The Effect of the PCSK9 Inhibitor Evolocumab on Aldosterone Secretion among High Cardiovascular Risk Patients: A Pilot Study

Elevated low-density lipoprotein (LDL) cholesterol is one of the leading causes of cardiovascular disease. Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors reduce LDL cholesterol levels with subsequent reductions in cardiovascular morbidity. Elevated aldosterone levels are also associated with a greater risk of cardiovascular morbidity. There are currently no published data on the impact of PCSK9 inhibitor monotherapy on the secretion of aldosterone. The aim of this study was to examine the effect of monotherapy with the PSCK9 inhibitor evolocumab on the lipid profile and aldosterone secretion level in high-risk cardiovascular patients. Lipid profile, sodium, potassium, aldosterone, cortisol, plasma renin activity, and adrenocorticotropic hormone (ACTH) levels were analyzed at baseline and after 3 months of evolocumab therapy. Each participant underwent a 250 mcg ACTH stimulation test upon study entry. Eight women and seven men were included in the study. Their median total cholesterol, LDL cholesterol, lipoprotein (a), apolipoprotein B100, and baseline and stimulated aldosterone levels were significantly lower after 3 months of evolocumab therapy. These heretofore unreported findings indicate that reductions in unstimulated and stimulated aldosterone secretion under evolocumab therapy could be associated with reductions in cardiovascular events, a possibility that warrants further investigation.

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Real-world use of PCSK9 inhibitors: A single-center experience

Journal of International Medical Research ◽

10.1177/0300060518800595 ◽

2018 ◽

Vol 47 (1) ◽

pp. 265-270 ◽

Cited By ~ 1

Author(s):

Sinan Sarsam ◽

Abeer Berry ◽

George Degheim ◽

Robby Singh ◽

Marcel Zughaib

Keyword(s):

Cardiovascular Disease ◽

Lipid Profile ◽

Real World ◽

Low Density Lipoprotein ◽

Density Lipoprotein ◽

Lipoprotein Cholesterol ◽

Atherosclerotic Cardiovascular Disease ◽

Pcsk9 Inhibitors ◽

Pcsk9 Inhibitor ◽

The Impact

Objective Hyperlipidemia is an important risk factor for atherosclerotic cardiovascular disease. Many patients are intolerant to or have limited benefit from statins. Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors have been approved for treating hyperlipidemia in these patients. We sought to investigate the impact of these medications in a real-world cardiology practice. Methods This was a retrospective study of 17 patients with either heterozygous familial hypercholesterolemia or established atherosclerotic cardiovascular disease with low-density lipoprotein cholesterol (LDL-C) levels above the treatment target despite maximally tolerated statins. Baseline lipid profile was compared with a repeat lipid profile obtained 4 to 6 weeks after initiating treatment with a PCSK9 inhibitor. Results The average duration of PCSK9 inhibitor treatment was 10.7 months. Lipid profile comparison showed that total cholesterol decreased from 243 ± 72 to 148 ± 39 (mg/dL) (39% reduction), triglycerides decreased from 185 ± 86 to 149 ± 62 (mg/dL) (19.5% reduction), high-density lipoprotein cholesterol increased from 56 ± 20 to 62 ± 26 (mg/dL) (10.7% increase), and LDL-C decreased from 154 ± 30 to 57 ± 32 (mg/dL) (63% reduction) from baseline. Conclusions PCSK9 inhibitors as add-on therapy to maximally tolerated statins resulted in an approximately 63% reduction in LDL-C.

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SAT-576 Possible Involvement of Thyroid Function in PCSK9 Inhibitor Therapy

Journal of the Endocrine Society ◽

10.1210/jendso/bvaa046.477 ◽

2020 ◽

Vol 4 (Supplement_1) ◽

Author(s):

Masayasu Iwabuchi

Keyword(s):

