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Contemporary Homozygous Familial Hypercholesterolemia in the United States: Insights From the CASCADE FH Registry

Cuchel, Marina; Lee, Paul C; Hudgins, Lisa C; Duell, P Barton; Ahmad, Zahid; Baum, Seth J; Linton, MacRae F; de Ferranti, Sarah D; Ballantyne, Christie M; Larry, John A; Hemphill, Linda C; Kindt, Iris; Gidding, Samuel S; Martin, Seth S; Moriarty, Patrick M; Thompson, Paul P; Underberg, James A; Guyton, John R; Andersen, Rolf L; Whellan, David J; Benuck, Irwin; Kane, John P; Myers, Kelly; Howard, William; Staszak, David; Jamison, Allison; Card, Mary C; Bourbon, Mafalda; Chora, Joana R; Rader, Daniel J; Knowles, Joshua W; Wilemon, Katherine; McGowan, Mary P
Background Homozygous familial hypercholesterolemia (HoFH) is a rare, treatment-resistant disorder characterized by early-onset atherosclerotic and aortic valvular cardiovascular disease if left untreated. Contemporary information on HoFH in the United States is lacking, and the extent of underdiagnosis and undertreatment is uncertain. Methods and Results Data were analyzed from 67 children and adults with clinically diagnosed HoFH from the CASCADE (Cascade Screening for Awareness and Detection) FH Registry. Genetic diagnosis was confirmed in 43 patients. We used the clinical characteristics of genetically confirmed patients with HoFH to query the Family Heart Database, a US anonymized payer health database, to estimate the number of patients with similar lipid profiles in a "real-world" setting. Untreated low-density lipoprotein cholesterol levels were lower in adults than children (533 versus 776 mg/dL; P=0.001). At enrollment, atherosclerotic cardiovascular disease and supravalvular and aortic valve stenosis were present in 78.4% and 43.8% and 25.5% and 18.8% of adults and children, respectively. At most recent follow-up, despite multiple lipid-lowering treatment, low-density lipoprotein cholesterol goals were achieved in only a minority of adults and children. Query of the Family Heart Database identified 277 individuals with profiles similar to patients with genetically confirmed HoFH. Advanced lipid-lowering treatments were prescribed for 18%; 40% were on no lipid-lowering treatment; atherosclerotic cardiovascular disease was reported in 20%; familial hypercholesterolemia diagnosis was uncommon. Conclusions Only patients with the most severe HoFH phenotypes are diagnosed early. HoFH remains challenging to treat. Results from the Family Heart Database indicate HoFH is systemically underdiagnosed and undertreated. Earlier screening, aggressive lipid-lowering treatments, and guideline implementation are required to reduce disease burden in HoFH.
PMID: 37119068
ISSN: 2047-9980
CID: 5465712

JCL Roundtable: From Gen Med to Clinical Lipidology

Willard, Kaye-Eileen; Soffer, Daniel; Underberg, James A; Guyton, John R
The prevalence of lipid-related risk for atherosclerotic cardiovascular disease surpasses half the population as individuals age, and thus generalists and primary care providers manage by far the bulk of treatment of lipid disorders. It should come as no surprise that many individuals who practice clinical lipidology, focusing on the care of patients with resistant or perplexing lipid disorders, come from a background of general or primary care medicine. Among 429 providers responding to a survey of National Lipid Association (NLA) members in 2010, 50% were internal medicine or family medicine practitioners, 32% cardiologists, 11% endocrinologists, and 7% with a variety of other specialty training. This JCL Roundtable brings together 3 NLA physician leaders who came from primary care. We discuss their career pathways, their blend of practice, teaching, research, and administration, and the settings in which they carry out the lipidology mission.
PMID: 36965957
ISSN: 1933-2874
CID: 5463002

LDL-C target attainment in secondary prevention of ASCVD in the United States: barriers, consequences of nonachievement, and strategies to reach goals

Underberg, James; Toth, Peter P; Rodriguez, Fatima
Atherosclerotic cardiovascular disease (ASCVD) is the leading cause of death in the United States. Elevated low-density lipoprotein cholesterol (LDL-C) is a major causal risk factor for ASCVD. Current evidence overwhelmingly demonstrates that lowering LDL-C reduces the risk of secondary cardiovascular events in patients with previous myocardial infarction or stroke. There is no lower limit for LDL-C: large, randomized studies and meta-analyses have found continuous benefit and no safety concerns in patients achieving LDL-C levels <25 mg/dL. As 'Time is plaque' in patients with ASCVD, early, sustained reductions in LDL-C are critical to slow or halt disease progression. However, despite use of lipid-lowering medications, <30% of patients with ASCVD achieve guideline-recommended reductions in LDL-C, resulting in a substantial societal burden of preventable cardiovascular events and early mortality. LDL-C goals are not met due to several factors: lipid-lowering therapy is not initiated and intensified as directed by clinical guidelines (clinical inertia); most patients do not adhere to prescribed medications; and high-risk patients are frequently denied access to add-on therapies by their insurance providers. Promoting patient and clinician education, multidisciplinary collaboration, and other interventions may help to overcome these barriers. Ultimately, achieving population-level guideline-recommended reductions in LDL-C will require a collaborative effort from patients, clinicians, relevant professional societies, drug manufacturers, and payers.
PMID: 36004573
ISSN: 1941-9260
CID: 5338352

