3.9 6.

Article

Effects of Novel Nutraceutical

Combination on Lipid Pattern of
Subjects with Sub-Optimal Blood
Cholesterol Levels

Nicola Vitulano, Pietro Guida, Vito Abrusci, Edmondo Ceci, Edy Valentina De Nicolò,
Stefano Martinotti, Nicola Duni, Federica Troisi, Federico Quadrini, Antonio di Monaco et al.

Special Issue
New Advances in Cardiovascular Drugs: In Memory of Professor Akira Endo
Edited by
Dr. Alfredo Caturano

https://doi.org/10.3390/biomedicines13081948
Article

Effects of Novel Nutraceutical Combination on Lipid Pattern of

Subjects with Sub-Optimal Blood Cholesterol Levels
Nicola Vitulano 1, *, Pietro Guida 1 , Vito Abrusci 1 , Edmondo Ceci 2 , Edy Valentina De Nicolò 2 , Stefano Martinotti 2,3 ,
Nicola Duni 1 , Federica Troisi 1 , Federico Quadrini 1 , Antonio di Monaco 1 , Massimo Iacoviello 4 ,
Andrea Passantino 5 and Massimo Grimaldi 1,3

1 Cardiology Department, Regional General Hospital ‘F. Miulli’, 70021 Acquaviva delle Fonti, Italy
2 Clinic Pathology Unit, Regional General Hospital ‘F. Miulli’, 70021 Acquaviva delle Fonti, Italy
3 Department of Medicine and Surgery, LUM University “Giuseppe Degennaro”, 70010 Casamassima, Italy
4 Department of Medical and Surgical Sciences, University of Foggia, 71122 Foggia, Italy
5 Istituti Clinici Scientifici Maugeri IRCCS, Cardiac Rehabilitation Unit of Bari Institute, 70121 Bari, Italy
* Correspondence: n.vitulano@miulli.it; Tel.: +39-803054111; Fax: +39-807814380

Abstract
Background/Objectives: High concentration of plasma low-density lipoprotein cholesterol
(LDL-C) is the predominant cause of atherosclerotic cardiovascular disease progression and
coronary heart disease. Nutraceutical combination together with a cholesterol-lowering ac-
tion provides an alternative to pharmacotherapy in patients reporting intolerance to statins
and in subjects with low cardiovascular risk. The effects on lipid parameters were evaluated
over 6 months for a food supplement containing aqueous extract of Berberis aristata and Olea
europea, fenugreek seed extract, water/ethanol extract of artichoke leaf and phytosterols
from sunflower seeds (Ritmon Colesystem® ). Methods: Laboratory data were obtained
at baseline from 44 otherwise healthy subjects (33 males, mean 50 ± 11 years) without
cardiovascular disease having LDL-C in the range 115 to 190 mg/dL pharmacologically
untreated for hypercholesterolemia. Subjects were re-evaluated at 1, 3 and 6 months during
which they took one tablet of Ritmon Colesystem® after dinner. Results: At baseline, the
Academic Editor: Alfredo Caturano mean values were 151 ± 21 mg/dL for LDL-C, 223 ± 24 mg/dL for total cholesterol (T-C),
Received: 4 July 2025 52 ± 14 mg/dL for high-density lipoprotein cholesterol (HDL-C), and 124 ± 58 mg/dL for
Revised: 4 August 2025 triglycerides. A significant reduction in LDL-C was observed; 9 mg/dL (95% confidence
Accepted: 8 August 2025 interval 3–14), 10 (4–17) and 7 (1–14) at 1, 3 and 6 months. A similar significant trend
Published: 9 August 2025
was detected for T-C while triglycerides did not show significant changes and HDL-C
Citation: Vitulano, N.; Guida, P.; had lower values only at 3 months. Conclusions: These nutraceuticals in individuals
Abrusci, V.; Ceci, E.; De Nicolò, E.V.;
with sub-optimal blood cholesterol levels at intermediate–low cardiovascular risk reduced
Martinotti, S.; Duni, N.; Troisi, F.;
LDL-C and T-C over 6 months contributing to the improvement of cholesterol control by
Quadrini, F.; di Monaco, A.; et al.
Effects of Novel Nutraceutical
dietary supplements.
Combination on Lipid Pattern of
Subjects with Sub-Optimal Blood Keywords: cardiovascular disease; cardiovascular risk factor; dyslipidemia; low-density
Cholesterol Levels. Biomedicines 2025, lipoprotein cholesterol; nutraceutical
13, 1948. https://doi.org/10.3390/
biomedicines13081948

Copyright: © 2025 by the authors.

