Unique features of dyslipidemia in women across a lifetime and a tailored approach to management.

Purpose of Review: Cardiovascular disease is a leading cause of death worldwide. Dyslipidemia is a critical modifiable risk factor for the prevention of cardiovascular disease. Dyslipidemia affects a large population of women and is especially pervasive within racial/ethnic minorities. Recent Findings: Dyslipidemia in pregnancy leads to worse outcomes for patients and creates increased cardiovascular risk for women at an older age. However, women remain underscreened and undertreated compared to men. Females also comprise a small portion of clinical trial participants for lipid lowering agents with increased disease prevalence compared to trial representation. However, recent lipid trials have shown different efficacies of therapies such as ezetimibe, inclisiran, and bempedoic acid with a greater relative benefit for women. Summary: Pathophysiology of dyslipidemia varies between men and women and across a woman's lifetime. While increased lipid levels or lipid imbalances are more common in postmenopausal women over age 50, conditions such as PCOS and FH produce higher cardiovascular risk for young women.Best practices for management of women with dyslipidemia include early screening with lifestyle intervention and pharmacotherapy with statin and non-statin agents to achieve guideline directed LDL-C thresholds.

A focused update to the 2019 NLA scientific statement on use of lipoprotein(a) in clinical practice.

Since the 2019 National Lipid Association (NLA) Scientific Statement on Use of Lipoprotein(a) in Clinical Practice was issued, accumulating epidemiological data have clarified the relationship between lipoprotein(a) [Lp(a)] level and cardiovascular disease risk and risk reduction. Therefore, the NLA developed this focused update to guide clinicians in applying this emerging evidence in clinical practice. We now have sufficient evidence to support the recommendation to measure Lp(a) levels at least once in every adult for risk stratification. Individuals with Lp(a) levels <75 nmol/L (30 mg/dL) are considered low risk, individuals with Lp(a) levels ≥125 nmol/L (50 mg/dL) are considered high risk, and individuals with Lp(a) levels between 75 and 125 nmol/L (30-50 mg/dL) are at intermediate risk. Cascade screening of first-degree relatives of patients with elevated Lp(a) can identify additional individuals at risk who require intervention. Patients with elevated Lp(a) should receive early, more-intensive risk factor management, including lifestyle modification and lipid-lowering drug therapy in high-risk individuals, primarily to reduce low-density lipoprotein cholesterol (LDL-C) levels. The U.S. Food and Drug Administration approved an indication for lipoprotein apheresis (which reduces both Lp(a) and LDL-C) in high-risk patients with familial hypercholesterolemia and documented coronary or peripheral artery disease whose Lp(a) level remains ≥60 mg/dL [∼150 nmol/L)] and LDL-C ≥ 100 mg/dL on maximally tolerated lipid-lowering therapy. Although Lp(a) is an established independent causal risk factor for cardiovascular disease, and despite the high prevalence of Lp(a) elevation (∼1 of 5 individuals), measurement rates are low, warranting improved screening strategies for cardiovascular disease prevention.

Harnessing RNA Interference for Cholesterol Lowering: The Bench-to-Bedside Story of Inclisiran.

Lowering low-density lipoprotein cholesterol (LDL-C) is a cornerstone of reducing risk for atherosclerotic cardiovascular disease. Despite the approval of nonstatin therapies for LDL-C lowering over the past 2 decades, these medications are underused, and most patients are still not at guideline-recommended LDL-C goals. Barriers include poor adherence, clinical inertia, concern for side effects, cost, and complex prior authorization processes. With atherosclerotic cardiovascular disease-related mortality increasing globally, there remains a need for additional therapeutic options for lowering LDL-C as part of an atherosclerotic cardiovascular disease prevention strategy. Following the identification of PCSK9 (proprotein convertase subtilisin/kexin type 9) as a promising therapeutic target, inclisiran was developed using the natural process of RNA interference for robust, sustained prevention of hepatic PCSK9 synthesis. Twice-yearly maintenance subcutaneous inclisiran (following initial loading doses at Day 1 and Day 90) reduces circulating LDL-C levels by ≈50% versus placebo when added to maximally tolerated statins. Long-term safety and tolerability of inclisiran have been assessed, with studies underway to evaluate the effects of inclisiran on cardiovascular outcomes and to provide additional safety and effectiveness data. In 2021, <20 years after the discovery of PCSK9, inclisiran became the first RNA interference therapeutic approved in the United States for LDL-C lowering in patients with established atherosclerotic cardiovascular disease or familial hypercholesterolemia and has since been approved for use in patients with primary hyperlipidemia. This article reviews the journey of inclisiran from bench to bedside, including early development, the clinical trial program, key characteristics of inclisiran, and practical points for its use in the clinic.

