BACKGROUND: Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition effectively lowers low-density lipoprotein cholesterol (LDL-C) and cardiovascular risk, but its pleiotropic effects remain insufficiently defin...BACKGROUND: Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition effectively lowers low-density lipoprotein cholesterol (LDL-C) and cardiovascular risk, but its pleiotropic effects remain insufficiently defined. This study examined whether PCSK9 inhibition influences vascular and systemic inflammation and high-density lipoprotein (HDL) antioxidant function. OBJECTIVE: To investigate the effects of PCSK9 inhibition on vascular inflammation, systemic inflammatory markers, and HDL antioxidant function in a real-world patient cohort. MATERIAL AND METHODS: In this monocentric, prospective study, blood samples from 89 patients were collected before and 3 to 6 months after initiation of PCSK9 inhibitor therapy. Lipoprotein-associated phospholipase A2 (LpPLA) was measured as a marker of vascular inflammation. HDL antioxidant function was assessed by HDL lipid peroxide content (HDL). Systemic inflammation was evaluated via high-sensitivity C-reactive protein (hsCRP) and a predefined cytokine panel. RESULTS: Seventy-three patients (82.0%) received alirocumab or evolocumab, and 16 (18.0%) received inclisiran. LDL-C decreased by 46.7% (120-64.5 mg/dL, P < .0001). LpPLA declined significantly (443.5-265.5 IU/L, P < .0001) and correlated with LDL-C reduction (R² = 0.58, P < .0001). HDL did not change (1.190-1.210, P = .3438). Interferon gamma-induced protein (IP) 10 (P = .0141) and interleukin (IL)-2 (P = .0371) decreased, whereas hsCRP and other cytokines-including IL-1β, IL-4, IL-6, IL-8, IL-10, IL-17A, tumor necrosis factor-α, monocyte chemotactic protein-1, interferon-γ, and free radicals-remained unchanged (all P > .05). CONCLUSION: PCSK9 inhibition reduces LpPLA and IP-10 without changing global inflammatory response or antioxidant function of HDL, which might indicate a decrease in chronic vascular inflammation without an undesired broad systemic immune alteration.
BACKGROUND: Lipoprotein(a) [Lp(a)] is an independent risk factor for atherosclerotic cardiovascular disease. Although Lp(a) levels are generally stable, the extent of intraindividual variation and the need for repeat Lp(...BACKGROUND: Lipoprotein(a) [Lp(a)] is an independent risk factor for atherosclerotic cardiovascular disease. Although Lp(a) levels are generally stable, the extent of intraindividual variation and the need for repeat Lp(a) testing remain unclear. OBJECTIVE: To evaluate the intraindividual variation in Lp(a) levels assess the clinical impact of repeat testing on cardiovascular risk classification. METHODS: This retrospective study analyzed 250 patients from a tertiary care lipid clinic with ≥2 Lp(a) measurements over a mean of 17.1 ± 15.5 months. RESULTS: Baseline levels were positively skewed (median of 56.0 nmol/L; interquartile range 21.0-154.3 nmol/L). Intraindividual coefficients of variation (CV) were 19.0% (mean-based) and 33.6% (log-transformed), exceeding the European Federation of Clinical Chemistry and Laboratory Medicine database CV (10.2%; 4.3%-26.7%). Cardiovascular risk reclassification occurred for 12.4% using the National Lipid Association thresholds (75 and 125 nmol/L) and 6.8% using the European Society of Cardiology threshold (105 nmol/L). Variability was not associated with time between measurements, medications, or biochemical parameters on multivariable analysis. CONCLUSION: Hence, repeat Lp(a) testing is generally unnecessary but could be considered in those near risk thresholds or those being evaluated for Lp(a)-lowering therapies.