Licensee MDPI, Basel, Switzerland. 1. Introduction
This article is an open access article
Cardiovascular diseases account for 32% of global deaths [1]. Atherosclerosis, often
distributed under the terms and
linked to aging, is primarily caused by hypercholesterolemia and it is the leading cause of
conditions of the Creative Commons
Attribution (CC BY) license
premature death, along with ischemic heart disease [2,3]. Low-density lipoprotein choles-
(https://creativecommons.org/ terol (LDL-C) increases cardiovascular risk, whereas high-density lipoprotein cholesterol
licenses/by/4.0/). (HDL-C) decreases it [3]. Clinical evidence supports the effectiveness of lowering LDL-C

Biomedicines 2025, 13, 1948 https://doi.org/10.3390/biomedicines13081948

Biomedicines 2025, 13, 1948 2 of 14

to prevent cardiovascular events. Studies show that LDL-C is both a high-risk marker
and a direct cause of cardiovascular disease [4]. Statins are the most commonly used
drugs to treat hypercholesterolemia, reducing LDL-C and major cardiovascular events
proportional to baseline risk [3,4]. Poor treatment compliance contributes to variability in
LDL-C reduction, with some patients discontinuing treatment long-term [3,5]. The most
common adverse effects of statins are muscle cramps, myalgia, or fatigue. Among the
strategies aimed at delaying or preventing pathological levels of cholesterolemia, the use
of food supplements can allow the improvement of the lipid profile in association with
a balanced diet and a healthy lifestyle through the reduction in a sedentary lifestyle in
favor of physical movement, reduction in stress, the abolition of alcohol consumption and
the habit of smoking [6]. A diet rich in natural antioxidants can play a significant role in
preventing atherosclerosis. Natural antioxidants, mainly phenolic compounds, present in
food of plant origin and in the human diet are responsible for protection of LDL against
oxidation by retarding and preventing foam cell formation, and further minimizing the pos-
sible damage of vessels caused by oxidized LDL [7]. The mechanism of antioxidant actions
involved either by hydrogen atom transfer, transfer of a single electron, sequential proton
loss electron transfer and chelation of transition metals. Phenolic compounds can inhibit
pro-inflammatory mediators’ activity or gene expression, up- or down-regulate transcrip-
tional elements involved in antioxidant pathways and reduce pro-inflammatory mediators.
The oxidative modification of LDL is the basis of deleterious process of atherosclerosis;
thus, its reduction could result in reduced vascular inflammation, oxidative stress and the
prevention of platelet aggregation.
This study evaluated a food supplement with five safe ingredients on subjects without
cardiovascular diseases and LDL-C levels of 115 to 190 mg/dL, who were not receiv-
ing pharmacological treatment for hypercholesterolemia. These ingredients have been
evaluated by the scientific community for their effects on dyslipidemia:
(1) aqueous extract of Berberis aristata (cortex ex ramis), titrated at 85% in berberine, an
alkaloid known for the treatment of hypercholesterolemia, known for its action on the
increased expression in the membrane of a receptor protein capable of internalizing
LDL-C [8];
(2) aqueous extract of Olea europea titrated in hydroxytyrosol (SelectSIEVE® OptiChol)
which has demonstrated, at a daily dosage of 100 mg, a significant improvement
in dyslipidemia in subjects with high cholesterol (115–190 mg/dL) after 1 month of
treatment, with a reduction in LDL by 24% [9];
(3) fenugreek seed extract (Trigonella foenum-graecum L.), an ingredient that may improve
dyslipidemia, even in type II diabetic patients [10];
(4) water/ethanol extract of artichoke leaf (Cynara scolymus L.) titrated at 0.5% in chloro-
genic acid, capable of inhibiting the HMGCoA-reductase 16 enzyme and which
represents an ingredient with high potential for lowering hypercholesterolemia [11];
(5) phytosterols from sunflower seeds (Helianthus annuus L.) titrated at 95%, of which
40–50% β-sitosterols, known for their ability to reduce hypercholesterolemia demon-
strated in several clinical studies and also recommended by the European Society of
Atherosclerosis [12].
The primary aim of the study was to evaluate the effects of a novel nutraceutical
combination of these ingredients in otherwise healthy subjects with sub-optimal blood
cholesterol on LDL-C levels and lipid pattern as secondary objective.
Biomedicines 2025, 13, 1948 3 of 14

