Changes In Low-density Lipoprotein Cholesterol Research Articles

Degree of serum LDL cholesterol reduction by simvastatin and ezetimibe is dependent on baseline LDL cholesterol concentration but not on baseline values and changes of cholesterol synthesis and absorption parameters.

We questioned whether the baseline status of low-density lipoprotein cholesterol (LDL-C), cholesterol synthesis and absorption, and the changes in these parameters determine the change in serum LDL-C under statin or ezetimibe treatment or under combination treatment. 37 mildly hypercholesterolemic healthy male subjects were studied under placebo, simvastatin (20mg/d), ezetimibe (10mg/d), and combination treatment. We correlated the change of LDL-C (ΔLDL-C) under treatment with the placebo end values of LDL-C (baseline), whole-body cholesterol synthesis, and hepatic cholesterol synthesis (serum lathosterol to cholesterol ratio) as well as fractional absorption rate (FAR) of cholesterol and serum campesterol to cholesterol ratio. The change in serum LDL-C was also correlated with the changes in synthesis and absorption parameters. ΔLDL-C was highly negatively related to baseline LDL-C under ezetimibe (p<0.0001), simvastatin (p<0.0001), and combination treatment (p<0.0001). Under combination treatment, LDL-C lowering appears possible from baseline values of 10 mg/dL upwards, while ΔLDL-C was independent of the baseline value (-50 to -60%). ΔLDL-C was positively associated with placebo FAR under ezetimibe (p=0.0106) and combination treatment (p=0.0457). No associations were found between ΔLDL-C and baseline values for synthesis nor between ΔLDL-C and changes in synthesis and absorption surrogate markers. Under ezetimibe, simvastatin, and combination treatment, ΔLDL-C is predominantly dependent on the baseline LDL-C concentration. We hypothesize that the concentration gradient between serum LDL-C and hepatic cellular cholesterol determines the efficiency of serum LDL-C lowering. Combination treatment is the preferred treatment.

Obicetrapib on Top of Maximally Tolerated Lipid-Modifying Therapies in Participants With or at High Risk for Atherosclerotic Cardiovascular Disease: Rationale and Designs of BROADWAY and BROOKLYN.

Obicetrapib, a novel, selective cholesteryl ester transfer protein (CETP) inhibitor, reduces low-density lipoprotein cholesterol (LDL-C), LDL particles, apolipoprotein (Apo) B, and lipoprotein(a) [Lp(a)] and increases high-density lipoprotein cholesterol (HDL-C) when added to statins with or without ezetimibe. By substantially reducing LDL-C, obicetrapib has the potential to lower atherogenic lipoproteins in patients with atherosclerotic cardiovascular disease (ASCVD) or heterozygous familial hypercholesterolemia (HeFH) whose LDL-C levels remain high despite treatment with available maximally tolerated lipid-modifying therapies, addressing an unmet medical need in a patient population at high risk for cardiovascular events. BROADWAY (NCT05142722) and BROOKLYN (NCT05425745) are ongoing placebo-controlled, double-blind, randomized Phase III trials designed to examine the efficacy, safety, and tolerability of obicetrapib as an adjunct to dietary intervention and maximally tolerated lipid-modifying therapies in participants with a history of ASCVD and/or underlying HeFH whose LDL-C is not adequately controlled. The primary efficacy endpoint was the percent change in LDL-C from baseline to day 84. Other endpoints included changes in Apo B, non-HDL-C, HDL-C, Apo A1, Lp(a) and triglycerides in addition to parameters evaluating safety, tolerability, and pharmacokinetics. BROADWAY also included an adjudicated assessment of major adverse cardiovascular events, measurements of glucose homeostasis, and an ambulatory blood pressure monitoring substudy. A total of 2532 participants were randomized in BROADWAY and 354 in BROOKLYN to receive obicetrapib 10 mg or placebo (2:1) for 365 days with follow-up through 35 days after the last dose. Results from both trials are anticipated in 2024. These trials will provide safety and efficacy data to support the potential use of obicetrapib among patients with ASCVD or HeFH with elevated LDL-C for whom existing therapies are not sufficiently effective or well-tolerated.

Remnant cholesterol, LDL cholesterol, and apoB absolute mass changes explain results of the PROMINENT trial

