Lipid Lowering Treatment Patterns and Risk of Subsequent Cardiovascular Outcomes Among Patients Initially Rejected for pcsk9 Inhibitor Therapy

Abstract Background Hypercholesterolemia is associated with endothelial dysfunction. While good evidence exists for the beneficial endothelial effects of first-line lipid-lowering drugs (statins), less is known on the new class of proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors. This is particularly true for the differential effects on micro- and macrovascular endothelial function and arterial stiffness. Purpose The goal of this study was to study the change in retinal microvascular dysfunction, brachial artery endothelial function and arterial stiffness in high-risk cardiovascular risk patients before and after initiation of PCSK9 inhibitor therapy with alirocumab or evolocumab. Methods In this prospective observational study, cardiovascular high-risk patients with a clinical indication for PCSK9 inhibitors were included for the measurement of retinal microvascular function (flicker light-induced dilatation of retinal arterioles and venules, FIDart and FIDven respectively; retinal arteriovenous ratio, AVR), brachial artery flow-mediated dilatation (FMD) and arterial stiffness (pulse wave velocity, PWV; augmentation index, AI). Measurements were performed at baseline, after 3 months and after 12 months of PCSK9 inhibitor therapy. The primary endpoint was the change in FIDart after 12 months of therapy compared to baseline. Results We recruited 48 patients (mean age 57±11 years, 27% female, 81% coronary artery disease) which began treatment with alirocumab or evolocumab in our lipid outpatient clinic. 6 patients were excluded from the analysis (n=3 stopped due to side effects, n=1 stopped due to new metastatic cancer, n=1 moved abroad, n=1 no retinal vessel analysis possible). LDL cholesterol was reduced from 3.8±1.2 to 1.5±0.8 and 1.8±0.9 mmol/L at 3 and 12 months respectively (all p<0.001). There was no significant change in systolic blood pressure during therapy. The primary endpoint FIDart was significantly increased after 12 months of PCSK9 inhibitor therapy compared to baseline (3.4±2.3 vs. 2.6±1.6%, p=0.01). Among the secondary endpoints, augmentation index improved at 12 months vs. baseline (21±12 vs. 24±9%, p=0.03). No significant change was seen for FIDven, AVR, FMD and PWV after 3 and 12 months of therapy. Conclusion In cardiovascular high-risk patients, PCSK9 inhibition is associated with an improvement of retinal microvascular function and augmentation index after one year of therapy. No effects were seen for macrovascular parameters such as FMD or PWV in our cohort. FUNDunding Acknowledgement Type of funding sources: Public hospital(s). Main funding source(s): University Hospital Zurich, AGLA Grant (sponsored by Amgen)

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LIPID LOWERING TREATMENT PATTERNS AND RISK OF SUBSEQUENT CARDIOVASCULAR OUTCOMES AMONG PATIENTS WITH A RECENT CORONARY REVASCULARIZATION

Journal of the American College of Cardiology ◽

10.1016/s0735-1097(20)30895-0 ◽

2020 ◽

Vol 75 (11) ◽

pp. 268

Author(s):

Pallavi Rane ◽

Matthew Aaron Cavender ◽

Sasikiran Nunna ◽

Jason Exter ◽

Mohdhar Habib ◽

...

Keyword(s):

Coronary Revascularization ◽

Treatment Patterns ◽

Cardiovascular Outcomes ◽

Lipid Lowering

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Neurocognitive effects associated with proprotein convertase subtilisin-kexin type 9 inhibitor use: a narrative review

Therapeutic Advances in Drug Safety ◽

10.1177/2042098620959271 ◽

2021 ◽

Vol 12 ◽

pp. 204209862095927

Author(s):

Wei C. Yuet ◽

Didi Ebert ◽

Michael Jann

Keyword(s):