2. Materials and Methods

This experimental single-center and single-arm study enrolled subjects aged 18 to
75 years with LDL-C levels between 115 and 190 mg/dL who were not receiving pharma-
cological treatment for hypercholesterolemia or who refused statin therapy. The exclusion
criteria were as follows: treatment, in the last 2 months, with lipid-lowering, hypoglycemic,
anorectic, psychotropic drugs, diuretics, beta-blockers, biologics, steroids, immunosup-
pressants, other food supplements; triglycerides above 400 mg/dL; history of ischemic
heart disease; obesity as Body Mass Index above 30 Kg/m2 ; diabetes mellitus; presence of
alterations in thyroid, hepatic or renal function; history of cancer, chronic inflammatory
intestinal diseases, malabsorption syndromes, psychiatric diseases, liver cirrhosis, pan-
creatitis, Human Immunodeficiency Virus; abuse of alcohol and/or drugs; pregnant or
breastfeeding women; inability to follow all study procedures.
The study was conducted at the ambulatory service of cardiovascular disease preven-
tion of Cardiology Department, Regional General Hospital ‘F. Miulli’, Acquaviva delle
Fonti, Italy. Informed consent was obtained from all patients before inclusion in the study
that was executed in accordance with the Declaration of Helsinki after the approval of
Ethical Committee “Gabriella Serio” of “IRCCS—Istituto Tumori Giovanni Paolo II di Bari”
(number 1472 of 18 December 2023).
At the baseline visit, subjects were encouraged to increase their physical activity; they
were given behavioral dietary suggestions to correct unhealthy habits and diet advice by the
cardiologist instructing them to follow a Mediterranean diet, avoid excessive intake of dairy
products and red meat-derived products during the study and maintain overall constant
dietary habits. The subjects were instructed to take one tablet of Ritmon Colesystem® after
dinner from the day after the enrolment visit to the end of study (6 months). This food
supplement contained aqueous extract of Berberis aristata and Olea europea, fenugreek seed
extract, water/ethanol extract of artichoke leaf and phytosterols from sunflower. None
of the extracts contained in the supplement are considered Novel Food (Regulation (EU)
2022/169) and all are suitable for food use. At each post-baseline evaluation, subjects were
interviewed about eventual adverse events raised between visits; all unused products were
retrieved for inventory and product compliance.
Clinical and laboratory data were collected at baseline, as well as at 1, 3, and 6 months.
At each visit, anthropometric measurement and vital signs were recorded, and a plasma
sample was obtained after a 12 h overnight fast. Venous blood samples were drawn by
a nurse from all patients between 8:00 a.m. and 9:00 a.m. Blood in the 8.5 mL tube (BD
Vacutainer® SST™ II Advance serum gel; Becton, Dickinson and Company, Franklin Lakes,
NJ, USA) was stored in an upright position for 30 min prior to centrifugation to allow
adequate clot formation. Tubes were centrifuged at 2000× g for 7 min. Specimens were
put onto a GLP automated track system and therefore analyzed in the same manner as
routine patient samples. Total cholesterol (T-C), HDL-C, LDL-C, triglycerides, creatinine,
aspartate transaminase, alanine transaminase, C-reactive protein (CPR), total and direct
bilirubin, urea nitrogen were tested using the Abbott Diagnostics Alinity® ci-series (Abbott
Laboratories, Chicago, IL, USA), in a single analytical run. D-Dimers were tested using
the Werfen ACL Top750 series. All measurements were performed by trained personnel
of the Clinic Pathology Unit at Regional General Hospital ‘F. Miulli’. Estimated GFR was
calculated according to Modification of Diet in Renal Disease (MDRD) formula [13].

Statistical Analysis
Data are reported as mean ± standard deviation, median and interquartile range.
Normality was assessed by Shapiro–Wilk test. Categorical data were described as fre-
quencies and percentage. For each parameter, mixed linear regression model was used
Biomedicines 2025, 13, 1948 4 of 14

to evaluate the overall effect over time considering repeated measurements as cluster of
observation within patient that was modeled as random effect. The intraclass correlation
coefficient (ICC) was used to estimate the proportion of variability attributed to the pa-
tient. Baseline characteristics of subjects by 10 mg/dL reduction from baseline in LDL-C
at 3 or 6 months were compared with Student’s t-test or Mann–Whitney test (continuous
variables) and chi-squared test (categorical data). The analyses were carried out using
STATA software, version 16 (StataCorp, College Station, TX, USA). A p value of <0.05 was
considered statistically significant.
We used the standard deviation of the LDL-C change, observed in the placebo group
of a randomized, double-blinded, placebo-controlled study that enrolled moderately hy-
percholesterolemic subjects to treatment with a combined nutraceutical [14]. A total of
44 patients were able to detect, with power of 90% and a significance of 0.05, a variation of
at least 10 mg/dL under the hypothesis of standard deviation of 20 mg/dL estimated in
the placebo group of a similar study [14]. A reduction in cholesterol of 10 mg/dL reduces
the cardiovascular risk at ten years of approximately 0.5% (12.2% to 11.7% in a man and
6.9% to 6.5% in a woman) in a non-smoker subject of 55 years without diabetes mellitus
and not treated for hypertension, with 130 mm Hg of systolic blood pressure, 50 mg/dL
of HDL-C and T-C from 220 to 210 mg/dL [15]. Secondary end-points are the changes
at each time-point from baseline in LDL-C, T-C, HDL-C and triglycerides. Primary and
secondary end-points were tested comparing the mean change from baseline than zero. A
95% confidence interval (95%CI) of mean change was graphically described.

