Polycystic ovary syndrome: A review of diagnosis and management, with special focus on atherosclerotic cardiovascular disease prevention.

Polycystic ovary syndrome (PCOS) is a common endocrinopathy worldwide with a heterogeneous clinical presentation including reproductive, metabolic, and endocrine elements. However, the assessment and management of PCOS remains inconsistent, with many women undiagnosed and untreated. We now also understand that the management of PCOS should extend throughout a woman's lifespan as many elements of the syndrome persist after menopause. Management has traditionally focused on the treatment of hyperandrogenism and oligomenorrhea. Women with PCOS often have dyslipidemia, hypertension, obesity, and metabolic syndrome, which may be worsened by the hormonal abnormalities, and are therefore at higher risk for cardiovascular disease morbidity and mortality, a risk that increases after menopause. While treatment with hormonal therapy, in particular combined oral contraceptives, may improve cardiovascular risk factors, management plans should incorporate specific diagnosis and management of these factors, if present, because of the strong contribution to the risk for atherosclerotic cardiovascular disease (ASCVD). Given the complexities of the syndrome, optimal management often requires a multi-disciplinary approach including the lipid and cardiometabolic specialist to provide counseling and support for lifestyle modification along with pharmacologic therapy as indicated to address the full range of any reproductive, endocrine, and cardiometabolic abnormalities.

Strategies of improving adherence to lipid-lowering therapy in patients with atherosclerotic cardiovascular disease.

PURPOSE OF REVIEW: Lowering LDL-C has been shown to reduce ASCVD events, yet many ASCVD patients do not achieve their guideline-directed LDL-C goals leaving patients at increased risk of another ASCVD event. This review discusses implementation strategies to improve guideline-directed lipid management in patients with ASCVD focusing on the provider, patient, and system level. RECENT FINDINGS: At a provider level, under-prescribing of statin intensity due most often to statin intolerance, clinical inertia, insufficient monitoring of LDL-C levels, and the difficulty and cost of prescribing other lipid-lowering therapies such as the PCSK9 inhibitors leads to suboptimal cholesterol management in ASCVD patients. Patients concerns about medication side effects and lack of understanding of their ASCVD risk are causes of poor adherence to their lipid-lowering therapy as are barriers at a system level. SUMMARY: To improve cholesterol management in ASCVD patients will require an integrated approach targeting the provider, the patient and the system. There is a need for further education of clinicians on the importance of intensive LDL-C lowering in ASCVD patients and greater use of nonstatin LDL-C-lowering therapies for those patients on a maximally tolerated statin who have not achieved their guideline-directed LDL-C goal. This will require shared decision-making with a focus on patient education and patient-clinician communication so that the clinician's goals and aims align with that of the patient.

Impact of the COVID-19 pandemic on the management of risk factors in patients with stable atherosclerotic vascular disease.

Background: Effective control of risk factors in patients with ASCVD is important to reduce recurrent cardiovascular events. However, many ASCVD patients do not have their risk factors controlled, and this may have worsened during the COVID-19 pandemic. Methods: We retrospectively evaluated risk factor control among 24,760 ASCVD patients who had at least 1 outpatient encounter both pre-pandemic and during the first year of the pandemic. Risk factors were uncontrolled if the blood pressure (BP) ≥ 130/80 mm Hg, LDL-C ≥ 70 mg/dL, HgbA1c ≥ 7 for diabetic patients, and patients were current smokers. Results: During the pandemic, many patients had their risk factors unmonitored. BP control worsened (BP ≥ 130/80 mmHg, 64.2 vs 65.7%; p = 0.01), while lipid management improved with more patients on a high-intensity statin (38.9 vs 43.9%; p<0.001) and more achieving an LDL-C < 70 mg/dL, less patients were smoking (7.4 vs 6.7%; p<0.001), and diabetic control was unchanged pre vs during the pandemic. Black (OR 1.53 [1.02-2.31]) and younger aged patients (OR 1.008 [1.001-1.015]) were significantly more likely to have missing or uncontrolled risk factors during the pandemic. Conclusions: During the pandemic risk factors were more likely to be unmonitored. While measured blood pressure control worsened, lipid control and smoking improved. Although some cardiovascular risk factor control improved during the COVID-19 pandemic, overall control of cardiovascular risk factors in patients with ASCVD was suboptimal, especially in Black and younger patients. This puts many ASCVD patients at increased risk of a recurrent cardiovascular event.

