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.

Familial hypercholesterolemia (FH) is a common genetic disorder characterized by lifelong elevated low-density lipoprotein cholesterol (LDL-C), leading to a high risk of early onset atherosclerotic cardiovascular disease (ASCVD). This document provides an update to the National Lipid Association's 2011 clinical guidance, summarizing the remarkable progress in the field. With a global prevalence of approximately 1 in 311, FH remains severely underdiagnosed. This guidance reviews current diagnostic criteria, including the expanding role of genetic testing to complement diagnosis and to facilitate cascade screening, and emphasizes a thorough differential diagnosis. It provides recommendations for universal pediatric screening and systematic cascade screening in families to improve detection. Management strategies include intensified LDL-C treatment goals for both primary and secondary prevention of ASCVD. A stepwise approach to optimal therapy is outlined, beginning with lifestyle interventions and pharmacotherapy with maximally tolerated statins and ezetimibe. This update incorporates newer agents, including proprotein convertase subtilisin/kexin type 9 inhibitors and bempedoic acid. Additional therapies, such as lomitapide and evinacumab for homozygous FH and lipoprotein apheresis for heterozygous and homozygous FH, are discussed. Further topics include cardiovascular imaging for risk stratification, management in specific populations and circumstances, such as planning for and during pregnancy and in pediatrics, and recognition of health disparities. This guidance equips clinicians with evidence-based strategies to improve the identification and care of patients with FH, ultimately reducing the high morbidity and mortality associated with this condition.

OBJECTIVE:Evaluate efficacy and tolerability of bempedoic acid in homozygous familial hyper cholesterolemia (HoFH). METHODS:A single-center retrospective study of HoFH patients prescribed bempedoic acid between February 2020 and May 2025. Patients were managed according to our clinical standard of care, with routine assessments of lipids, medication tolerability, and adherence. The primary endpoint was percent change in low-density lipoprotein cholesterol (LDL-C) from baseline to first follow-up. Secondary endpoints evaluated LDL-C changes at other timepoints, LDL-C goal attainment, medication access, and tolerability. RESULTS:Of the 14 HoFH patients treated within our clinic, 5 (mean age 41.4 years, 60% female) were initiated on bempedoic acid, and 4 continued treatment. Pre-existing atherosclerotic cardiovascular disease (ASCVD) was present in 4 of 5 patients, and baseline mean ± SD LDL-C was 131 ± 62.4 mg/dL. Patients were managed on a mean of 3.8 lipid-lowering therapies at baseline, all with statins (60% high-intensity). Bempedoic acid reduced LDL-C by a mean ± SD of -33.2% ± 15.1% to an on-treatment LDL-C of 71 ± 30.9 mg/dL at first follow-up (median 2.9 months). LDL-C reduction of -29.4% ± 13.1% to an on-treatment LDL-C of 75 ± 29.6 mg/dL was seen at most recent follow-up (median 25.6 months). Two patients achieved recommended LDL-C goals on bempedoic acid. The medication was well tolerated, with 60% free from adverse events. CONCLUSION:Bempedoic acid in patients with HoFH was both effective for LDL-C lowering and tolerable in this cohort of patients. This represents a novel treatment approach in a very high-risk patient population requiring multi-drug regimen for lipid optimization and cardiovascular protection.