A Head-to-Head Comparison of a Free Fatty Acid Formulation of Omega-3 Pentaenoic Acids Versus Icosapent Ethyl in Adults With Hypertriglyceridemia: The ENHANCE-IT Study

Maki, Kevin C; Bays, Harold E; Ballantyne, Christie M; Underberg, James A; Kastelein, John J P; Johnson, Judith B; Ferguson, James J
Background MAT9001 is an omega-3 free fatty acid (FFA) formulation containing mainly eicosapentaenoic acid (EPA) and docosapentaenoic acid (DPA). Compared with icosapent ethyl (EPA-ethyl esters [EE]), EPA+DPA-FFA previously showed enhanced triglyceride lowering and higher plasma EPA when both were administered once daily with a very-low fat diet. This trial compared pharmacodynamic responses and plasma omega-3 levels following twice daily dosing, with meals, of EPA+DPA-FFA and EPA-EE in hypertriglyceridemic subjects consuming a Therapeutic Lifestyle Changes diet. Methods and Results This open-label, randomized, 2-way crossover trial, with 28-day treatment periods separated by ≥28-day washout, was conducted at 8 US centers and included 100 subjects with fasting triglycerides 1.70 to 5.64 mmol/L (150-499 mg/dL) (median 2.31 mmol/L [204 mg/dL]; 57% women, average age 60.3 years). The primary end point was least squares geometric mean percent change from baseline plasma triglycerides. In the 94 subjects with analyzable data for both treatment periods, EPA+DPA-FFA and EPA-EE reduced least squares geometric mean triglycerides from baseline: 20.9% and 18.3%, respectively (P=not significant). EPA+DPA-FFA reduced least squares geometric mean high-sensitivity C-reactive protein by 5.8%; EPA-EE increased high-sensitivity C-reactive protein by 8.5% (P=0.034). EPA+DPA-FFA increased least squares geometric mean plasma EPA, DPA, and total omega-3 (EPA+docosahexaenoic acid+DPA) concentrations by 848%, 177%, and 205%, respectively, compared with corresponding changes with EPA-EE of 692%, 140%, and 165% (all P<0.001). EPA+DPA-FFA increased docosahexaenoic acid by 1.7%; EPA-EE decreased docosahexaenoic acid by 3.3% (P=0.011). Lipoprotein cholesterol and apolipoprotein responses did not differ between treatments. Conclusions EPA+DPA-FFA raised plasma EPA, DPA, and total omega-3 significantly more than did EPA-EE. EPA+DPA-FFA also reduced triglycerides and high-sensitivity C-reactive protein without increasing low-density lipoprotein cholesterol. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT04177680.
PMID: 35232215
ISSN: 2047-9980
CID: 5174372

JCL Roundtable: Global Think Tank on Lipoprotein(a)

Maher, Lisa L; TokgözoÄŸlu, S Lale; Sanchez, Eduardo J; Underberg, James A; Guyton, John R
Lipoprotein(a) operates in causal pathways to promote atherosclerosis, arterial thrombosis, and aortic stenosis. It has been associated with rare cases of nonatherosclerotic arterial thrombotic stroke at any age. Inherited variation of lipoprotein(a) levels substantially increases cardiovascular risk in 20% of people worldwide. Recent progress in identifying the risk associated with lipoprotein(a) and in pursuing effective treatment has led to a recent Global Think Tank including representatives from the European Atherosclerosis Society, American Heart Association, Preventive Cardiovascular Nurses Association, National Lipid Association, and other groups. The need for standardized laboratory measurement in nanomoles per liter met with unanimous consensus. Atherosclerotic risk is linearly associated with plasma lipoprotein(a) levels, so that persons with the highest levels may have risk similar to other severe inherited lipoprotein disorders. Universal once-in-lifetime screening has been recommended by European and Canadian cardiovascular societies, but not by U.S. organizations. Current pharmacologic therapies are limited to 20-30% lowering of lipoprotein(a) levels, and no pharmacologic treatment for lowering lipoprotein(a) has yet been proven to reduce risk in a cardiovascular outcomes trial. Treatment for high-risk patients focuses on reducing low density lipoprotein cholesterol and other risk factors. New therapies targeting messenger RNA for apolipoprotein(a) can achieve 80-90% reduction of lipoprotein(a) levels. One such therapy using a liver-directed antisense oligonucleotide is currently being tested in a large cardiovascular outcomes trial. Increased recognition of lipoprotein(a)-associated risk and emergence of potentially effective therapy together lead to a mandate for a unified global effort on education, standardization, and clinical management.
PMID: 34144765
ISSN: 1933-2874
CID: 4924682