Background and aimsThe PROMINENT trial, a cardiovascular outcome trial of the triglyceride- and remnant cholesterol-lowering agent pemafibrate, has shown neutral results despite reduction in plasma triglycerides and remnant cholesterol. We tested the hypothesis that absolute mass changes in remnant cholesterol, LDL cholesterol, and apolipoprotein B explain the results of the PROMINENT trial. MethodsAmong 108,431 individuals from the Copenhagen General Population Study (CGPS), those who met the key inclusion criteria of the PROMINENT trial were analyzed to mimic the trial design. Endpoint atherosclerotic cardiovascular disease (ASCVD) was cardiovascular death, myocardial infarction, ischemic stroke, and coronary revascularization as defined in PROMINENT. ResultsIn the PROMINENT trial, treatment with pemafibrate resulted in -7 mg/dL (−0.18 mmol/L; -18 %) change in remnant cholesterol, +10 mg/dL (+0.26 mmol/L; +12 %) LDL cholesterol, and +5 mg/dL (+0.05 g/L; +5 %) apolipoprotein B. In the CGPS mimicking PROMINENT, the estimated hazard ratios for ASCVD were 0.97 (95 % confidence interval: 0.94–0.99) for a -7 mg/dL (−0.18 mmol/L) change in remnant cholesterol, 1.04 (1.01–1.07) for a +10 mg/dL (+0.26 mmol/L) change in LDL cholesterol, and 1.02 (1.01–1.03) for a +5 mg/dL (+0.05 g/L) change in apolipoprotein B. When combining absolute changes in remnant cholesterol, LDL cholesterol, and apolipoprotein B, the estimated hazard ratio for ASCVD was 1.05 (0.96–1.14) in the CGPS mimicking PROMINENT compared to 1.03 (0.91–1.15) in the PROMINENT trial. ConclusionsAbsolute mass changes in remnant cholesterol, LDL cholesterol, and apolipoprotein B can explain results of the PROMINENT trial. The 3 mg/dL (0.08 mmol/L) higher total atherogenic cholesterol together with 5 mg/dL (0.05 g/L) higher apolipoprotein B seem to explain the trend toward more ASCVD in the pemafibrate arm.

A Technology-Assisted Web Application for Consumer Access to a Nonprescription Statin Medication.

Although statins reduce adverse cardiovascular outcomes, less than half of eligible patients receive treatment. A nonprescription statin has the potential to improve access to statins. To assess concordance between clinician and consumer assessment of eligibility for nonprescription statin treatment using a Technology Assisted Self-Selection (TASS) Web Application (Web App) and evaluate effect on low-density lipoprotein cholesterol (LDL-C) levels. A prospective actual use 6-month study to evaluate use of a Web App to qualify participants without a medical background for a moderate intensity statin based on current guidelines. Participants entered demographic information, cholesterol values, blood pressure and concomitant medications into the Web App, resulting in three possible outcomes- "Do Not Use," "Ask a Doctor" or "OK to Use". The study included 1196 participants, median age 63 (IQR, 57-68), 39.6% women, 79.3% White, 11.7% Black, and 4.1% with limited literacy. Mean LDL-C was 139.6 mg/dL (SD, 28.3) and median calculated 10-year risk of atherosclerotic cardiovascular disease was 10.1% (IQR, 7.3-14.0). Initial Web App self-selection resulted in an outcome concordant with clinician assessment in 90.7% (95% CI, 88.9-92.3) of participants and 98.1% (95% CI, 97.1-98.8) had a concordant final use outcome during treatment. Mean percent change in LDL-C was -35.5% (95% CI, -36.6 to -34.3). Serious adverse events occurred in 27 (2.3%) participants, none related to study drug. In this actual use study, a technology assisted Web App allowed >90% of consumers to correctly self-select for statin use and achieve clinically important LDL-C reductions.

An Inclisiran First Strategy vs Usual Care in Patients with Atherosclerosis.

Most patients with atherosclerotic cardiovascular disease (ASCVD) fail to achieve guideline-directed low-density lipoprotein cholesterol (LDL-C) goals. Twice-yearly inclisiran lowers LDL-C by ∼50% when added to statins. To evaluate the effectiveness of an "inclisiran first" implementation strategy (adding inclisiran immediately upon failure to reach LDL-C <70 mg/dL despite receiving maximally tolerated statins) versus representative usual care in US patients with ASCVD. VICTORION-INITIATE, a prospective, pragmatically designed trial, randomized patients 1:1 to inclisiran (284 mg at Days 0, 90, and 270) plus usual care (lipid management at treating physician's discretion) versus usual care alone. Primary endpoints were percentage change in LDL-C from baseline and statin discontinuation rates. We randomized 450 patients (30.9% female, 12.4% Black, 15.3% Hispanic); mean baseline LDL-C 97.4 mg/dL. The "inclisiran first" strategy led to significantly greater reductions in LDL-C from baseline to Day 330 versus usual care (60.0% vs 7.0%; p<0.001). Statin discontinuation rates with "inclisiran first" (6.0%) were noninferior versus usual care (16.7%). More "inclisiran first" patients achieved LDL-C goals vs usual care (<70 mg/dL: 81.8% vs 22.2%; <55 mg/dL: 71.6% vs 8.9%; p<0.001). Treatment-emergent adverse event (TEAE) and serious TEAE rates compared similarly between treatment strategies (62.8% vs 53.7% and 11.5% vs 13.4%, respectively). Injection-site TEAEs and TEAEs causing treatment withdrawal occurred more commonly with "inclisiran first" than usual care (10.3% vs 0.0%, and 2.6% vs 0.5%, respectively). An "inclisiran first" implementation strategy led to greater LDL-C lowering compared with usual care without discouraging statin use or raising new safety concerns.

The Lipid Intensive Drug Therapy for Sepsis Phase II Pilot Clinical Trial.