Is Lipoprotein(a) Clinically Actionable with Today's Evidence? The Answer is Yes.

PURPOSE OF REVIEW: Lipoprotein(a) is an independent risk factor for cardiovascular disease. We review the ongoing shifts in consensus guidelines for the testing and management of Lp(a) and provide insight into whether current evidence suggests that awareness and testing of Lp(a) is clinically actionable. RECENT FINDINGS: GWAS and Mendelian randomization studies have established causal links between elevated Lp(a) and forms of CVD, including CAD and calcific aortic valve disease. Testing of Lp(a) identifies patients with similar risk to that of heterozygous FH, enhances risk stratification in patients with borderline/intermediate risk as determined through traditional factors, and facilitates the assessment of inherited CVD risk through cascade screening in patients with known family history of elevated Lp(a). Reductions in Lp(a) through non-targeted therapies including PCSK9 inhibition and lipoprotein apheresis have demonstrated reductions in ASCVD risk that are likely attributable to lowering Lp(a). Targeted therapies to potently lower Lp(a) are in clinical development. Lp(a) is actionable, and can be used to identify high risk patients for primary prevention and their family members through cascade screening, and to guide intensification of therapy in primary and secondary prevention of ASCVD.

Evolving Management of Low-Density Lipoprotein Cholesterol: A Personalized Approach to Preventing Atherosclerotic Cardiovascular Disease Across the Risk Continuum.

Management of elevated low-density lipoprotein cholesterol (LDL-C) is central to preventing atherosclerotic cardiovascular disease (ASCVD) and key to reducing the risk of ASCVD events. Current guidelines on the management of blood cholesterol recommend statins as first-line therapy for LDL-C reduction according to an individual's ASCVD risk and baseline LDL-C levels. The addition of nonstatin lipid-lowering therapy to statins to achieve intensive LDL-C lowering is recommended for patients at very high risk of ASCVD events, including patients with familial hypercholesterolemia who have not achieved adequate LDL-C lowering with statins alone. Despite guideline recommendations and clinical trial evidence to support the use of lipid-lowering therapies for ASCVD risk reduction, most patients at high or very high risk do not meet LDL-C thresholds. This review explores the challenges associated with LDL-C lowering in contemporary clinical practice and proposes a framework for rethinking the binary definition of ASCVD, shifting from "primary" versus "secondary" prevention to a "continuum of risk." The approach considers the role of plaque burden and progression in subclinical disease and emphasizes the importance of early risk assessment and treatment for preventing first cardiovascular events. Patients at high risk of ASCVD events who require significant LDL-C lowering should be considered for combination therapies comprising statin and nonstatin agents. Practical guidance for the pharmacological management of elevated LDL-C, both now and in the future, is provided.

Trends in LDL-C following coronary angiography involving assessment by fractional flow reserve in obstructive vs non-obstructive coronary artery disease.

Background: We sought to determine whether management of LDL-C following invasive angiography and assessment by fractional flow reserve (FFR) differs between those with obstructive vs non-obstructive CAD. Methods: Retrospective study of 721 patients undergoing coronary angiography involving assessment by FFR between 2013 and 2020 at a single academic center. Groups with obstructive vs non-obstructive CAD by index angiographic and FFR findings were compared over 1 year of follow-up. Results: Based on index angiographic and FFR findings, 421 (58%) patients had obstructive CAD vs 300 (42%) with non-obstructive CAD, mean (±SD) age 66±11 years, 217 (30%) women, and 594 (82%) white. There was no difference in baseline LDL-C. At 3-months follow-up, LDL-C was lower than baseline in both groups, with no between group difference. In contrast, at 6-months, median (Q1, Q3) LDL-C was significantly higher in non-obstructive vs obstructive CAD (LDL-C 73 (60, 93) vs 63 (48, 77) mg/dL, respectively (p = 0.003), (p = 0.001 in multivariable linear regression)). At 12-months, LDL-C remained higher in non-obstructive vs obstructive CAD (LDL-C 73 (49, 86) vs 64 (48, 79) mg/dL, respectively, although not statistically significant (p = 0.104)). The rate of high-intensity statin use was lower among those with non-obstructive CAD vs obstructive CAD at all time points (p < 0.05). Conclusions: After coronary angiography involving FFR, there is intensification of LDL-C lowering at 3-months follow-up in both obstructive and non-obstructive CAD. However, by 6-months follow-up LDL-C is significantly higher among those with non-obstructive CAD vs obstructive CAD. Following coronary angiography involving FFR, patients with non-obstructive CAD may benefit from greater attention to LDL-C lowering to reduce residual ASCVD risk.