Cognitive Impairment ◽

Adverse Events ◽

The United States ◽

Narrative Review ◽

Lipid Lowering ◽

Patient Specific ◽

Proprotein Convertase ◽

Pcsk9 Inhibitors ◽

Pcsk9 Inhibitor ◽

Receptor Modulation

Neurocognitive adverse events have been observed with the widespread use of 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors or “statins,” which reduce low-density lipoprotein cholesterol (LDL-C) levels and subsequently cardiovascular risk. The United States Food and Drug Association directed manufacturers of proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitors to monitor for neurocognitive adverse events due to their potent effects on LDL-C reduction, which is a proposed mechanism for neuronal cell dysfunction. Other proposed mechanisms for PCSK9 inhibitor-associated neurocognitive adverse events include N-methyl-d-aspartate receptor modulation, dysregulation of lipid and glucose metabolism, and patient-specific risk factors for cognitive impairment. The purpose of this narrative review article is to describe the proposed mechanisms, incidence of neurocognitive adverse events from phase II and III trials for PCSK9 inhibitors, neurocognitive assessments utilized in clinical trials, and clinical implications. Given the increasing prevalence of PCSK9 inhibitor use and the neurocognitive adverse events observed with prior lipid-lowering therapies, clinicians should be aware of the risks associated with PCSK9 inhibitors, especially when therapy is indicated for patients at high risk for cardiovascular events. Overall, the incidence of PCSK9 inhibitor-associated neurocognitive appears to be uncommon. However, additional prospective studies evaluating cognitive impairment may be beneficial to determine the long-term safety of these agents.

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Real-world data on metabolic effects of PCSK9 inhibitors in a tertiary care center in patients with and without diabetes mellitus

Cardiovascular Diabetology ◽

10.1186/s12933-021-01283-w ◽

2021 ◽

Vol 20 (1) ◽

Author(s):

Laurenz T. Fischer ◽

Daniel A. Hochfellner ◽

Lisa Knoll ◽

Tina Pöttler ◽

Julia K. Mader ◽

...

Keyword(s):

Retrospective Analysis ◽

Real World ◽

Cardiovascular Events ◽

Care Center ◽

Tertiary Care ◽

Lipid Lowering ◽

Tertiary Care Center ◽

Pcsk9 Inhibitors ◽

Real World Data ◽

Pcsk9 Inhibitor

Abstract Background The lipid-lowering and positive cardiovascular effect of proprotein convertase subtilisin kexin type 9 (PCSK9) inhibitors was shown in several studies, hence, they are more widely used in the lipid-lowering management of individuals with high cardiovascular risk. As real-world data are still scarce, specifically in patients with type 2 diabetes (T2D), the aim of this retrospective analysis was to investigate the efficacy of PCSK9 inhibitors in lowering low-density lipoprotein cholesterol (LDL-C) in an outpatient clinic of a tertiary care center in routine care. Methods A retrospective analysis of data extracted from the electronic patient record was performed. Patients who were routinely prescribed with PCSK9 inhibitor therapy (alirocumab or evolocumab) during the years 2016 and 2019 were included in the analysis. Characteristics of the patient population, the effects on LDL-C and HbA1c levels as well as subsequent cardiovascular events were assessed over an observation period of 18 months. Results We identified 237 patients treated with PCSK9 inhibitors between January 2016 and September 2019. Almost all patients (97.5%) received PCSK9 inhibitors for secondary prevention. 26.2% of the population had a concomitant diabetes diagnosis. Intolerance to statins (83.1%), ezetimibe (44.7%) or both agents (42.6%) was reported frequently. Three months after initiation of PCSK9 inhibitor therapy, 61.2% of the patients achieved LDL-C levels < 70 mg/dl, and 44.1% LDL-C levels < 55 mg/dl. The median LDL-C was lowered from 141 mg/dl at baseline, to 60 mg/dl after 3 months and 66 mg/dl after 12 months indicating a reduction of LDL-C as follows: 57.5% after 3 months and 53.6% after 12 months. After 3 months of observation, target achievement of LDL-C was higher in patients with T2D compared to non-diabetes patients; < 55 mg/dl: 51% vs. 41.5%; < 70 mg/dl 69.4 vs. 58.5%. After 12 months even more pronounced target LDL achievement in T2D was demonstrated < 55 mg/dl: 58.8% vs. 30.1%; < 70 mg/dl 70.6 vs. 49.6%. Patients with insufficiently controlled T2D (HbA1c > 54 mmol/mol) had a higher reduction in LDL-C but still were more likely to subsequent cardiovascular events. Conclusions Significant reductions in LDL-C and a high percentage of patients achieving recommended treatment targets were observed. The percentage of patients with T2D meeting recommended LDL-C targets was higher than in those without T2D. Still some patients did not achieve LDL-C levels as recommended in current guidelines. Special attention to the characteristics of these patients is required in the future to enable achievement of treatment goals and avoid adverse cardiovascular outcomes.