3. Results
A total of 44 subjects (33 males; aged from 24 to 72 years, mean 50 ± 11) were enrolled
from 1 February 2024 to 30 June 2024. Table 1 shows baseline characteristics of subjects. At
the enrolment visit, the mean value of LDL-C was 151 ± 21 mg/dL, T-C 223 ± 24 mg/dL,
HDL-C 52 ± 14 mg/dL, triglycerides 124 ± 58 mg/dL, CPR 0.20 ± 0.18 mg/L (maximum
observed 0.80 mg/L). The estimated 10-year and lifetime risks for atherosclerotic cardiovas-
cular disease was 12.6 ± 11.8% (no subject had diabetes mellitus or hypertension or under
hypertension medication).
A total of six subjects missed a single visit: one at 3 months and five at 6 months.
During the study, no adverse event was recorded. Table 2 displays laboratory values at 1, 3
and 6 months and their changes from baseline. At the analysis for repeated measurements,
by using a mixed linear regression model, a significant change in LDL-C, T-C and HDL-C
values was observed (respectively, p = 0.002, p < 0.001 and p = 0.012) but not in triglycerides
(p = 0.994). The ICC, as measure of proportion of variability explained by the subject, was
0.66 for LDL-C, 0.56 for T-C, 0.84 for HDL-C and 0.53 for triglycerides. Figure 1 shows
mean change with 95%CI than baseline in LDL-C (panel A), LDL-C/HDL-C ratio (panel
B) and T-C (panel C) at 1, 3 and 6 months. A significant reduction was observed at each
time-point in LDL-C (9 mg/dL with 95%CI 3–14 at 1-month, 10 mg/dL with 95%CI 4–17
and 7 mg/dL with 95%CI 1–14, respectively, at 3 and 6 months). The LDL-C/HDL-C ratio
had a significant reduction at 1 month (0.11 with 95%CI 0.05–0.22) and 6 months (0.18
with 95%CI 0.03–0.33). Compared to baseline, T-C values were significantly reduced at
each evaluation (15 mg/dL with 95%CI 8–22 at 1 month, 18 mg/dL with 95%CI 10–27 and
12 mg/dL with 95%CI 3–22, respectively, at 3 and 6 months). Figure 2 shows the relative
reduction at 1, 3 and 6 months to baseline for LDL-C (panel A) and T-C (panel B). No
significant changes across evaluations were detected for HDL-C and triglycerides (Figure 3,
respectively, panel A and B) with the exception of slightly lower values for HDL-C at
3 months than baseline. All remaining parameters did not show significant difference
between post-baseline values.
Biomedicines 2025, 13, 1948 5 of 14

Table 1. Baseline characteristics of 44 subjects enrolled into the study.

N = 44
Age (years) 54 (43;58)
<50 years 18 (41%)
50–60 years 21 (48%)
>60 years 5 (11%)
Male 33 (75%)
Current smoker 19 (43%)
Weight (Kg) 76 (68;85)
Body Mass Index (Kg/m2 ) 26.0 ± 3.7
Waist circumference (cm) 87 (80;95)
Heart rate (b/min) 68 (60;75)
Systolic blood pressure (mm Hg) 126 ± 16
Diastolic blood pressure (mm Hg) 75 ± 8
Total cholesterol (mg/dL) 223 ± 24
HDL cholesterol (mg/dL) 52 ± 14
LDL cholesterol (mg/dL) 151 ± 21
LDL/HDL ratio 3.2 ± 0.9
Triglycerides (mg/dL) 124 ± 58
D-Dimers (ng/mL) 283 (170;442)
Creatinine (mg/dL) 0.86 ± 0.12
Estimated GFR (mL/min/1.73 m2 ) 100 ± 11
Azotemia (mg/dL) 33 ± 9
Aspartate transaminase (U/L) 22 ± 5
Alanine transaminase (U/L) 24 ± 13
C-Reactive Protein (mg/L) 0.20 ± 0.18
Total bilirubin (mg/dL) 0.81 ± 0.36
Direct bilirubin (mg/dL) 0.240 ± 0.089
Mean ± Standard Deviation or median (Interquartile range). GFR = Glomerular Filtration Rate.

Table 2. Laboratory values at 1, 3 and 6 months and their changes from baseline in the 44 subjects
enrolled into the study.