Current and Emerging Therapies for Atherosclerotic Cardiovascular Disease Risk Reduction in Hypertriglyceridemia.

Hypertriglyceridemia (HTG) is a prevalent medical condition in patients with cardiometabolic risk factors and is associated with an increased risk of atherosclerotic cardiovascular disease (ASCVD), if left undiagnosed and undertreated. Current guidelines identify HTG as a risk-enhancing factor and, as a result, recommend clinical evaluation and lifestyle-based interventions to address potential secondary causes of elevated triglyceride (TG) levels. For individuals with mild to moderate HTG at risk of ASCVD, statin therapy alone or in combination with other lipid-lowering medications known to decrease ASCVD risk are guideline-endorsed. In addition to lifestyle modifications, patients with severe HTG at risk of acute pancreatitis may benefit from fibrates, mixed formulation omega-3 fatty acids, and niacin; however, evidence does not support their use for ASCVD risk reduction in the contemporary statin era. Novel therapeutics including those that target apoC-III and ANGPTL3 have shown to be safe, well-tolerated, and effective for lowering TG levels. Given the growing burden of cardiometabolic disease and risk factors, public health and health policy strategies are urgently needed to enhance access to effective pharmacotherapies, affordable and nutritious food options, and timely health care services.

Nonadherence to lipid-lowering therapy and strategies to improve adherence in patients with atherosclerotic cardiovascular disease.

Despite the availability of effective therapies that lower low-density lipoprotein cholesterol (LDL-C) levels in patients with atherosclerotic cardiovascular disease, many eligible patients are inadequately treated and their LDL-C levels remain suboptimal. Patient nonadherence to lipid-lowering therapy (LLT) is a major contributor to the failure of LDL-C goal attainment. Several factors have been identified as contributing to LLT nonadherence, including healthcare disparities due to socioeconomic status, age, race, sex, and cost; limited access to healthcare; perceived side effects associated with LLT; health literacy; and the presence of comorbidities. Suboptimal LLT use has also been associated with clinician factors, including failure to identify patients who require LDL-C reassessment, insufficient LDL-C monitoring, and clinical inertia such as a lack of therapy intensification. Several strategies to enhance LLT adherence have been shown to be effective, including the implementation of educational initiatives and tools for both patients and physicians, the use of clinical protocols and algorithms to identify patients at risk and optimize treatment, and improvements in electronic healthcare records. Pharmacy-based programs designed to help patients with prescription refills, including reminders or the use of prescription delivery by mail, have also proven effective. Drugs requiring frequent administration can represent a barrier to treatment adherence; therefore, newer, more effective LLTs with lower frequency of administration and lower potential for polypharmacy may improve patient adherence to LLT. Implementation of strategies to identify patients at risk for LLT nonadherence and the use of flexible tools such as telemedicine to overcome geographical barriers may improve LLT adherence.

Awareness, diagnosis and treatment of heterozygous familial hypercholesterolemia (HeFH) - Results of a US national survey.

