Atherosclerotic cardiovascular disease (ASCVD) is the number one cause of morbidity and mortality worldwide. Low‐density lipoprotein cholesterol (LDL‐C) has been implicated as one of the major risk ...factors causing ASCVD based on multiple hierarchical levels of evidence. The advent of powerful LDL‐C lowering therapies, such as the proprotein convertase subtilisin/kexin type 9 inhibitor, have raised the question of how low to target LDL‐C and whether there are any adverse safety events associated with a very low LDL‐C level. The present review summarizes the available evidence and concludes that even a very low LDL‐C is associated with cardiovascular benefit, although the magnitude of benefit depends on baseline ASCVD risk and the absolute change in LDL‐C with pharmacologic therapy. The safety data in patients treated for very low LDL‐C is reassuring, although it is inconsistent and requires longer term follow‐up.
Lomitapide is a lipid-lowering agent indicated as adjunct therapy for homozygous familial hypercholesterolemia (HoFH) in adults.
The Lomitapide Observational Worldwide Evaluation Registry is an ...international, observational registry assessing long-term safety, tolerability, and effectiveness of lomitapide.
This analysis examines 5-year data from the registry up to February 28, 2019.
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.
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.
•The Lomitapide Observational Worldwide Evaluation Registry (LOWER) reports data on 187 patients with homozygous familial hypercholesterolemia, the largest cohort to date.•Risk benefit profile is unchanged; no new safety signals were identified in LOWER.•LOWER reported a global median dose of 10 mg/d vs 40 mg/d in pivotal trials•33% mean reduction in low-density lipoprotein cholesterol (LDL-C) (45% in patients remaining on lomitapide).•65.4% reached LDL-C <100 mg/dL, and 41.1% achieved LDL-C <70 mg/dL at any time point.
Purpose of Review
Many guidelines exist for the use of statins in the primary prevention of atherosclerotic cardiovascular disease (ASCVD). Few have focused on disease specific states that predispose ...to ASCVD. This review is intended to focus on the recommendations and evidence in inflammatory diseases that predispose to an increased risk of ASCVD beyond what conventional cardiac risk scores would predict.
Recent Findings
Certain autoimmune inflammatory diseases such as rheumatoid arthritis (RA), systemic lupus erythematous (SLE), and psoriasis/psoriatic arthritis have all been shown to increase the risk of ASCVD. Other diseases such as human immunodeficiency virus (HIV) and mediastinal radiation have also been correlated with increased ASCVD. In RA and HIV, the evidence suggests a benefit to added statin therapy and society guidelines favor early initiation. The evidence for statin therapy in RA is limited to observational studies with small secondary analysis. In HIV, there is a large ongoing clinical trial to assess efficacy. In those with psoriasis and psoriatic arthritis, there is limited evidence for or against statin therapy independent of a calculated cardiac risk score. Finally, in SLE and in those with exposure to mediastinal radiation, cardiac events remain high, but evidence is limited on the beneficial effects of statin therapy.
Summary
There are many individuals who have an increased risk for ASCVD above what is predicted from a cardiac risk score. It would be beneficial to create risk prediction models with statin therapy recommendations that are tailored to those predisposed to accelerated atherosclerosis.
The proprotein convertase subtilisin/kexin type 9 inhibitors or monoclonal antibodies likely represent the greatest advance in lipid management in 30 years. In 2015 the US Food and Drug ...Administration approved both alirocumab and evolocumab for high‐risk patients with familial hypercholesterolemia (FH) and clinical atherosclerotic cardiovascular disease requiring additional lowering of low‐density lipoprotein cholesterol. Though many lipid specialists, cardiovascular disease prevention experts, endocrinologists, and others prescribed the drugs on label, they found their directives denied 80% to 90% of the time. The high frequency of denials prompted the American Society for Preventive Cardiology (ASPC), to gather multiple stakeholder organizations including the American College of Cardiology, National Lipid Association, American Association of Clinical Endocrinologists (AACE), and FH Foundation for 2 town hall meetings to identify access issues and implement viable solutions. This article reviews findings recognized and solutions suggested by experts during these discussions. The article is a product of the ASPC, along with each author writing as an individual and endorsed by the AACE.