BACKGROUND:Homozygous familial hypercholesterolemia (HoFH) is an autosomal semidominant disorder characterized by extreme elevations in LDL-C (low-density lipoprotein cholesterol) and early-onset atherosclerotic cardiovascular disease. Evinacumab is a monoclonal antibody administered by monthly intravenous infusion that binds ANGPTL3 (angiopoietin-like 3) and when added to standard lipid-lowering therapies lowers LDL-C by ≈50% in HoFH clinical trials. Studies examining the real-world effectiveness and safety of evinacumab are limited. METHODS:We performed a retrospective study to assess the effectiveness and safety of evinacumab in patients with HoFH in clinical practice at 6 US academic medical centers. The primary end point was the percent change in LDL-C from baseline to first follow-up and to the most recent follow-up after evinacumab initiation. Secondary end points were percent change in non-high-density lipoprotein cholesterol (non-HDL-C), triglycerides, total cholesterol, HDL-C, and achievement of an LDL-C <70 mg/dL. Adverse events were recorded. RESULTS:Twenty-four patients (mean age, 40 [range, 5-84] years) with HoFH were followed for a median of 48 weeks. Fifty percent were female, 66.7% had atherosclerotic cardiovascular disease, 87.5% were on a statin, 83.3% were on ezetimibe, 66.7% were on PCSK9i (proprotein convertase subtilisin/kexin type 9 inhibitors), 24% were on lomitapide, and 33.3% were undergoing lipoprotein apheresis. Significant reductions in LDL-C, non-HDL-C, total cholesterol, triglycerides, and HDL-C were observed both at the first follow-up (4 weeks) and the most recent follow-up (48 weeks); mean±SEM percent change from baseline to the most recent follow-up was as follows: LDL-C, -53.2% (±4.1); non-HDL-C, -52.7% (±3.9); triglycerides, -47.4% (±5.1); total cholesterol, -48.9% (±4.0); and HDL-C, -30.2% (±4.1); P<0.001 for all. Significantly more patients achieved LDL-C <70 mg/dL after evinacumab was added. Nine (37.5%) patients reported adverse events during or following evinacumab infusions. Treatment was discontinued by 1 patient because of back pain. CONCLUSIONS:Across 6 US academic medical centers, evinacumab was generally well tolerated by patients with HoFH and lowered LDL-C by ≈50%, consistent with results from clinical trials.

Outcome benefits for HMG-CoA reductase inhibitor (statin) use in the prevention of atherosclerotic cardiovascular disease (ASCVD) are well established and yet, statins remain underutilized with only half of eligible individuals receiving them among certain vulnerable populations. This review critically examines available data to provide a summary of the current evidence for statin use in select populations. Lipid management can be more complex in patients with chronic kidney disease (CKD), organ transplants, metabolic dysfunction associated with steatotic liver disease (MASLD), and human immunodeficiency virus (HIV). Statins are generally safe and effective to reduce the burden of ASCVD among these highly heterogeneous groups of patients and should be considered with careful attention to their concomitant disease state. Herein, we focus on appropriate statin use in these challenging to treat conditions, their relationship with increased ASCVD risk, and approaches to statin use for ASCVD risk reduction. Although further research is needed to define optimal therapy in select high risk groups for ASCVD prevention, statins are proven to be clinically efficacious, safe, and cost-effective for ASCVD prevention, warranting greater efforts to increase their use.

Atherosclerotic cardiovascular diseases continue to be a leading cause of death globally. Although statin medications remain the cornerstone of treatment for lowering low‐density lipoprotein cholesterol and reducing cardiovascular risk, there is a proportion of patients in whom treatment with statins may not achieve the guideline recommended low‐density lipoprotein cholesterol targets despite using maximally tolerated doses, or for various reasons, patients are unable or unwilling to intensify or continue statins. In these instances, use of nonstatin medications like ezetimibe, bempedoic acid, or PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitors (alirocumab, evolocumab, inclisiran) in addition to maximally tolerated statin therapy can lead to additional lowering of low‐density lipoprotein cholesterol and beneficial reductions in cardiovascular events. This review provides an overview of the evidence supporting the use of nonstatin low‐density lipoprotein cholesterol lowering medications for cardiovascular risk reduction and practical considerations for the use of these agents.

