Journal of clinical lipidology最新文献

Background/Synopsis

Chronic kidney disease (CKD) is a major risk factor for cardiovascular disease. Non-variceal upper gastrointestinal bleeding (NVUGIB) can be associated with various medical conditions, including heart failure (HF) and CKD. CKD and HF has been shown to further increase cardiovascular risks.

Objective/Purpose

Nevertheless, there is limited scientific evidence of clinical outcomes of NVUGIB in patients with CKD & HF. Hence, we sought to investigate this population.

Methods

We queried National Inpatient Sample between 2017-2020 for adult patients who were hospitalized with NVUGIB and had CKD & HF. The primary outcome was inpatient mortality. The secondary outcomes were cardiogenic shock, cardiac arrest, acute kidney injury (AKI), intubation, length of stay (LOS) and total hospital charge. Multivariable logistic regression analysis was used to estimate clinical outcomes. P-value < 0.05 was significant.

Results

There were 3,349,779 hospitalizations with NVUGIB and 459,980 (13.7%) had CKD & HF. HF & CKD and non-HF & CKD cohorts were with mean age of 74 vs. 66 yrs; males 46.9% vs 53.1%; Caucasians 63.5% vs 66.6%; HTN 8% vs 39%; dyslipidemia 53.3% vs 37.2%; PE 3.9% vs 4.9%; DM 56% vs 30.4%; AF 24.4% vs 23.5%; obesity 19.5% vs 13.3%; AF 50.2% vs 21.1%; history of stroke 2.0% both, COPD 33.5% vs 18.4%; alcohol use 3% vs 13.8%, respectively. HF & CKD cohort had significantly higher mortality and worse clinical outcomes (Table 1).

Conclusions

HF & CKD cohort demonstrated significantly higher mortality, worse clinical outcomes and resource utilization. Patients were older, obese, female, fewer Caucasians, with more frequent dyslipidemia, DM, AF and COPD. HF & CKD is associated with greater risk for cardiovascular events, renal failure, GIB, and ICU care. HF & CKD is an important predictor of adverse outcomes in NVUGIB population. Further research is necessary to describe long-term outcomes.

Study Funding

Kaneka Pharma America: “Lipoprotein(a) Testing at URMC and Referral to Preventive Cardiology Program".

Background/Synopsis

Lipoprotein(a) (Lp(a)) is a cholesterol-containing, genetically determined molecule in our blood. Studies show that an elevated level of Lp(a) can independently predict an increased risk of atherosclerotic cardiovascular disease (ASCVD) events. There are currently no FDA-approved drugs to reduce Lp(a) and cardiovascular disease event risk.

Objective/Purpose

Using the electronic health record (EHR) from the University of Rochester Medical Center (URMC), we determined how well Lp(a) levels predict future cardiovascular disease events currently and over time.

Methods

Data were collected from the URMC EHR database of patients >= 18 years with and without at least one Lp(a) measurement from January 1st, 2011 to August 1st 2023 . Cox regression analysis was performed to investigate the effect of Lp(a) level on ASCVD events, while adjusting for several demographic factors and previous ASCVD event status. The Lp(a) level was dichotomized into a normal-level group (<=30 mg/dL) and a high-level group (>30 mg/dL).

Results

From January 1st, 2011 to August 1st, 2023, we identified 2,698 patients with at least one Lp(a). Among these individuals, 1,594 did not have an ASCVD event after a baseline Lp(a), while 611 individuals did have an ASCVD event after an Lp(a) baseline measurement. The remaining individuals did not have data on ASCVD status. The mean Lp(a) level was 48 mg/dL among all patients, 45.2 mg/dL among patients without an ASCVD event, and 55.2 mg/dL among patients with an ASCVD event. The normal Lp(a) level range in the URMC lab is <30 mg/dL. Among patients without ASCVD history at baseline, the hazard of an ASCVD event in the high Lp(a) level group is 1.44 times the hazard for the normal Lp(a) level group, with a p-value of 0.008. For patients with a previous ASCVD event, the hazard of an ASCVD event in the high Lp(a) level group is 0.87 times the hazard for the normal Lp(a) level group but not at a statistically significant level (p-value = 0.206).

