Synopsis</h3> We review a clinical scenario involving a 66-year-old male seen in clinic for acute change in clinical status. This is intended to highlight reduction in HDL levels associated with progressive anemia, thrombocytopenia, and splenomegaly suspicious for B-cell predominant lymphoma. <h3>Objective/Purpose</h3> To review the relationship of HDL cholesterol levels and inflammatory states suspected for lymphoma and its impact on clinical management. <h3>Methods</h3> In addition to close follow-up at primary care clinic, he was referred to hematology for further evaluation for workup such as bone marrow biopsy. <h3>Results</h3> A 66-year-old male with history of hypothyroidism, chronic kidney disease, and dyslipidemia on statin was now found to have progressive worsening fatigue over weeks along with hematologic changes such as anemia, thrombocytopenia and splenomegaly. Initial referral to hematology for clinical change did not raise any concern due to grossly borderline hematologic laboratory values. However, importantly, patient was noted to have significant acute drop of ∼40% in HDL levels during this period. This finding along with a clinical change prompted further workup from hematology revealing atypical lymphocytes observed on peripheral smear with 43.6% CD19 positive B cells with CD5 and CD10 negative on flow cytometry as well as a bone marrow and lymph node biopsy. <h3>Conclusions</h3> Cholesterol plays an integral role in structural maintenance of cell membranes, intracellular and intercellular signaling, and metabolism. Several cohort studies have shown an inverse correlation between serum HDL cholesterol levels and malignancy such as breast cancer, lymphoma and leukemia, particularly non-hodgkin's lymphoma (NHL). Based on many epidemiologic and prospective studies, it has been hypothesized that chronic inflammation may result in reduction of HDL cholesterol and perhaps may act as a potential marker of severity of systemic inflammation and inflammation-induced NHL risk. Interestingly, HDL cholesterol seems to modulate inflammatory responses independent of non-HDL cholesterol levels by inhibiting cytokine-induced expression of endothelial cell adhesion molecules and by suppressing chemotactic activity of monocytes and lymphocytes. In our clinical case, our patient may not be adequately evaluated based on borderline hematological laboratory abnormalities. However, a drastic drop (∼40%) in HDL cholesterol levels along with a change in clinical status promptly acted as a marker for further evaluation of a concerning and potentially fatal inflammatory state.

Rate of 30-day Readmission & Economic Burden of Patients with Acute Congestive Heart Failure with Co-existing Metabolic Syndrome

<h3>Lead Author's Financial Disclosures</h3> Nothing to disclose. <h3>Study Funding</h3> None. <h3>Background/Synopsis</h3> Heart failure (HF) and meta-bolic syndrome (MetS) are commonly co- exist. MetS are known to be one of the risk factors of HF, and it can also act as a comorbidity in HF. Mets is an independent risk factor for cardiovascular disease, however its impact on HF outcomes is incompletely understood. <h3>Objective/Purpose</h3> We sought to determine the 30-Day Readmission rate (30-DRr) of patients with Acute Congestive Heart Failure (aCHF) & Co-existing Metabolic Syndrome (MetS) & its impact on mortality, clinical outcomes & healthcare utilization in the United States. <h3>Methods</h3> Using the 2017 & 2018 National Readmission Database, we conducted a retrospective analysis of patient discharges with aCHF as a principal diagnosis & MetS as a secondary diagnosis according to ICD-10 codes. Readmission was defined as the first admission to any hospital for any non-trauma diagnosis within 30 days of the index admission. Same-day admissions & discharges were excluded. The primary outcome was 30DRr, while secondary outcomes were readmission mortality rate, most common diagnoses (MCD's) for readmission, & resource utilization defined by length of stay (LOS), Average & Total Patient Charge (TPC), & Average and Total Hospital Cost (THC). <h3>Results</h3> A total of 530 index hospitalization for aCHF with co-existing MetS. Index vs. Readmission Cohorts had a mean age of 62.2 years vs. 60.6 years, Males (51.6% vs. 61.1%). In- hospital mortality rate for index admission was 1.7%, while 30-DRr was 13.6% (Figure 1). Among this group of readmitted patients, in-hospital mortality rate was 2.2%, compared to index admission (2.2% vs. 1.7%, adjusted p-value=0.1). The total hospital days associated with readmission were 460 days, with a THC of $1,144,028 & TPC of $3,555,453. <h3>Conclusions</h3> In patients with aCHF & MetS, we observed a high readmission rate of ∼1 in 7 readmitted. There was subsequent higher mortality with the readmitted patient, but this was not statistically significant. Heart Failure, Acute Kidney Injury, Atrial Fibrillation, ASCVD were the most common reasons for readmission and were associated with a higher economic health care burden. A higher risk for hypertensive heart failure among MetS patients & a more significant proportion of patients with CKD & AF may indicate a higher risk for HFpEF. Comprehensive management involving a multidisciplinary team is necessary for managing patients with metabolic syndrome and heart failure to help alleviate the health care burden. Further research focusing on the HF subtypes among MetS & HF is needed to help understand specific patient populations at risk & thereby help alleviate the health care burden.