1 Month 3 Month 6 Month

Total cholesterol (mg/dL) 208 ± 28 205 ± 32 210 ± 27
Change than baseline (mg/dL) −15 ± 22 −18 ± 28 −12 ± 29
HDL cholesterol (mg/dL) 49 ± 12 49 ± 11 51 ± 11
Change than baseline (mg/dL) −2 ± 8 −3 ± 8 −1 ± 7
LDL cholesterol (mg/dL) 142 ± 24 141 ± 27 144 ± 25
Change than baseline (mg/dL) −9 ± 19 −10 ± 21 −7 ± 22
LDL/HDL ratio 3.0 ± 0.8 3.0 ± 0.9 3.0 ± 0.9
Change than baseline −0.1 ± 0.4 −0.1 ± 0.6 −0.2 ± 0.5
Triglycerides (mg/dL) 122 ± 72 120 ± 66 114 ± 59
Change than baseline (mg/dL) 1 ± 68 0 ± 68 1 ± 49
D-Dimers (ng/mL) 256 (127;404) 283 (163;478) 307 (162;561)
Change than baseline (ng/mL) −43 (−110;17) 10 (−78;89) −22 (−128;163)
Creatinine (mg/dL) 0.87 ± 0.12 0.84 ± 0.12 0.83 ± 0.13
Change than baseline (mg/dL) 0.009 ± 0.073 −0.018 ± 0.081 −0.033 ± 0.085
Estimated GFR (mL/min/1.73 m2 ) 100 ± 10 102 ± 10 102 ± 9
Change than baseline (mL/min/1.73 m2 ) 0±7 2±8 3±8
Azotemia (mg/dL) 35 ± 8 34 ± 9 35 ± 9
Change than baseline (mg/dL) 2±8 1±8 2±8
Aspartate transaminase (U/L) 21 ± 5 23 ± 5 31 ± 52
Change than baseline (U/L) −1 ± 6 0±5 9 ± 53
Alanine transaminase (U/L) 22 ± 11 20 ± 11 25 ± 21
Change than baseline (U/L) −2 ± 9 −3 ± 9 2 ± 21
C-reactive protein (mg/L) 0.22 ± 0.22 0.31 ± 0.66 0.22 ± 0.31
Change than baseline in (mg/L) 0.03 ± 0.20 0.13 ± 0.72 0.02 ± 0.24
Total bilirubin (mg/dL) 0.77 ± 0.35 0.76 ± 0.42 0.81 ± 0.53
Change than baseline (mg/dL) −0.03 ± 0.32 −0.06 ± 0.34 0.01 ± 0.39
Direct bilirubin (mg/dL) 0.25 ± 0.100 0.27 ± 0.11 0.26 ± 0.13
Change than baseline (mg/dL) 0.01 ± 0.10 0.022 ± 0.096 0.02 ± 0.10
Mean ± Standard Deviation or median (Interquartile range). GFR = Glomerular Filtration Rate.
Biomedicines 2025, 13, 1948 6 of 14

Figure 1. Plasma low-density lipoprotein cholesterol (LDL-C), LDL/HDL ratio and total cholesterol
(respectively, panel (A–C)) change from baseline to 1, 3 and 6 months. 95%CI = 95% Confidence
Interval.

The 22 (50%) subjects with baseline LDL-C higher than 150 mg/dL, in comparison to
those with lower values, had significant post-baseline higher values of LDL-C (p < 0.001)
and T-C (p < 0.001) while HDL-C (p = 0.250) and triglycerides (p = 0.318) were not different.
The LDL-C before the supplement was not associated with change during the study period
for LDL-C (p = 0.706), T-C (p = 0.139) and triglycerides (p = 0.623) while HDL-C increased
significantly in those with LDL-C above 150 mg/dL (p = 0.005).
Table 3 reports baseline characteristics of subjects by at least 10 mg/dL reduction at 3
or 6 months in LDL-C than baseline. No association was detected, including lipid profile
parameters, except for Aspartate transaminase that were associated with a greater LDL-C
reduction.
Biomedicines 2025, 13, 1948 7 of 14

Figure 2. Relative reduction to baseline in plasma low-density lipoprotein cholesterol (LDL-C) and
total cholesterol (respectively, panel (A) and (B)) at 1, 3 and 6 months.

Figure 3. Plasma high-density lipoprotein cholesterol (HDL-C) and triglycerides (respectively, panels
(A) and (B)) change from baseline to 1, 3 and 6 months. 95%CI = 95% Confidence Interval.
Biomedicines 2025, 13, 1948 8 of 14

Table 3. Comparison of subjects’ baseline characteristics by reduction at 3 or 6 months in LDL than

baseline.

<10 mg/dL ≥10 mg/dL

n = 22 n = 22 p
Age (years) 50 ± 8 50 ± 14 0.606
Males 77% 73% 0.728
Weight (Kg) 77 ± 13 78 ± 17 0.752
Body Mass Index (Kg/m2 ) 26.0 ± 3.1 25.9 ± 4.2 0.976
Waist circumference (cm) 89 ± 11 87 ± 12 0.654
Heart rate (b/min) 69 ± 11 68 ± 6 0.612
Systolic blood pressure (mm Hg) 127 ± 19 124 ± 11 0.759
Diastolic blood pressure (mm Hg) 76 ± 9 75 ± 8 0.574
Total cholesterol (mg/dL) 220 ± 23 225 ± 25 0.557
LDL cholesterol (mg/dL) 147 ± 21 156 ± 20 0.159
HDL cholesterol (mg/dL) 51 ± 14 52 ± 15 0.833
LDL/HDL ratio 3.1 ± 1.0 3.2 ± 0.9 0.700
Triglycerides (mg/dL) 119 ± 48 129 ± 67 0.880
D-Dimers (ng/mL) 259 (147;580) 285 (198;442) 0.766
Creatinine (mg/dL) 0.87 ± 0.13 0.85 ± 0.12 0.620
Estimated GFR (mL/min/1.73 m2 ) 100 ± 10 101 ± 12 0.786
Azotemia (mg/dL) 34 ± 9 32 ± 8 0.429
Aspartate transaminase (U/L) 20 ± 4 25 ± 5 0.002
Alanine transaminase (U/L) 20 ± 5 28 ± 16 0.089
C-reactive protein (mg/L) 0.21 ± 0.21 0.20 ± 0.15 0.187
Total bilirubin (mg/dL) 0.75 ± 0.30 0.87 ± 0.42 0.510
Direct bilirubin (mg/dL) 0.227 ± 0.077 0.255 ± 0.100 0.317
Mean ± Standard Deviation or median (Interquartile range). GFR = Glomerular Filtration Rate.

