BACKGROUND:Lipoprotein(a) [Lp(a)] is a genetically determined, independent risk factor for atherosclerotic cardiovascular disease (ASCVD) and calcific aortic valve disease. Currently, the only Food and Drug Administration-approved treatment for Lp(a) reduction is lipoprotein apheresis. Emerging targeted pharmacotherapies have shown significant reductions in Lp(a) levels in phase 2 trials. Phase 3 trials are currently underway to assess whether those significant Lp(a) reductions reduce the risk of major adverse cardiovascular events (MACE). SOURCES OF MATERIAL:PubMed, ClinicalTrials.gov. ABSTRACT OF FINDINGS: Certain lipid-lowering pharmacotherapies, such as proprotein convertase subtilisin/kexin type 9 inhibitor monoclonal antibodies and small-interfering RNA therapeutics, have shown modest reductions in Lp(a) in conjunction with their primary low-density lipoprotein cholesterol-lowering effect. Lp(a)-targeted pharmacotherapies, such as antisense oligonucleotides, small interfering RNA therapeutics, and small molecule inhibitors, significantly reduce Lp(a) levels in phase 2 clinical trials. CONCLUSION:The Lp(a) clinical trials landscape now includes multiple therapies in development, including several in phase 3 CV outcomes trials. Results are highly anticipated and will reveal whether significant Lp(a) reduction prevents MACEs in various groups of patients with different forms of ASCVD or CV risk factors, different degrees of baseline Lp(a) elevation, and in the setting of different absolute and percentage reductions in Lp(a).

OBJECTIVE:Examine time-restricted eating (TRE) as a strategy to promote weight loss and cardiometabolic health in adults with obesity. METHODS:TRE in obesity and ADipose Tissue (TREAD) was a single-center 12-week RCT, involving 1:1 randomization to 10-h TRE versus standard of care (SOC) in adults with obesity (BMI 30-50 kg/m2) without diabetes and baseline eating window ≥ 14 h/day. The primary endpoint was change in weight (kg). Exploratory RNA-seq in subcutaneous abdominal adipose tissue was performed in a subgroup of participants. RESULTS:A total of 61 participants were randomized, and 52 (26 TRE, 26 SOC) completed the study. Mean ± SD age was 55 ± 12.1 years, n = 35 were (58%) women, n = 35 were non-Hispanic White (58%), and BMI was 35.5 ± 4.8 kg/m2. With TRE, the mean total reduction in weight from baseline to end of study was -4.59 kg (95% CI -5.51, -3.67) (-4.6%) versus -1.68 kg (95% CI -2.59, -0.77) (-1.7%) with SOC (between-group difference -2.91 kg [-4.21, -1.60]) (p < 0.001), primarily through loss of body fat. Downregulation of proinflammatory genes was observed in adipose tissue during TRE. CONCLUSIONS:In adults with obesity, compared with SOC dietary counseling alone, TRE promotes weight loss, healthier body composition, and, in exploratory analyses, reduction in adipose tissue proinflammatory gene expression. TRIAL REGISTRATION:ClinicalTrials.gov identifier: NCT04916730.

Summarize current literature on the use of coronary artery imaging modalities in examining the atherosclerotic and arterial inflammatory manifestations of elevated lipoprotein(a) [Lp(a)]. Evaluate the evolving role of coronary imaging in risk stratification and treatment decisions. While Lp(a) and calcium scoring (CAC) are independently associated with cardiovascular risk, Lp(a) is associated with CAC incidence and progression. Lp(a) is associated with greater plaque prevalence, multivessel disease, and high-risk morphologies, while also being linked to accelerated progression of mixed and lipid-rich plaque by coronary CT angiography. Intravascular imaging modalities further show associations between Lp(a) and thin-cap fibroatheroma, lipid-rich plaque, percent atheroma volume, and plaque progression. Lp(a) is associated with non-calcified or mixed coronary plaque morphology and progression, as well as increased risk of high-risk plaque features. While additional research is needed, current literature suggests that coronary imaging may be an important tool in cardiovascular risk stratification for individuals with elevated Lp(a).