Characterization of Lipoprotein(a) Measurement in a Large US Healthcare Dataset

Lead Author's Financial Disclosures Nothing to disclose. Study Funding Family Heart Foundation. Background/Synopsis Elevated lipoprotein(a) [Lp(a)] is a well-recognized, independent risk factor for atherosclerotic cardiovascular disease (ASCVD) that is estimated to be present in 20% of the general population according to an NLA 2019 Scientific Statement, "Use of Lipoprotein(a) in Clinical Practice: A Biomarker Whose Time Has Come." Nonetheless, this genetic lipoprotein is rarely assessed. Objective/Purpose To characterize individuals receiving Lp(a) measurement and their providers using real-world data within the Family Heart Foundation integrated dataset of Americans screened or treated for ASCVD. Methods A cohort of individuals with at least one Lp(a) measurement and sufficient healthcare data was identified within an extensive dataset of >112 million individuals with laboratory data and diagnostic, procedural, and prescription claims from 2012-2019. Demographics (mean +/- standard deviation), ASCVD history, and healthcare provider at time of Lp(a) measurement were characterized. Probable familial hypercholesterolemia (FH) status was determined using a validated machine learning model. Results Lp(a) was rarely measured; 0.3% (n=335,726) of individuals had at least one Lp(a) measurement; they were aged 59.9 +/- 39.7 years, female (52.5%), Black (7.8%), Hispanic (7.1%), White (53.6%), and Other/Unknown (31.5%). Risk factors included hypertension (53.7%), hyperlipidemia (50.6%), and diabetes (24.6%). Cardiovascular history included ASCVD-only (29.1%), probable FH with ASCVD (1.2%), probable FH without ASCVD (1.7%), diagnosed FH with ASCVD (0.4%), diagnosed FH without ASCVD (0.6%), or no ASCVD or FH (70.8%). A small number of healthcare providers (n=629 of 810,119; <0.1%) were responsible for ordering the Lp(a) lab tests for 50% of individuals with a measurement; these providers most frequently specialized in internal medicine (26%), family medicine (23%), and internal medicine/CVD (14%), or were Physician Assistants & Advanced Practice Nursing Providers/Nurse Practitioner/Family (5%). Within this classification system, lipidology was not represented as a separate specialty. Conclusions Measurement of Lp(a) was rare within a large US healthcare dataset. Individuals who had Lp(a) assessed were older and had ASCVD risk factors; 31% had ASCVD. Ordering Lp(a) was concentrated within a very small number of all healthcare providers. Additional research is needed to characterize the barriers and facilitators related to ordering Lp(a) by healthcare providers for individuals with ASCVD and/or risk factors. Nothing to disclose.