Abstract An Expert Panel convened by the National Lipid Association was charged with updating the recommendations on the use of proprotein convertase subtilisin/kexin type 9 (PCSK9) antibody therapy ...that were provided by the 2015 National Lipid Association Recommendations for the Patient-Centered Management of Dyslipidemia: Part 2. Recent studies have demonstrated the efficacy of these agents in reducing low-density lipoprotein cholesterol and non–high-density lipoprotein cholesterol and have confirmed their excellent safety profile. A cardiovascular outcomes study has shown that these agents reduce incident atherosclerotic cardiovascular disease (ASCVD) events in patents with stable ASCVD and concomitant risk factors. The current update provides the Expert Panel's evidence-based recommendations on the clinical utility of PCSK9 inhibitors in patients with stable ASCVD, progressive ASCVD, LDL-C ≥ 190 mg/dL (including polygenic hypercholesterolemia, heterozygous familial hypercholesterolemia and the homozygous familial hypercholesterolemia phenotype) and very-high-risk patients with statin intolerance.
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 (
=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% (
=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
<0.001). EPA+DPA-FFA increased docosahexaenoic acid by 1.7%; EPA-EE decreased docosahexaenoic acid by 3.3% (
=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.
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.
•In selected patients, genetic testing can help in diagnosis and management.•Pursuit of genetic testing must weigh potential benefits, risks, and patient preference.•Genetic counseling is recommended before and after genetic testing.•Understanding limitations of genetic testing is central to deriving the greatest benefit.
Calcium is the dominant mineral present in bone and a shortfall nutrient in the American diet. Supplements have been recommended for persons who do not consume adequate calcium from their diet as a ...standard strategy for the prevention of osteoporosis and related fractures. Whether calcium with or without vitamin D supplementation is beneficial or detrimental to vascular health is not known.
The National Osteoporosis Foundation and American Society for Preventive Cardiology convened an expert panel to evaluate the effects of dietary and supplemental calcium on cardiovascular disease based on the existing peer-reviewed scientific literature. The panel considered the findings of the accompanying updated evidence report provided by an independent evidence review team at Tufts University.
The National Osteoporosis Foundation and American Society for Preventive Cardiology adopt the position that there is moderate-quality evidence (B level) that calcium with or without vitamin D intake from food or supplements has no relationship (beneficial or harmful) to the risk for cardiovascular and cerebrovascular disease, mortality, or all-cause mortality in generally healthy adults at this time. In light of the evidence available to date, calcium intake from food and supplements that does not exceed the tolerable upper level of intake (defined by the National Academy of Medicine as 2000 to 2500 mg/d) should be considered safe from a cardiovascular standpoint.
Purpose
This systematic review was performed to summarize published experience using low density lipoprotein particle number (LDL-P) to monitor the efficacy of lipid-lowering pharmacotherapies.
...Methods
Studies were identified from a literature search of MEDLINE (January 1, 2000 – June 30, 2012); and abstract searches of select conferences. All accepted studies reported mean (or median) nuclear magnetic resonance (NMR)-based LDL-P values for at least 10 subjects receiving lipid lowering pharmacotherapy.
Results
Searches revealed 36 studies (with 61 treatment arms) in which LDL-P measurements were reported pre- and post-treatment. Most studies also reported changes in low-density lipoprotein cholesterol (LDL-C), but fewer studies reported changes in apolipoprotein B (apoB)(
n
= 20) and non-HDL-C (
n
= 28). Treatments included statins (22 arms/15 studies), fibrates (7 arms/7studies), niacin (7 arms/6 studies), bile acid sequestrants (5 arms/2 studies), an anti-apoB oligonucleotide (2 arms/2 studies), combination therapies (8 arms/6 studies), anti-diabetics (5 arms/4 studies), and, other treatments (5 arms/2 studies). Lipid-lowering pharmacotherapy resulted in reductions in mean LDL-P in all but two studies. In several statin studies, the percent reductions in LDL-P were smaller than reductions in LDL-C, comparable changes were reported when LDL-P and apoB, were reported.
Conclusions
Study-level data from this systemic review establish that different lipid lowering agents can lead to discordance between LDL-P and LDL-C, therefore, basing LDL-lowering therapy only on the achievement of cholesterol goals may result in a treatment gap. Therefore, the use of LDL-P for monitoring lipid-lowering therapy, particularly for statins, can provide a more accurate assessment of residual cardiovascular risk.
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