Low cholesterol levels in early sepsis patients are associated with mortality. We sought to test if IV lipid emulsion administration to sepsis patients with low cholesterol levels would prevent a decline or increase total cholesterol levels at 48 hours. Phase II, adaptive, randomized pilot clinical trial powered for 48 patients. Emergency department or ICU of an academic medical center. Sepsis patients (first 24 hr) with Sequential Organ Failure Assessment greater than or equal to 4 or shock. Patients meeting study criteria, including screening total cholesterol levels less than or equal to 100 mg/dL or high-density lipoprotein cholesterol (HDL-C) + low-density lipoprotein cholesterol (LDL-C) less than or equal to 70 mg/dL, were randomized to receive one of three doses of lipid emulsion administered twice in 48 hours or no drug (controls). The primary endpoint was a change in serum total cholesterol (48 hr - enrollment) between groups. Forty-nine patients were enrolled and randomized. Two patients randomized to lipid emulsion were withdrawn before drug administration. Data for 24 control patients and 23 lipid emulsion patients were analyzed. The mean change in total cholesterol from enrollment to 48 hours was not different between groups and was 5 mg/dL (sd 20) for lipid emulsion patients, and 2 mg/dL (sd 18) for control patients (p = 0.62). The mean changes in HDL-C and LDL-C were similar between groups. Mean change in triglycerides was elevated in lipid emulsion patients (61 mg/dL, sd 87) compared with controls (20 mg/dL, sd 70, p = 0.086). The 48-hour change in SOFA score was -2 (interquartile range [IQR] -4, -1) for control patients and -2 (IQR -3, 0) for lipid emulsion patients (p = 0.46). Administration of IV lipid emulsion to early sepsis patients with low cholesterol levels did not influence change in cholesterol levels from enrollment to 48 hours.

Effect of sodium-glucose cotransporter 2 inhibitors on serum low-density lipoprotein cholesterol in Japanese patients with type 2 diabetes mellitus.

We aimed to evaluate factors that influence changes in blood low-density lipoprotein cholesterol (LDL-C) levels after treatment with sodium-glucose cotransporter 2 (SGLT2) inhibitors in Japanese patients with type 2 diabetes. We retrospectively analyzed clinical data of outpatients newly initiated on SGLT2 inhibitors (n = 176) and other oral antidiabetic drugs (n = 227). The patients were classified into four subgroups according to statin administration and baseline LDL-C levels (<120 or ≥120 mg/dL). Clinical characteristics were compared among the subgroups. Multivariate analysis was carried out to identify factors contributing to changes in LDL-C. The median follow-up period was 13.0 weeks (range 11.9-14.1 weeks, min 8 weeks, maximum 16 weeks) in the SGLT2i group, and 12.0 weeks (range 10.0-14.0 weeks, min 8 weeks, maximum 16 weeks) in the control group. Both groups showed a significant decrease in LDL-C (SGLT2i group -3.8 ± 24.7 mg/dL, control group -3.4 ± 15.0 mg/dL). Multivariate regression analyses showed that in both groups, the change in LDL-C depended on statin use and baseline LDL-C levels. Stratified analyses showed that LDL-C level was significantly decreased in statin users with baseline LDL-C ≥120 mg/dL (from 148.9 ± 33.5 to 109.3 ± 17.9 mg/dL, P = 0.002), and significantly increased in statin non-users with baseline LDL-C <120 mg/dL (from 96.3 ± 27.3 to 104.7 ± 24.8 mg/dL, P = 0.002). These changes were more characteristic for SGLT2 inhibitors than for other oral antidiabetic drugs (P for interaction = 0.010 and <0.001, respectively). LDL-C levels and statin medication at baseline influence changes in LDL-C after SGLT2 inhibitors treatment in Japanese patients with type 2 diabetes.

Non-Interventional Weight Changes Are Associated with Alterations in Lipid Profiles and in the Triglyceride-to-HDL Cholesterol Ratio.

Obesity is associated with dyslipidemia, and weight loss can improve obese patients' lipid profile. Here, we assessed whether non-interventional weight changes are associated with alterations in lipid profile, particularly the triglyceride (TG)-to-high-density lipoprotein cholesterol (HDL-C) ratio (TG/HDL-C). In this retrospective analysis of subjects referred to medical screening, body mass index (BMI), low-density lipoprotein cholesterol (LDL-C), TG, and HDL-C levels were measured annually. Patients were divided according to BMI changes between visits. The primary outcomes were the changes in LDL-C, TG, HDL-C, and the TG/HDL-C ratio between visits. The final analysis included 18,828 subjects. During the year of follow-up, 9.3% of the study population lost more than 5% of their weight and 9.2% gained more than 5% of their weight. The effect of weight changes on TG and on the TG/HDL-C ratio was remarkable. Patients with greater BMI increases showed greater increases in their TG/HDL-C ratio, and conversely, a decreased BMI level had lower TG/HDL-C ratios. This is true even for moderate changes of more than 2.5% in BMI. Non-interventional weight changes, even modest ones, are associated with significant alterations in the lipid profile. Understanding that modest, non-interventional weight changes are associated with alterations in the TG/HDL-C ratio may aid in better risk stratification and primary prevention of CV morbidity and mortality.