Statin-associated muscle symptoms (SAMS) are the most common form of statin intolerance and are associated with increased risk of cardiovascular events that manifest from statin underutilization and discontinuation. The reported frequencies of SAMS are divergent in the literature. The writing group estimates the prevalence of SAMS, namely all muscle symptoms temporally related to statin use but without regard to causality, to be about 10% (range 5% to 25%), and the prevalence of pharmacological SAMS, specifically muscle symptoms resulting from pharmacological properties of the statin, to be about 1-2% (range 0.5% to 4%). In clinical practice, SAMS are likely to result from a combination of pharmacological and nonpharmacological effects, however this does not make the symptoms any less clinically relevant. Regardless of the etiology, SAMS need to be addressed in accordance with patients’ preferences and experiences. This clinical perspective reviews the epidemiology and underlying pathophysiology of SAMS, and the cardiovascular consequences resulting from statin discontinuation. We present patient-centered clinical and communication strategies to mitigate SAMS and improve medication adherence and outcomes among statin users. Treatment strategies include 1) optimizing lifestyle interventions, 2) modulating risk factors that may contribute to muscle symptoms, 3) optimizing statin tolerability by dose reduction, decreased dosing frequency, or use of an alternate statin with more favorable pharmacokinetic properties, and 4) use of non-statins, emphasizing those with evidence for atherosclerotic risk reduction, either in combination with or in place of statin therapy depending on the patient's circumstances. The focus of this clinical perspective is sustainable lipoprotein goal achievement, which is important for cardiovascular risk reduction.

Cardiovascular disease remains the leading cause of death and disability in the United States and globally. Disease burden continues to escalate despite technological advances associated with improved life expectancy and quality of life. As a result, longer life is associated with multiple chronic cardiovascular conditions. Clinical guidelines provide recommendations without considering prevalent scenarios of multimorbidity and health system complexities that affect practical adoption. The diversity of personal preferences, cultures, and lifestyles that make up one's social and environmental context is often overlooked in ongoing care planning for symptom management and health behavior support, hindering adoption and compromising patient outcomes, particularly in groups at high risk. The purpose of this scientific statement was to describe the characteristics and reported outcomes in existing person-centered care delivery models for selected cardiovascular conditions. We conducted a scoping review using Ovid MEDLINE, Embase.com, Web of Science, CINAHL Complete, Cochrane Central Register of Controlled Trials through Ovid, and ClinicalTrials.gov from 2010 to 2022. A range of study designs with a defined aim to systematically evaluate care delivery models for selected cardiovascular conditions were included. Models were selected on the basis of their stated use of evidence-based guidelines, clinical decision support tools, systematic evaluation processes, and inclusion of the patient's perspective in defining the plan of care. Findings reflected variation in methodological approach, outcome measures, and care processes used across models. Evidence to support optimal care delivery models remains limited by inconsistencies in approach, variation in reimbursement, and inability of health systems to meet the needs of patients with chronic, complex cardiovascular conditions.

Introduction: Homozygous familial hypercholesterolemia (HoFH) is an autosomal co-dominant disorder characterized by extreme elevations in LDL-C and early onset ASCVD. Unfortunately, patients with HoFH generally experience poor LDL-C lowering with standard lipid-lowering therapy and rarely achieve LDL-C goals. Evinacumab is a monoclonal antibody administered by monthly IV infusion that binds angiopoietin-like 3 and when added to standard lipid-lowering therapies lowers LDL-C by ~50% in clinical trials involving patients with HoFH. Real-world effectiveness and safety of evinacumab is unknown. Methods: We performed retrospective chart review to assess effectiveness and safety of evinacumab in patients with HoFH in clinical practice at six US academic medical centers. The primary efficacy endpoint was the percent change in LDL-C from baseline to first follow-up and to most recent follow-up after evinacumab initiation. Secondary efficacy endpoints were percent change in non-HDL-C, triglycerides, total cholesterol, HDL-C, and achievement of an LDL-C <70 mg/dL. Adverse events were recorded. Results: Twenty-four patients (mean age 38 yrs; range 5-75) with HoFH were followed for a median of 63 weeks. Fifty percent were female, 66.7% had ASCVD, 87.5% were on a statin, 83.3% on ezetimibe, 66.7% on a PCSK9i, 24% on lomitapide, and 33.3% were undergoing lipoprotein apheresis. Significant reductions in LDL-C, non-HDL-C, total cholesterol, triglycerides, and HDL-C were observed both at first follow-up (4 weeks) and most recent follow-up (63 weeks) (p < 0.001 for all) (Table). Significantly more patients achieved LDL-C <70 mg/dL after evinacumab was added. No serious adverse events occurred and evinacumab was generally well-tolerated. Conclusions: Across six US academic medical centers, evinacumab was generally well-tolerated by patients with HoFH and lowered LDL-C by ~50%, consistent with results from clinical trials.