Thyroid Function ◽

Ldl Cholesterol ◽

Inhibitor Therapy ◽

Thyroid Peroxidase ◽

Thyroid Function Tests ◽

Pcsk9 Inhibitors ◽

Free T4 ◽

Hyperthyroid Patient ◽

Pcsk9 Inhibitor ◽

The Impact

Abstract INTRODUCTION Proprotein convertase subtilisin kexin type 9 (PCSK9) inhibition is an effective strategy for lowering plasma LDL-cholesterol and enhancing the LDL-cholesterol lowering ability of statins. PCSK9, a serine protease that binds to the LDL receptor promoting its degradation, is an important regulator of LDL metabolism. In addition, LDL-cholesterol is also controlled by TSH and thyroid hormones via PCSK9. TSH has received increasing attention as being closely associated with increased LDL-cholesterol level and higher atherosclerotic risks. In vitro study, the effects of TSH on hepatic PCSK9 expression in HepG2 cells were reported (1). I here report a case of transient hyperthyroidism secondary to PCSK9 inhibitor therapy. This case highlights the involvement of thyroid function in PCSK9 Inhibitor therapy. CLINICAL CASE A 65-year-old man had a weight loss of 6 kg (13 lbs.) in 4 months, accompanied with fatigue. He had a past history of myocardial infarction and his LDL was 83 mg/dL by 2.5mg of rosuvastatin and heart rate was controlled by 10mg of carvedilol. Six months ago, he started a PCSK9 Inhibitor therapy with 140mg of evolocumab every 2 weeks for 6 weeks. He had no preceding viral illness and denied anterior neck pain or tenderness. His height was 1.53 m, weight 52.6 kg (115 lbs.), and body mass index (BMI) 22.46 kg/m2. His thyroid was not enlarged and non-tender without clear palpable thyroid nodules or neck lymph nodes. Hyperthyroidism was suspected and confirmed by thyroid function tests: TSH was less than 0.0005 μIU/mL (normal 0.35–4.94), and free T4 1.830 ng/dL (0.70–1.48). Graves’ disease was considered, and thyroid antibody tests performed. Thyroid peroxidase (TPO) antibody titer was less than 9 IU/mL (<9), and TSI 141% (<120%). To confirm the diagnosis of this hyperthyroid patient, Technetium-99m uptake and scan was done which showed uptake of 0.8% (0.5–7%). After careful observation for 2 months with 5mg of carvedilol, he turned asymptomatic and free T4 lowered to 1.480 ng/dL and TSH remained less than 0.0005 μIU/mL. CLINICAL LESSONS I here report a case of transient hyperthyroidism secondary to PCSK9 inhibitor therapy. There has been no report of hyperthyroidism induced by PCSK9 inhibitors. Immunological influence of anti-PCSK9 therapy on thyroid is unknown. In this case, the decrease of TSH due to hyperthyroidism was considered to reduce hepatic PCSK9 expression, leading to additive effect to PCSK9 inhibitor. PCSK9 inhibitors may modify the effects of hyperlipidemia treatment by causing changes in thyroid function. When using PCSK9 inhibitors, follow-up of thyroid function should be considered. This case highlights the involvement of thyroid function in PCSK9 inhibitor therapy. Reference (1) Gong, Y., Ma, Y., et al. Thyroid stimulating hormone exhibits the impact on LDLR/LDL-c via up-regulating hepatic PCSK9 expression. Metabolism. 2017;76;32–41

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Role of PCSK9 Inhibitors in High Risk Patients with Dyslipidemia: Focus on Familial Hypercholesterolemia

Current Pharmaceutical Design ◽

10.2174/1381612824666181010124657 ◽

2019 ◽

Vol 24 (31) ◽

pp. 3647-3653 ◽

Cited By ~ 3

Author(s):

Vasilios Papademetriou ◽

Konstantinos Stavropoulos ◽

Christodoulos Papadopoulos ◽

Konstantinos Koutsampasopoulos ◽

Kiriakos Dimitriadis ◽

...