4. Discussion
This study assessed the 6-month impact of dietary supplements containing extracts
from Berberis aristata, Olea europea, fenugreek seeds, artichoke leaves and sunflower seed
phytosterols on lipid profiles in subjects without cardiovascular disease and sub-optimal
blood cholesterol levels. In 44 subjects with LDL-C in the range of 115 to 190 mg/dL not
taking lipid-lowering drugs, we evaluated lipid parameters at 1, 3 and 6 months after
starting the food supplement with the combined nutraceuticals. Both LDL-C and T-C
plasma levels significantly decreased at each time-point, indicating improved cholesterol
control by dietary supplements.
Among cardiovascular diseases, responsible for more than 4 million deaths in Europe
each year, the coronary heart disease is the most common single cause of mortality, resulting
in 20% of deaths in women and 19% of deaths in men [16]. Myocardial infarction and
ischaemic stroke are clinical manifestations of atherosclerotic cardiovascular disease, a
condition associated with multiple exposures having low-density lipoprotein as the most
extensively studied [17]. An elevated plasma cholesterol is associated with an increased risk
to develop atherosclerosis and, consequently, cardiovascular heart disease [18,19]. High
plasma LDL-C concentration is considered the most atherogenic and predominant cause of
atherosclerotic cardiovascular disease progression [20].
Cholesterol is an essential component of cell membranes transported to peripheral
cells largely by the apoB-containing lipoproteins in plasma. The retention and accumula-
tion of cholesterol-rich apoB-containing lipoproteins within the arterial intima at sites of
predilection for plaque formation is the initiation of atherosclerotic cardiovascular disease
with progressive dose-dependent development of atherosclerotic plaque [21,22]. The LDL
particles, approximately 90% of circulating apoB-containing lipoproteins in fasting blood,
Biomedicines 2025, 13, 1948 9 of 14

are estimated in clinical practice from cholesterol concentration LDL-C that measures the
total amount of cholesterol contained in LDL particles [17]. In the majority of clinical stud-
ies for assessing cardiovascular risk and for evaluating therapeutic benefit in randomized
clinical trials, plasma LDL-C is used as estimate of the concentration of circulating LDL and
a measure of the cholesterol mass carried by LDL particles [23]. Our study was powered to
detect a variation of at least 10 mg/dL in LDL-C after 3 months of treatment. We observed
a significant effect in terms of plasma levels LDL-C reduction after 1, 3 and 6 months in
parallel to T-C lowering without a relevant effect on HDL-C and triglycerides that showed
normal baseline values in most of the enrolled subjects. The LDL-C/HDL-C ratio showed a
significant reduction at 1 and 6 months. The relative change in LDL-C was in the range
4–7% for LDL-C and 5–8% for T-C. At an exploratory analysis for predictors of LDL-C
reduction greater than 10 mg/dL, only greater values of Aspartate transaminase were
significantly associated with LDL-C improvement. The baseline LDL-C was not related to
changes for lipid profile, excluding an improvement in HDL-C in those with higher values
before the supplement.
It is important to note that, after 3 months, the baseline atherosclerotic cardiovascular
risk according to the multivariable algorithms used to assess 10-year probability of specific
atherosclerotic cardiovascular disease events (coronary, cerebrovascular and peripheral
arterial disease and heart failure) [15] on the basis of gender, age, systolic blood pressure,
T-C and smoking status had a significant absolute reduction of 1.4% (approximately 10%
relatively to baseline risk).
Plasma LDL-C lowering is initiated to decrease the risk for cardiovascular disease
development; it has been estimated that a reduction of 1 mmol/L (39 mg/dL) is associated
with 22% in risk reduction for coronary artery disease [24]. Pharmacological treatment
is recommended for the treatment of hypercholesteromia, starting with statin treatment,
which reduces endogenous C synthesis and increases LDL-receptor activity [25]. How-
ever, LDL-C lowering is highly variable with many patients that may experience statin
intolerance with serious side effects leading to the choice of another statin or alternative
regimen. Muscular adverse effects, the predominant statin-associated symptoms, are sub-
jective myalgias reported in 1% to 5% patients in randomized controlled trials and in 5% to
20% within observational research [26]. In case the high-dose statin treatment is not well
tolerated or in case the LDL-C lowering by a statin does not reach the intended goal for LDL
lowering, the statin dose can be lowered and treatment is combined with ezetimibe [25].
Recent data from an observational and prospective study that documented the use of
lipid-lowering therapies in patients ≥18 years at high or very high cardiovascular risk
across primary and secondary care settings in 14 European countries has showed that more
than 20% of patients are not treated irrespectively by risk classification and atherosclerotic
cardiovascular disease status, and a proportion higher than a quarter of patients did not
reach the LDL-C goal [27].
In individuals with borderline lipid profile levels or with drug intolerance, the use of
lipid-lowering nutraceuticals may be considered when the cholesterol control goal is not
achieved [28]. A nutraceutical treatment is considered as modification of food composition
leading to a lower plasma LDL-C concentration. The nutraceutical combination together
with a cholesterol-lowering action, associated with an adequate lifestyle, provides an
alternative to pharmacotherapy in patients who report intolerance to statins and in subjects
with low cardiovascular risk [29]. Nutraceuticals and their synergetic combinations have
demonstrated a beneficial effect in the management of dyslipidaemia. Several nutraceuticals
have been shown to positively modulate lipid metabolism while having different functions;
plant sterols and soluble fibers may reduce the intestinal assimilation of lipids and increase
their elimination; berberine and soybean proteins improve the cholesterol uptake in the
Biomedicines 2025, 13, 1948 10 of 14