Intima-media Thickness Measured at the Common-carotid Artery in Patients Treated with Lipoprotein Apheresis

<h3>Lead Author's Financial Disclosures</h3> Nothing to disclose. <h3>Study Funding</h3> None. <h3>Background/Synopsis</h3> Common carotid intima-thickness (CIMT) is as a marker of arterial wall injury and arteriosclerosis. Healthy asymptomatic young and middle-aged individuals of the European-ancestry show mean CIMT of 610 + /-110μmmicrometers with a strong linear relation between age and CIMT. In the general population, an annual rate of change in mean common CIMT is estimated at 15μm (95% CI, 12 to 17), with a median standard deviation of 53. <h3>Objective/Purpose</h3> We sought to compare annual CIMT progression rates in 10 patients with severe hypercholesterolemia treated with lipoprotein apheresis with published annual CIMT progression estimates in age-comparable 1) healthy individuals based on the nomograms, 2) patients with elevated lipoprotein(a), and 3) familial hypercholesterolemia (FH). <h3>Methods</h3> Patients (mean age 60+/-9 years, 70% female, 80% statin intolerant) were treated with the dextran sulfate adsorption apheresis system for primary and secondary atherosclerotic cardiovascular disease (ASCVD) prevention every two weeks between 2005 and 2020 (mean duration, 10+/-4 years). To minimize intra-individual and inter-individual variability in CIMT assessment we used computerized algorithms with measurements performed by the same sonographer. <h3>Results</h3> The baseline mean CIMT was 850+/-170μm and maximum CIMT was 1040+/-220um across the age range of 46 to 70 years. The baseline median levels of total cholesterol were 317 (interquartile range (IQR), 262 to 361); LDL-C, 214 (133 to 253); HDL-C, 56 (44 to 68); triglycerides, 170 (121 to 215), lipoprotein(a), 26 (9 to 120), all in mg/dL. 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 lipoprotein(a) levels, respectively. Regular treatment with lipoprotein apheresis resulted in average reduction in the mean CIMT of −40μm (IQR, −50 to 20). An annual CIMT progression rate was associated with the combined percentage reduction in the lipoprotein(a) (P=0.032) and LDL-C levels (P=0.029). Using the Bayesian Estimation Supersedes the t -Test (BEST) method, the annual rate of CIMT progression was compared to those reported in the literature (Table 1). <h3>Conclusions</h3> Composite CIMT progression rates were slowed with lipoprotein apheresis. In this cohort of high-risk patients with poor statin tolerance, the use of CIMT surveillance was noted to increase compliance with long-term lipid-modifying therapies in the clinical setting.

*An Unsolved Case: FH or Sitosterolemia?

<h3>Lead Author's Financial Disclosures</h3> Nothing to disclose. <h3>Study Funding</h3> None. <h3>Background/Synopsis</h3> A 51-year-old woman with diabetes mellitus (A1c 6.7%), obesity (BMI 34), hyperlipidemia, and recurrent choledocholithiasis pending cholecystectomy, presents to UVA Prevention Clinic. Hyperlipidemia was diagnosed at age 22. Cholesterols have ranged from 290 to 520ng/dL on rosuvastatin 40mg daily. Family history was negative for premature coronary artery disease, but notable for high cholesterol in her mother and teenage child. Exam demonstrated left eyelid xanthelasma and red-yellow scaly patch on her left elbow. Labs revealed cholesterol 400ng/dL, LDL 307ng/dL, HDL 43ng/dL, triglycerides 223ng/dL, and HgA1c 6.7%. Colestipol 1mg BID and ezetimibe 10mg daily were initiated. Follow-up labs demonstrated cholesterol 284ng/dL, HDL 43ng/dL, LDL 199ng/dL and triglycerides 199ng/dL. Genetic testing for familial hypercholesteremia (FH) revealed an Increased Risk Allele on ABCG8 (c.55G>C, p.Asp19His) and a Variant of Uncertain Significance on ABCG8 f(c.275G>A, p.Ser92Asn). Subsequent sitosterol level testing, on medications, was 4.3mg/L (normal < 6.0). <h3>Objective/Purpose</h3> This abstract serves as an educational unsolved clinical vignette. <h3>Methods</h3> Sitosterolemia is an autosomal recessive disorder of lipid metabolism characterized by net increased intestinal absorption via decreased biliary excretion of plant sterols. Sitosterolemia has considerable overlap with FH but is significantly rarer1. Both cause xanthomas and premature coronary atherosclerosis sitosterolemia presentation also causes choledocholithiasis, hemolysis, splenomegaly, and arthralgia/arthritis. LDL levels in FH are consistently high whereas in sitosterolemia levels vary considerably with diet. <h3>Results</h3> Diagnostic criteria for sitosterolemia is comprised of four categories: clinical manifestations, serum sitosterol levels, exclusion of FH and cerebroteinous xanthomatosis, and pathogenic mutations. For definitive diagnosis, pathogenic mutations in ABCG5 or ABCG8 must be identified. Accurate diagnosis is changing management. Lower intake of plant sterol rich foods are recommended in sitosterolemia, foods usually considered beneficial in FH3. Ezetimibe and bile-acid sequestrants are shown to reduce sitosterol and cholesterol levels through decreased intestinal sterol absorption. <h3>Conclusions</h3> The patient described above has findings possibly consistent with sitosterolemia. Her Dutch FH score of 9, used for clinical diagnosis of FH, is consistent with definitive FH. The diagnostic dilemma has multiple potential approaches: A) Stopping colestipol and ezetimibe, liberalizing diet, and retesting sitosterol levels. B) Continuing current medications, reinforcing a traditional heart-healthy diet, and adding a PCSK-9i for presumed FH. C) Continuing current medications, adding a PCSK-9i for presumed FH, but encouraging a sitosterolemia diet low in plant sterols. D) Continuing current medications, reinforcing a sitosterolemia diet low in plant sterols, and rechecking lipids in 3-4 months.