Conclusions

The level of Lp(a) has a varied effect on the hazard of a future ASCVD event. While high Lp(a) level increased the hazard of future ASCVD event for patients with no ASCVD history, high Lp(a) level does not significantly affect the hazard of future ASCVD event for patients with an ASCVD history. It is vital to measure Lp(a) levels to make active steps toward prevention of ASCVD events in the future.

Study Funding

89bio, Inc.

Background/Synopsis

Severe hypertriglyceridemia (SHTG; defined as greater than or equal to 500 mg/dL) increases the risk of acute pancreatitis, non-alcoholic fatty liver disease and cardiovascular disease. Currently available medications often do not reduce triglycerides to desired levels, highlighting the need for new therapeutic options. Fibroblast growth factor 21 (FGF21) is an endogenous hormone, mainly secreted by the liver, which functions as a master metabolic regulator of lipid and glucose metabolism, as well as energy expenditure. Pegozafermin (PGZ), a long acting FGF21 analog, is in development for the treatment of SHTG and non-alcoholic steatohepatitis. Previous Phase 2 data demonstrated PGZ significantly reduced TGs and hepatic steatosis and improved atherogenic lipoprotein particles and glycemic control, with a good safety and tolerability profile. These promising results led to the design of the first Phase 3 trial of PGZ for the treatment of SHTG.

Objective/Purpose

To determine the effect of Pegozafermin on fasting serum triglyceride levels in subjects with Severe Hypertriglyceridemia (TG greater than or equal to 500 to less than or equal to 2000 mg/dL) after 26 weeks of treatment.

Methods

ENTRUST is a global 52-week Phase 3, randomized, double-blind, placebo-controlled study designed to evaluate the efficacy and safety of pegozafermin in patients with SHTG. Approximately 360 patients aged 22 years old or older, with baseline triglycerides between 500 and 2000 mg/dL and receiving background standard-of-care lipid-modifying therapy will be randomized in a 3:3:2 ratio to weekly subcutaneous injections of PGZ 30 mg, PGZ 20 mg, or placebo. Exclusion criteria include uncontrolled or newly diagnosed T2DM, T1DM, symptomatic gallstone/biliary disease, uncontrolled hypertension, or an acute pancreatitis event within 6 months. The primary endpoint will be percent change in fasting serum TGs from baseline after 26 weeks of PGZ/placebo treatment. Key secondary endpoints include changes in serum lipids, lipoproteins, glycemic control, liver steatosis and safety. Final efficacy analysis will be based on 52 weeks of treatment.

Results

The study was initiated in June 2023 and has an estimated primary completion date of August 2025. NCT05852431.

Conclusions

ENTRUST is a pivotal Phase 3 clinical trial designed to confirm the efficacy and safety of PGZ in the treatment of SHTG. Expected clinical benefits include significant reductions of triglycerides and hepatic steatosis, as well as other metabolic improvements.

Study Funding

NewAmsterdam Pharma.

Background/Synopsis

Obicetrapib is a selective cholesteryl ester transfer protein (CETP) inhibitor currently in clinical development for the treatment of hypercholesterolemia and reduction of cardiovascular risk that strongly reduces apolipoprotein B (ApoB) and low-density lipoprotein cholesterol (LDL-C) and concomitantly increases plasma high-density lipoprotein cholesterol (HDL-C). Ezetimibe reduces absorption of biliary and dietary cholesterol from the small intestine, thereby reducing LDL-C levels.

Objective/Purpose

The current study was carried out to elucidate the mechanism of action responsible for the observed decrease in non-HDL-C by obicetrapib monotherapy and in combination with ezetimibe in a translational mouse model for hyperlipidemia and atherosclerosis.

Methods

Female ApoE*3-Leiden.CETP transgenic mice were fed a Western diet with 0.05% w/w cholesterol (equivalent to daily human intake) or this diet containing obicetrapib alone (2 mg/kg/day), ezetimibe alone (1 mg/kg/day) or the combination of obicetrapib and ezetimibe.