Keyword(s):

Familial Hypercholesterolemia ◽

Low Density Lipoprotein ◽

Density Lipoprotein ◽

Population Characteristics ◽

Lipid Lowering ◽

Pcsk9 Inhibitors ◽

Autosomal Dominant Disorder ◽

Pcsk9 Inhibitor ◽

Cv Disease ◽

The Impact

Background: Familial hypercholesterolemia (FH) is an inherited autosomal dominant disorder that is characterized by substantially increased Low-Density Lipoprotein Cholesterol (LDL-C) levels. Patients with FH have a significantly higher risk for Cardiovascular (CV) events, and the timely reduction of LDL-C is of paramount importance to ameliorate the risk for CV disease. Among the available lipid-lowering therapies, the novel Proprotein Convertase Subtilisin/Kexin type 9 (PCSK9) inhibitors have emerged as a very promising class of drugs for the management of such patients. Objective: The purpose of this review is to present available data on the efficacy and safety of the two available PCSK9 inhibitors in patients with FH, and importantly to discuss potential differences between the two drugs. Methods: A comprehensive literature search was performed to identify available data from clinical studies evaluating the impact of evolocumab or alirocumab on lipid and CV parameters in patients with FH. Results: Several studies have assessed the lipid-lowering profile of PCSK9 inhibitors in patients with FH. Both evolocumab and alirocumab were found to significantly reduce LDL-C by more than 50-60% in FH patients. Furthermore, data also support a lower rate of lipid apheresis in FH patients receiving a PCSK9 inhibitor. In terms of CV outcomes, both drugs were found to possess CV-ameliorating effects of the same extent in patients with CV disease. However, alirocumab reduced all-cause mortality, as well, a finding not observed with evolocumab. Several differences in the study population characteristics might explain this and other mild differences observed in the CV trials of these drugs. Conclusion: Available evidence suggests similar potency of alirocumab and evolocumab in reducing lipids and CV events.

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The Impact of Opium Abuse on Lipid Profile in Patients with Diabetes: A Systematic Review and Meta-Analysis

International Journal of Environmental Research and Public Health ◽

10.3390/ijerph16234795 ◽

2019 ◽

Vol 16 (23) ◽

pp. 4795

Author(s):

Omorogieva Ojo ◽

Xiao-Hua Wang ◽

Osarhumwese Osaretin Ojo ◽

Jude Ibe

Keyword(s):

Systematic Review ◽

Body Mass Index ◽

Lipid Profile ◽

Ldl Cholesterol ◽

Meta Analysis ◽

Density Lipoprotein ◽

Hdl Cholesterol ◽

Patients With Diabetes ◽

Opium Abuse ◽

The Impact

There is an increasing prevalence of diabetes worldwide and substance abuse has been observed as a problem among some people with diabetes. Therefore, there is an urgent need to understand the association between unhealthy drug use including the abuse of opium and clinical outcomes including its impact on lipid profile in patients with diabetes as the presence of these conditions can increase the risk of cardiovascular morbidity and mortality. Aim: This was a systematic review and meta-analysis which evaluated the impact of opium abuse on lipid profile in patients with diabetes. Method: This systematic review was conducted in line with the preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines. Three databases (Embase, PubMed, and PsycINFO) plus Google Scholar were searched for relevant articles from database inception to 18 July 2019 based on the Population, Intervention, Comparator, and Outcomes (PICO) framework. The studies included were based on a set of inclusion and exclusion criteria including patients with diabetes who abused opium. Articles were evaluated for risk of bias and the meta-analysis was conducted using Revman. Results: Six articles that met the criteria were included in the systematic review and meta-analysis. The type of substance abused was opium in all the studies. The results of the meta-analysis showed that opium abuse significantly (P = 0.01) lowered total cholesterol compared to control with a mean difference of −0.17 (95% CI, −0.29, −0.04) in patients with diabetes. With respect to high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, triglycerides, and body mass index, the differences were not statistically significant (P > 0.05) between those who abused opium compared with the control. Nutritional deficiencies, weight loss and lipid dysregulation due to liver dysfunction which are found in people who abuse substances may explain the findings of the current review with respect to lipid profile in patients with diabetes who abuse opium compared with the control. Conclusion: The findings of this systematic review and meta-analysis have shown that opium abuse significantly decreased total cholesterol (P < 0.05) in patients with diabetes. However, the effect of opium abuse on HDL cholesterol, triglycerides, body mass index (BMI) and LDL cholesterol in these patients were not statistically significant (P > 0.05) compared with the control. This result has public health significance in terms of ensuring the promotion of adequate nutritional intake in patients with diabetes who abuse opium.