Characterization of PCSK9 in the Blood and Skin of Psoriasis

Garshick, Michael S; Baumer, Yvonne; Dey, Amit K; Grattan, Ryan; Ng, Qimin; Teague, Heather L; Yu, Zu-Xi; Chen, Marcus Y; Tawil, Michael; Barrett, Tessa J; Underberg, James; Fisher, Edward A; Krueger, James; Powell-Wiley, Tiffany M; Playford, Martin P; Berger, Jeffrey S; Mehta, Nehal N
Mechanisms explaining the link between psoriasis, a proinflammatory condition, and cardiovascular disease are not fully known. PCSK9 is predominantly expressed in hepatocytes as a critical regulator of lipid metabolism, and clinical trials targeting PCSK9 reduce cardiovascular disease. Independent of its role in lipid metabolism, PCSK9 levels associate with endothelial dysfunction and predict cardiovascular events. We used two separate human psoriasis cohorts and the K14-Rac1V12-/+ murine model of psoriasis to investigate PCSK9 and cardiovascular risk in psoriasis. In both psoriasis cohorts (n = 88 and n = 20), PCSK9 levels were 20% and 13% higher than in age-, sex-, and cholesterol-matched controls, respectively (P < 0.05 for each comparison) and correlated with PASI (r = 0.43, P < 0.05). Despite no difference in hepatocyte expression, K14-Rac1V12-/+ mice demonstrated skin-specific PCSK9 staining, which was confirmed in human psoriatic lesional skin. In patients with psoriasis, PCSK9 levels correlated with impaired endothelial vascular health (e.g., early atherosclerosis, β = 4.5, P < 0.01) and log converted coronary artery calcium score (β = 0.30, P = 0.01), which remained significant after adjustment for Framingham risk, body mass index, and active biologic use. Taken together, these findings suggest, independent of cholesterol, an association between circulating PCSK9 and early as well as advanced stages of atherosclerosis in psoriasis.
PMID: 32615123
ISSN: 1523-1747
CID: 4580932

New cardiovascular prevention guidelines: How to optimally manage dyslipidaemia and cardiovascular risk in 2021 in patients needing secondary prevention?

Atar, Dan; Jukema, J Wouter; Molemans, Bart; Taub, Pam R; Goto, Shinya; Mach, François; CerezoOlmos, Cesar; Underberg, James; Keech, Anthony; TokgözoÄŸlu, Lale; Bonaca, Marc P
Elevated low-density lipoprotein cholesterol (LDL-C) is a principally modifiable cause of atherosclerotic cardiovascular disease; accordingly, recent European and US multisociety dyslipidaemia guidelines emphasise the importance of lowering LDL-C to reduce cardiovascular risk. This review provides perspectives on established and emerging agents that reduce LDL-C to help providers synthesize the abundance of new evidence related to prevention of cardiovascular disease. We provide hypothetical cases of patients with different cardiovascular risk factors and medical histories to illustrate application of current lipid-lowering guidelines in various clinical settings. As a core focus of preventive therapy, both European and US lipid management guidelines emphasise the importance of identifying patients at very high cardiovascular risk and treating to achieve LDL-C levels as low as possible, with European guidelines setting a goal of <1.4 mmol/L (<55 mg/dL) in patients with very high-risk cardiovascular disease. The proprotein convertase subtilisin/kexin type 9 inhibitors are now included in the guidelines and may fulfil an important unmet need for very high-risk patients who are not able to achieve LDL-C goals with conventional agents. The recently approved bempedoic acid and other promising agents under development will add to the armamentarium of lipid-lowering drugs available for clinicians to help patients meet their treatment goals.
PMID: 33476944
ISSN: 1879-1484
CID: 4771612

Long-term safety and efficacy of lomitapide in patients with homozygous familial hypercholesterolemia: Five-year data from the Lomitapide Observational Worldwide Evaluation Registry (LOWER)