Background/Synopsis Homozygous familial hypercholesterolemia (HoFH) is an autosomal co-dominant disorder characterized by extreme elevations in LDL-C and early onset ASCVD. Unfortunately, patients with HoFH generally experience poor LDL-C lowering with standard lipid-lowering therapy and rarely achieve LDL-C goals. Evinacumab is a monoclonal antibody administered by monthly IV infusion that binds angiopoietin-like 3 and when added to standard lipid-lowering therapies lowers LDL-C by ∼50% in clinical trials involving patients with HoFH. Real-world effectiveness and safety of evinacumab is unknown. Objective/Purpose Examine the safety and efficacy of evinacumab in the real-world treatment of patients with HoFH across multiple US academic medical centers. Methods We performed retrospective chart review to assess safety and efficacy of evinacumab in patients with HoFH in clinical practice at six US academic medical centers. The primary efficacy endpoint was the percent change in LDL-C from baseline to first follow-up and to most recent follow-up after evinacumab initiation. Secondary efficacy endpoints were percent change in non-HDL-C, triglycerides, total cholesterol, HDL-C, and achievement of an LDL-C <70 mg/dL. Adverse events were recorded. Results Twenty-four patients (mean age 38 yrs; range 5-75) with HoFH were followed for a median of 48 weeks. Fifty percent were female, 16 (66.7%) had ASCVD, 21 (87.5%) on a statin, 20 (83.3%) on ezetimibe, 16 (66.7%) on PCSK9i, 6 (24%) on lomitapide, and 8 (33.3%) undergoing lipoprotein apheresis (Table 1). Significant reductions in LDL-C, non-HDL-C, total cholesterol, triglycerides, and HDL-C were observed both at first follow-up (4 weeks) and most recent follow-up (48 weeks) (p < 0.001 for all). Significantly more patients achieved LDL-C <70 mg/dL after evinacumab was added (Table 2, Figure). No serious adverse events occurred and evinacumab was generally well-tolerated. 9 patients (37.5%) reported side-effects which were generally mild. Side-effects led to discontinuation of therapy in 1 patient due to fatigue and back pain. Conclusions Across six US academic medical centers, evinacumab was generally well-tolerated by patients with HoFH and lowered LDL-C by ∼50%, consistent with results from clinical trials.

Background: Lipid management for prevention and treatment of cardiovascular disease remains insufficient for many with currently available therapies. Objective: Evaluate real-world use of bempedoic acid. Methods: Retrospective study of patients in our Center for Preventive Cardiology who were prescribed bempedoic acid between February 2020 and July 2021. Patients were managed according to clinical standards of care, with lipid assessments at months <3, 6, and 12 post-bempedoic acid initiation. Results: Seventy-three patients were prescribed bempedoic acid, with 64 initiating therapy. The majority had atherosclerosis (89%), familial hypercholesterolemia (64%), and statin intolerance (74%), with baseline low-density lipoprotein cholesterol (LDL-C) 120 mg/dL. Prior authorization requests and appeals of denials were required in 90% and 19% of cases, respectively. Cost-mitigating strategies reduced median monthly drug costs from $432 pre-insurance approval to $80 post-insurance approval, to $10 after financial assistance intervention. Bempedoic acid reduced LDL-C by -36.7%, -31%, and -20.3% at 3, 6, and 12, respectively, with 20% achieving LDL-C < 70 mg/dL. There was substantial interindividual heterogeneity in LDL-C lowering. We observed high rates of drug discontinuation (35.9%), mostly related to treatment-emergent adverse events (TEAEs) (32.8%), primarily musculoskeletal complaints. Use of reduced dose bempedoic acid ( < 180 mg) was associated similar LDL-C lowering but TEAE and drug discontinuation were still common. Conclusions: Real-world use of bempedoic acid was limited by insurance and cost barriers requiring substantial post-prescription interventions. In patients at heightened risk for atherosclerotic events and statin intolerance, bempedoic acid was associated with clinically meaningful LDL-C lowering, but high rates of TEAEs and drug discontinuations. (c) 2021 National Lipid Association. Published by Elsevier Inc. All rights reserved.