BACKGROUND: HeFH is a common inherited disorder that leads to markedly elevated LDL-cholesterol from birth and premature cardiovascular disease. HeFH is frequently underdiagnosed and undertreated. OBJECTIVE: To compare how well primary care physicians and cardiologists recognize and treat HeFH. METHODS: The National Lipid Association surveyed 500 primary care physicians and 500 cardiologists in the US who have patients with baseline LDL-cholesterol ≥ 190 mg/dL. The survey was conducted between August 29 and September 30, 2019. RESULTS: For a hypothetical case of HeFH, 57% of cardiologists versus 43% of primary care physicians made the correct diagnosis (P<0.001). Among respondents, 21% of cardiologists versus 29% of primary care physicians have never made a diagnosis of HeFH in a patient with an LDL-cholesterol ≥ 190 mg/dL (P<0.004). Only 7% of cardiologists versus 5% of primary care physicians would refer to a lipid specialist (P=0.05). For additional LDL-cholesterol lowering after statins, 58% of cardiologists versus 48% of primary care physicians would prescribe a PCSK9 inhibitor (P=0.004); however, 30% of cardiologists versus 53% of primary care physicians have never prescribed a PSCK9 inhibitor in an HeFH patient (P<0.001). CONCLUSION: Although cardiologists compared to primary care physicians are somewhat more likely to recognize and treat HeFH patients according to guidelines, both physician specialties do not adequately recognize or treat HeFH. There is a need for more education and training in recognizing and treating HeFH, greater access to lipid specialists, and fewer barriers for PCSK9 inhibitor use.

Trends in PCSK9 Inhibitor Prescriptions before and after the Price Reduction in Patients with Atherosclerotic Cardiovascular Disease.

BACKGROUND: Proprotein convertase subtilisin kexin type 9 (PCSK9) inhibitors reduce low-density lipoprotein (LDL) cholesterol and cardiovascular event rates, yet due to their high price remain underutilized and difficult to prescribe in clinical practice. In March 2018, their price was significantly reduced. We evaluated whether the price reduction would improve prescribing patterns of PCSK9 inhibitors in eligible patients with atherosclerotic cardiovascular disease (ASCVD). METHODS: We identified the number of eligible ASCVD patients and those prescribed a PCSK9 inhibitor for each year between July 2015 and December 2019. Patient demographics and clinical characteristics for those prescribed a PCSK9 inhibitor were extracted from their electronic health record. RESULTS: In total 1059 patients of eligible patients received a new prescription for a PCSK9 inhibitor. From 2015 to 2019, the rate of new prescriptions among eligible patients increased from 0.5 to 3.3% (p < 0.001) and continuation rates increased from 18 to 60% (p < 0.001). Following the price reduction, patients who were prescribed a PCSK9 inhibitor were younger and more likely to be female, but less likely to have Medicare insurance. CONCLUSIONS: Despite the reduction in the cost of PCSK9 inhibitors, most eligible patients are not prescribed one. The reduction in cost has improved adherence, primarily in patients with commercial insurance. Older patients and those on Medicare still face significant barriers in accessing a PCSK9 inhibitor. Further reductions in the price of the PCSK9 inhibitors are needed as is further study of the barriers that exist in prescribing one.

Cascade Screening and Treatment Initiation in Young Adults with Heterozygous Familial Hypercholesterolemia.

Heterozygous familial hypercholesterolemia (HeFH) creates elevated low-density lipoprotein cholesterol (LDL-C), causing premature atherosclerotic cardiovascular disease (ASCVD). Guidelines recommend cascade screening relatives and starting statin therapy at 8-10 years old, but adherence to these recommendations is low. Our purpose was to measure self-reported physician practices for cascade screening and treatment initiation for HeFH using a survey of 500 primary care physicians and 500 cardiologists: 54% "always" cascade screen relatives of an individual with FH, but 68% would screen individuals with "strong family history of high cholesterol or premature ASCVD", and 74% would screen a child of a patient with HeFH. The most likely age respondents would start statins was 18-29 years, with few willing to prescribe to a pediatric male (17%) or female (14%). Physicians who reported previously diagnosing a patient with HeFH were more likely to prescribe to a pediatric patient with HeFH, either male (OR = 1.34, 95% CI = 0.99-1.81) or female (OR = 1.31, 95% CI = 0.99-1.72). Many physicians do not cascade screen and are less likely to screen individuals with family history of known HeFH compared to "high cholesterol or premature ASCVD". Most expressed willingness to screen pediatric patients, but few would start treatment at recommended ages. Further education is needed to improve diagnosis and treatment of HeFH.