Alirocumab in Pediatric Patients With Heterozygous Familial Hypercholesterolemia

Many pediatric patients with heterozygous familial hypercholesterolemia (HeFH) cannot reach recommended low-density lipoprotein cholesterol (LDL-C) concentrations on statins alone and require adjunct lipid-lowering therapy (LLT); the use of alirocumab in pediatric patients requires evaluation. To assess the efficacy of alirocumab in pediatric patients with inadequately controlled HeFH. This was a phase 3, randomized clinical trial conducted between May 2018 and August 2022 at 43 centers in 24 countries. Pediatric patients aged 8 to 17 years with HeFH, LDL-C 130 mg/dL or greater, and receiving statins or other LLTs were included. Following consecutive enrollment into dosing cohorts, 25 of 99 patients screened for dosing every 2 weeks (Q2W) failed screening; 25 of 104 patients screened for dosing every 4 weeks (Q4W) failed screening. A total of 70 of 74 Q2W patients (95%) and 75 of 79 Q4W patients (95%) completed the double-blind period. Patients were randomized 2:1 to subcutaneous alirocumab or placebo and Q2W or Q4W. Dosage was based on weight (40 mg for Q2W or 150 mg for Q4W if <50 kg; 75 mg for Q2W or 300 mg for Q4W if ≥50 kg) and adjusted at week 12 if LDL-C was 110 mg/dL or greater at week 8. After the 24-week double-blind period, patients could receive alirocumab in an 80-week open-label period. The primary end point was percent change in LDL-C from baseline to week 24 in each cohort. Among 153 patients randomized to receive alirocumab or placebo (mean [range] age, 12.9 [8-17] years; 87 [56.9%] female), alirocumab showed statistically significant reductions in LDL-C vs placebo in both cohorts at week 24. Least squares mean difference in percentage change from baseline was -43.3% (97.5% CI, -56.0 to -30.7; P < .001) Q2W and -33.8% (97.5% CI, -46.4 to -21.2; P < .001) Q4W. Hierarchical analysis of secondary efficacy end points demonstrated significant improvements in other lipid parameters at weeks 12 and 24 with alirocumab. Two patients receiving alirocumab Q4W experienced adverse events leading to discontinuation. No significant difference in adverse event incidence was observed between treatment groups. Open-label period findings were consistent with the double-blind period. The findings in this study indicate that alirocumab Q2W or Q4W significantly may be useful for reducing LDL-C and other lipid parameters and be well tolerated in pediatric patients with HeFH inadequately controlled with statins. ClinicalTrials.gov Identifier: NCT03510884.

A 6-month exercise intervention clinical trial in women: effects of physical activity on multi-omics biomarkers and health during the first wave of COVID-19 in Korea

BackgroundCoronavirus disease 2019 (COVID-19) was first reported in December 2019 and the first case in Korea was confirmed on January 20, 2020. Due to the absence of therapeutic agents and vaccines, the Korean government implemented social distancing on February 29, 2020. This study aimed to examine the effect of physical activity (PA) on health through changes in multi-omics biomarkers with a 6-month of exercise intervention during the first wave of COVID-19 in Korea.MethodsTwenty-seven healthy middle-aged women were recruited and 14 subjects completed the exercise intervention. The mean age (± SD) was 46.3 (± 5.33) and the mean BMI (± SD) was 24.9 (± 3.88). A total of three blood and stool samples were collected at enrollment, after period 1, and after period 2 (3-month intervals). The amount of PA was measured with an accelerometer and by questionnaire. Clinical variables were used, including blood pressure, grip strength, flexibility, and blood glucose levels and lipid markers obtained from laboratory tests. The concentration of blood metabolites was measured by targeted metabolomics. Fecal microbiome data were obtained by 16 S rRNA gene amplicon sequencing.ResultsDuring the second half period (period 2), Coronavirus disease 2019 occurred and spread out in Korea, and PA decreased compared with the first half period (period 1) (185.9 ± 168.73 min/week to 102.5 ± 82.30 min/week; p = 0.0101). Blood pressure, hemoglobin A1c (HbA1c), and low-density lipoprotein cholesterol (LDL-C) decreased in period 1 (p < 0.05) and tended to increase again during period 2 (p < 0.05). Forty metabolites were changed significantly during period 1 (FDR p < 0.05), and we found that 6 of them were correlated with changes in blood pressure, HbA1c, and LDL-C via network analysis.ConclusionsOur results may suggest that exercise improves health through changes in biomarkers at multi-omics levels. However, reduced PA due to COVID-19 can adversely affect health, emphasizing the necessity for sustained exercise and support for home-based fitness to maintain health.Trial RegistrationThe trial is retrospectively registered on ClinicalTrials.gov (NCT05927675; June 30, 2023).

Propolis extract supplementation in the complementary treatment of adults and elderly with Type 2 Diabetes Mellitus: a systematic review of clinical trial

Background &amp; aims: bee products, such as propolis, have important natural properties to help reduce the risk of chronic noncommunicable diseases. Therefore, the objective of this review was to determine whether propolis intake helps to improve laboratory and anthropometrics indicators related to metabolic changes in type 2 Diabetes mellitus. Methods: systematic review of randomized clinical trials, published between 2000 and 2021, in Pubmed, Lilacs and SciELO databases, which indicated significant effects of propolis on laboratory indicators related to glycemic homeostasis, antioxidant and anti-inflammatory status. The articles were obtained according to the model recommended by PRISMA. After general analysis, protocols were used to assess the quality of evidence, using the Jadad scale, Consort and Cochrane. Results: glycemic homeostasis was evaluated using the following laboratory indicators: HOMA-IR, HOMA-β, fructosamine, fasting glucose and glycated hemoglobin. Significant changes in fasting glucose, 2-hour postprandial glucose were indicated in 71.43% of the studies. The antioxidant potential of propolis was evaluated in 71.43% of clinical trials. There was a significant reduction in pro-inflammatory cytokines, an increase in catalase activity and an increase in the antioxidant capacity of glutathione. The lipid profile was analyzed in 42.86% of the studies, indicating significant changes in total, LDL and HDL cholesterol. Conclusion: propolis can be considered an aggregating alternative for the conventional treatment of type 2 Diabetes mellitus. However, this food supplement is not a “miraculous” product, which eliminates the need for changes in lifestyle, including eating habits and regular physical activity, as well as the use of drugs, when necessary.

