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1.
Artichoke and Bergamot Phytosome Alliance: A Randomized Double Blind Clinical Trial in Mild Hypercholesterolemia.
Riva, A, Petrangolini, G, Allegrini, P, Perna, S, Giacosa, A, Peroni, G, Faliva, MA, Naso, M, Rondanelli, M
Nutrients. 2021;(1)
Abstract
Botanicals are natural alternatives to pharmacological therapies that aim at reducing hypercholesterolemia. In this context, despite bergamot being effective in modulating lipid profile, some subjects failed to achieve a satisfactory response to supplementation. The aim of this study was to evaluate whether the association of 600 mg of bergamot phytosome® (from Citrus Bergamia Risso) and 100 mg of artichoke leaf standardized dry extract (from Cynara cardunculus L.) can be an alternative in patients with mild hypercholesterolemia who are poor responders to bergamot in a 2-month randomized placebo-controlled trial. Sixty overweight adults were randomized into two groups: 30 were supplemented and 30 received a placebo. The metabolic parameters and DXA body composition were evaluated at the start, after 30 and 60 days. Between the two groups, total and LDL cholesterol in the supplemented group (compared to placebo) showed significant decreases overtime. A significant reduction of waist circumference and visceral adipose tissue (VAT) was recorded in the supplemented group (compared to placebo), even in subjects who did not follow a low-calorie diet. In conclusion, the synergism between Citrus Bergamia polyphenols and Cynara cardunculus extracts may be an effective option and may potentially broaden the therapeutic role of botanicals in dyslipidemic patients.
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Targeting the Cholesterol Paradigm in the Risk Reduction for Atherosclerotic Cardiovascular Disease: Does the Mechanism of Action of Pharmacotherapy Matter for Clinical Outcomes?
Zhou, R, Stouffer, GA, Smith, SC
Journal of cardiovascular pharmacology and therapeutics. 2021;(6):533-549
Abstract
Hypercholesterolemia is a well-established risk factor for atherosclerotic cardiovascular disease (ASCVD). Low-density lipoprotein cholesterol (LDL-C) has been labeled as "bad" cholesterol and high-density lipoprotein cholesterol (HDL-C) as "good" cholesterol. The prevailing hypothesis is that lowering blood cholesterol levels, especially LDL-C, reduces vascular deposition and retention of cholesterol or apolipoprotein B (apoB)-containing lipoproteins which are atherogenic. We review herein the clinical trial data on different pharmacological approaches to lowering blood cholesterol and propose that the mechanism of action of cholesterol lowering, as well as the amplitude of cholesterol reduction, are critically important in leading to improved clinical outcomes in ASCVD. The effects of bile acid sequestrants, fibrates, niacin, cholesteryl ester transfer protein (CETP) inhibitors, apolipoprotein A-I and HDL mimetics, apoB regulators, acyl coenzyme A: cholesterol acyltransferase (ACAT) inhibitors, cholesterol absorption inhibitors, statins, and proprotein convertase subtilisin kexin 9 (PCSK9) inhibitors, among other strategies are reviewed. Clinical evidence supports that different classes of cholesterol lowering or lipoprotein regulating approaches yielded variable effects on ASCVD outcomes, especially in cardiovascular and all-cause mortality. Statins are the most widely used cholesterol lowering agents and have the best proven cardiovascular event and survival benefits. Manipulating cholesterol levels by specific targeting of apoproteins or lipoproteins has not yielded clinical benefit. Understanding why lowering LDL-C by different approaches varies in clinical outcomes of ASCVD, especially in survival benefit, may shed further light on our evolving understanding of how cholesterol and its carrier lipoproteins are involved in ASCVD and aid in developing effective pharmacological strategies to improve the clinical outcomes of ASCVD.
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Bergamot phytosome improved visceral fat and plasma lipid profiles in overweight and obese class I subject with mild hypercholesterolemia: A randomized placebo controlled trial.