BACKGROUND: The role of the apoptosis inhibitor of macrophages (AIM) in human lipid metabolism remains unclear. OBJECTIVE: This study aimed to investigate the cross-sectional associations between serum AIM and plasma met...BACKGROUND: The role of the apoptosis inhibitor of macrophages (AIM) in human lipid metabolism remains unclear. OBJECTIVE: This study aimed to investigate the cross-sectional associations between serum AIM and plasma metabolites and to determine if baseline AIM concentrations predict incident dyslipidemia. METHODS: This study used a community-based cohort of 3139 participants for cross-sectional metabolomic analysis. Among them, 1292 participants without dyslipidemia at baseline were followed prospectively for up to 8.5 years. Cox proportional hazards models were used to estimate hazard ratios for incident high low-density lipoprotein cholesterol (LDL-C) and metabolic dyslipidemia (high triglycerides and/or low high-density lipoprotein cholesterol [HDL-C]) across AIM tertiles. RESULTS: Cross-sectionally, higher AIM concentrations were associated with elevated acylcarnitines and tricarboxylic acid cycle intermediates. Longitudinally, higher baseline AIM was associated with an increased risk of developing metabolic dyslipidemia in women (highest vs lowest tertile hazard ratio, 1.84) and showed a similar but smaller nonsignificant trend in men. The risk for high LDL-C was significantly increased in women but not in men. These associations remained robust after multivariable adjustment. CONCLUSION: Elevated baseline AIM concentrations were prospectively associated with the development of metabolic dyslipidemia in women, with a similar but nonsignificant trend in men, and with high LDL-C in women. The related metabolomic profile suggests enhanced lipolysis and altered lipid metabolism. Therefore, AIM may serve as a biomarker for future dyslipidemia, particularly for triglyceride and HDL-C dysregulation.
We present a case of a young adult diagnosed with homozygous familial hypercholesterolemia despite a normal lipid panel. A deeper dive into the details of the genotype resulted in recharacterization of the genetic diagno...We present a case of a young adult diagnosed with homozygous familial hypercholesterolemia despite a normal lipid panel. A deeper dive into the details of the genotype resulted in recharacterization of the genetic diagnosis. The observed phenotype-genotype discordance reflects the importance of a team-based approach to guide patients and avoid misdiagnosis and optimize treatment strategies.
Familial hypercholesterolemia (FH) is one of the most common inherited dyslipidemias and a major risk factor for premature coronary artery disease. Statins are the primary lipid-lowering therapy for FH but are usually in...Familial hypercholesterolemia (FH) is one of the most common inherited dyslipidemias and a major risk factor for premature coronary artery disease. Statins are the primary lipid-lowering therapy for FH but are usually insufficient for reducing low-density lipoprotein cholesterol to normal levels, necessitating additional medications such as proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors. However, the safety of long-term PCSK9 inhibition is unclear. Here, we report an extremely rare family where FH phenotypes are mitigated by co-existing familial hypobetalipoproteinemia caused by a protein-truncating variant of PCSK9. This case suggests that long-term PCSK9 inhibitor treatment may be safe and effective for patients with FH.
J Clin Lipidol
· 2026 Apr · PMID 41708458
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BACKGROUND: Hydroxychloroquine (HCQ) is an immunomodulatory agent used in autoimmune conditions. Observational studies suggest that HCQ may lower circulating cholesterol and triglyceride levels, indicating a potential ca...BACKGROUND: Hydroxychloroquine (HCQ) is an immunomodulatory agent used in autoimmune conditions. Observational studies suggest that HCQ may lower circulating cholesterol and triglyceride levels, indicating a potential cardiovascular benefit. However, the specific changes in lipoprotein particle concentrations driving these effects have not been characterized in detail. OBJECTIVE: To evaluate the effects of HCQ on circulating lipids and on lipoprotein concentration and composition. METHODS: A post hoc analysis was conducted within a randomized, placebo-controlled, double-blind trial investigating the effects of HCQ on glucose metabolism in adults at risk for type 2 diabetes. Outcomes were analyzed as changes from baseline (placebo-adjusted) using mixed-effects models, with adjustments for sex, age, body mass index, and statin use. RESULTS: Compared with placebo, HCQ reduced total cholesterol (10.4%), low-density lipoprotein (LDL) cholesterol (12.9%), and non-high-density lipoprotein (HDL) cholesterol (15.0%). LDL particle concentration decreased by 15.1% and apolipoprotein B (ApoB) by 9.7%. HCQ had no effect on HDL cholesterol, HDL particle concentration, or apolipoproteinA1 (ApoA1). However, small HDL particle concentrations fell by 20.0%, while large HDL particle concentrations increased by 17.1%. HCQ reduced triglycerides by 27.8%, which was associated with a 20.6% reduction in triglyceride content per very low-density lipoprotein (VLDL) particle. Lipoprotein(a) levels were unaffected. CONCLUSION: HCQ changes lipoprotein concentration and composition, though the effects are distinct for each lipoprotein class. Our results suggest that HCQ lowers total cholesterol by reducing LDL particle concentration, decreases triglyceride by reducing the triglyceride content of VLDL particles, and alters the relative distribution of small vs large HDL particle concentration. These findings suggest protective benefits against atherosclerosis that warrant further investigation.