Genetic Architecture and Cardiovascular Risk of Familial Combined Hyperlipidemia

<h3>Lead Author's Financial Disclosures</h3> Nothing to disclose. <h3>Study Funding</h3> None. <h3>Background/Synopsis</h3> Familial combined hyperlipidemia (FCHL) is one of most common inherited lipid phenotypes and is characterized by elevated plasma concentrations of apolipoprotein B-100 and triglycerides. However, many aspects of FCHL remain incompletely understood, such as its genetic basis and the magnitude of cardiovascular risk with which it is associated. <h3>Objective/Purpose</h3> The goals of this study were to investigate the genetic architecture and cardiovascular risk associated with FCHL. <h3>Methods</h3> We identified individuals with a FCHL phenotype among 349,222 unrelated participants of European ancestry in the UK Biobank using modified versions of 5 different diagnostic criteria. The prevalence of the FCHL phenotype was 11.44% (n=39,961), 5.01% (n=17,485), 1.48% (n=5,153), 1.10% (n=3,838), and 0.48% (n=1,688) according to modified versions of the Consensus Conference, Dutch, Mexico, Brunzell, and Goldstein clinical criteria, respectively. We performed discovery, case-control genome-wide association studies for these different FCHL criteria. <h3>Results</h3> We identified 175 independent loci associated with FCHL at genome-wide significance. All loci have known associations with plasma lipid levels. We investigated the combined impact of genetic and environmental risk on FCHL and found that the combination of polygenic susceptibility to hypercholesterolemia or hypertriglyceridemia and features of metabolic syndrome was associated wa ith greater prevalence of FCHL. Lastly, we observed that individuals with an FCHL phenotype had a comparable risk of incident coronary artery disease compared to individuals with monogenic Familial Hypercholesterolemia (FH) (adjusted hazard ratio vs controls [95% confidence interval]: 2.72 [2.31-3.21] and 1.90 [1.30-2.78]) <h3>Conclusions</h3> Our results suggest that, rather than being a single genetic entity, the FCHL phenotype represents a polygenic susceptibility to dyslipidemia in combination with metabolic abnormalities. Importantly, the cardiovascular of the FCHL phenotype is similar to that of monogenic FH, despite being at least 5 times more common.

Improvement in Housestaff Knowledge of Novel Antihyperglycemic Agents Through a Cross-Specialty Beyond Diabetes“Educational Initiative”