Increased low-density lipoprotein cholesterol on a low-carbohydrate diet in adults with normal but not high body weight: A meta-analysis

BackgroundLow-density lipoprotein (LDL) cholesterol change with consumption of a low-carbohydrate diet (LCD) is highly variable. Identifying the source of this heterogeneity could guide clinical decision-making. ObjectivesTo evaluate LDL cholesterol change in randomized controlled trials involving LCDs, with a focus on body mass index (BMI) in kg/m2. MethodsThree electronic indexes (Pubmed, EBSCO, and Scielo) were searched for studies between 1 January, 2003 and 20 December, 2022. Two independent reviewers identified randomized controlled trials involving adults consuming <130 g/d carbohydrate and reporting BMI and LDL cholesterol change or equivalent data. Two investigators extracted relevant data, which were validated by other investigators. Data were analyzed using a random-effects model and contrasted with results of pooled individual participant data. ResultsForty-one trials with 1379 participants and a mean intervention duration of 19.4 wk were included. In a meta-regression accounting for 51.4% of the observed variability on LCDs, mean baseline BMI had a strong inverse association with LDL cholesterol change [β = –2.5 mg/dL/BMI unit, 95% confidence interval (CI): –3.7, –1.4], whereas saturated fat amount was not significantly associated with LDL cholesterol change. For trials with mean baseline BMI <25, LDL cholesterol increased by 41 mg/dL (95% CI: 19.6, 63.3) on the LCD. By contrast, for trials with a mean of BMI 25–<35, LDL cholesterol did not change, and for trials with a mean BMI ≥35, LDL cholesterol decreased by 7 mg/dL (95% CI: –12.1, –1.3). Using individual participant data, the relationship between BMI and LDL cholesterol change was not observed on higher-carbohydrate diets. ConclusionsA substantial increase in LDL cholesterol is likely for individuals with low but not high BMI with consumption of an LCD, findings that may help guide individualized nutritional management of cardiovascular disease risk. As carbohydrate restriction tends to improve other lipid and nonlipid risk factors, the clinical significance of isolated LDL cholesterol elevation in this context warrants investigation.This trial was registered at PROSPERO as CRD42022299278.

Effectiveness of Lipid-lowering Therapy for the Secondary Prevention and Achievement of Therapeutic Goals in Atherosclerotic Cardiovascular Diseases in Accordance with the American College of Cardiology/American Heart Association 2018 Guidelines on the Management of Blood Cholesterol

Introduction: According to the India Report 2020, Kerala had the highest prevalence of atherosclerotic cardiovascular diseases (ASCVDs). Dyslipidemia is a modifiable risk factor that can prevent secondary events. American College of Cardiology/American Heart Association 2018 Guidelines for the management of blood cholesterol for secondary prevention of clinical ASCVD recommend high-intensity statins and moderate-intensity statin combination therapy for achieving target low-density lipoprotein-cholesterol (LDL-C). We conducted a study to evaluate the achievement of therapeutic goals in accordance with the guidelines in a tertiary care hospital in Kerala. Materials and Methods: Three hundred and twenty adult patients prescribed with high-intensity statin monotherapy (atorvastatin 40 mg, rosuvastatin 20 mg, and rosuvastatin 40 mg) or moderate-intensity statin combination therapy (atorvastatin 10 mg and fenofibrate 145 mg) for the secondary prevention of ASCVD event were included. Data were collected from the medical records and patient interviews. Achievement of the therapeutic goal of LDL-C ≤70 mg/dL in accordance with guidelines was evaluated and compared; the mean percentage change in LDL-C was at the baseline and after 3 months. Patients were counselled on lifestyle modifications and educated about hypolipidemic agents. Since we are aiming for secondary prevention, the patients were given appropriate counselling concerning their disease and medications they are on. Dietary lifestyle modifications were also taught. Results: One hundred and thirty-eight patients achieved the therapeutic goal, with atorvastatin 40 mg (89.37%) being the most prescribed drug, followed by rosuvastatin 20 mg (5.62%) while rosuvastatin 40 mg had a higher efficacy with mean LDL reduction 65.71 ± 15.93 at 3 months follow-up. Comparing the adherence scores before and after patient counseling, the P value was found to be &lt; 0.001, indicating it is significant. Conclusion: Lifestyle modifications and lipid-lowering therapy are crucial to tackle dyslipidemia. Poor achievement of therapeutic goals implies the need for adopting measures to improve adherence and health-related outcomes for patients with ASCVD.

Thyroid markers and body composition predict LDL-cholesterol change in lean healthy women on a ketogenic diet: experimental support for the lipid energy model.