Rondanelli, M, Peroni, G, Riva, A, Petrangolini, G, Allegrini, P, Fazia, T, Bernardinelli, L, Naso, M, Faliva, MA, Tartara, A, et al
Phytotherapy research : PTR. 2021;(4):2045-2056
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Abstract
Bergamot has been traditionally used for the relief of diseases related to oxidative stress. Our aim was to investigate the effect of bergamot phytosome on visceral adipose tissue (VAT) and on metabolic profile, in overweight and obese subjects with mild hypercholesterolemia. A total of 64 participants were randomized into two groups for 12 weeks: a supplemented group (33 individuals, BMI 27 ± 3 kg/m2 receiving 500 mg of bergamot phytosome, two daily tablets) and placebo group (31 subjects, BMI 28 ± 3 kg/m2 , two daily tablets). As to the within differences, the parameters of VAT, total and LDL-cholesterol were significantly decreased in the bergamot phytosome group, but not in the placebo group. As to between-group differences, a statistically significant interaction between time and group, that is, the change in score over time differs between the two groups was observed 30 days after supplementation for VAT (p-value = .005), total cholesterol (p-value <.0002), and LDL (p = .004) in respect to placebo. The other parameters (glucose, insulin, Homeostasis Model Assessment, high-density lipoprotein cholesterol, triglycerides, fat free mass, fat mass) were not significant. In conclusion, this clinical study gives evidence that bergamot phytosome provides beneficial effects, such as decrease of VAT and modulation of metabolic alterations, after just 30 days of supplementation, resulting a very promising protection of cardiovascular health.
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4.
Clinical development of bempedoic acid: phase 2 and phase 3 clinical trials.
Lekuona, I, Pintó, X
Clinica e investigacion en arteriosclerosis : publicacion oficial de la Sociedad Espanola de Arteriosclerosis. 2021;:58-64
Abstract
We review all the phase II and III studies carried out with bempedoic acid at the dose of 180mg, alone or in combination with different lipid-lowering drugs and in different subgroups of patients that unequivocally show the efficacy and safety of the drug. We point out some of the potential advantages of its use in clinical practice in patients with statin intolerance and the efficacy in reducing LDL-c when combined with statins, and with statins and ezetimibe, as well as in reducing inflammation markers pending the results of the CV Clear Outcomes trial that will end in 2022.
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Virgin Olive Oil Phenolic Compounds Modulate the HDL Lipidome in Hypercholesterolaemic Subjects: A Lipidomic Analysis of the VOHF Study.
Fernández-Castillejo, S, Pedret, A, Catalán, Ú, Valls, RM, Farràs, M, Rubió, L, Castañer, O, Macià, A, Fitó, M, Motilva, MJ, et al
Molecular nutrition & food research. 2021;(9):e2001192
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Abstract
SCOPE The lipidomic analysis of high-density lipoprotein (HDL) could be useful to identify new biomarkers of HDL function. METHODS AND RESULTS A randomized, controlled, double-blind, crossover trial (33 hypercholesterolaemic subjects) is performed with a control virgin olive oil (VOO), VOO enriched with its own phenolic compounds (FVOO), or VOO enriched with additional phenolic compounds from thyme (FVOOT) for 3 weeks. HDL lipidomic analyses are performed using the Lipidyzer platform. VOO and FVOO intake increase monounsaturated-fatty acids (FAs) and decrease saturated and polyunsaturated FAs in triacylglyceride (TAG) species, among others species. In contrast, FVOOT intake does not induce these FAs changes. The decrease in TAG52:3(FA16:0) after VOO intake and the decrease in TAG52:5(FA18:2) after FVOO intake are inversely associated with changes in HDL resistance to oxidation. After FVOO intake, the decrease in TAG54:6(FA18:2) in HDL is inversely associated with changes in HDL cholesterol efflux capacity. CONCLUSION VOO and FVOO consumption has an impact on the HDL lipidome, in particular TAG species. Although TAGs are minor components of HDL mass, the observed changes in TAG modulated HDL functionality towards a cardioprotective mode. The assessment of the HDL lipidome is a valuable approach to identify and characterize new biomarkers of HDL function.
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New and Emerging Therapies for Reduction of LDL-Cholesterol and Apolipoprotein B: JACC Focus Seminar 1/4.
Nurmohamed, NS, Navar, AM, Kastelein, JJP
Journal of the American College of Cardiology. 2021;(12):1564-1575
Abstract
Adding to the foundation of statins, ezetimibe and proprotein convertase subtilisin-kexin type 9 inhibitors (PCSK9i), novel, emerging low-density lipoprotein cholesterol (LDL-C)-lowering therapies are under development for the prevention of cardiovascular disease. Inclisiran, a small interfering RNA molecule that inhibits PCSK9, only needs to be dosed twice a year and has the potential to help overcome current barriers to persistence and adherence to lipid-lowering therapies. Bempedoic acid, which lowers LDL-C upstream from statins, provides a novel alternative for patients with statin intolerance. Angiopoetin-like 3 protein (ANGPTL3) inhibitors have been shown to provide potent LDL-C lowering in patients with homozygous familial hypercholesterolemia without major adverse effects as seen with lomitapide and mipomersen, and may reduce the need for apheresis. Finally, CETP inhibitors may yet be effective with the development of obicetrapib. These novel agents provide the clinician the tools to effectively lower LDL-C across the entire range of LDL-C-induced elevation of cardiovascular risk, from primary prevention and secondary prevention to null-null homozygous familial hypercholesterolemia patients.