Lead Author's Financial Disclosures Nothing to disclose. Study Funding AstraZeneca Pharmaceutical Industry Company. Background/Synopsis Novel antihyperglycemic agents, including sodium-glucose cotransporter-2 inhibitors (SGLT2i) and glucagon-like-peptide-1 receptor agonists (GLP1-RA), demonstrate significant benefits in select patients with and without diabetes (T2DM). These benefits include improvements in cardiovascular, kidney and metabolic outcomes. Despite these benefits, these medications remain underutilized, attributed in part to a lack of provider knowledge across specialties. Our "Beyond-Diabetes" initiative is a health system-wide, multidisciplinary collaboration to raise awareness and prescriber utilization of these medications through a variety of informatics and educational modalities. Objective/Purpose The goal of this component of our initiative was to assess whether lecture based (grand rounds) and case-based conferences delivered via a virtual platform could improve understanding of SGLT2i and GLP1-RA among residents and fellows as part of their core curriculum. Methods We administered a 6-question electronic survey to assess knowledge of SGLT2i and GLP1-RA before and after a 1-hour, virtual case-based education that highlighted clinical uses, contraindications, dosing, adverse effects, and prescribing barriers. The housestaff were previously offered a grand rounds on the topic. The lectures and pre/post surveys were provided to internal medicine residents, as well as cardiology, nephrology, and endocrinology fellows. Efficacy was measured by analyzing the percent correct between pre/post-test questionnaires by a paired, two-sided t-test. Results After evaluating the pre-test and post-test results of the trainees, we found that among all disciplines (n = 119 pre/63 post), the average increase was 15% correct between pre-test and post-test (p-value <0.01) using random pre-test sampling. Limitations of this data include a low response rate with 28% of trainees completing the pre-test (119/418) and 53% completing the post-test (63/119). Cardiology fellows showed the greatest improvement in their overall scores with a 17% change. Endocrinology fellows had the least improvement, with a difference of 6%, likely attributable to having the highest baseline pre-test questionnaire scores. Analysis of each question showed that there was an increase in the percentage answered correctly, with the exception of one question, which had no change after education. Conclusions Our intervention demonstrates that a 1-hour virtual lecture can improve the knowledge of trainees across four disciplines regarding novel antihyperglycemic medications. This data supports the use of virtual lecture and case-based didactics to enhance provider knowledge regarding SGLT2i and GLP1-RA medications. However, further research into the most effective educational initiatives is warranted. This knowledge is essential to increase the utilization of these effective medications, which have been demonstrated to improve clinical outcomes and reduce healthcare expenditures. Nothing to disclose.

A Randomized Study to Evaluate the Effect of an Inclisiran First Implementation Strategy vs Usual Care in Patients with ASCVD and Elevated Low-density Lipoprotein Cholesterol: Rationale and Design of the VICTORION-INITIATE Trial

Lead Author's Financial Disclosures Nothing to disclose. Study Funding Novartis Pharmaceuticals Corporation, East Hanover, NJ. Background/Synopsis Most patients with atherosclerotic cardiovascular disease (ASCVD) have elevated low-density lipoprotein cholesterol (LDL-C). Compared to placebo, inclisiran has been shown to be safe, tolerable, and effective at reducing LDL-C in patients with ASCVD. It is unknown whether an inclisiran first strategy compared to usual care (allowing for changes in lipid-lowering therapy to mimic routine clinical decision-making) can improve LDL-C control in patients with ASCVD when inclisiran is added to statin therapy. Objective/Purpose Describe the rationale and design of the ongoing VICTORION-INITIATE (NCT04929249) trial. Methods VICTORION-INITIATE is a phase 3, randomized, 2-arm, parallel-group, open-label, U.S.-based trial assessing the efficacy of an inclisiran first strategy vs usual care to treat ASCVD. Patients in the inclisiran arm will receive both inclisiran and maximally tolerated statin therapy immediately upon failure to reach LDL-C less than 70 mg/dL with statins alone. Patients in the usual care arm will continue to receive maximally tolerated statin therapy and may receive other non-statin therapies per usual care. Sites were selected based on geography, population, and lipid management practices. The trial will enroll ∼444 patients (aged greater than or equal to 18 years) with established ASCVD and elevated LDL-C (greater than or equal to 70 mg/dL) or non-high-density lipoprotein cholesterol (greater than or equal to 100 mg/dL) despite receiving maximally tolerated statin therapy, fasting triglycerides less than 500 mg/dL, and an estimated glomerular filtration rate greater than 30 mL/min. The study has 6 planned visits over 330 days from screening to completion. Results Primary outcomes are percent change from baseline in LDL-C and proportion of patients discontinuing statins during the 330-day trial. Key secondary outcomes include the proportion of patients achieving prespecified LDL-C targets, proportion of patients achieving greater than or equal to 50% LDL-C reductions, absolute and time-averaged changes in LDL-C, changes in other lipids, changes in and adherence to ongoing lipid-lowering therapy, visit-to-visit variability in LDL-C, and inclisiran safety and tolerability. Conclusions VICTORION-INITIATE is ongoing and planned to complete in early 2023. This trial aims to determine the efficacy of adding inclisiran first when maximally tolerated statin therapy fails to achieve LDL-C less than 70 mg/dL in those with ASCVD. Nothing to disclose.