Elevated levels of lipoprotein(a) [Lp(a)] are a prevalent and causative risk factor for atherosclerotic cardiovascular disease (ASCVD), but effective pharmacologic strategies for Lp(a) lowering are needed. Antisense oligonucleotides (ASOs) are effective for gene silencing and reducing production of unwanted proteins. Pelacarsen, a subcutaneously administered third-generation ASO directed against apolipoprotein(a) japo(a)J, prevents translation of and induces degradation of apo(a) messenger ribonucleic acid (mRNA). Pelacarsen has multiple side-chain modifications, including conjugation with N-acetylgalactosamine (GalNAc), which increases drug potency, half-life and drug tolerance. Pelacarsen significantly reduces Lp(a) concentrations by up to 80-90%, which may allow many patients to achieve normal Lp(a) levels. Pelacarsen has a good safety profile, bypassing toxicities associated with second-generation ASOs. The medical community awaits the results of the phase III Lp(a)HORIZON trial evaluating use of pelacarsen in patients with elevated Lp(a) and established ASCVD, which will provide the first definitive evidence of whether Lp(a) lowering reduces ASCVD risk.

The investigation of a DNase-hypersensitive site upstream of the CD7 gene on chromosome 17q25 has led to the discovery of a novel human gene designated K12 (SECTM1, the HGMW assignment). This gene spans approximately 14 kb and encodes a 1.8-kb mRNA detected at the highest levels in peripheral blood leukocytes and breast cancer cell lines. The open reading frame predicts a 248-amino-acid protein with the hydropathic characteristics of a type 1a membrane protein. Western blots show that the K12 protein exists as a cluster of bands around 27 kDa, and extractions using nonionic detergents or high pH conditions demonstrate that it behaves as an integral membrane protein. Immunofluorescence localization studies reveal that K12 is not detectable on the cell surface, but instead is found in a perinuclear Golgi-like pattern and colocalizes with a well-known Golgi marker. In addition, an approximately 20-kDa soluble form of the K12 protein derived from the N-terminal domain is specifically secreted by cells into the culture medium. Immunohistochemical analysis of peripheral blood cells shows that K12 is found in leukocytes of the myeloid lineage, with the strongest staining observed in granulocytes and no detectable expression in lymphocytes. Based on its range of expression, its broad structural characteristics that resemble cytokines and growth factors, and the chromosomal location of the gene in an area already associated with myelogenous leukemias and other malignant neoplasms, this study concludes that K12 is a novel molecule with potential importance in hematopoietic and/or immune system processes.

Introduction: Familial hypercholesterolemia (FH) is characterized by lifelong elevation of low-density lipoprotein cholesterol (LDL-C), early onset coronary atherosclerosis, and premature death. FH is underdiagnosed and undertreated, but requires aggressive LDL-C-lowering to prevent complications. Current treatment strategies such as lifestyle modification and numerous LDL-C-lowering medications are often insufficient to achieve lipid goals in FH.Areas covered: Angiopoietin-like 3 protein (ANGPTL3) is intricately involved in lipid metabolism. Loss-of-function mutations in ANGPTL3 are associated with panhypolipidemia and reduced coronary atherosclerosis. Evinacumab, a fully human monoclonal antibody, inhibits ANGPTL3 and reduces multiple lipoprotein fractions ~50%, including LDL-C. The use of evinacumab within the FH population is described as well as its regulatory journey to an approved therapeutic.Expert opinion: Evinacumab, with its capacity to lower multiple lipoprotein fractions, particularly LDL-C, independently of LDLR function has potential to revolutionize treatment for FH patients. Current FDA-approval is only for homozygous FH (HoFH), arguably the most impactful indication, but use in other lipid disorders is under investigation. The short-term tolerability of evinacumab is very good, with infrequent, mild, and transient adverse events; however, long-term safety data are needed. The high cost and requirement for intravenous administration may limit adoption of evinacumab, but dramatic LDL-C-lowering and need for new therapeutic options for HoFH will drive interest.