Inclisiran creates unique opportunities and challenges for patient access to therapy: early experience in a United States Lipid Clinic.

We report an early experience with inclisiran, an siRNA targeting PCSK9 administered by a healthcare professional, in an academic lipid clinic. 37 patients were prescribed inclisiran, age (mean±SD) 66±13 years, 26 (70%) women, 32 (87%) White, LDL-C 113±62 mg/dL, 18 (49%) with ASCVD and 19 (51%) with HeFH. Most patients were referred to alternate injection centers. Inclisiran was approved by insurance for 25 (68%), denied for 9 (24%), with 3 under review. While 100% of patients with Medicare obtained access to inclisiran, only 3 of 12 (25%) patients with non-Medicare insurance received approval. Approved patients were older (72±8 vs 52±13 years, p<0.001), disproportionately Medicare enrollees (88%, p<0.001), less had HeFH (40% vs 89%, p=0.019), more had ASCVD (60% vs 11%, p=0.019), less were on a statin (28% vs 78%, p=0.017), and pre-treatment LDL-C was higher (121±65 vs 77±40 mg/dL, p=0.039). These findings have implications for the future of inclisiran in the U.S. and whether inclisiran can be made more accessible, including to younger patients with non-Medicare insurance.

Risk of advanced fibrosis in first-degree relatives of patients with nonalcoholic fatty liver disease.

BACKGROUNDA pilot, single-center study showed that first-degree relatives of probands with nonalcoholic fatty liver disease (NAFLD) cirrhosis have a high risk of advanced fibrosis. We aimed to validate these findings using 2 independent cohorts from the US and Europe.METHODSThis prospective study included probands with NAFLD with advanced fibrosis, NAFLD without advanced fibrosis, and non-NAFLD, with at least 1 first-degree relative. A total of 396 first-degree relatives - 220 in a derivation cohort and 176 in a validation cohort - were enrolled in the study, and liver fibrosis was evaluated using magnetic resonance elastography and other noninvasive imaging modalities. The primary outcome was prevalence of advanced fibrosis in first-degree relatives.RESULTSPrevalence of advanced fibrosis in first-degree relatives of probands with NAFLD with advanced fibrosis, NAFLD without advanced fibrosis, and non-NAFLD was 15.6%, 5.9%, and 1.3%, respectively (P = 0.002), in the derivation cohort, and 14.0%, 2.6%, and 1.3%, respectively (P = 0.004), in the validation cohort. In multivariable-adjusted logistic regression models, age of ≥50 years (adjusted OR [aOR]: 2.63, 95% CI 1.0-6.7), male sex (aOR: 3.79, 95% CI 1.6-9.2), diabetes mellitus (aOR: 3.37, 95% CI 1.3-9), and a first-degree relative with NAFLD with advanced fibrosis (aOR: 11.8, 95% CI 2.5-57) were significant predictors of presence of advanced fibrosis (all P < 0.05).CONCLUSIONFirst-degree relatives of probands with NAFLD with advanced fibrosis have significantly increased risk of advanced fibrosis. Routine screening should be done in the first-degree relatives of patients with advanced fibrosis.FUNDINGSupported by NCATS (5UL1TR001442), NIDDK (U01DK061734, U01DK130190, R01DK106419, R01DK121378, R01DK124318, P30DK120515, K23DK119460), NHLBI (P01HL147835), and NIAAA (U01AA029019); Academy of Finland grant 309263; the Novo Nordisk, EVO, and Sigrid Jusélius Foundations; and the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement 777377. This Joint Undertaking receives support from the European Union's Horizon 2020 research and innovation program and the EFPIA.

Lipoprotein(a): Evidence for Role as a Causal Risk Factor in Cardiovascular Disease and Emerging Therapies.

Lipoprotein(a) (Lp(a)) is an established risk factor for multiple cardiovascular diseases. Several lines of evidence including mechanistic, epidemiologic, and genetic studies support the role of Lp(a) as a causal risk factor for atherosclerotic cardiovascular disease (ASCVD) and aortic stenosis/calcific aortic valve disease (AS/CAVD). Limited therapies currently exist for the management of risk associated with elevated Lp(a), but several targeted therapies are currently in various stages of clinical development. In this review, we detail evidence supporting Lp(a) as a causal risk factor for ASCVD and AS/CAVD, and discuss approaches to managing Lp(a)-associated risk.