Barriers and Facilitators to Identification, Cascade Testing, and Treatment for Familial Hypercholesterolemia: A Scoping Review

Lead Author's Financial Disclosures Nothing to disclose. Study Funding National Heart, Lung, and Blood Institute. Background/Synopsis Familial hypercholesterolemia (FH) is an underdiagnosed and undertreated genetic condition that results in premature cardiovascular disease. Barriers and facilitators to caring for individuals with FH exist, however, research is limited on the extent to their impact on care delivery. Objective/Purpose To determine prevalence of barriers and facilitators documented in the literature related to three aspects of FH care: identification, cascade testing, and treatment. Methods The PubMed database was searched from inception to December 1, 2021, using the following search strategy: ``familial hypercholesterolemia'' and (``barriers'' OR ``enablers'' OR ``facilitators''). Eighty-six articles were returned. Articles not mentioning barriers or facilitators, and those that were not relevant to FH, non-English, or animal studies were excluded during abstract screening. Protocol papers were excluded during full-text screening. Results Forty-six of the 86 articles (53.5%) met inclusion criteria after screening. Of these, 26 were original research, 13 were reviews, and 7 were commentaries. Upon assessment of the barriers and facilitators reported, 41% (19/46) were determined to be related to treatment only, 17% (8/46) to identification only, 15% (7/46) to cascade testing only, and 26% (12/46) were some combination of two or more aspects of care. Cost was the most prevalent barrier to FH care discussed, reported in 65% (30/46) of the articles. Other barriers included general gaps in knowledge about FH care (14/46), limited access to specialists (8/46), competing health and life priorities (6/46), and non-adherence to and/or prior authorization requirements for medication therapies (11/46). The most common facilitators discussed in the literature included access to resources (2/46), health insurance coverage for genetic testing (2/46), and assistance with the medication prior authorization process (2/46), and those that were not relevant to FH. Conclusions There is substantial literature on the barriers and facilitators to FH care that can help inform interventions. Considerable overlap among barriers and facilitators exists across all three aspects of FH care. Future interventions should target barriers reported across several studies or address combinations of identification, cascade testing, and treatment. Likewise, facilitators that have positively impacted multiple aspects of FH care should be promoted and incorporated into care delivery. Nothing to disclose.

Why Are Patients Presenting with STEMI Already on Statin Not Treated with Additional Aggressive Lipid-lowering Agents?

<h3>Lead Author's Financial Disclosures</h3> Nothing to disclose. <h3>Study Funding</h3> None. <h3>Background/Synopsis</h3> We found that 16 % of patients presenting with STEMI are on lipid-lowering therapy already, almost exclusively statin medications. Of those presenting on statin therapy, Lp(a) level was rarely measured during their hospitalization. Additional lipid-lowering therapy was also rarely prescribed. <h3>Objective/Purpose</h3> Previous data regarding lipid-lowering therapy at the time of presentation of STEMI has shown that 10-35% of patients are on some lipid-lowering medication. We sought to determine what percentage of our STEMI patients were on lipid-lowering, to see how often additional lipid-lowering therapy was recommended as well as whether other lipid disorders, such as FH or elevated Lp(a) or homocysteine levels were recognized or investigated. <h3>Methods</h3> Consecutive patients presenting with STEMI were canvased for entry lipid-lowering therapy (statin or others), as well as baseline LDL and HDL. For those entering on statin, we determined whether lipid therapy was advanced, or whether other lipid abnormalities such as elevated Lp(a) were present or even investigated. <h3>Results</h3> In 50 consecutive STEMI patients seen in one year, 16% were already on lipid-lowering therapy, almost exclusively statins, and typically atorvastatin. At least 30% should have been on lipid lowering agents based on LDL and risk level. Two patients were identified with baseline LDL meeting criteria for familial hypercholesterolemia. Baseline and follow-up after treatment LDL was 106.6 and 51.8 mg/dl respectively. For HDL, baseline was 39.5 and follow-up was 42.3 mg/dl. Of those on baseline lipid-lowering agents, additional lipid-lowering therapy was instituted only 2% of the time and Lp(a) level was drawn 1% of the time. Homocysteine levels or hypobetalipoproteinemia or other metabolic abnormalities were never assessed. <h3>Conclusions</h3> In this population of STEMI patients, aggressive additional lipid-lowering when patients are already on therapy should be instituted and other lipid abnormalities should be sought after.