BACKGROUND Monoclonal antibodies against proprotein convertase subtilisin/kexin type 9 (PCSK9i) lower LDL-C by up to 60% and increase plasma proprotein convertase subtilisin/kexin type 9 (PCSK9) levels by 10-fold. OBJECTIVES The authors studied the reasons behind the robust increase in plasma PCSK9 levels by testing the hypothesis that mechanisms beyond clearance via the low-density lipoprotein receptor (LDLR) contribute to the regulation of cholesterol homeostasis. METHODS In clinical cohorts, animal models, and cell-based studies, we measured kinetic changes in PCSK9 production and clearance in response to PCSK9i. RESULTS In a patient cohort receiving PCSK9i therapy, plasma PCSK9 levels rose 11-fold during the first 3 months and then plateaued for 15 months. In a cohort of healthy volunteers, a single injection of PCSK9i increased plasma PCSK9 levels within 12 hours; the rise continued for 9 days until it plateaued at 10-fold above baseline. We recapitulated the rapid rise in PCSK9 levels in a mouse model, but only in the presence of LDLR. In vivo turnover and in vitro pulse-chase studies identified 2 mechanisms contributing to the rapid increase in plasma PCSK9 levels in response to PCSK9i: 1) the expected delayed clearance of the antibody-bound PCSK9; and 2) the unexpected post-translational increase in PCSK9 secretion. CONCLUSIONS PCSK9 re-entry to the liver via LDLR triggers a sensing loop regulating PCSK9 secretion. PCSK9i therapy enhances the secretion of PCSK9, an effect that contributes to the increased plasma PCSK9 levels in treated subjects. (J Am Coll Cardiol 2021;78:1437-1449) (c) 2021 The Authors. Published by Elsevier on behalf of the American College of Cardiology Foundation. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Heart failure with reduced ejection fraction (HFrEF) is a debilitating disease that is associated with substantial morbidity, mortality, and societal costs. The past three decades have brought about significant advancements in the pharmacologic management of HFrEF, and a corresponding reduction in morbidity and mortality. However, the progress to improve clinical outcomes in real-world settings has stalled in recent years, largely due to underutilization of guideline directed medical therapies (GDMT). The discovery of significant cardio-renal protection from sodium-glucose co-transporter 2 inhibitors (SGLT2i) has ushered in a new treatment paradigm for HFrEF management with SGLT2i therapy becoming an essential component of GDMT. Our Preventive Cardiology and Heart Failure services have established an innovative, multi-disciplinary, collaborative protocol to optimize management of cardiovascular risk factors and facilitation SGLT2i use in patients with HFrEF. The goal of this collaboration is to enhance utilization and safety of SGLT2i for HFrEF management by circumventing medication access issues, the major obstacle to therapy initiation. Within this protocol, our heart failure providers identify patients for the addition of SGLT2i to a background of heart failure GDMT. The patient is then referred to preventive cardiology where the team performs a comprehensive cardiovascular risk assessment, optimizes cardiovascular risk factors, and initiates SGLT2i with an emphasis on medication access, cost minimization, and mitigation of potential side effects. The heart failure team assumes responsibility for modification of heart failure-based therapies, and the preventive team manages diabetes, lipid, and metabolic-based therapies. The patient is followed by both cardiology services in a structured fashion, comparing outcome measures at regular intervals and utilizing our patient registry and bio-repository. This clinical practice statement provides a detailed evidentiary review on the cardiovascular and renal benefits of SGLT2i, outlines the rational for creation of a collaborative protocol, details a structured program that may serve as a template for enhanced heart failure management in other health systems, and addresses challenges encountered and recommendations for use.

