INTRODUCTION

It has been known for over 50 years that plant sterols are the most effective natural substances for lowering plasma cholesterol.

This document reviews the effects of plant sterols for treating dyslipidemia and describes how they can be used for several therapeutic strategies in order to maximize benefits for patients.

CARDIOSMILE‘s additional benefits will also be presented, particularly in comparison with other plant sterols available on the market. What makes CARDIOSMILE unique are its additional effects besides decreasing non-HDL cholesterol: lower triglycerides and smaller waist size, both of which are markers that are linked to cardiovascular risk and can be treated for an overall improvement of people’s lipid profile.

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Cardiosmile and Juice

WHAT MAKES CARDIOSMILE UNIQUE?

After a decade of research focused on adding plant sterols to aqueous matrices to make them easier to consume, we formulated a micro-dispersion of fat-free plant sterols in a solid state and a spherical configuration with extremely high exposed surface to enhance its interaction with the intestinal micelle, where it blocks cholesterol absorption.

This new formulation, dubbed Cardiosmile, unlike other plant sterols leads to a decrease in plasma triglyceride levels. This enhanced effect makes it a good candidate for treating dyslipidemias as it modifies the number and structure of plasma lipoproteins, leading reduced cardiovascular risk by minimizing LDL cholesterol particles oxidization.

CLINICAL STUDIES

Various studies have scientifically proven that a daily intake of CARDIOSMILE significantly contributes to an improvement of cardiovascular health. Below are some interesting facts about their results:

Clinical studies

1. UNIVERSITY OF MANITOBA, CANADA

This study proved the efficacy of CARDIOSMILE, a water-dispersible formulation of free plant sterols (WD-PS) versus plant sterol esters (PS esters), thus supporting the claim that there may be additional advantages in a more highly solubilized form of WD-PS in comparison with traditional PS esters in terms of controlling lipid levels.

Treatment with CARDIOSMILE showed the following results:

All participants showed good tolerance to experimental treatments and no secondary effects were reported.

In particular, there was a reduction (p <0.001) in the total cholesterol and LDL cholesterol levels at the end compared to control. LDL cholesterol averaged 11.7%.

The TC to HDL-C and non-HDL-C to HDL-C ratios showed significant reductions (10.5%, 15.2%, p <0.05), during the treatment period.

There was a decrease in TG levels (13.9%, p <0.05); i.e. it helped regulate circulating TG levels.

A reduction of TG circulation in serum in individuals with high TG background levels. Please note that this is the first study to observe a positive effect of free plant sterol intake on TG levels.

The 2 g/d dose of WD-PS or PS esters did not impact negatively the level of vitamins or fat-soluble carotenoids before or after adjusting the LDL-C levels, compared to control.

There was a favorable modification of lipid profiles in blood, without altering plasma hepatic enzymes or PCR concentrations. Interestingly, compared to PS ester-enriched yogurt, the consumption of WD-PS-en- riched yogurt in hypercholesterolemic individuals not only lowered their total cholesterol and LDL cholesterol very similarly, but it also lowered their triglycerides and the TC / HDL-C ratio.

Clinical Efficacy:

Results Chart

(*) Shaghaghi M.A., Harding S.V., Jones P.J.H. (2014). Water dispersible plant sterol formulation shows improved effect on lipid profile compared to plant sterol esters. J. Funct. Foods, 6:280-9.

2. UNIVERSITY OF LOS ANDES, CHILE

This study determined the possible link between a reduction in waist size and triglycerides levels, with an increase in intestinal transit. Waist size and high triglyceride levels have been identified as two of the most relevant risk factors for cardiovascular disease, and become good indicators of the potential efficacy of plant sterols as a plausible treatment for conditions such as metabolic syndrome.

Observations were the following:

A higher proportion of individuals in the intervention group went from altered triglyceride levels to being below 150 mg / dl, showing real improvement for this parameter.

A reduction in the trend linked to waist size, particularly in women. Please note that this parameter is closely connected to cardiovascular disease.

VLDL cholesterol decreases by 10% in the intervention group, while HDL cholesterol shows an upward trend, particularly among men.

Triglycerides go down in both men and women, with a statistically significant difference of 12% at the end of the study.

Improved intestinal transit in women with constipation issues.

Downward trend in the total cholesterol to HDL cholesterol ratio, showing improvement in the quality of lipoproteins among patients treated with plant sterols.