Brassica and Sinapis Seeds in Medieval Archaeological Sites: An Example of Multiproxy Analysis for Their Identification and Ethnobotanical Interpretation.

The genus Brassica includes some of the most important vegetable and oil crops worldwide. Many Brassica seeds (which can show diagnostic characters useful for species identification) were recovered from two archaeological sites in northern Italy, dated from between the Middle Ages and the Renaissance. We tested the combined use of archaeobotanical keys, ancient DNA barcoding, and references to ancient herbarium specimens to address the issue of diagnostic uncertainty. An unequivocal conventional diagnosis was possible for much of the material recovered, with the samples dominated by five Brassica species and Sinapis. The analysis using ancient DNA was restricted to the seeds with a Brassica-type structure and deployed a variant of multiplexed tandem PCR. The quality of diagnosis strongly depended on the molecular locus used. Nevertheless, many seeds were diagnosed down to species level, in concordance with their morphological identification, using one primer set from the core barcode site (matK). The number of specimens found in the Renaissance herbaria was not high; Brassica nigra, which is of great ethnobotanical importance, was the most common taxon. Thus, the combined use of independent means of species identification is particularly important when studying the early use of closely related crops, such as Brassicaceae.

Greenhouse Spatial Effects Detected in the Barley (Hordeum vulgare L.) Epigenome Underlie Stochasticity of DNA Methylation.

Environmental cues are known to alter the methylation profile of genomic DNA, and thereby change the expression of some genes. A proportion of such modifications may become adaptive by adjusting expression of stress response genes but others have been shown to be highly stochastic, even under controlled conditions. The influence of environmental flux on plants adds an additional layer of complexity that has potential to confound attempts to interpret interactions between environment, methylome, and plant form. We therefore adopt a positional and longitudinal approach to study progressive changes to barley DNA methylation patterns in response to salt exposure during development under greenhouse conditions. Methylation-sensitive amplified polymorphism (MSAP) and phenotypic analyses of nine diverse barley varieties were grown in a randomized plot design, under two salt treatments (0 and 75 mM NaCl). Combining environmental, phenotypic and epigenetic data analyses, we show that at least part of the epigenetic variability, previously described as stochastic, is linked to environmental micro-variations during plant growth. Additionally, we show that differences in methylation increase with time of exposure to micro-variations in environment. We propose that subsequent epigenetic studies take into account microclimate-induced epigenetic variability.

Ten-Hour Time-Restricted Eating Reduces Weight, Blood Pressure, and Atherogenic Lipids in Patients with Metabolic Syndrome.

In animal models, time-restricted feeding (TRF) can prevent and reverse aspects of metabolic diseases. Time-restricted eating (TRE) in human pilot studies reduces the risks of metabolic diseases in otherwise healthy individuals. However, patients with diagnosed metabolic syndrome often undergo pharmacotherapy, and it has never been tested whether TRE can act synergistically with pharmacotherapy in animal models or humans. In a single-arm, paired-sample trial, 19 participants with metabolic syndrome and a baseline mean daily eating window of ≥14 h, the majority of whom were on a statin and/or antihypertensive therapy, underwent 10 h of TRE (all dietary intake within a consistent self-selected 10 h window) for 12 weeks. We found this TRE intervention improves cardiometabolic health for patients with metabolic syndrome receiving standard medical care including high rates of statin and anti-hypertensive use. TRE is a potentially powerful lifestyle intervention that can be added to standard medical practice to treat metabolic syndrome. VIDEO ABSTRACT.

Heart Failure and Diabetes Mellitus: Defining the Problem and Exploring the Interrelationship.

Type 2 diabetes mellitus and congestive heart failure are highly prevalent diseases with significant morbidity and mortality. These 2 diseases often occur concurrently because of shared risk factors such as coronary artery disease, and also because type 2 diabetes mellitus has direct cardiotoxic effects. Type 2 diabetes mellitus likely has a causative role in the development and prognosis of patients with heart failure. Optimal prevention and treatment of type 2 diabetes mellitus and heart failure likely involves identifying and treating their shared pathophysiologic features. Novel drug therapies, such as sodium-glucose co-transporter 2 inhibitors, offer an exciting potential to better understand the relationship between type 2 diabetes mellitus and heart failure, and may prove to have beneficial effects on cardiovascular outcomes in patients affected by these diseases.