liver; policosanols, monacolins and bergamot inhibit hydroxy-methyl-glutaryl coenzyme

A reductase enzyme action determining the cholesterol hepatic synthesis; red yeast rice
and berberine play an important role on endothelial dysfunction and psyllium; plant sterols
and bergamot have positive effects on LDL subclasses [30]. The nutraceutical approach is
based on dietary supplements enriched in phytosterols and phytostanols that competitively
reduce the uptake of cholesterol into intestinal micelles, transporting fats and sterols
through the intestine [31]. This leads to a reduction in cholesterol absorption and, on
average, a 10% reduction in plasma LDL-C [32].
Regarding what has also been described in the literature, in healthy subjects without
significant cardiac history, the new finding of LDL-C values is moderately high, that is,
when they exceed the levels considered optimal but not so much as to require pharmaco-
logical treatment such as statins, which could be beneficial as a first approach to a new
nutraceutical compound [33]. Ritmon Colesystem is a food supplement in capsules specifi-
cally formulated to help regulate the metabolism of cholesterol and triglycerides thanks
to the presence of fenugreek and the functionality of the cardiovascular system thanks to
the presence of Berbera Aristata. The capsule generally is recommended to take one per
day, preferably during or immediately after one of the main meals. It should be taken as
part of a varied and balanced diet. Its benefits are regulation of lipid metabolism, support
for the functionality of the cardiovascular system, reduction in intestinal absorption of
cholesterol and the antioxidant and protective properties of olive and artichoke on blood
vessels. The ingredients present in the compound are as follows: fenugreek, berberine, an
alkaloid isolated from the bark, root and rhizomes of plants of the genus Berberis phytos-
terols, which reduce intestinal absorption of cholesterol, and olive and artichoke, which
have antioxidant and protective properties on blood vessels. Fenugreek seeds consist of
galactomannan, insoluble fiber and protein, fat and alkaloids. The mechanisms responsible
for the beneficial effects of fenugreek are diverse. Galactomannan, the soluble dietary
fiber, influences glycemic response by delaying gastric emptying, inhibition of digestive
enzymes, increasing the gut motility and optimizing microbiome balance. Moreover, galac-
tomannan acts as a lipid-lowering agent through inhibition of pancreatic lipases action
and reduction in hepatic lipoprotein production, which can explain fenugreek’s effect on
triglycerides and visceral fat as waist circumference [34,35]. Also, 4-OH-Ile could decrease
triglycerides and increase HDL-C by insulin-secreting and insulin-sensitizing effects in
hepatic cells and peripheral tissues [35]. Additionally, diosgenin has both insulin secreta-
gogue and sensitizing impact by reducing oxidative stress of beta cells. Diosgenin improves
glucose uptake in peripheral tissue by targeting white adipose tissue directly, reducing
hepatic lipid accumulation and increasing biliary cholesterol excretion [34,35]. Furthermore,
trigonelline can affect adipocyte lipid accumulation with hypoglycemic and hypolipidemic
properties [35]. Fenugreek supplementation significantly improves fasting plasma glucose,
triglycerides, HDL-C, systolic blood pressure and waist circumference [36]. Artichoke and
its bioactive components reduce cholesterol levels, particularly LDL-C. Several studies
have demonstrated that artichoke extracts influence lipid metabolism by decreasing the
production of cholesterol and endogenous triglycerides by acting on their excretion or
redistribution in the organism [37]. Various studies have demonstrated its potential as
an anti-inflammatory, antimicrobial and neuroprotective agent due to its phytochemical
composition [37]. Although based on studies involving heterogeneous populations and
variable artichoke formulations, artichoke seems to exhibit cardiovascular therapeutic
potential, supported by its vasorelaxant effects, angiotensin-converting enzyme-inhibitory
activity and clinical evidence of improved flow-mediated dilation [38]. Berberine belongs
to the class of protoberberines found in several plants and has shown LDL-C lowering
effects by inhibiting proprotein convertase subtilisin/kexin type 9 at both transcriptional
Biomedicines 2025, 13, 1948 11 of 14