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A phase I study assessing the safety, tolerability, immunogenicity, and low-density lipoprotein cholesterol-lowering activity of immunotherapeutics targeting PCSK9.
Zeitlinger, M, Bauer, M, Reindl-Schwaighofer, R, Stoekenbroek, RM, Lambert, G, Berger-Sieczkowski, E, Lagler, H, Oesterreicher, Z, Wulkersdorfer, B, Lührs, P, et al
European journal of clinical pharmacology. 2021;(10):1473-1484
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Abstract
PURPOSE AT04A and AT06A are two AFFITOPE® peptide vaccine candidates being developed for the treatment of hypercholesterolemia by inducing proprotein convertase subtilisin/kexin type 9 (PCSK9)-specific antibodies. This study aimed to investigate safety, tolerability, antibody development, and reduction of low-density lipoprotein cholesterol (LDLc) following four subcutaneous immunizations. METHODS This phase I, single-blind, randomized, placebo-controlled study was conducted in a total of 72 healthy subjects with a mean fasting LDLc level at baseline of 117.1 mg/dL (range 77-196 mg/dL). Each cohort enrolled 24 subjects to receive three priming immunizations at weeks 0, 4, and 8 and to receive a single booster immunization at week 60 of either AT04A, AT06A, or placebo. In addition to safety (primary objective), the antigenic peptide- and PCSK9-specific antibody response and the impact on LDLc were evaluated over a period of 90 weeks. RESULTS The most common systemic treatment-related adverse events (AEs) reported were fatigue, headache, and myalgia in 75% of subjects in the AT06A group and 58% and 46% of subjects in the placebo and AT04A groups, respectively. Injection site reactions (ISR) representing 63% of all treatment-emergent adverse events (TEAEs), were transient and mostly of mild or moderate intensity and rarely severe (3%). Both active treatments triggered a robust, long-lasting antibody response towards the antigenic peptides used for immunization that optimally cross-reacted with the target epitope on PCSK9. In the AT04A group, a reduction in serum LDLc was observed with a mean peak reduction of 11.2% and 13.3% from baseline compared to placebo at week 20 and 70 respectively, and over the whole study period, the mean LDLc reduction for the AT04A group vs. placebo was -7.2% (95% CI [-10.4 to -3.9], P < 0.0001). In this group, PCSK9 target epitope titers above 50 were associated with clinically relevant LDLc reductions with an individual maximal decrease of 39%. CONCLUSIONS Although both AT04A and AT06 were safe and immunogenic, only AT04A demonstrated significant LDLc-lowering activity, justifying further development. TRIAL REGISTRATION EudraCT: 2015-001719-11. ClinicalTrials.gov Identifier: NCT02508896.
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Fixed-dose combination of rosuvastatin and ezetimibe: treating hypercholesteremia according to cardiovascular risk.
Barrios, V, Escobar, C
Expert review of clinical pharmacology. 2021;(7):793-806
Abstract
Introduction: Reducing low-density lipoprotein cholesterol (LDL-C) with lipid-lowering therapies has been associated with a decrease in the frequency of cardiovascular events.Areas covered: A systematic search was conducted on PubMed (MEDLINE), using the MeSH terms [Rosuvastatin] + [Ezetimibe] + [Dyslipidemia] + [treatment]. Original data from clinical trials, prospective and retrospective studies and more useful reviews were selected.Expert opinion: While statins continue to be the cornerstone of dyslipidemia management, many patients do not attain LDL-C targets with high-intensity statins alone. Rosuvastatin is a high-intensity statin with a low risk of adverse effects and drug-drug interactions and proven benefits in the prevention of cardiovascular disease. Rosuvastatin and ezetimibe have complementary mechanisms of action that enhance their ability to reduce LDL-C levels. Various studies have shown that the combination of rosuvastatin 10-40 mg and ezetimibe 10 mg enables considerable reductions in LDL-C (up to 60-75%) with a good safety profile in a broad spectrum of patients with hypercholesterolemia, including those at high risk and those with atherosclerotic cardiovascular disease. In addition, a fixed-dose combination of rosuvastatin and ezetimibe may improve adherence to medication. In this review, the available evidence on the combination of rosuvastatin and ezetimibe is updated.
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Bempedoic Acid and Ezetimibe for the Treatment of Hypercholesterolemia: A Systematic Review and Meta-Analysis of Randomized Phase II/III trials.