Results

Obicetrapib, ezetimibe and the combination thereof reduced total plasma cholesterol levels (-42%, -23% and -62%), mainly attributed to a decrease in non-HDL-C levels (-61%, -24% and -80%). Obicetrapib alone and in combination with ezetimibe nearly completely blocked CETP activity (-99% and -100%) resulting in increased HDL-C (+260% and +245%) and ApoA1 levels (98% and 81%). Obicetrapib, ezetimibe and to a larger extent the combination thereof enhanced clearance of VLDL-like particles (half-life: -44%, -23% and -57%) and enhanced hepatic LDL receptor expression (+63% and +74%). Fecal analysis demonstrated increased bile acid excretion in obicetrapib-treated mice (+41%) and increased neutral sterol excretion in ezetimibe-treated mice, which was even more pronounced in combination with obicetrapib (+68% and +100%), resulting in a net fecal sterol loss.

Conclusions

Obicetrapib alone and the combination with ezetimibe reduce non-HDL-C levels by increased VLDL lipolysis, increased VLDL clearance and elevated LDL receptor levels accompanied by an enhanced fecal bile acid and neutral sterol excretion.

Study Funding

NewAmsterdam Pharma.

Background/Synopsis

The oral selective cholesteryl ester transfer protein (CETP) inhibitor, obicetrapib, is in development for dyslipidemia in patients unable to achieve sufficient low-density lipoprotein cholesterol (LDL-C) lowering with other lipid-lowering medications. Previous Phase 1 and 2 trials evaluated obicetrapib as monotherapy, in combination with statins and on top of high-intensity statins (HIS).

Objective/Purpose

In this study we tested the efficacy and safety of obicetrapib in combination with ezetimibe on top of HIS.

Methods

ROSE2 enrolled men and women without current clinically manifest cardiovascular disease who had LDL-C >70 mg/dL and triglycerides <400 mg/dL, while taking HIS. Participants continued their HIS and were randomized to obicetrapib 10 mg + ezetimibe 10 mg (n=40), obicetrapib 10 mg (n=39), or placebo (n=40) for 12 weeks. Endpoints included the LDL-C response to combination therapy vs. placebo (primary), and non-high-density lipoprotein cholesterol (non-HDL-C), nuclear magnetic resonance-assessed lipoprotein particles (-P), apolipoprotein B (ApoB), lipoprotein (a) [Lp(a)], small dense (sd)LDL-C, other lipid biomarkers and safety.

Results

Obicetrapib monotherapy and with ezetimibe, respectively, significantly (all P<0.05) reduced LDL-C (43.5 and 63.4%), non-HDL-C (37.5 and 55.6%), ApoB (24.2 and 34.4%), total LDL-P (54.8 and 72.1%), small LDL-P (92.7 and 95.4%), sdLDL-C (30.9 and 44.4%), and Lp(a) (47.2 and 40.2%), and increased HDL-C (142 and 136%). Obicetrapib was well tolerated, with no dose-related adverse events or clinically significant changes in vital signs, electrocardiograms, hematology or biochemistry. The tremendous lowering of LDL particles with obicetrapib + ezetimibe suggests a synergistic effect perhaps due to an additional mechanism of action (MoA) for CETP inhibition; it upregulates LDL receptors (as previous studies have indicated), but also increases cholesterol removal through transintestinal cholesterol excretion (TICE). Ezetimibe meanwhile prevents reuptake of the excreted cholesterol removed via the inhibition of Niemann-Pick C1-like 1 (Figure).

Conclusions

Obicetrapib monotherapy, in combination with HIS, and with HIS plus ezetimibe is safe, well-tolerated and produces robust reductions in LDL-C, LDL particles, sdLDL-C, and Lp(a). ROSE2 obicetrapib monotherapy results concur with findings across the phase 1/2 development program, while combination therapy results support a synergistic effect of obicetrapib + ezetimibe on circulating LDL particles, consistent with the drugs’ known and hypothesized MoAs.