Lipoprotein(a) in Patients Undergoing Transcatheter Aortic Valve Replacement.

Lipoprotein(a) [Lp(a)] is a genetically determined risk factor for calcific aortic valve stenosis (CAVS) for which transcatheter aortic valve replacement (TAVR) is increasingly utilized as treatment. We evaluated the effect of a program to increase testing of and define the prevalence of elevated Lp(a) among patients undergoing TAVR. Educational efforts and incorporation of a "check-box" Lp(a) order to the preoperative TAVR order set were instituted. Retrospective chart review was performed in 229 patients requiring TAVR between May 2013 and September 2018. Of these patients, 57% had an Lp(a) level measured; testing rates increased from 0% in 2013 to 96% in 2018. Lipoprotein(a) testing occurred in 11% of patients before and in 80% of patients after the "check-box" order set ( P < .001). The prevalence of elevated Lp(a) (≥30 mg/dL) was 35%; these patients had a higher incidence of coronary artery disease requiring revascularization compared with patients with normal Lp(a) (65% vs 47%; P = .047). Patients with Lp(a) ≥30 mg/dL also had higher incidence of paravalvular leak compared with those with normal Lp(a) (13% vs 4%; P = .04). This study defines the prevalence of elevated Lp(a) in advanced stages of CAVS and provides a practice pathway to assess procedural complications and long-term outcomes of TAVR in patients with elevated Lp(a) levels.

Inappropriate ICD Shock From Perceived Ventricular Fibrillation During Balloon Manipulation at the Time of Percutaneous Coronary Intervention.

The authors demonstrate that device manipulation during percutaneous coronary intervention can result in "noise," which can be perceived as an arrhythmia resulting in an inappropriate shock. Although rare, this possibility should be considered when an operator encounters a difficult to traverse lesion in a patient with an ICD.

The Prevalence of Lipoprotein(a) Measurement and Degree of Elevation Among 2710 Patients With Calcific Aortic Valve Stenosis in an Academic Echocardiography Laboratory Setting.

Lipoprotein(a; Lp[a]) and its associated oxidized phospholipids are causal, genetic risk factors for calcific aortic valve stenosis (CAVS). We determined the prevalence of Lp(a) measurement among 2710 patients with CAVS and 1369 control patients (∼50% of study group) without CAVS with an echocardiogram between January 2010 and February 2016 in an academic echocardiography laboratory. Lipoprotein(a) measurements were performed at a referral laboratory using an isoform-independent assay. The prevalence of any Lp(a) measurement was 4.6% (124 of the 2710) in patients with CAVS and 3.1% (42 of the 1369) in the control group ( P = .021). In patients with CAVS, mean (standard deviation) Lp(a) levels were 38 (54) mg/dL and median (interquartile range) Lp(a) levels were 14 (6-48) mg/dL. Of the 124 patients with CAVS having Lp(a) measurements, 83 (66.9%) had Lp(a) <30 mg/dL and 41 (33.1%) had Lp(a) ≥30 mg/dL. This study reflects low physician testing of Lp(a) levels in CAVS. Given the role of Lp(a) as a causal risk factor for CAVS, and the ongoing development of therapies to normalize Lp(a) levels, our results suggest that Lp(a) measurements in CAVS should be more widely obtained in clinical practice.

Orbital Epstein-Barr Virus-Positive Polymorphic B-Cell Lymphoproliferative Disorder in an Apparently Immunocompetent Woman.

We report a rare case of Epstein-Barr virus (EBV)-positive polymorphic B-cell lymphoproliferative disorder (LPD) involving the lacrimal gland of a 28-year-old, apparently immunocompetent woman. She presented with a chief complaint of orbital swelling and tenderness and was found to have a lesion involving the right lacrimal gland and distal superior and lateral rectus muscles. Histology of the lesion revealed histiocytes with pleomorphic nuclei, reactive lymphocytes, and scattered cells that resembled the Reed-Sternberg (R-S) cells of classical Hodgkin lymphoma. The R-S-like cells were positive for PAX5 and CD30 and negative for CD15, supporting a diagnosis of polymorphic B-cell LPD. In situ hybridization for EBV-encoded RNA demonstrated the presence of EBV. Most EBV-positive polymorphic B-cell LPDs are associated with immunodeficiency. However, the patient described is HIV-negative and has no identifiable defects in immunoglobulin levels or cell-mediated immunity. This raises the question of whether she has an underlying immunodeficiency resulting from subtle changes in T-cell physiology, or whether chronic EBV infection contributed to her immune dysfunction through an unclear mechanism. The orbital mass partially regressed with chemotherapy, and the patient has done well clinically with no recurrence of this EBV-LPD for over 2 years.