Background There is a complex interplay between inflammation and lipoprotein(a) [Lp(a)]. Objectives Examine whether individuals with autoimmune or inflammatory diseases (AIIDs) are more likely to have elevated Lp(a). Methods Cross-sectional study assessing the relationship between Lp(a) and 6 AIIDs using data from electronic health records from 5 University of California Health Systems between January 1, 2012 and December 31, 2024. Included patients had at least 1 Lp(a) measurement and were stratified by the presence of one or more AIID diagnosis vs individuals with atherosclerotic cardiovascular disease (ASCVD) vs controls (without AIIDs or ASCVD). Results A total of 49,431 patients with at least 1 Lp(a) measurement were included (7,995 with AIID, 8,633 with ASCVD, 34,741 controls). Those with AIIDs had a mean (SD) age of 61.1 (13.7) years, 45.7% were women, and 66.9% were White individuals. Among those with AIIDs, 28.3% (n = 2,259) had Lp(a) >50 mg/dL vs 24.6% (n = 8,560) of controls (P < 0.001) and 21.3% had Lp(a) >70 mg/dL vs 17.2% of controls (P < 0.001). The adjusted odds (95% CI) of Lp(a) >50 mg/dL was 1.22 (1.15-1.29) in those with AIIDs vs controls and was especially high in those with gout (1.33 [1.23-1.44]), inflammatory bowel disease (1.26 [1.06-1.49]), and ankylosing spondylitis (1.21 [1.09-1.34]). The prevalence of Lp(a) >50 mg/dL for AIIDs was between that of controls and those with ASCVD. Conclusions Individuals with AIIDs are more likely to have elevated Lp(a) (>50 mg/dL and >70 mg/dL). Further study of the relationship between inflammation and Lp(a) in this population is needed.

The recent 2026 American College of Cardiology/American Heart Association Multisociety Guideline on the Management of Dyslipidemia joins the growing international consensus that lipoprotein(a) [Lp(a)] should be tested at least once in all adults. Despite the estimation that approximately 1 in 5 individuals have Lp(a) levels at or above those that are clearly associated with an increased risk for atherosclerotic cardiovascular disease and calcific aortic valve stenosis (≥50 mg/dL or ≥125 nmol/L), data from recent studies reveal very low testing rates across the general population. Thus, expanded Lp(a) testing is urgently needed. Along with guidance to test all adults for Lp(a), solutions are needed to help address remaining knowledge gaps, barriers to testing, and nuances in the clinical use of Lp(a). Studies designed to address these unmet needs should be prioritized as we enter the era of universal Lp(a) testing in adults.

Type 2 diabetes mellitus (T2DM), marked by insulin resistance and impaired blood glucose regulation, can lead to serious complications when poorly controlled. Recent studies highlight interactions between diet, sleep, and metabolic disorders, showing that elevated nighttime glucose levels are associated with a higher risk of cardiometabolic disorders. Time-restricted eating (TRE) is a lifestyle strategy that aligns dietary intake with the circadian system with a consistent 8- to 10-hour eating window during the day. TRE is a safe and effective lifestyle intervention that improves cardiovascular health and glycemic control, and may provide additional benefits beyond stable use of a glucagon-like peptide-1 receptor agonist (GLP-1RA). The three patients presented here participated in a clinical trial for adults with T2DM in which they were instructed to follow a consistent 8 to 10-hour TRE intervention for 3 months (NCT05365529). Assessments, including fasted blood draws, 10-day continuous glucose monitor (CGM) use, and 14-day actigraphy to measure sleep-wake cycles, were conducted at baseline and 3 months. At baseline, all 3 patients were on stable GLP-1RA and exhibited high mean glucose levels (>130mg/dL) during their nightly sleep. Following the 3-month TRE intervention, all 3 patients experienced reductions in hemoglobin A1c (HbA1c) and nighttime glucose, along with improved time in range (TIR) during sleep. This case series highlights the potential benefits of TRE, alongside GLP-1RA use, on nighttime glucose levels, while also underscoring the potential of CGM to identify glycemic phenotypes that may predict specific responses to TRE, demonstrating the importance of a personalized approach.

BACKGROUND:Ischemic stroke in adults younger than 60 years often occurs in the setting of underrecognized cardiometabolic risk. OBJECTIVE AND METHODS:We conducted a retrospective cohort study of 323 patients of <60 years admitted with ischemic stroke (2021-2025) to evaluate whether incidentally detected fatty liver is associated with subclinical vascular disease and lipid-lowering therapy use. RESULTS:Fatty liver was identified in 26% of patients and was associated with higher triglycerides, diabetes, and antihypertensive use. Vascular calcification in any bed was more prevalent among those with fatty liver (84.5% vs. 66.9%, P = 0.002) with significant associations across coronary, carotid, thoracic aortic and valvular sites. In multivariable analysis, fatty liver remained independently associated with vascular calcification (OR 2.94, P = 0.009). Despite this, lipid-lowering therapy use was low overall (32.8%) not independently associated with fatty liver or calcification. CONCLUSION:These findings suggest fatty liver is an underrecognized marker of vascular risk and highlight a gap between imaging-detected disease burden and preventive treatment in younger stroke patients.