BACKGROUND: The obesity epidemic in the United States affects not only adults, but children and adolescents. SOURCES OF MATERIAL: An extensive review of the literature including 85 articles has been completed with the ai...BACKGROUND: The obesity epidemic in the United States affects not only adults, but children and adolescents. SOURCES OF MATERIAL: An extensive review of the literature including 85 articles has been completed with the aim of providing the most current definitions and recommendations for this chronic condition. ABSTACT OF FINDINGS: This article reviews the definition of pediatric obesity, the increasing prevalence of obesity in children and adolescents, genetic and environmental risk factors, as well as the unique aspects and implications of this condition and its associated comorbidities for this population in comparison to adults. Current management recommendations are also discussed which include Intensive Health Behavioral and Lifestyle Treatment (IHBLT), metabolic surgery, and pharmacologic therapy including glucago-like peptide-1 receptor agonists (GLP-1RAs). CONCLUSION: Childhood obesity is a unique condition in its progression and management requirements, and should be approached with a focus on prevention as well as on the high-risk individual.
The global obesity epidemic poses significant challenges for patients, providers, and our public health system. Early identification of patients at risk for obesity-related disease is essential to address these challenge...The global obesity epidemic poses significant challenges for patients, providers, and our public health system. Early identification of patients at risk for obesity-related disease is essential to address these challenges and requires clear definitions and characterizations of obesity at all stages of disease. Reliance on body mass index (BMI) to define obesity overlooks crucial phenotypic heterogeneity and its impact on cardiometabolic risk. This review summarizes the benefits and disadvantages of current and proposed measures to characterize obesity. We summarize methods to diagnose obesity that have a greater association with atherosclerotic cardiovascular disease and mortality. These methods include anthropometric measurements, inflammatory biomarkers, dual energy X-ray absorptiometry (DEXA) and magnetic resonance imaging (MRI)-measured visceral adiposity, and cardiorespiratory fitness. We further review proposed frameworks for defining obesity and assess their ability for early and appropriate identification of patients with and without obesity-related organ dysfunction. The way we define obesity has implications for clinical diagnosis and management and can impact how third-party payors reimburse for specific interventions.
BACKGROUND: Obesity is a chronic disease, rooted in genetic predisposition and homoeostatic counter-regulatory adaptive and hormonal responses, with escalating prevalence rates and numerous associated health consequences...BACKGROUND: Obesity is a chronic disease, rooted in genetic predisposition and homoeostatic counter-regulatory adaptive and hormonal responses, with escalating prevalence rates and numerous associated health consequences. SOURCES OF MATERIAL: Historically, interventions beyond lifestyle for the treatment of obesity have been underutilized, stigmatized, and held to different standards of validation compared to treatments for other chronic cardiovascular risk factors. ABSTRACT OF FINDINGS: Contemporary management of obesity requires implementation of lifestyle modifications, employment of pharmacotherapy, and in more severe cases, surgical intervention. The purpose of this manuscript is to review obesity medication (OM) use in adults, with an emphasis on glucagon-like peptide-1 receptor agonists (GLP-1 RA) and GLP-1 RA/glucose- dependent insulinotropic polypeptide (GIP) dual receptor agonists, focusing on patient selection, strategies for initiation and titration of these medications in clinical practice, emerging evidence of benefit and potential risk, as well as medication access and cost considerations. CONCLUSION: GLP-1 RAs have emerged as a highly effective, safe, and well tolerated pharmacotherapy option for the management of obesity, possessing a myriad disease-modifying outcomes and capable of curtailing the rapid rise in obesity and related complications.