Unique Case of Management of Severe Hypertriglyceridemia Secondary to Familial Chylomicronemia Syndrome

<h3>Lead Author's Financial Disclosures</h3> Nothing to disclose. <h3>Study Funding</h3> None. <h3>Background/Synopsis</h3> We review a case of a 61-year-old female diagnosed at age 21 with severe hypertriglyceridemia with debilitating, recurrent episodes of acute pancreatitis. <h3>Objective/Purpose</h3> To review a clinical scenario involving severe hypertriglyceridemia and the role of novel therapies in management. <h3>Methods</h3> Clinical management at tertiary care lipid program. <h3>Results</h3> A 61-year-old slightly overweight female with a history of congenital aplasia of the pancreas, coronary artery disease post stents, pre-diabetes, and non-alcoholic fatty liver disease was diagnosed with severe hypertriglyceridemia secondary to chylomicronemia syndrome at age 21. No secondary causes were identified. She was trialed on several cholesterol and triglyceride lowering medications including niacin, rosuvastatin, gemfibrozil, fenofibrate, fish oil supplements with minimal improvement in symptoms and/or reduction in recurrent hospitalizations for acute pancreatitis. Interestingly, she showed a dramatic ∼70% reduction in triglycerides on evinacumab based on compassionate use, resulting in significant improvement in quality of life with no episodes of acute pancreatitis while on therapy for 12 months. <h3>Conclusions</h3> Familial chylomicronemia syndrome (FCS) is an autosomal recessive disorder with a lack of lipoprotein lipase (LPL) functionality, thereby markedly impairing clearance of chylomicrons from the plasma. The primary reason for concern is an increased risk of acute pancreatitis with an estimated odds ratio of 360 in patients with FCS. Acute pancreatitis, in fact, is responsible for a significant economic burden in the United States with an estimated annual cost of care of over $2 billion, accounting for about 50% higher healthcare-related costs compared to patients without acute pancreatitis. Additionally, studies have shown that patients on statin with high residual cardiovascular risk as well as high triglycerides had higher risk for nonfatal myocardial infarction and nonfatal stroke compared to patients with normal triglycerides. Unfortunately, there are currently no FDA-approved treatments for FCS. For this reason, novel therapies are crucially needed to relieve the debilitating state of these patients. One such concept is the use of ANGPTL3 inhibitor, evinacumab, currently FDA approved for homozygous familial hypercholesterolemia. ANGPTL3 inhibition enhances the activities of endothelial lipase and lipoprotein lipase, thereby reducing levels of LDL-C independent of LDL receptor activity, HDL and triglycerides. Based on meta-analysis and a few Phase 1-2 trials, evinacumab is shown to reduce triglycerides from 50% to 80% in patients with severe hypertriglyceridemia. In our patient, with TG/TC ratio >8:1 and normal to low apoB, FCS is more likely the culprit for severe triglyceride burden, contributing to recurrent acute pancreatitis. Furthermore, our patient also suffers from mixed dyslipidemia and metabolic syndrome, which significantly raises her lifetime atherosclerotic cardiovascular risk. Thus, we propose the use of evinacumab in such patients to not only target high triglycerides to reduce risk of acute pancreatitis but also optimize overall cardiovascular risk.