Bhagavathula, AS, Al Matrooshi, NO, Clark, CCT, Rahmani, J
Clinical drug investigation. 2021;(1):19-28
Abstract
UNLABELLED BACKGROUND AND OBJECTIVE A limited number of trials have evaluated the efficacy of a fixed-dose combination of bempedoic acid and ezetimibe for the treatment of hypercholesterolemia. The aim of this meta-analysis of existing studies was to evaluate the efficacy and safety of fixed-dose bempedoic acid and ezetimibe combination therapy for the treatment of hypercholesterolemia. METHODS A systematic literature search was conducted to identify randomized controlled trials (RCTs) comparing bempedoic acid and ezetimibe, versus placebo or ezetimibe alone, to 30 August 2020. A meta-analysis was conducted to investigate the efficacy of bempedoic acid and ezetimibe on lipid parameters and highly sensitive C-reactive protein (hsCRP) levels in patients with hypercholesterolemia or established atherosclerotic cardiovascular disease (ASCVD). Mean differences (MDs) or relative risk (RR) with their corresponding 95% confidence intervals (CIs), using random-effects models, were used to provide pooled estimates. RESULTS A total of three phase II and III RCTs, comprising 388 patients, of whom 49.2% were treated with bempedoic acid and ezetimibe, and 197 controls, were identified. The duration of treatment was 12 weeks. Bempedoic acid and ezetimibe significantly reduced low-density lipoprotein cholesterol (MD - 29.14%, 95% CI - 39.52 to - 18.76; p < .001), total cholesterol (MD - 15.78%, 95% CI - 20.84 to - 10.72; p = 0.01), non-high-density lipoprotein cholesterol (MD - 18.36%, 95% CI - 24.60 to - 12.12; p = 0.01), and hsCRP levels (MD - 30.48%, 95% CI - 44.69 to - 16.28; p = 0.04). No significant effects on triglycerides (MD - 8.35%, 95% CI - 16.08 to - 0.63; p = 0.72) and improvement in high-density lipoprotein cholesterol (MD 1.63%, 95% CI - 4.03 to 7.28; p = 0.92) were observed with the fixed-dose combination therapy. Regarding safety, bempedoic acid and ezetimibe combination was associated with a non-significant increased risk of drug-related adverse events (RR 1.61, 95% CI 0.86-2.35) and overall adverse events (RR 1.16. 95% CI 0.97-1.35); however, the incidence of discontinuation of therapy (RR 0.75, 95% CI 0.35-1.49) was lower. CONCLUSION This review found bempedoic acid and ezetimibe significantly lowered lipid parameters, attenuated hsCRP levels, and had an acceptable safety profile for the treatment of hypercholesterolemia and ASCVD.
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Cerebrotendinous xanthomatosis, sitosterolemia, Smith-Lemli-Opitz syndrome and the seminal contributions of Gerald Salen, MD (1935-2020).
Schaefer, EJ, Tint, GS, Duell, PB, Steiner, RD
Journal of clinical lipidology. 2021;(4):540-544
Abstract
Cerebrotendinous xanthomatosis (CTX), sitosterolemia, and Smith-Lemli Opitz syndrome (SLOS) are rare inborn errors of metabolism. The diagnoses of CTX and sitosterolemia are often delayed for many years because of lack of physician awareness, often resulting in significant and unnecessary progression of disease. CTX may present with chronic diarrhea, juvenile onset cataracts, strikingly large xanthomas, and neurologic disease in the setting of a normal serum cholesterol, but markedly elevated serum or plasma cholestanol levels. These patients have a defect in producing the bile acid chenodoxycholate, and oral chenodeoxycholate therapy is essential for these patients in order to prevent neurologic complications. Sitosterolemia can present with xanthomas, anemia, thrombocytopenia, splenomegaly, very premature heart disease, and serum cholesterol levels that may be normal or elevated, along with marked elevations of plasma β-sitosterol. These patients have a defect causing overabsorption of β-sitosterol, and the treatment of choice is oral ezetimibe. SLOS presents with growth delay, intellectual disability, multiple structural anomalies, and low serum cholesterol levels, and the defect is reduced cholesterol production. Treatment consists of dietary cholesterol supplementation and oral bile acid therapy which raises serum cholesterol levels and may improve symptoms. The metabolic and genetic defects in these disorders have been defined. There is no one in our field that has contributed more to the diagnosis and treatment of these disorders than Gerald Salen, MD, who died in late 2020 at 85 years of age. He will be greatly missed by his family, friends, and colleagues from around the world.