There is a large heterogeneity in LDL-cholesterol change among individuals adopting ketogenic diets. Interestingly, lean metabolically healthy individuals seem to be particularly susceptible, with an inverse association between body mass index and LDL-cholesterol change. The lipid energy model proposes that, in lean healthy individuals, carbohydrate restriction upregulates systemic lipid trafficking to meet energy demands. To test if anthropometric and energy metabolism markers predict LDL-cholesterol change during carbohydrate restriction. Ten lean, healthy, premenopausal women who habitually consumed a ketogenic diet for ≥6 months were engaged in a three-phase crossover study consisting of continued nutritional ketosis, suppression of ketosis with carbohydrate reintroduction, and return to nutritional ketosis. Each phase lasted 21 days. The predictive performance of all available relevant variables was evaluated with the linear mixed-effects models. All body composition metrics, free T3 and total T4, were significantly associated with LDL-cholesterol change. In an interaction model with BMI and free T3, both markers were significant independent and interacting predictors of LDL-cholesterol change. Neither saturated fat, HOMA-IR, leptin, adiponectin, TSH, nor rT3 was associated with LDL-cholesterol changes. Among lean, healthy women undergoing carbohydrate restriction, body composition and energy metabolism markers are major drivers of LDL-cholesterol change, not saturated fat, consistent with the lipid energy model.

An association between PPARα-L162V polymorphism and increased plasma LDL cholesterol levels after risperidone treatment

Peroxisome proliferator-activated receptor alpha (PPARα) and antipsychotic medications both influence polyunsaturated fatty acids (PUFA) homeostasis, and thus PPARα polymorphism may be linked to antipsychotic treatment response. Here we investigated whether the functional leucine 162 valine (L162V) polymorphism in PPARα influenced antipsychotic treatment in a group of psychosis patients (N = 186), as well as in a patient subgroup with risperidone, paliperidone, or combination treatment (N = 65). Antipsychotic-naïve first-episode patients and nonadherent chronic individuals were genotyped by polymerase chain reaction analysis. At baseline, and after 8 weeks of treatment with various antipsychotic medications, we assessed the patients’ Positive and Negative Syndrome Scale (PANSS) scores; PANSS factors; and metabolic syndrome-related parameters, including fasting plasma lipid and glucose levels, and body mass index. In the total patient group, PPARα polymorphism did not affect PANSS psychopathology or metabolic parameters. However, in the subgroup of patients with risperidone, paliperidone, or combination treatment, PPARα polymorphism influenced changes in plasma LDL cholesterol. Specifically, compared to PPARα-L162L homozygous patients, PPARα-L162V heterozygous individuals exhibited significantly higher increases of LDL cholesterol levels after antipsychotic treatment. The PPARα polymorphism had a strong effect size, but a relatively weak contribution to LDL cholesterol level variations (∼12.8 %).

Differential effect of atorvastatin and pravastatin on thoracic spine attenuation: A sub-analysis of a randomized clinical trial

BackgroundStatins reduce cardiovascular events and may improve bone mineral density. MethodsWe conducted a sub-analysis of a randomized clinical trial that investigated the differential effect of moderate vs intensive low-density lipoprotein cholesterol (LDL-C) lowering therapies on coronary artery calcium (CAC) scores, and used the acquired images to assess the change in radiological attenuation of selected thoracic vertebrae. Baseline and 12-month unenhanced chest CT scans were performed in 420 hyperlipidemic, postmenopausal women randomized to atorvastatin (ATV) 80 mg/day or pravastatin (PRV) 40 mg/day in the Beyond Endorsed Lipid Lowering with Electron Beam Tomography Scanning (BELLES) trial. Bone attenuation was measured in three contiguous thoracic vertebrae at baseline and 12 months. ResultsThere were no differences in baseline demographic and clinical characteristics between treatment arms. The median percent lowering (interquartile range) in LDL-C was significantly greater with ATV than PRV [-53 (-69 to 20)% vs −28 (-55 to 74)%, p < 0.001], although the CAC score change was similar [12 (-63 to 208)% vs 13 (-75 to 358)%; p = 0.44]. At follow-up, the median bone attenuation loss was significantly greater with PRV than with ATV [-2.6 (-27 to 11)% vs 0 (-11 to 25)%; p < 0.001]. The attenuation loss in the PRV group was comparable to that of a historical untreated general population sample. In the entire cohort, the changes in LDL-C and total cholesterol were inversely correlated with bone attenuation change (p < 0.01). In adjusted multivariable linear regression analyses, race and percent change in LDL-C were independent predictors of bone attenuation change. Age, body mass index, history of smoking, diabetes mellitus, hypertension, peripheral vascular disease, or hormone replacement therapy did not affect percent change in BMD. ConclusionsThese findings support the hypothesis that there is an interaction between bone and cardiometabolic health and that intensive lipid lowering has a beneficial effect on bone health.