Orbital Expansion for Congenital Anophthalmia May Be Achievable in Infancy But Not in Childhood.

BACKGROUND: Congenital anophthalmia is a rare anomaly that results in micro-orbitism and craniofacial microsomia. Treatment with static conformers is labor-intensive and provides minimal stimulation for orbital growth that requires eventual reconstruction with orbital osteotomies after skeletal maturity. METHODS: A protocol for the treatment of congenital anophthalmia is presented. Patients underwent a preoperative low-dose radiation computed tomography (CT) scan of the facial bones to assess orbital volume. An intraorbital expander was placed and was filled on a monthly basis. Quantitative changes in the affected and unaffected orbits were assessed by a repeat CT scan obtained 1 year postoperatively. RESULTS: Two patients with left unilateral congenital anophthalmia were prospectively followed. In a 4-month-old, the affected orbital width and height increased by 171.6% and 116.7% respectively compared with the unaffected orbit. In a 4-year-old, the affected orbital width increased by 36.1% but the height decreased by 35.3% compared with the unaffected orbit. At 18 months follow-up, no complications, ruptures, infections, or extrusions have been observed. CONCLUSIONS: Our results support that accelerated expansion can be achieved in a 4-month-old orbit reversing the effects of anophthalmia. However, in a 4-year-old, minimal growth was observed. The lack of accelerated growth in this study may be explained by synostosis of the orbital sutures. As such, expansion should be initiated at the earliest age possible. Further longitudinal study is ongoing to determine if sustained catch-up growth will obviate or reduce the complexity of a secondary correction.

Lipoprotein(a) and oxidized phospholipids in calcific aortic valve stenosis.

PURPOSE OF REVIEW: As the incidence of calcific aortic valve stenosis increases with the aging of the population, improved understanding and novel therapies to reduce its progression and need for aortic valve replacement are urgently needed. RECENT FINDINGS: Lipoprotein(a) is the only monogenetic risk factor for calcific aortic stenosis. Elevated levels are a strong, causal, independent risk factor, as demonstrated in epidemiological, genome-wide association studies and Mendelian randomization studies. Lipoprotein(a) is the major lipoprotein carrier of oxidized phospholipids, which are proinflammatory and promote calcification of vascular cells, two key pathophysiological drivers of aortic stenosis. Elevated plasma lipoprotein(a) and oxidized phospholipids predict progression of pre-existing aortic stenosis and need for aortic valve replacement. The failure of statin trials in pre-existing aortic stenosis may be partially due to an increase in lipoprotein(a) and oxidized phospholipid levels caused by statins. Antisense oligonucleotides targeted to apo(a) are in Phase 2 clinical development and shown to lower both lipoprotein(a) and oxidized phospholipids. SUMMARY: Lipoprotein(a) and oxidized phospholipids are key therapeutic targets in calcific aortic stenosis. Strategies aimed at potent lipoprotein(a) lowering to normalize levels and/or to suppress the proinflammatory effects of oxidized phospholipids may prevent progression of this disease.

Overcoming toxicity and side-effects of lipid-lowering therapies.

Lowering serum lipid levels is part of the foundation of treating and preventing clinically significant cardiovascular disease. Recently, the American Heart Association/American College of Cardiology released cholesterol guidelines which advocate for high efficacy statins rather than LDL-c goals for five patient subgroups at high risk for cardiovascular disease. Therefore, it is critical that clinicians have an approach for managing side-effects of statin therapy. Statins are associated with myopathy, transaminase elevations, and an increased risk of incident diabetes mellitus among some patients; connections between statins and other processes, such as renal and neurologic function, have also been studied with mixed results. Statin-related adverse effects might be minimized by careful assessment of patient risk factors. Strategies to continue statin therapy despite adverse effects include switching to another statin at a lower dose and titrating up, giving intermittent doses of statins, and adding non-statin agents. Non-statin lipid-lowering drugs have their own unique limitations. Management strategies and algorithms for statin-associated toxicities are available to help guide clinicians. Clinical practice should emphasize tailoring therapy to address each individual's cholesterol goals and risk of developing adverse effects on lipid-lowering drugs.