BACKGROUND: Lifestyle modification through diet and exercise remains the first-line therapy for obesity; however, long-term success is limited for many individuals. Metabolic and bariatric surgery (MBS) has emerged as th...BACKGROUND: Lifestyle modification through diet and exercise remains the first-line therapy for obesity; however, long-term success is limited for many individuals. Metabolic and bariatric surgery (MBS) has emerged as the most effective intervention for durable weight loss and obesity-related comorbidity reduction. OBJECTIVE: To assess the efficacy, safety, and clinical significance of the effect of MBS in the management of obesity. METHODS: Data from recent clinical trials and advances in surgical and endoscopic techniques were reviewed, with an emphasis on durability of weight loss, resolution of comorbidities, cardiovascular outcomes, and procedural risk profiles. RESULTS: MBS consistently achieves superior and sustained weight loss compared with nonsurgical strategies. Substantial improvements, and in many cases resolution, of obesity-associated comorbidities-including type 2 diabetes, hypertension, and dyslipidemia-have been observed. Additionally, MBS significantly reduces major adverse cardiovascular events, particularly myocardial infarction and stroke. Advances in minimally invasive MBS and endoscopic techniques have improved safety and reduced perioperative risk. Nonetheless, both short- and long-term complications may occur. Indications for MBS differ between adult and pediatric populations, requiring individualized evaluation and selection. CONCLUSION: MBS is an effective long-term treatment for obesity, offering durable weight reduction and meaningful improvements in metabolic and cardiovascular health. Although not without potential adverse events, evolving surgical and endoscopic approaches have enhanced safety and broadened applicability. These findings underscore the importance of incorporating MBS into shared decision-making and highlight its critical role within a comprehensive, evidence-based strategy for obesity management.
BACKGROUND: Lifestyle modification remains the cornerstone of obesity management, serving as an essential component of all treatment plans, even in an era of effective pharmacotherapy. SOURCES OF MATERIAL: This review ex...BACKGROUND: Lifestyle modification remains the cornerstone of obesity management, serving as an essential component of all treatment plans, even in an era of effective pharmacotherapy. SOURCES OF MATERIAL: This review examines the key elements of lifestyle interventions, their mechanisms of action, implementation strategies, and challenges in clinical practice. It additionally discusses the evolving role of lifestyle modification when integrated alongside new pharmaceutical advances, particularly glucagon-like peptide-1 receptor agonists, and how these combined approaches may optimize outcomes in obesity treatment. ABSTRACT OF FINDINGS: Effective implementation of lifestyle modification requires a multidisciplinary approach, incorporating exercise counseling, medical nutrition therapy, and behavioral change strategies to address the complex nature of obesity. Nutritional approaches, including various evidence-based dietary patterns, function by creating energy deficits and altering metabolic pathways that influence weight regulation. Physical activity complements dietary interventions by increasing energy expenditure, improving body composition, and enhancing metabolic health. Studies have demonstrated benefits of physical activity for both weight loss and maintenance. Behavioral change techniques are critical for developing sustainable habits, overcoming psychological barriers, and facilitating long-term adherence to lifestyle modifications. CONCLUSION: Despite evidence supporting lifestyle modification, challenges limit its use within obesity care, including poor long-term adherence, limited access to specialized facilities and professionals, and inadequate reimbursement for these clinical services.
BACKGROUND: The prevalence of obesity in the U.S. continues in epidemic proportions-for both children and adults. We have a growing body of information and resources with which to understand and manage obesity including...BACKGROUND: The prevalence of obesity in the U.S. continues in epidemic proportions-for both children and adults. We have a growing body of information and resources with which to understand and manage obesity including scientific research on the pathophysiology and how socioeconomic impact on the disease, as well as potent new drugs and proposed legislative changes. SOURCES OF MATERIAL: This paper reviews population studies, clinical studies, and review of current legislation regarding obesity in the United States. ABSTRACT OF FINDINGS: Obesity is highly prevalent with predictions of continued growth. Medications, specifically newer GLP-1 receptor agonists are available but concerns remain regarding cost, accessibility, and long-terms safety. Proposed changes to public health laws and policies have the potential to improve management and access to effective treatments but the path forward for these remains unclear. CONCLUSIONS: Despite the growing prevalence that was first realized decades ago, we have not been able to address the many complex issues that have resulted in the current epidemic of obesity.