OBJECTIVE:To determine the real-world use of pharmacotherapy with new evidence-based cardiovascular indications in an academic Preventive Cardiology Clinic.METHODS:A retrospective study of patients seen in our Center for Preventive Cardiology (CPC) and who received a new prescription, according to Food and Drug Administration (FDA) approved indications, for one of the following pharmacotherapies with new evidence-based cardiovascular indications from May 2019 to May 2020: proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i), eicosapentaenoic acid (EPA), sodium-glucose cotransporter 2 inhibitors (SGLT2i), and glucagon-like peptide-1 receptor agonists (GLP-1 RA). Treatment endpoints were prescription patterns, medication access, patient out-of-pocket expenses, medication tolerability, and clinical cardiovascular events while on these therapies.RESULTS:Of the 2390 patients seen in our CPC clinic over the observation period, 532 (22.3%) had already started and 291 (12.2%) were newly initiated on pharmacotherapy with new evidence-based cardiovascular indications with a median treatment duration of 9.1 months. Of these, 291 patients (for a total of 320 separate drug orders) - 93 (29.1%) were prescribed PCSK9i, 131 (40.9%) EPA, 46 (14.4%) SGLT2i, and 50 (15.6%) GLP-1 RA. Nearly 80% of cases required some form of provider intervention post-prescription (authorization, appeal, financial assistance, and/or side effect management). A total of 70% of adult patients with type 2 diabetes on metformin and with an HgbA1C >7% were treated with a SGLT2i and/or GLP-1 RA - either initiated prior to or during the study period. Median monthly drug cost for the total cohort was reduced from $595.00 pre-insurance approval to $70.50 post-insurance approval, to $7.00 post-financial assistance intervention. The medications were well tolerated with any side effect occurring in 28.3%, and discontinuation due to side effects in 5.8% of cases. Clinical cardiovascular events occurred in 2.7%, of which 1.9% was due to ASCVD and 0.8% to hospitalization for heart failure. Differences in medication access, cost, tolerability and clinical cardiovascular events varied widely between the medication classes.CONCLUSIONS:Initiation and management of pharmacotherapy with new evidence-based cardiovascular indications in a real-world setting requires substantial provider intervention, a workflow amenable to a multi-disciplinary approach which allows for high rates of medication access and cost minimization, and low rates of medication side effects and clinical cardiovascular events.

Abstract: Hypercholesterolemia is a leading cause of cardiovascular morbidity and mortality. Accordingly, efforts to lower apolipoprotein B–containing lipoproteins in plasma are the centerpiece of strategies for cardiovascular prevention and treatment in primary and secondary management. Despite the importance of this endeavor, many patients do not achieve appropriate low-density lipoprotein cholesterol (LDL-C) and non–high-density lipoprotein cholesterol (non-HDL-C) goals, even among those who have experienced atherosclerotic cardiovascular disease. The development of new LDL-C-lowering medications with alternative mechanisms of action will facilitate improved goal achievement in high-risk patients. Inclisiran is a novel small interfering RNA–based drug that is experimental in the United States and approved for clinical use in the European Union. It lowers LDL-C and other apolipoprotein B–containing lipoproteins by reducing production of proprotein convertase subtilisin/kexin Type 9 (PCSK9), a protein that normally contributes to LDL-receptor degradation, thereby increasing LDL-receptor density and recycling in hepatocytes. Although the lipid-lowering efficacy of inclisiran is comparable with results achieved with PCSK9-blocking monoclonal antibodies (alirocumab and evolocumab), there are several important differences between the 2 drug classes. First, inclisiran reduces levels of PCSK9 both intracellularly and extracellularly by blocking translation of and degrading PCSK9 messenger RNA. Second, the long biological half-life of inclisiran produces sustained LDL-C lowering with twice yearly dosing. Third, although PCSK9-blocking monoclonal antibodies drugs are proven to reduce atherosclerotic cardiovascular disease events, clinical outcomes trials with inclisiran are still in progress. In this article, we review the clinical development of inclisiran, its mechanism of action, lipid-lowering efficacy, safety and tolerability, and potential clinical role of this promising new agent.