SCD Dyslipidemia Normalizes Long-Term Following Nonmyeloablative Hematopoietic Cell Transplantation

Dyslipidemia is common in patients with sickle cell disease (SCD). Individuals with SCD have a unique type of dyslipidemia. This SCD dyslipidemia (hypocholesterolemia subtype) is characterized by low total cholesterol (TC), low-density lipoprotein cholesterol (LDL-c), and high-density lipoprotein cholesterol (HDL-c), and normal triglycerides (TG). This SCD dyslipidemia state is theorized to be cardioprotective regarding atherosclerotic risk due to the hypolipidemic condition. Hematopoietic cell transplantation (HCT) is a potentially curative therapy for SCD. Nonmyeloablative HCT has been employed at the National Institutes of Health (NIH) and internationally with good results. Long-term survivors of HCT, specifically for hematologic malignancies, are at increased risk for dyslipidemia (hypercholesterolemia subtype), thus increasing atherosclerotic risk long-term. There are no studies investigating the short or long-term effects of HCT on SCD dyslipidemia. Therefore, we report a novel study to characterize lipid profiles at baseline and after HCT for SCD. This cohort study analyzes data from patients who received their first nonmyeloablative HLA-matched sibling or haploidentical HCT for SCD at the NIH from May 2009 to December 2021. All patients received sirolimus as GVHD prophylaxis. Total cholesterol, HDL-c, LDL-c, and triglycerides were collected pre-HCT, one-year post-HCT, and annually thereafter via a fasting serum-based lipid panel (median follow-up of 4 years). Data were analyzed using linear generalized estimating equation regression models to measure the influence of factors such as year of HCT, sirolimus use, gender, age, and graft failure on TC, LDL-c, HDL-c, and TG levels. A total of 116 patients were included in this analysis. There were 72 male and 44 female patients. The median age was 31 (range 10 to 64) years. 90% of the patients had Hb-SS, 3% Hb-SC, 5% Hb-Sβ 0, and 2% Hb-Sβ +. Overall survival is 87%, and 19% experienced graft failure. The median time on sirolimus post-HCT was one year. Baseline, one-year, and two-year mean (25th, 75th percentile) values, respectively, for the TC, LDL-c, HDL-c, and TG are as follows: TC [130.7 (107.0, 147.0), 183.2 (144.5, 220.0), 175.2 (144.5, 209.0)], LDL-c [72.5 (50.0, 87.0), 109 (73.5, 130), 104.2 (75.5, 128.0)], HDL-c [32.3 (23.8, 39.3), 49.4 (38.0, 55.5), 49.2 (41.5, 58.0)] and TG [127.3 (88.5, 156.5), 125.9 (87.0, 153.5), 112.6 (72.0, 133.5)]. Generally, the first-year post-HCT changes were maintained annually thereafter. (Figure 1). According to linear regression modeling, the change in TC, LDL-c, HDL-c, and TG at one-year post-HCT was +50.3 mg/dL (p&amp;lt;0.0001), +36.4 mg/dL (p &amp;lt;0.0001), +20.4 mg/dL (p&amp;lt;0.0001) and -26.5 mg/dL (p&amp;lt;0.0001), respectively. For failed grafts, the estimated changes after one-year post-HCT in TC, LDL-c, HDL-c, and TG were +6.5 mg/dL (p=0.45), -2.1 mg/dL (p=0.78), +14.8 mg/dL (p&amp;lt;0.0001), and -28.0 (p=0.03), respectively. The use of sirolimus only resulted in a significant change in TG (+32.8 mg/dL (p = 0.004)). Age had statistically significant changes only on TC (+1.08 mg/dL for a one-year change in age, p=0.005) and LDL-c (+0.73 mg/dL for a one-year change in age, p=0.03). There were no significant differences in TC, LDL-c, HDL-c, and TG levels (p&amp;gt;0.05) based on gender and HCT type. To summarize, HCT with sustained grafts led to significant rises in TC, LDL-c, and HDL-c and a decline in TG from baseline to one-year post-HCT, resulting in the normalization of lipid profiles. These changes were maintained annually thereafter. Graft failure most notably resulted in TC and LDL-c level declines back to pre-HCT baseline (Figure 2), while HDL-c and TG levels did not completely revert to baseline values. Sirolimus effects were significant on TG levels alone. These findings suggest that the mechanism underlying SCD dyslipidemia is corrected with the reversal of SCD. Long-term follow-up studies are indicated to assess patients' risk for atherosclerosis and adverse cardiac outcomes.

Clinical characteristics and treatment patterns in patients with atherosclerotic cardiovascular disease with hypercholesterolemia: a retrospective analysis of a large US real-world database cohort

Objective Guidelines developed by the American College of Cardiology/American Heart Association (ACC/AHA) recommend lipid-lowering therapies (LLTs) to reduce low-density lipoprotein cholesterol (LDL-C) and atherosclerotic cardiovascular disease (ASCVD) risk. This study described LLT utilization patterns and LDL-C goal achievement (to <70 mg/dL) among patients with ASCVD in the United States. Methods This retrospective study was conducted using Optum’s de-identified Clinformatics Data Mart Database (CDM). Patients with their first ASCVD diagnosis (index date) in the CDM database between July 1, 2015, and December 31, 2018, were followed for ≥12 months to assess LLT utilization patterns and change in LDL-C. LLTs included were statins and non-statin LLTs (ezetimibe, fibrates, and proprotein convertase subtilisin/kexin type 9 inhibitors). Adherence was measured as the proportion of days covered (PDC), defined as the number of days with drug on-hand (or number of days exposed to drug) divided by the 12-month follow-up period. Patients with PDC ≥0.8 were considered adherent. Results Among the patients with ASCVD (N = 1,424,893) included in this study, only 621,978 (43.7%) had at least one LDL-C measurement at baseline (6 months prior to and 3 months after the index date). The mean age was 71.5 years, and almost half of the patients were female. Patients were followed for a mean (standard deviation [SD]) duration of 30.6 (11.4) months (median of 29.9 months). During the follow-up, about one-quarter of the patients did not receive any LLT. Among treated patients, 89.5% received statins and 10.5% received non-statin LLT. Less than half (47.6%) of the patients were adherent to the index treatment during the 12-month follow-up. Even in patients receiving combination therapy (statin + non-statin LLT), a sizable proportion (35.8%) showed an increase in LDL-C over the follow-up period. Conclusions This retrospective study highlighted limited LDL-C monitoring in patients with ASCVD, and unmet need in terms of suboptimal utilization of non-stain LLTs, limited adherence to LLTs, and inadequate lipid control after treatment (among those with LDL-C measurements during the follow-up period) need to be addressed to improve outcomes in this patient cohort.