BACKGROUND: Obesity is a global epidemic with rapidly increasing prevalence over the recent years. Its rise is paralleled by a similar trend in cardiovascular disease (CVD) risk factors and events, which have become the...BACKGROUND: Obesity is a global epidemic with rapidly increasing prevalence over the recent years. Its rise is paralleled by a similar trend in cardiovascular disease (CVD) risk factors and events, which have become the leading cause of death in many countries. SOURCES OF MATERIAL: This review focuses on the relationship between obesity, CVD risk, and risk factors and the management strategies that can treat both the resulting co-morbidities as well as the underlying obesity. ABSTRACT OF FINDINGS: Obesity is associated with overall CVD events and atherosclerosis as well as the individual risk factors including diabetes mellitus, obstructive sleep apnea, dyslipidemia, hypertension, arrhythmias, preeclampsia and gestational diabetes. Treatment with lifestyle interventions, approved medications and surgical procedures lead to improvements in CVD risk factors and events, proportional to the rates' and the effects' duration of weight loss achieved. Resources used to prepare this review include the latest international clinical practice guidelines, the largest meta-analyses of prospective, randomized, controlled trials, observational studies and obesity treatment studies, along with pertinent review articles on the effects of obesity and its treatments on CVD risk and risk factors. CONCLUSION: Diagnosis and management of CVD risk factors is an important aspect of an obesity management plan along with the overarching goal of addressing the causes of this global epidemic through collaboration and incorporation of preventive, diagnostic and therapeutic strategies individualized to the ethnic, social and financial needs of each population with the aim to reduce the prevalence of CVD risk factors and the incidence of CVD events.
BACKGROUND: Obesity is an increasingly common, multifactorial condition with significant consequences for patients and the healthcare system. Obesity represents a major modifiable risk factor for cardiovascular disease,...BACKGROUND: Obesity is an increasingly common, multifactorial condition with significant consequences for patients and the healthcare system. Obesity represents a major modifiable risk factor for cardiovascular disease, type 2 diabetes and metabolic syndrome. Understanding of the pathways and mechanisms involved in the development of obesity will allow for further advancement in treatment modalities. SOURCES OF MATERIAL: Evidence was drawn from current peer-reviewed literature addressing the pathophysiology of obesity identified via PubMed searches. ABSTRACT OF FINDINGS: Obesity results from impaired energy homeostasis and chronic positive energy balance. The etiology of the positive energy balance is often a complex interplay of genetic, environmental, neurohormonal, and psychosocial factors. This paper discusses the pathophysiology of obesity. Topics included in this discussion are the genetics of obesity, the process of energy regulation and metabolism of adipose tissue. Also discussed is how visceral obesity is especially harmful, as it promotes insulin resistance, altered lipid metabolism, and inflammation. CONCLUSION: Understanding the underlying pathophysiology of obesity is crucial for making advances in treating this condition with a more individualized approach.
BACKGROUND: Obesity is a chronic, multifactorial disease associated with significant metabolic, physical, and psychosocial complications. Although advances in pharmacologic therapy-particularly glucagon-like peptide-1 (G...BACKGROUND: Obesity is a chronic, multifactorial disease associated with significant metabolic, physical, and psychosocial complications. Although advances in pharmacologic therapy-particularly glucagon-like peptide-1 (GLP-1)-based agents-have expanded treatment options, challenges persist in the effective management of obesity. SOURCES OF MATERIAL: This paper reviews current literature, including clinical trial data, national guidelines, and recent policy updates, to identify key barriers to optimal obesity management. Primary sources include studies and reviews published between 2021 and 2025, as well as data from the Centers for Medicare & Medicaid Services (CMS), the U.S. Food and Drug Administration (FDA), and the World Health Organization (WHO). ABSTRACT FINDINGS: There are 4 major challenges in obesity management highlighted in this paper: (1) determining which healthcare providers should prescribe and manage obesity pharmacotherapy, (2) the necessity for lifelong treatment to sustain benefits from pharmacotherapy, (3) inconsistent third-party reimbursement that limits patient access, and (4) drug shortages compounded by high demand and direct-to-consumer (DTC) marketing. GLP-1-based agents demonstrate substantial weight reduction but require ongoing therapy to maintain outcomes. Reimbursement barriers persist across Medicaid, Medicare, and commercial plans, while drug shortages and compounded formulations pose safety and ethical concerns. CONCLUSION: Effective obesity management requires a coordinated, multidisciplinary approach supported by equitable insurance coverage and regulatory oversight. Providers must balance pharmacotherapy with behavioral and lifestyle interventions and educate patients on the risks of unapproved or compounded products. Addressing these systemic challenges will be essential to ensure sustained, safe, and accessible care for individuals with obesity.