BACKGROUND:Homozygous familial hypercholesterolemia (HoFH) is challenging to treat, requiring intensive lipid-lowering therapy often with novel therapies like evinacumab (angiopoietin-like 3 (ANGPLT3) inhibitor) and procedures like lipoprotein apheresis or therapeutic plasma exchange. CASE SUMMARY:A 47-year-old woman with HoFH and recurrent atherosclerotic cardiovascular disease events presented with intolerance to multiple lipid-lowering therapies and lipoprotein apheresis. She was treated with therapeutic plasma exchange and maximally-tolerated pharmacotherapies, including evinacumab. Treatment was successful but required medical flights every 2 weeks and premedication to prevent anaphylactoid-like reactions. DISCUSSION:Novel therapies like evinacumab and less-frequently used treatments like therapeutic plasma exchange are important options for patients with HoFH experiencing intolerance to standard lipid-lowering therapies. Premedications can be used to manage allergic and allergy-like reactions. TAKE-HOME MESSAGES:Persistence and use of combination therapies are required in treating HoFH, especially when patients experience intolerance to commonly used treatments. Premedications can prevent allergic and allergy-like reactions to therapies in HoFH.

This National Lipid Association Expert Clinical Review (ECR) describes the roles of multidisciplinary care team members in optimizing the management of lipid disorders and promoting cardiometabolic health, including the contributions of physicians, advanced practice providers, pharmacists, registered dietitian nutritionists, nurses, and genetic counselors. Patients benefit from a collaborative approach to the management of dyslipidemias and cardiometabolic risk through improved diagnosis and treatment, access to comprehensive and evidence-based lifestyle interventions, optimization of pharmacotherapy, and patient education and empowerment. Certain multidisciplinary team members may not be readily accessible in all practice settings. Therefore, this ECR provides suggestions for accessing community resources to expand the reach of multidisciplinary care to a greater number of patients.

Introduction The efficacy of statin therapy in improving cardiac allograft vasculopathy (CAV)-free survival in heart transplant (HTx) recipients is well established. Drug interactions with calcineurin inhibitors is a major barrier to statin utilization and uptitration. Patients are frequently on a fixed statin dose regardless of comorbidities or lipid profile. Purpose: The aim of this study is to describe differences in statin regimen, lipid profile and CAV development between HTx recipients with high and low pre-HTx cardiovascular (CV) risk. Methods This single-center, retrospective study included all HTx recipients from 2019-2020 with survival ≥1 year, 2 lipid panels, and ≥1 intravascular ultrasound (IVUS) assessment. Recipient demographics, IVUS and medication data, and lipid profile prior to HTx and annually post-HTx were collected. Patients were categorized as high-CV risk if indication for HTx was ischemic heart disease, patient had a history of diabetes, and/or pre-HTx A1C was ≥6.5. All other patients were categorized as low CV risk. Severe CAV was defined as Stanford classification ≥4 on IVUS. Results Of 87 HTx recipients included, 43 (49%) were considered high-risk and more likely to be male (Table 1). At baseline, high-intensity statin use was more prevalent in high-risk patients, but by year 2, there was no difference in statin intensity between groups (Table 1). There was no difference in baseline lipid profiles; however, by year 2, LDL-C, HDL-C, and non-HDL-C at year 1 and non-HDL-C was higher in high-risk patients (Table 1). Severe CAV developed in 37 (43%) patients within the first 2 years post-HTx, with a trend (RR 1.5, p=0.1) toward increased risk in the high-risk CV group (22, 51%) compared to the low-risk CV group (15, 34%). Conclusions Downgrading of statin intensity after HTx was observed in high-risk patients, with a trend towards higher risk for CAV in this group. Further studies assessing individualized statin regimens informed by pre-HTx CV risk and post-HTx lipid trends on CAV development are needed.