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Clinical Investigations of the Effect of Citrus unshiu Peel Pellet on Obesity and Lipid Profile

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2018/4341961 ◽

2018 ◽

Vol 2018 ◽

pp. 1-6 ◽

Cited By ~ 3

Author(s):

Seongil Kang ◽

Sangyeol Song ◽

Joosang Lee ◽

Hyekyung Chang ◽

Sanghun Lee

Keyword(s):

Lipid Profile ◽

Total Cholesterol ◽

Cholesterol Level ◽

Weight Control ◽

Large Scale ◽

Total Cholesterol Level ◽

Experimental Studies ◽

Density Lipoprotein ◽

Citrus Unshiu ◽

The Impact

Objectives. Several experimental studies have reported antiobesity and lipid-improving effects of Citrus unshiu. However, clinical studies on its effects are lacking. This study was designed to evaluate the impact of Citrus unshiu peel pellet (CUPP) on obesity and lipid profile. Methods. For 118 patients with body mass index (BMI) > 23 who took Citrus unshiu peel pellet (CUPP) for 4 weeks in a Public Health Center, laboratory and biometric readings before and after CUPP administration were analyzed. Results. Mean age of these subjects was 53.8±10.6 years (range: 18-75 years). There were 88 (74.6%) females in the study sample (n = 118). A significant (p < 0.01) decrease in BMI from 27.47±2.24 to 27.27±2.22 was observed in all subjects after CUPP treatment and 65.3% (N = 77) of them lost 1.03±0.83 kg of weight after 4 weeks of treatment. Total cholesterol level was significantly (p < 0.01) decreased from 204.0±37.4 mg/dL to 193.5±36.5 mg/dL. Significant (p < 0.05) decreases in levels of low-density lipoprotein, cholesterol, and triglyceride were also observed. Conclusions. These results suggest that CUPP in practice could help weight control and improve total cholesterol level. Findings of this study provide clinical foundation for future large-scale trials to establish clinical benefits of CUPP.

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A Comparative Study of Lipid Profile in Obese and Nonobese Men attending Master Health Checkup

Indian Journal of Medical Biochemistry ◽

10.5005/jp-journals-10054-0024 ◽

2017 ◽

Vol 21 (2) ◽

pp. 73-75

Author(s):

S Vinod Babu ◽

Anusha R Jagadeesan ◽

Jothimalar Ramalingam

Keyword(s):

Comparative Study ◽

Lipid Profile ◽

Total Cholesterol ◽

Ldl Cholesterol ◽

Density Lipoprotein ◽

Hdl Cholesterol ◽

P Value ◽

Health Checkup ◽

Group I ◽

Significant Difference

ABSTRACT Introduction Obesity is emerging as an epidemic worldwide. Obesity is associated with a number of comorbid conditions, such as diabetes mellitus, hypertension, cancer, dyslipidemia, cardiovascular abnormalities, anemia, obstructive sleep apnea, and psychosocial abnormalities. Aim This study aims at comparing the lipid profile levels of obese and nonobese men. Materials and methods This was a case—control study conducted at a tertiary care center. Totally, 80 men in the age group of 20 to 47 years attending the master health checkup were included in the study, out of which 40 men with normal body mass index (BMI) of 18 to 25 belonged to group I and 40 men with increased BMI of 30 and above belonged to group II. Lipid profile parameters, such as triglycerides (TGLs), total cholesterol, high-density lipoprotein (HDL) cholesterol, and low-density lipoprotein (LDL) cholesterol were estimated in them. The data were statistically analyzed using Statistical Package for the Social Sciences (SPSS) software version 15.0. Results Statistically significant difference was found in the total cholesterol levels with a p-value of 0.040 while the difference in LDL cholesterol was statistically highly significant with a p-value of 0.040. Conclusion Among lipid profile parameters, only total cholesterol and LDL cholesterol showed significant difference between the obese and nonobese individuals. However, the other parameters like HDL cholesterol and TGLs did not show any significant difference. How to cite this article Babu SV, Jagadeesan AR, Ramalingam J. A Comparative Study of Lipid Profile in Obese and Nonobese Men attending Master Health Checkup. Indian J Med Biochem 2017;21(2):73-75.