BACKGROUND: Obesity is a complex, chronic disease influenced by genetic, environmental, behavioral, and psychosocial factors. While lifestyle modification remains the foundation of treatment, it is often insufficient for...BACKGROUND: Obesity is a complex, chronic disease influenced by genetic, environmental, behavioral, and psychosocial factors. While lifestyle modification remains the foundation of treatment, it is often insufficient for sustained weight loss and cardiometabolic risk reduction. The rising prevalence of obesity and its link to comorbidities such as type 2 diabetes, hypertension, dyslipidemia, and atherosclerotic cardiovascular disease necessitate a comprehensive, multidisciplinary approach to care. OBJECTIVES: To correlate the pathophysiology of adiposopathic atherogenic dyslipidemia with the need for patient-centered, team-based management strategies that improve long-term outcomes. METHODS: This review describes the structure and function of interdisciplinary obesity care teams, highlighting the roles of lipid specialists, physicians, advanced practice providers, clinical pharmacists, registered dietitians, behavioral health professionals, and exercise specialists. The use of shared care plans, case reviews, electronic health record tools, and emerging technologies such as nutrigenetic testing is explored. RESULTS: Multidisciplinary care improves outcomes by addressing obesity's complexity, supporting adherence to evidence-based therapies, and reducing barriers to treatment. Challenges such as payer-related prior authorization delays and the social stigma of obesity remain obstacles to engagement and long-term success, underscoring the need for scalable, collaborative care models. CONCLUSIONS: Team-based, proactive, and individualized care is essential for effective obesity management. Health systems that invest in interdisciplinary approaches are better positioned to reduce the clinical, psychological, and economic burden of obesity and its complications.
Hamid A, Sewell T, Bhatt S
… +7 more, Spencer S, Hostin D, Metcalf GA, Gibbs RA, Nambi V, Abushamat LA, Ballantyne CM
J Clin Lipidol
· 2026 Mar · PMID 41702822
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BACKGROUND: Although familial hypercholesterolemia (FH) is a US Centers for Disease Control and Prevention tier 1 condition for genetic testing, the impact of testing on clinical outcomes is unclear. OBJECTIVE: We aimed...BACKGROUND: Although familial hypercholesterolemia (FH) is a US Centers for Disease Control and Prevention tier 1 condition for genetic testing, the impact of testing on clinical outcomes is unclear. OBJECTIVE: We aimed to assess whether genetic testing alters lipid management in HeartCare participants. METHODS: For participants with pathogenic/likely pathogenic variants for FH observed at Baylor College of Medicine cardiology clinics, data on laboratory values, medication prescriptions, and diagnoses were collected and compared before and after genetic testing. RESULTS: In the 20 participants with APOB/LDLR variants and complete data, low-density lipoprotein cholesterol (LDL-C) was numerically lower but not significantly different before vs after genetic testing (103 vs 79.5 mg/dL). Sixteen (80%) participants were from the lipid clinic; the majority had a preexisting FH diagnosis. LDL-C levels were numerically lower, and more patients received proprotein convertase subtilisin/kexin type 9 inhibitor prescriptions after genetic testing; however, the difference was not statistically significant. CONCLUSIONS: The majority of patients with FH achieved LDL-C <100 mg/dL after genetic testing; however, most patients with APOB/LDLR variants were from the lipid clinic and had been diagnosed with FH by clinical criteria.