Perceptions and Barriers on the Use of Proprotein Subtilisin/Kexin Type 9 Inhibitors in Heterozygous Familial Hypercholesterolemia (From a Survey of Primary Care Physicians and Cardiologists).

Heterozygous familial hypercholesterolemia (HeFH) results in significant elevations in LDL-C and premature atherosclerotic cardiovascular disease (ASCVD). Current guidelines recommend add-on proprotein subtilisin/kexin type 9 inhibitor (PCSK9i) therapy for additional LDL-C lowering beyond statins. Data are sparse, however, regarding treatment patterns and barriers relating to PCSK9i in HeFH patients. We examined physician attitudes, use, and barriers for treatment in patients with HeFH. We surveyed 1,000 physicians (500 primary care providers [PCPs] and 500 cardiologists in the US regarding their preferred treatments, experience and barriers associated with using PCSK9is. Cardiologists compared to PCPs were more likely to rank a PCSK9i as most important for an HeFH patient needing additional LDL-C lowering (68.6% vs. 64.8%; p <0.05), as well as prescribing and having a patient on a PCSK9i. PCPs vs. cardiologists were less likely (odds ratio [OR] [95% confidence interval] = 0.46 [0.34-0.63]), private vs. academic practice more likely (OR = 1.53 [1.02-2.28]), and those who would prescribe a PCSK9i in an HeFH patient with (OR = 3.86 [2.57-5.78]) or without (OR = 1.96 [1.40-2.72]) ASCVD needing additional LDL-C reduction beyond a statin were more likely to actually prescribe a PCSK9i. Those practicing in an urban vs. rural setting were less likely (OR = 0.56 [0.34-0.93]), and those indicating they would prescribe a PCKS9i in an HeFH patient with (OR = 2.80 [1.74-4.49]) or without (OR = 1.43 [1.02-2.02]) ASCVD needing additional LDL-C lowering beyond a statin were more likely to face difficulty prescribing a PCSK9i (all p <0.05 to p <0.01). Greater physician education and assistance among both cardiologists and PCPs are needed to address the gaps in understanding and treatment regarding PCSK9is.

Managing cardiometabolic risk factors across a woman's lifespan: A lipidologist's perspective.

A recent rise in atherosclerotic cardiovascular disease (ASCVD) mortality in women warrants a heightened focus on the cardiometabolic risk factors that are closely tied to increasing trends in obesity and suboptimal lifestyle. Polycystic ovarian syndrome (PCOS), adverse pregnancy outcomes (APOs) and nonalcoholic fatty liver disease (NAFLD) are often manifestations of cardiometabolic disease that convey cardiovascular risk requiring recognition foremost, as well as a targeted approach to treatment. Similarly, menopause is a time to reflect on a woman's cardiovascular risk as multiple cardiometabolic changes occur during this time. Contraceptives and menopausal replacement therapy (MRT) should be considered along with a woman's individual thrombotic and cardiovascular risk. Clinicians should be attuned to cardiometabolic risk factors throughout a woman's lifespan and familiar with strategies to reduce cardiovascular risk.

Correction to: Recognition and Treatment of Homozygous Familial Hypercholesterolemia by Primary Care Physicians: a Survey from the National Lipid Association.

The funding information in this paper was presented incorrectly.

Statin utilization and low-density lipoprotein cholesterol in statin-treated patients with atherosclerotic cardiovascular disease: Trends from a community-based health care delivery system, 2002-2016.