Underberg, James A; Cannon, Christopher P; Larrey, Dominique; Makris, Lukas; Blom, Dirk; Phillips, Helen
BACKGROUND:Lomitapide is a lipid-lowering agent indicated as adjunct therapy for homozygous familial hypercholesterolemia (HoFH) in adults. OBJECTIVE:The Lomitapide Observational Worldwide Evaluation Registry is an international, observational registry assessing long-term safety, tolerability, and effectiveness of lomitapide. METHODS:This analysis examines 5-year data from the registry up to February 28, 2019. RESULTS:At lomitapide initiation, enrolled patients (N = 187) were a mean ± SD age of 52.2 ± 15.3 years with a mean ± SD low-density lipoprotein cholesterol (LDL-C) measurement of 232.0 ± 94.9 mg/dL. Exposure duration was up to 5.9 years (median, 1.98 years), and median dose was 10 mg (range, 5 mg QOD to 40 mg QD). After treatment, there was a mean 33% reduction in LDL-C (45% in patients remaining on lomitapide), 65.4% achieved LDL-C <100 mg/dL, and 41.1% achieved LDL-C <70 mg/dL. At year 4, the absolute mean change from baseline in LDL-C was -70.6 ± 76.21 mg/dL. Adverse events (AEs) occurred in 75.7% of patients, treatment-related AEs in 54.6%, and serious AEs in 22.2%; 23.2% of patients discontinued because of an AE. Events of special interest included gastrointestinal (13.5%), hepatic (15.1%), major adverse cardiovascular events (10.8%, resulting in 5 deaths), tumors (2.2%), and 4 pregnancies in 3 of 32 women of childbearing potential. CONCLUSION/CONCLUSIONS:The efficacy and safety of lomitapide are consistent with phase III trial data despite using a much lower median dose of 10 mg vs 40 mg in phase III. No new safety signals were identified. The incidence of AEs, serious AEs, and aminotransferase alanine transaminase elevations was lower than that seen in the phase III trial, potentially related to the lower median dose.
PMID: 33023859
ISSN: 1933-2874
CID: 4636692

Genetic testing in dyslipidemia: A scientific statement from the National Lipid Association

Brown, Emily E; Sturm, Amy C; Cuchel, Marina; Braun, Lynne T; Duell, P Barton; Underberg, James A; Jacobson, Terry A; Hegele, Robert A
The genetic basis for more than 2 dozen monogenic dyslipidemias has largely been defined. Genetic technologies, such as DNA sequencing, can detect both rare and common DNA variants underlying dyslipidemias, and these methods are increasingly available. Although patients with extreme abnormalities in low-density lipoprotein cholesterol, triglycerides, or high-density lipoprotein cholesterol may be considered for genetic testing, it is only in a minority of patients that the results will alter treatment or outcomes. Currently, there is potential clinical utility of genetic testing for familial hypercholesterolemia, familial chylomicronemia syndrome, sitosterolemia, lysosomal acid lipase deficiency, and a few other rare disorders, and this will increase the demand for reliable genetic diagnostic methods at lower cost. Clinical indications for genetic testing for most dyslipidemias are not clearly established and currently no guidelines exist. A shared decision-making model between the patient and the provider is essential as patient values and preferences play a very strong role. Potential benefits of genetic testing include providing a firm diagnosis in many cases, guiding optimal management and prevention strategies, advancing care strategies beyond currently available treatments, and contributing to overall scientific progress. Understanding the limitations and risks of genetic testing techniques is also important, as is careful interpretation of genetic test results to achieve the greatest benefit. Here we review laboratory methods, as well as technical, biological, clinical, and ethical implications and applications of genetic testing in dyslipidemias.
PMID: 32507592
ISSN: 1933-2874
CID: 4489452

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

Duell, P Barton; Gidding, Samuel S; Andersen, Rolf L; Knickelbine, Thomas; Anderson, Lars; Gianos, Eugenia; Shrader, Peter; Kindt, Iris; O'Brien, Emily C; McCann, Dervilla; Hemphill, Linda C; Ahmed, Catherine D; Martin, Seth S; Larry, John A; Ahmad, Zahid S; Kullo, Iftikhar J; Underberg, James A; Guyton, John; Thompson, Paul; Wilemon, Katherine; Roe, Matthew T; Rader, Daniel J; Cuchel, Marina; Linton, MacRae F; Shapiro, Michael D; Moriarty, Patrick M; Knowles, Joshua W
BACKGROUND AND AIMS/OBJECTIVE:There are limited data from the US on outcomes of patients in specialty care for familial hypercholesterolemia (FH). METHODS:CASCADE 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. RESULTS:The 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. CONCLUSIONS:With 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.
PMID: 31487564
ISSN: 1879-1484
CID: 4067662