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An oral antisense oligonucleotide for PCSK9 inhibition

Science Translational Medicine ◽

10.1126/scitranslmed.abe9117 ◽

2021 ◽

Vol 13 (593) ◽

pp. eabe9117

Author(s):

Peter Gennemark ◽

Katrin Walter ◽

Niclas Clemmensen ◽

Dinko Rekić ◽

Catarina A.M. Nilsson ◽

...

Keyword(s):

Steady State ◽

Oral Administration ◽

Antisense Oligonucleotide ◽

Oral Delivery ◽

Ldl Cholesterol ◽

Low Density Lipoprotein ◽

Density Lipoprotein ◽

Pcsk9 Inhibitors ◽

Sodium Caprate ◽

Subcutaneous Dose

Inhibitors of proprotein convertase subtilisin/kexin type 9 (PCSK9) reduce low-density lipoprotein (LDL) cholesterol and are used for treatment of dyslipidemia. Current PCSK9 inhibitors are administered via subcutaneous injection. We present a highly potent, chemically modified PCSK9 antisense oligonucleotide (ASO) with potential for oral delivery. Past attempts at oral delivery using earlier-generation ASO chemistries and transient permeation enhancers provided encouraging data, suggesting that improving potency of the ASO could make oral delivery a reality. The constrained ethyl chemistry and liver targeting enabled by N-acetylgalactosamine conjugation make this ASO highly potent. A single subcutaneous dose of 90 mg reduced PCSK9 by >90% in humans with elevated LDL cholesterol and a monthly subcutaneous dose of around 25 mg is predicted to reduce PCSK9 by 80% at steady state. To investigate the feasibility of oral administration, the ASO was coformulated in a tablet with sodium caprate as permeation enhancer. Repeated oral daily dosing in dogs resulted in a bioavailability of 7% in the liver (target organ), about fivefold greater than the plasma bioavailability. Target engagement after oral administration was confirmed by intrajejunal administration of a rat-specific surrogate ASO in solution with the enhancer to rats and by plasma PCSK9 and LDL cholesterol lowering in cynomolgus monkey after tablet administration. On the basis of an assumption of 5% liver bioavailability after oral administration in humans, a daily dose of 15 mg is predicted to reduce circulating PCSK9 by 80% at steady state, supporting the development of the compound for oral administration to treat dyslipidemia.

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The Impact of Dietary Supplementation of Whole Foods and Polyphenols on Atherosclerosis

Nutrients ◽

10.3390/nu12072069 ◽

2020 ◽

Vol 12 (7) ◽

pp. 2069 ◽

Cited By ~ 2

Author(s):

Abigail E. Cullen ◽

Ann Marie Centner ◽

Riley Deitado ◽

Javier Fernandez ◽

Gloria Salazar

Keyword(s):

Lipid Profile ◽

Low Density Lipoprotein ◽

Rice Variety ◽

Density Lipoprotein ◽

Lipoprotein Receptor ◽

Agaricus Blazei ◽

Dietary Interventions ◽

Density Lipoprotein Receptor ◽

The Impact ◽

Whole Foods

The purpose of this review is to highlight current research on the benefits of supplementation with foods with a diverse polyphenol composition, including fruits, vegetables, nuts, grains, oils, spices, and teas in blunting atherosclerosis. We searched PubMed for publications utilizing whole food or polyphenols prepared from whole foods in Apolipoprotein E (ApoE) or Low-Density Lipoprotein Receptor (LDLR) knockout mice, and identified 73 studies in which plaque was measured. The majority of the studies reported a reduction in plaque. Nine interventions showed no effect, while three using Agaricus blazei mushroom, HYJA-ri-4 rice variety, and safrole-2’, 3’-oxide (SFO) increased plaque. The mechanisms by which atherosclerosis was reduced include improved lipid profile, antioxidant status, and cholesterol clearance, and reduced inflammation. Importantly, not all dietary interventions that reduce plaque showed an improvement in lipid profile. Additionally, we found that, out of 73 studies, only 9 used female mice and only 6 compared both sexes. Only one study compared the two models (LDLR vs. ApoE), showing that the treatment worked in one but not the other. Not all supplementations work in both male and female animals, suggesting that increasing the variety of foods with different polyphenol compositions may be more effective in mitigating atherosclerosis.