(*) Palmeiro, Y., et al. (2020). Effects of Daily Consumption of an Aqueous Dispersion of Free-Phytosterols Nanoparticles on Individuals with Metabolic Syndrome: A Randomised, Double-Blind, Placebo-Controlled Clinical Trial. Nutrients, 12(8): 2392.

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3. ONGOING STUDIES

Part of our philosophy is to continue working on innovation, development, and scientific evidence. This is why we are permanently conducting new studies to prove the effectiveness of free plant sterols (WD-PS), and particularly of CARDIOSMILE.

This will allow us to continue to guarantee its contribution to cardiovascular health, which is aligned with our purpose of accompanying people in the adoption of a lasting healthy lifestyle.

Toronto University

University of Toronto, Canada.

Completion date: December 2022.

The purpose of this study is to determine whether a dietary portfolio of cholesterol-lowering foods (viscous fibers, soy protein, plant sterols and nuts) further enhanced by increased levels of monounsaturated fatty acids (MUFA) and low glycemic index foods; together with a structured exercise program reduce the progression of carotid and coronary atheromatous lesions, Low density lipoprotein-cholesterol (LDL-C), and blood pressure, while reducing the number of individuals requiring statins.

For research agreements or support in the formulation or development of a clinical study of interest, please contact Gonzalo Vega, Nutrartis Technical Director: gonzalo.vega@nutrartis.com.

THERAPEUTIC STRATEGIES

Combining plant sterols with statins

In addition to primary prevention among the general population, foods with added plant sterols may provide a further reduction of LDL-C for patients with dyslipidemia who have a high cardiovascular risk and who are treated with lipid-lowering medications. It is therefore relevant to define the lipid-modifying effects of plant sterols in the diet (2 to 3 g / day) combined with drug therapies to optimize their clinical use.

In clinical studies, dietary plant sterols lead to an incremental decrease of LDL-C levels by 10% to 15% when combined with treatment with statins, which is higher than 6% when the statin dosage is doubled.

In general, a 10% reduction in the concentration of LDL-C in serum is typical when using foods with added plant sterols. Since foods with added plant sterols reduce cholesterol absorption, they may also reduce the production of chylomicrons and chylomicron remnants derived from the intestine.

Today, foods with added plant sterols or plant sterol supplements may be used for people with high cholesterol levels, but also for people with an intermediate or low global cardiovascular risk who do not qualify for drug therapy.

Finally, given the rising importance of early preventive strategies in hypercholesterolemia, including plant-sterol enriched foods in the diet of adults and children (6+) with familial hypercholesterolemia (FH) can complement lifestyle changes and drug therapy.

(*) Gylling H., Plat J., Turley S., Ginsberg H. N., Ellegård L., Jessup W., et al. (2014). Plant sterols and plant stanols in the management of dyslipidaemia and prevention of cardiovascular disease. Atherosclerosis 232 346–360.

Lowering statin dosages due to secondary effects

Statin intake has increased over the last 50 years and they have become well known all around the world. The benefits of statins for lowering LDL cholesterol are proven for short-term intake periods; i.e. their effectiveness is much quicker than that of other medicinal products.

It has been proven that a higher daily intake of statins has various side effects, depending on the clinical history of the consumer and the prescribed amounts. The indiscriminate use of statins has now been questioned by the medical community, the World Health Organization (WHO), and consumers themselves.

Between 10% and 25% of patients who take statins are estimated to have side effects. According to the US Food and Drug Administration (FDA), some of these effects are:

Muscle pain

Liver disorders

Diabetes

Confusion and memory loss

 Increased blood sugar

Among others

Side effects

Statin intake also has restrictions for people under 18 and pregnant women.

Recommendations suggest evaluating the combination of statins and plant sterols, whose additive effect has been widely demonstrated. The potential to reach LDL-C goals can therefore be improved, while reducing the side effects that come with high doses of statins.

(*) Gylling H., Plat J., Turley S., Ginsberg H. N., Ellegård L., Jessup W., et al. (2014). Plant sterols and plant stanols in the management of dyslipidaemia and prevention of cardiovascular disease. Atherosclerosis 232 346–360.
(*) US Food and Drug Administration (FDA).

Doctor

Other effects

There are additional effects linked to the use of plant sterols, such as a reduction of high levels of plasma triglycerides, particularly when those levels are high before treatment begins.

This is highly beneficial for patients as it contributes to prevention and improved cardiovascular health. Triglycerides are important markers of cardiovascular risk, indirectly showing a high presence of small LDL particles.