Background/Synopsis

Inclisiran is a first-in-class small interfering ribonucleic acid (siRNA) which prevents hepatic PCSK9 production. It is indicated as an adjunct to diet or in combination with other cholesterol-lowering medications for adults with Heterozygous familial hypercholesterolemia, clinical atherosclerotic cardiovascular disease and expanded indication for primary prevention for patients with high LDL and without a history of cardiovascular disease. It is administered every 6 months (after initial and 3-month doses) providing a convenient approach to lower LDL cholesterol in a clinic setting. If a scheduled administration is missed by less than 3 months inclisiran should be given as soon as possible and continued the regular schedule. If it is missed by more than 3 months inclisiran dosing schedule should be restarted again.

Objective/Purpose

A dedicated clinic was started under the supervision of Dr. Sarah Qureshi to provide team-based care for the patients who were started on inclisiran in the practice to improve compliance.

Methods

Clinic lead was responsible for facilitating the clinic by coordinating with the physicians, pharmacists scheduler and clinic nurse. After the first dose of inclisiran was prescribed by the physician, the specialty pharmacists will obtain insurance approval. After the approval was obtained, the patient was notified and a clinic visit was scheduled. Inclisiran was administered at the clinic visit and the patient was educated by the clinic nurse about the side effects. A telephone visit was done 1 week prior to next injection for any side effects and prescribing the medicine. Monthly meetings were conducted to review patient's clinical progress.

Results

A total of 204 were prescribed inclisiran from July 26, 2021 - December 31, 2023. 152 patients are on schedule. 52 patients stopped follow up in the clinic:

• ○

  29 refused when contacted to come for the initial injection.

• ○

  8 patients stopped after one dose (6 after the 1st dose, 1 after the 2nd dose and 1 after the 3rd dose).

• ○

  3 patients moved on to different clinic.

• ○

  2 were non responders and switched to other PCSK9 inhibitors.

• ○

  2 stopped due to terminal care.

• ○

  3 rejected by insurance.

• ○

  5 were unreachable.

Conclusions

Team-based care for twice yearly dosing of Inclisiran improves adherence to therapy, monitoring of side effects with minimal effort from the prescribing physician.

Study Funding

Research reported in this abstract was supported by the National Heart, Lung, and Blood Institute of the National Institutes of Health under award number: R01HL159182.

Background/Synopsis

Genetic studies suggest that severe hypercholesterolemia (defined as LDL-C >190mg/dL) can be categorized into four subtypes: monogenic familial hypercholesterolemia (FH), polygenic hypercholesterolemia, elevated lipoprotein(a), and severe hypercholesterolemia with or without a positive family history in the absence of a genetic cause. This information has the potential to improve atherosclerotic cardiovascular disease (ASCVD) risk stratification of individuals affected with severe hypercholesterolemia. By improving understanding and management of the subtypes, health systems can reduce the burden of ASCVD morbidity and mortality in this high-risk population.

Objective/Purpose

Due to the complexity and heterogeneity of the severe hypercholesterolemia phenotype, we assessed the readiness and needs of providers who communicate ASCVD risk information to affected individuals.

Methods

Semi-structured interviews were conducted via videoconference with providers who care for patients with severe hypercholesterolemia. Interviewers described the four classification subtypes to participants and invited responses to hypothetical scenarios involving communication with a patient with each subtype. Interviewers also asked participants how they would respond to a scenario in which a risk stratification tool included genomic information. Participants were compensated after interviews were completed.

Results

Interviews were completed with 11 providers (5 primary care providers (PCPs), 3 cardiology specialists, and 3 genetic counselors) from a single integrated healthcare system. Four patterns from provider interviews emerged about managing each subtype (see Table 1). First, providers described how they would treat and talk with patients across subtypes, which revealed key differences between clinical professions. Most PCPs described a lack of knowledge about the differences among subtypes but expressed interest in understanding and following treatment recommendations for each subtype. Second, providers recommended varying communication resources they and their patients would need to effectively talk about and address the ASCVD risks of each subtype. Next, most PCPs and genetic counselors responded with positive reactions to an ASCVD risk stratification tool that incorporates genomic information, however, cardiology specialists expressed hesitancy to trust this such a tool. Finally, providers gave recommendations for how to implement a program including the genomics informed risk stratification tool to better care for patients with each subtype.

Conclusions

To design and implement a program to identify and manage severe hyper