Abstract 16434: 104-Week Safety and Effectiveness of Low-Density Lipoprotein Cholesterol-Lowering Therapy With Evolocumab in Patients With Familial Hypercholesterolemia/Hypercholesterolemia in Japan: Results of Post-Marketing Surveillance

Introduction: Evolocumab is the first monoclonal antibody against proprotein convertase subtilisin/kexin type 9 approved in Japan for familial hypercholesterolemia (FH) and hypercholesterolemia (HC). Aims: This study assessed the 104-week safety and effectiveness of low-density lipoprotein cholesterol (LDL-C)-lowering therapy with evolocumab in patients with FH (homo/heterozygous) and HC in a real-world setting in Japan. Methods: Overall, 3721 and 2792 patients (108 and 91 homozygous FH, 2007 and 1613 heterozygous FH, 1606 and 1088 HC) from 668 clinical sites comprised the safety and effectiveness analysis sets, respectively. Primary safety endpoints: incidence (%) and number of patients with adverse drug reactions and serious adverse events. Effectiveness endpoints: % change in LDL-C from baseline at Week 12 (n=2386, primary endpoint) and Weeks 4-104 (secondary endpoint). Results: Mean age: 63.2 years; female: 33.8%. The mean±SD follow-up duration was 545.5±218.8 days. Adverse drug reaction subject incidence was 5.2%. Serious adverse event subject incidence was 8.9% (330/3721). The adverse event incidences of myocardial infarction and stroke were 0.6% (n=23/3721) and 0.6% (n=21/3721; 0.3% ischemic stroke [n=12]/0.2% hemorrhagic stroke [n=9]), respectively. Table 1 shows adverse events by lowest achieved LDL-C levels. The mean±SD % change in LDL-C from baseline to Weeks 12 and 104 were –45.7%±28.2% (n=84) and –50.9±21.1% (n=48) in homozygous FH patients ( P &lt;0.001 vs baseline; two-sided paired t -test), –56.0%±28.9% (n=1440) and –54.5±28.3% (n=905) in heterozygous FH patients ( P &lt;0.001), and –63.3%±23.7% (n=862) and –60.8±28.1% (n=352) in HC patients ( P &lt;0.001), respectively. Conclusions: There were no trends between the lowest achieved LDL-C levels and adverse events in Japanese patients. Evolocumab was well tolerated and sustained LDL-C reduction in patients with FH and HC in a real-world clinical setting in Japan.

Abstract 11893: Efficacy and Safety of Ongericimab in Chinese Patients With Primary Hypercholesterolemia and Mixed Dyslipidemia

Background: Ongericimab, a monoclonal antibody that inhibits proprotein convertase subtilisin/kexin type 9 (PCSK9), significantly reduced low-density lipoprotein cholesterol (LDL-C) levels in the phase 2 trial. A phase 3 trial was conducted to evaluate the efficacy and safety of ongericimab in Chinese patients with primary hypercholesterolemia and mixed dyslipidemia on background lipid-lowering therapy (LLT). Methods: This was a randomized, double-blind, placebo-controlled, 52-week trial conducted in China (NCT02662569). Eligible patients receiving stable statin (±ezetimibe) therapy but not achieving LDL-C goals were enrolled. Patients were randomly assigned in a 2:1:2:1 ratio to receive either ongericimab 150 mg or placebo subcutaneously every 2 weeks (Q2W), or ongericimab 300 mg or placebo subcutaneously every 4 weeks (Q4W) for 52 weeks. The primary endpoint was percent change in LDL-C from baseline to week 24. Results: A total of 806 patients were randomized, 802 patients received at least one dose of ongericimab or placebo. The least-squares (LS) mean difference between ongericimab and placebo in LDL-C from baseline to week 24 was -67.7% (95% CI: -72.49%, -62.99%; p &lt; 0.0001) in Q2W group and -61.2% (95% CI: -67.09%, -55.21%; p &lt; 0.0001) in Q4W group. LDL-C reductions were maintained to Week 52. Ongericimab also favorably altered other lipid parameters (Table 1). The overall incidence of adverse events was similar between ongericimab and placebo. Conclusion: Ongericimab on stable background LLT significantly reduced LDL-C and was well tolerated in Chinese patients with primary hypercholesterolemia and mixed dyslipidemia.