(*) Atherosclerosis 232 (2014) 346-360
https://www.atherosclerosis-journal.com/article/S0021-9150(13)00694-1/fulltext

Clinical Trends

One of the most frequent problems of treating dyslipidemia is identifying those patients who need treatment. Once a lipid disorder is found, doctors usually assess the seriousness of the lipid levels plus the global risk, and then encourage their patients to follow a prescribed therapy. This is additional to the level of heart protection offered by current agents.

Most specialists will suggest that they make changes in lifestyle as a first measure to reduce patients’ total risk in the early stages, as well as secondary prevention. If a modified lifestyle yields no results, doctors will tend to recommend drug therapy to correct patients’ lipid profile, as there is solid evidence that improved levels of lipids correlate to lower cardiovascular risk.

Today, patients with lower cardiovascular risk can be treated with changes in their lifestyle plus a low- or moderate- power generic statin (such as simvastatin). Higher-risk patients are usually treated with more powerful statins such as atorvastatin or rosuvastatin. Statins are firmly rooted hypercholesterolemia as an isolated disorder or as part of a mixed dyslipidemia, with an LDL-C reduction efficacy of approximately 60% when used as treatment for patients with statins, and approximately 45% when used as monotherapy.

However, this reality is changing and there is a search for new alternatives to statins for treating dyslipidemia with LDL-C-lowering therapies, for patients who are beginning their treatment, have a moderate risk, and/or may require urgent TG reduction. If statins cannot be replaced completely, additional therapies are implemented if there is enough evidence of lipid modification with acceptable tolerability and reduction of LDL-C. This represents an opportunity for finding an alternative to statins which can provenly lower cardiovascular morbidity and mortality. Here, plant sterols appear as a strong, effective innovation for treating this pathology, due to the following reasons:

Doctors’ main challenge is to keep their patients on in lipid-modifying diets due to a lack of dyslipidemia symptoms, drug side effects, and the treatment burden.

The route of administration and dose frequency may have a significant impact on the patients’ adherence rates. Dyslipidemia is a chronic condition which may require daily treatment over several years.

(*) Decision Resources, LLC.

HEALTH PROFESSIONAL SURVEY

France

France

Data analysis considers a panel of 50 general practitioners, 26 cardiologists, and 11 nutritionists from all regions of France.

Findings are summarized below:

General practitioners are very concerned with dyslipidemia among their patients because they are the only doctors who treat them throughout all stages of the disease, either initial or chronic. They do, however, consider CARDIOSMILE as an option for patients with no serious risks.

CARDIOSMILE fits well in the prescription logic of general GPs and specialists who are looking for a product which has no side effects and is easy to take. This approach is evident in the intentions of doctors from all three specialties, who unanimously begin treatment with healthy lifestyle changes plus CARDIOSMILE. However, CARDIOSMILE only comes as third choice among cardiologists (while statins come first).

Nutritionists claim that they would recommend CARDIOSMILE as first choice in their prescriptions.

This means that CARDIOSMILE has proved to have a strong projected market share for treating early dyslipidemias among the three medical specialties. It is a particularly interesting option when the drop in LDL is linked to its action on triglycerides and HDL.

The study concludes that 51% of doctors declare that they are ready to prescribe the product and 30% are waiting for samples and tests.

(*) Cardiosmile, private studies.

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Chile

Chile

Data analysis considers a panel of 21 doctors of the following specialties: 7 cardiologists, 4 internists, 4 nutriologists, 3 endocrinologists, and 3 gynecologists, in representation of Chilean specialists.

Findings are summarized below:

Doctors who treat more patients with cholesterol levels are cardiologists, internists, and nutriologists. Most specialists choose drug therapy as first-line treatment, and the great protagonists are statins. They are seldom combined with other drugs or treatments.

Nutriologists are the specialists who make greatest use of plant sterols in their treatments.

Nutriologists are the specialists who make greatest use of plant sterols in their treatments.

Most specialists know about plant sterols and have prescribed them, or still do, but only in certain cases. It is worth noting that they favor plant sterols over Benecol (yogurt with added plant stanols).

Most specialists know about CARDIOSMILE, either from sales reps or congresses. Frequent prescribers report positive experience (mostly nutriologists).

Seminars, courses, symposiums, and congresses organized by labs are well received. There is also considerable interest in attending medical refresher courses.

Nutriologists are the most receptive and open to using CARDIOSMILE as monotherapy and complement.

The recommendation is to position CARDIOSMILE’s benefits as complement for drug therapy with statins, mostly among cardiologists and internists.

(*) Cardiosmile, private studies.

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