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Naturally Occurring PCSK9 Inhibitors

Nutrients ◽

10.3390/nu12051440 ◽

2020 ◽

Vol 12 (5) ◽

pp. 1440

Author(s):

Maria Pia Adorni ◽

Francesca Zimetti ◽

Maria Giovanna Lupo ◽

Massimiliano Ruscica ◽

Nicola Ferri

Keyword(s):

Ldl Cholesterol ◽

Current Knowledge ◽

Therapeutic Option ◽

Low Density Lipoprotein ◽

Density Lipoprotein ◽

Inhibitory Effect ◽

Pcsk9 Inhibitors ◽

Beneficial Effects ◽

Naturally Occurring ◽

Starting Point

Genetic, epidemiological and pharmacological data have led to the conclusion that antagonizing or inhibiting Proprotein convertase subtilisin/kexin type 9 (PCSK9) reduces cardiovascular events. This clinical outcome is mainly related to the pivotal role of PCSK9 in controlling low-density lipoprotein (LDL) cholesterol levels. The absence of oral and affordable anti-PCSK9 medications has limited the beneficial effects of this new therapeutic option. A possible breakthrough in this field may come from the discovery of new naturally occurring PCSK9 inhibitors as a starting point for the development of oral, small molecules, to be used in combination with statins in order to increase the percentage of patients reaching their LDL-cholesterol target levels. In the present review, we have summarized the current knowledge on natural compounds or extracts that have shown an inhibitory effect on PCSK9, either in experimental or clinical settings. When available, the pharmacodynamic and pharmacokinetic profiles of the listed compounds are described.

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Amaranth Oil Increases Total and LDL Cholesterol Levels without Influencing Early Markers of Atherosclerosis in an Overweight and Obese Population: A Randomized Double-Blind Cross-Over Study in Comparison with Rapeseed Oil Supplementation

Nutrients ◽

10.3390/nu11123069 ◽

2019 ◽

Vol 11 (12) ◽

pp. 3069

Author(s):

Monika Dus-Zuchowska ◽

Jaroslaw Walkowiak ◽

Anna Morawska ◽

Patrycja Krzyzanowska-Jankowska ◽

Anna Miskiewicz-Chotnicka ◽

...

Keyword(s):

Lipid Profile ◽

Rapeseed Oil ◽

Ldl Cholesterol ◽

Density Lipoprotein ◽

High Sensitivity ◽

Anthropometric Parameters ◽

Double Blind ◽

Early Markers ◽

Amaranth Oil ◽

Overweight Subjects

Background: Atherosclerosis (AT) is a chronic inflammatory process in which oxidative stress is the key event. Amaranth oil (AmO) has potential hypolipidemic and antiatherogenic effects. The aim of the study was to compare the effects of AmO and rapeseed oil (RaO) supplementation on expression of early markers of AT and lipid profile in obese or overweight subjects. Methods: A randomized, double-blinded cross-over study was conducted, in which participants took 20 mL of AmO in the first arm and 20 mL RaO in the second arm, switching after the washout period. Serum concentrations of adhesion molecules (sP-selectin, sVCAM-1), high-sensitivity C-reactive protein (hsCRP), asymmetric dimethylarginine (ADMA), and lipid profile were assessed before and after nutritional interventions. In addition, anthropometric parameters were measured. Results: The total (TC) and low-density lipoprotein (LDL) cholesterol concentrations increased significantly in the AmO group in comparison with RaO (ΔTC 5.52 ± 35 vs. −8.43 ± 17.65 mg/dL; p = 0.002 and 4.43 ± 34.96 vs. −7.55 ± 16.41 mg/dL; p = 0.002, respectively). There were no significant differences in other parameters analyzed between the groups. Conclusion: The use of AmO instead of RaO may increase cardiovascular risk in obese and overweight subjects.

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