BACKGROUND:Inclisiran is a Food and Drug Administration-approved small interfering RNA targeting proprotein convertase subtilisin/kexin type 9 (PCSK9) that lowers low-density lipoprotein cholesterol (LDL-C) by ∼50% in clinical trials. Real-world studies with inclisiran are limited. OBJECTIVE:Examine patient characteristics and the real-world safety and efficacy of inclisiran. METHODS:From 3/2022 to 11/2023, 60 patients at University of California San Diego Health met inclusion criteria of at least one follow-up LDL-C measurement ≥30 days after initiating inclisiran. Patients were examined for baseline characteristics and follow-up lipid levels measured as part of routine medical care. RESULTS:Patients were a mean (± SD) age of 71 ± 9.2 years, 31 (52%) were women, and 54 (90%) were White individuals. A total of 52 (87%) had a history of atherosclerotic cardiovascular disease. Mean ± SD LDL-C decreased 38% from 107 ± 47 mg/dL at baseline to 66 ± 41 mg/dL at first follow-up (P < .001). Excluding patients who switched from a PCSK9 inhibitor monoclonal antibody (PCSK9i mAb) within 1 month prior to starting inclisiran treatment (n = 12), a 45% decrease in LDL-C was observed (114 ± 45 mg/dL to 62 ± 41 mg/dL, P < .001). Excluding patients who switched from a PCSK9i mAb (n = 12) and patients on no background lipid-lowering therapy at time of inclisiran initiation (n = 9), LDL-C decreased 47% (102 ± 42 mg/dL to 54 ± 40 mg/dL, P < .001). Three patients (5%) reported mild side-effects that resolved by their second injection. CONCLUSION:Inclisiran in real-world practice was well-tolerated and patients on background lipid-lowering therapy who were not switching from a PCSK9i mAb to inclisiran observed LDL-C reductions of approximately 50%, consistent with clinical trials.

Lifestyle intervention is the cornerstone of the prevention of atherosclerotic cardiovascular disease (ASCVD). Several health authorities and scientific organizations have provided dietary guidance for ASCVD prevention, including recommendations for healthful dietary patterns. Recently, intermittent fasting and time-restricted eating (TRE) have become popular dietary approaches. Findings from clinical studies suggest that intermittent fasting and TRE may result in improvements in cardiometabolic risk factors, especially in patients with metabolic dysfunction. This Journal of Clinical Lipidology Roundtable presents a conversation between Drs. Carol F. Kirkpatrick, Kevin C. Maki, Kristina S. Petersen, and Michael J. Wilkinson about dietary recommendations, intermittent fasting, and TRE. The discussion highlights the current dietary recommendations for ASCVD prevention and the potential roles of intermittent fasting and TRE for improving cardiometabolic health.

BACKGROUND: Cardiac allograft vasculopathy (CAV) is a leading cause of morbidity and mortality after heart transplantation (HTx). There are limited contemporary studies examining post-transplant lipid management and cardiometabolic health. OBJECTIVE: We study the burden of cardiometabolic derangements post transplantation and its impact on CAV in a modern cohort of HTx recipients. METHODS: All HTx recipients between January 2019 and December 2020, with 2 lipid assessments and angiographic surveillance were included. Logistic regression was used to assess association of lipid levels with cardiovascular outcomes and CAV. RESULTS: Among 87 HTx recipients, atherogenic lipids were significantly elevated after Htx. Median low-density lipoprotein cholesterol increased from a baseline level of 69.5 mg/dL to 86.5 mg/dL, p = .002, non-high-density lipoprotein cholesterol (non-HDL-C) 91.5 mg/dL to 118 mg/dL, p < .001, triglycerides 94.5 mg/dL to 133 mg/dL, p < .001, and remnant cholesterol 19 mg/dL to 27 mg/dL, p < .001. Increases in non-HDL-C, triglycerides, and remnant cholesterol were significantly associated with increased risk of CAV (Stanford Grade 4 and intimal thickness). Increases in triglycerides and remnant cholesterol were associated with increased risk of composite major adverse cardiovascular events (MACE). CONCLUSION: We demonstrate a significant increase in atherogenic lipids 2 years following transplantation with low use (20%) of high-intensity statin. Increase in atherogenic lipids was associated with increased risk of CAV and increase in triglycerides and remnant cholesterol with increased MACE. Future studies examining cardiometabolic consequences of HTx and optimal treatment strategies to reduce risk of CAV and MACE are needed. (c) 2024 National Lipid Association. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license ( http://creativecommons.org/licenses/by-nc-nd/4.0/)

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.