BACKGROUND: A better understanding of patterns in statin utilization and low-density lipoprotein cholesterol (LDL-C) among patients with atherosclerotic cardiovascular disease (ASCVD) in a clinical practice setting is needed. OBJECTIVES: The objective of this study was to examine statin utilization and LDL-C among new statin users with ASCVD. METHODS: This retrospective study used an electronic health record database from a community-based health care system. We identified ASCVD patients ≥21 years of age with a new statin prescription during the study period (2002-2016). Outcomes included high-intensity statin therapy (HIST) prescribing at treatment initiation, medication adherence (defined as proportion of days covered ≥0.80), statin therapy titrations rates, and changes in LDL-C during follow-up. RESULTS: Among 6199 eligible patients, mean follow-up was 16.8 months. At treatment initiation, 16.6% of patients received HIST. Approximately 53% of patients were adherent to statin regimens. Mean percent reduction in LDL-c was 25% during follow-up; 18% of patients, overall, and 30% of those initiating on HIST attained LDL-C reductions >50%. Rates of statin intensity-level increases were 8.4 per 100 person-years. HIST prescribing increased over time, beginning after generic atorvastatin availability and preceded treatment guidelines by two years. Initiation on HIST, higher adherence, and treatment intensification during follow-up were independent predictors of attaining LDL-C goals of <70 mg/dL or <100 mg/dL. CONCLUSIONS: In a community-based health care system, modest LDL-C lowering for secondary ASCVD prevention is likely driven by suboptimal adherence and low HIST prescribing and treatment intensification rates. Clinician and patient education are needed to reduce clinical inertia and improve medication adherence to better manage ASCVD.

JCL roundtable: Lipid treatment targets.

This Roundtable discussion concerns atherogenic risk markers and treatment targets used by clinical lipidologists in daily practice. Our purpose is to understand the risk marker framework that supports and enables the new ACC/AHA/Multisociety Cholesterol Guidelines. Some biomarkers are highly associated with atherogenic risk but fail to qualify as treatment targets. Prominent examples are high-density lipoprotein cholesterol, for which targeted treatment has failed to reduce cardiovascular risk, and lipoprotein(a), which currently lacks a highly effective mode of treatment. As a consequence, guidelines have focused consistently on low-density lipoprotein cholesterol (LDL-C) and more recently on non-high-density lipoprotein cholesterol. We discuss a new calculation for LDL-C that shows greater accuracy than the commonly performed Friedewald calculation. LDL-C treatment goals have renewed prominence in the 2018 Guidelines. Thresholds for treatment initiation or intensification inherently establish goals of reducing atherogenic cholesterol levels below the thresholds. Treatment goals may be absolute, such as less than 70 mg/dL for LDL-C in very high-risk secondary prevention or relative, such as 50% or greater reduction of LDL-C. The timeframe of treatment is another consideration because milder treatment started earlier may sometimes be preferred over stronger treatment given late in the course of atherosclerotic progression. Advanced lipid testing and vascular imaging, particularly coronary artery calcium, also have their place in risk assessment to guide clinical lipid practice.

Prescribing Patterns of Proprotein Convertase Subtilisin-Kexin Type 9 Inhibitors in Eligible Patients With Clinical Atherosclerotic Cardiovascular Disease or Heterozygous Familial Hypercholesterolemia.

Two proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitors are approved for patients with atherosclerotic cardiovascular disease or heterozygous familial hypercholesterolemia who require additional low-density lipoprotein cholesterol (LDL-C) lowering. This retrospective study sought to determine differences between eligible patients who were prescribed and those who were not prescribed a PCSK9 inhibitor. Patients from an electronic medical record database were included in the analysis, and their demographic, clinical, and treatment characteristics were evaluated. Of 368,624 PCSK9 inhibitor-eligible patients, 1,752 (<0.5%) received a PCSK9 inhibitor prescription. Patients who received a PCSK9 inhibitor were more frequently associated with a higher cardiovascular disease risk category and a higher baseline LDL-C level (139.4 vs 103.5 mg/dl; p <0.0001) compared with those who did not. Patients with a PCSK9 inhibitor prescription were significantly more likely to be on ezetimibe, alone or in combination with a statin, at baseline compared with those without (29% vs 5%; p <0.0001). The use of a PCSK9 inhibitor was very low in the 2 groups of patients identified as PCSK9 inhibitor-eligible based on the American College of Cardiology Expert Consensus Decision Pathway. In conclusion, this study demonstrates that most PCSK9 inhibitor-eligible patients do not receive a PCSK9 inhibitor prescription, highlighting that many high-risk patients could benefit from additional LDL-C lowering with a PCSK9 inhibitor.