and protein levels [39]. Nutraceutical pill containing berberine was found to lower LDL-C
by 32% after 6 months of follow-up [40]. A 12-week treatment with a nutraceutical formu-
lation containing berberine, chitosan and red yeast rice was effective in lowering plasma
non-HDL-C and LDL-C compared with placebo [41]. The effectiveness of Olea europea in
providing antioxidant benefits is linked to the breaking of peroxide chain reactions or by
averting the copper sulfate-induced oxidation of LDL. The existence of these mechanisms
was proved using metal-independent oxidative systems and stable free radicals [42].
Our single-arm trial has some relevant limitations. Although the study was sufficiently
powered to detect a variation of 10 mg/dL in LDL-C, the lack of a control group, as well
as the absence of an active treatment with a standard pharmacological approach, makes
difficult the evaluation of the net impact of intervention based on lifestyle advice and
dietary supplements. Study results should be interpreted as exploratory to generate formal
hypotheses to be tested in a future randomized clinical trial including a placebo or active
drug. Subjects in this study included mainly those with sub-optimal blood cholesterol levels
without comorbidities; generalization of findings to individuals at high cardiovascular
risk should be made with caution. The emerging evidence of the improvement in plasma
cholesterol control by nutraceutical approaches requires more experimental research to also
better evaluate long-term effects.

5. Conclusions
With the growing evidence unequivocally demonstrating a causal relationship be-
tween LDL-C levels and cardiovascular events, such as myocardial infarction and stroke,
LDL-C has become a crucial therapeutic target in the management of cardiovascular dis-
ease. The greater the absolute reduction in C-LDL, the greater the benefit in terms of
cardiovascular risk reduction; it is therefore important to have more useful compounds in
the therapeutic armamentarium currently available for the reduction in cardiovascular risk,
without forgetting to include in the initial approach to dyslipidemia the modification of
lifestyle combined with moderate physical activity. The results of this study provide further
elements available to the clinician in tailoring the best lipid-lowering therapy according to
the patient’s characteristics. In young patients with sub-optimal blood cholesterol levels
at intermediate–low cardiovascular risk and free from significant carotid atherosclerosis,
nutraceuticals containing extracts of Berberis aristata, Olea europea, fenugreek seed, artichoke
leaf and sunflower phytosterols reduce both total cholesterol and LDL-C levels at 6 months.
Further randomized studies are needed to confirm the maintenance of this effect over time,
the benefit of these nutraceuticals on lipid patterns also in terms of control in atherosclerosis
progression and prevention of cardiovascular disease.

Author Contributions: Conceptualization, N.V., P.G. and M.G.; Data Curation. P.G.; Writing—
Original Draft Preparation, N.V., P.G. and M.G.; Writing—Review and Editing, V.A., E.C., E.V.D.N.,
S.M., N.D., F.T., F.Q., A.d.M., M.I. and A.P. Supervision, N.V. and M.G. All authors have read and
agreed to the published version of the manuscript.

Funding: The study was supported by unrestricted grants from Dompé farmaceutici S.p.A., Milano,
Italy to Regional General Hospital “F. Miulli”, Bari, Italy. The founding sponsor had no role in the
design of the study, in collection, analyses, or interpretation of data, in the manuscript writing and
in the decision to publish the results. The study was independently conducted at Regional General
Hospital ‘F. Miulli’, Acquaviva delle Fonti, Italy. Data were collected by Investigators and stored
onsite with analysis and reporting that involves only the authors of the manuscript.

Institutional Review Board Statement: The study was conducted according to the guidelines of the
Declaration of Helsinki, and approved by the Ethical Committee “Gabriella Serio” of “IRCCS—Istituto
Tumori Giovanni Paolo II di Bari” (protocol code 1472 of 18 December 2023).
Biomedicines 2025, 13, 1948 12 of 14

Informed Consent Statement: Informed consent was obtained from all subjects involved in the
study.

Data Availability Statement: The original data presented in this study are included in the article.
Further inquiries can be directed to the corresponding author.

Conflicts of Interest: The authors of this manuscript do not have direct financial relationships with
the commercial identity mentioned in this paper.

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