AIMS:With no currently available targeted therapies for lipoprotein(a) [Lp(a)] lowering, proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) may be an option for management of increased cardiovascular risk in individuals with elevated Lp(a). However, Lp(a) lowering with PCSK9i is variable. We aimed to evaluate the real-world change in Lp(a) and predictors of response. METHODS:Using data from the University of California Health Data Warehouse, we conducted a multi-center retrospective study among adults prescribed PCSK9i therapy with available Lp(a) measurement before and after prescription. We evaluated change in Lp(a) compared to baseline and evaluated potential predictors of Lp(a) reduction using multivariable linear regression, including among patients with multiple serial Lp(a) measurements. RESULTS:Among 453 included individuals, PCSK9i use was associated with a median 17.3 [IQR 35.3, 0.0]% and 11.3 [31.7, 0.0] mg/dL reduction in Lp(a) overall. Among those with Lp(a) >50 mg/dL, a 17.7 [33.6, 0.0]% and 19.2 [42.0, 0.0] mg/dL reduction was observed. Higher baseline Lp(a) level (β -0.31, p<0.001) was a significant predictor of greater Lp(a) reduction, while female sex was associated with less reduction (β 9.28, p=0.02). Results were consistent across Lp(a) assay types and by PCSK9i type and sustained in those with serial Lp(a) measurements (n=274). In contrast, in a control group of 6750 individuals, a median change of 0.00 [-2.00, 3.00] mg/dL in Lp(a) was noted in serial measurements. CONCLUSIONS:PCSK9i are associated with modest Lp(a) lowering of approximately 17% in real-world clinical practice, with a consistent percent reduction by baseline Lp(a) level, PCSK9i type and Lp(a) assay type. Predictors of Lp(a) reduction include baseline Lp(a) level and sex without significant variation by age, race/ethnicity or other evaluated comorbidities.

BACKGROUND:Aldosterone dysregulation contributes to hypertension. Lorundrostat is an aldosterone synthase inhibitor, but data on its efficacy and safety in patients with hypertension are limited. METHODS:In this multicenter, double-blind, randomized, placebo-controlled trial, we assigned participants who were receiving two to five antihypertensive medications and had a blood-pressure measurement of 140/90 mm Hg or higher obtained during an office visit to undergo a standardized antihypertensive regimen for 3 weeks. Subsequently, participants with an average 24-hour ambulatory blood pressure of 130/80 mm Hg or higher were assigned to receive placebo, lorundrostat at a stable dose of 50 mg daily (the stable-dose group), or lorundrostat at a starting dose of 50 mg daily, with an increase to 100 mg daily if systolic blood pressure was 130 mm Hg or higher after 4 weeks (the dose-adjustment group). The primary end point was the change in 24-hour average systolic blood pressure from baseline to week 12, assessed as the least-squares mean difference from placebo (the placebo-adjusted change) in each lorundrostat group. A key secondary end point was the change in 24-hour average systolic blood pressure from baseline to week 4, assessed as the placebo-adjusted change in the combined lorundrostat groups. RESULTS:A total of 285 participants underwent randomization; 94 were assigned to the stable-dose group, 96 to the dose-adjustment group, and 95 to the placebo group. The mean age was 60 years, and 150 participants (53%) were Black. After 12 weeks, the least-squares mean change in 24-hour average systolic blood pressure was -15.4 mm Hg in the stable-dose group, -13.9 mm Hg in the dose-adjustment group, and -7.4 mm Hg in the placebo group. The placebo-adjusted change in blood pressure was -7.9 mm Hg (97.5% confidence interval [CI], -13.3 to -2.6) in the stable-dose group and -6.5 mm Hg (97.5% CI, -11.8 to -1.2) in the dose-adjustment group. The placebo-adjusted change in 24-hour average systolic blood pressure from baseline to week 4 in the combined lorundrostat groups was -5.3 mm Hg (95% CI, -8.4 to -2.3). A potassium level above 6.0 mmol per liter occurred in 5 participants (5%) in the stable-dose group, 7 participants (7%) in the dose-adjustment group, and no participants in the placebo group. CONCLUSIONS:Lorundrostat was associated with greater reductions in 24-hour average blood pressure than placebo in participants with uncontrolled and treatment-resistant hypertension. (Funded by Mineralys Therapeutics; Advance-HTN ClinicalTrials.gov number, NCT05769608.).