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Lipoprotein(a) and Cardiovascular Outcomes after Revascularization of Carotid and Lower Limbs Arteries

Biomolecules ◽

10.3390/biom11020257 ◽

2021 ◽

Vol 11 (2) ◽

pp. 257

Author(s):

Marat V. Ezhov ◽

Narek A. Tmoyan ◽

Olga I. Afanasieva ◽

Marina I. Afanasieva ◽

Sergei N. Pokrovsky

Keyword(s):

Primary Endpoint ◽

Cardiovascular Events ◽

Cardiovascular Outcomes ◽

Lower Limbs ◽

Lipid Lowering ◽

Lipid Lowering Therapy ◽

Cox Regression Analysis ◽

Lipoprotein A ◽

Secondary Endpoints

Background: Despite high-intensity lipid-lowering therapy, there is a residual risk of cardiovascular events that could be associated with lipoprotein(a) (Lp(a)). It has been shown that there is an association between elevated Lp(a) level and cardiovascular outcomes in patients with coronary heart disease. Data about the role of Lp(a) in the development of cardiovascular events after peripheral revascularization are scarce. Purpose: To evaluate the relationship of Lp(a) level with cardiovascular outcomes after revascularization of carotid and lower limbs arteries. Methods: The study included 258 patients (209 men, mean age 67 years) with severe carotid and/or lower extremity artery disease, who underwent successful elective peripheral revascularization. The primary endpoint was the composite of nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death. The secondary endpoint was the composite of primary endpoint and repeated revascularization. Results: For 36-month follow-up, 29 (11%) primary and 128 (50%) secondary endpoints were registered. There was a greater risk of primary (21 (8%) vs. 8 (3%); hazard ratio (HR), 3.0; 95% confidence interval (CI) 1.5–6.3; p < 0.01) and secondary endpoints (83 (32%) vs. 45 (17%), HR, 2.8; 95% CI 2.0–4.0; p < 0.01) in patients with elevated Lp(a) level (≥30 mg/dL) compared to patients with Lp(a) < 30 mg/dL. Multivariable-adjusted Cox regression analysis revealed that Lp(a) was independently associated with the incidence of cardiovascular outcomes. Conclusions: Patients with peripheral artery diseases have a high risk of cardiovascular events. Lp(a) level above 30 mg/dL is significantly and independently associated with cardiovascular events during 3-year follow-up after revascularization of carotid and lower limbs arteries.

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Clinical impact of PCSK9 inhibitor on stabilization and regression of lipid-rich coronary plaques: a near-infrared spectroscopy study

European Heart Journal - Cardiovascular Imaging ◽

10.1093/ehjci/jeab034 ◽

2021 ◽

Author(s):

Hideaki Ota ◽

Hiroyuki Omori ◽

Masanori Kawasaki ◽

Akihiro Hirakawa ◽

Hitoshi Matsuo

Keyword(s):

Infrared Spectroscopy ◽

Near Infrared Spectroscopy ◽

Near Infrared ◽

Coronary Plaque ◽

Lipid Lowering ◽

Control Group ◽

Open Label ◽

Pcsk9 Inhibitor ◽

Single Centre Study ◽

Atheroma Volume

Abstract Aims This study aimed to determine the effects of a proprotein convertase subtilisin-kexin type 9 inhibitor (PCSK9i) on coronary plaque volume and lipid components in patients with a history of coronary artery disease (CAD). Methods and results This prospective, open-label, single-centre study analysed non-culprit coronary segments using near-infrared spectroscopy-intravascular ultrasound (NIRS-IVUS) at baseline and follow-up angiography. Following changes in the lipid-lowering treatment based on the most recent guideline, the enrolled subjects were divided into two groups: treatment with PCSK9i and statins (PCSK9i: 21 patients and 40 segments) and statins only (control: 32 patients and 50 segments). The absolute and percent LDL-C reductions were significantly greater in the PCSK9i group than in the control group (between group difference: 59.3 mg/dL and 46.4%; P < 0.001 for both). The percent reduction in normalized atheroma volume and absolute reduction in percent atheroma volume (PAV) were also significantly greater in the PCSK9i group (P < 0.001 for both). Furthermore, the PCSK9i group showed greater regression of maximal lipid core burden index for each of the 4-mm segments (maxLCBI4mm) than the control group (57.0 vs. 25.5; P = 0.010). A significant linear correlation was found between the percent changes in LDL-C and maxLCBI4mm (r = 0.318; P = 0.002), alongside the reduction in PAV (r = 0.386; P < 0.001). Conclusion The lipid component of non-culprit coronary plaques was significantly decreased by PCSK9i. The effects of statin combined with PCSK9i might be attributed to the stabilization and regression of residual vulnerable coronary plaques in patients with CAD.

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