Barriers to PCSK9 inhibitor prescriptions for patients with high cardiovascular risk: Results of a healthcare provider survey conducted by the National Lipid Association.

BACKGROUND: Statin therapy is recommended for reducing atherosclerotic cardiovascular disease (ASCVD) risk. Significant risk can remain because of insufficient clinical response or statin intolerance. Proprotein convertase subtilisin/kexin type-9 (PCSK9) therapy lowers low-density lipoprotein cholesterol and has recently been shown to lower ASCVD events. OBJECTIVE: The aim of the study was to assess the barriers and challenges experienced with the access and approval reimbursement process for PCSK9 inhibitor prescriptions. METHODS: In 2016, the National Lipid Association conducted an online survey on PCSK9 inhibitor use and barriers to prescription among experienced healthcare workers who provide care to high-risk patients with ASCVD or familial hypercholesterolemia (FH). RESULTS: There were 434 respondent healthcare workers with extensive experience in treating lipid disorders. PCSK9 inhibitors are considered by 71.3% of respondent providers with statin-intolerant patients. There were high rates (>85%) of initial denial. The major barriers to approvals were insurer processes, provider documentation (inadequate documentation of maximally tolerated statin dose, diagnostic criteria for FH, number of statins failed if statin intolerant and most recent low-density lipoprotein cholesterol), and administrative burden (time, staff, paperwork, and appeals). Provider approval rates for getting ≥75% patients approved were higher for FH (43%) than for ASCVD patients (36%). Among providers with good approval rates, documentation was the most critical factor. Barriers more difficult to overcome include perceived higher threshold requirements by payers, drugs not on formulary, and drug costs. CONCLUSIONS: Healthcare providers encounter significant barriers to PCSK9 inhibitor prescriptions; many of these are related to documentation issues and can be overcome with checklists, staff support, and experience.

A Review of Clinical Practice Guidelines for the Management of Hypertriglyceridemia: A Focus on High Dose Omega-3 Fatty Acids.

Cardiovascular (CV) disease remains the leading cause of preventable death in the US. Hyperlipidemia is a major modifiable risk factor for CV disease, and after numerous clinical trials have demonstrated that reductions in low-density lipoprotein (LDL) cholesterol with statin therapy can prevent major adverse CV events, statins have emerged as the drug of choice to lower LDL cholesterol and reduce CV risk. However, some statin-treated patients remain at high residual risk of CV events despite achieving low LDL cholesterol levels, especially if their triglyceride (TG) levels are elevated or their high-density lipoprotein (HDL) cholesterol levels low. Evidence from genetic and observational studies has linked elevated TG levels to an increased risk of CV events. Furthermore, very high TG levels are associated with acute pancreatitis. Consequently, several clinical practice guidelines provide recommendations for the management and treatment of high and very high TG levels. This review focuses on the clinical practice guidelines for the management of hypertriglyceridemia and the role of prescription omega-3 fatty acids in preventing pancreatitis and CV disease in individuals with high and very high TG levels.

The risks of statin use in pregnancy: A systematic review.

Statins are contraindicated in pregnancy; however, as women delay pregnancy and statin use increases the risk of statin exposure in pregnancy is likely to rise. In contrast to some early reports that statins are teratogenic, more recent observational studies have called into question the teratogenic risk of statins. Therefore, whether statins are associated with congenital anomalies or other pregnancy complications remains an important clinical question. This article provides an up-to-date systematic review on the risks of statins in pregnancy. We conducted a literature search to identify relevant English language studies related to statin exposure and pregnancy. Single case reports, animal studies, studies only published in abstract form, and non-English language studies were excluded. A total of 16 clinical studies were included in this systematic review. Although early uncontrolled case series reported congenital anomalies associated with statin use, more recent observational studies did not report an increased risk of congenital anomalies with statin exposure in pregnancy when compared to control groups or the prevalence of congenital anomalies in the general population. Our findings show no clear relationship of congenital anomalies with statin use in pregnancy, and our study supports the findings that statins are probably not teratogenic. However, until more information is available, statins should still be avoided in pregnancy.