|Dyslipidemia; Atherosclerosis; Cholesterol; Diabetes;
|Dyslipidemia is a common disorder of an abnormal amount of
lipids in the blood which favors atherosclerosis and its consequences,
primarily ischemic heart disease. The Mexican National Health and
Nutrition Survey  estimated for 2012 in Mexican adults 20 years or
older, the prevalence of dyslipidemia for Total Cholesterol (TC) ≥ 200
mg/dl was 50.6% and for Triglycerides (TG) ≥ 150 mg/dl, 32.5%.
Furthermore, the estimation for overweight was 38.8% (BMI ≥
25.0-29.9 kg/m2) and for obesity 32.4% (BMI ≥ 25.0-29.9 kg/m2).
Finally, a combined prevalence for overweight and obesity was 71.2%
, considering these last two statistics as the highest observed in the
American continent, even higher than the United States of America
. Other studies have reported higher mean values for TG and lower
values for HDL cholesterol (HDL-c) in the presence of other
cardiovascular risk factors such as diabetes, hypertension and obesity
. These diseases not only represent a serious public health problem
with a social and economic impact, but the prophylaxis and treatment
by several specialists is also required .
|In the administration of hypolipidemic agents, a higher emphasisis
placed on reducing cardiovascular risk (secondary prevention) than
the management of initial dyslipidemia (primary intervention) .
Statins inhibit 3-hydroxy-3-methylglutaryl coenzyme A reductase in
the conversion to mevalonate resulting in decreased production of
cholesterol de novo, but this mechanism can increase creatine kinase
levels, however, a small percentage of patient’s present myalgias and the
increase of hepatic enzymes . Furthermore, the cost effectiveness of
treatment has a great influence on treatment adherence, mainly in the
first primary care level . Consequently, it becomes very important to
continue evaluating easy-access therapies at lower cost with less or null
|It has been proposed that some carbohydrates, which are fermented
in the caeco-colon, might be of particular interest in the field of
dyslipidemia and obesity. Fructans are non-digestible and fermentable
carbohydrates, which have interesting metabolic effects (decrease in fat
mass development, steatosis and glycaemia), by acting through a
mechanism different from the common dietary fibers prone to act on
lipid metabolism to decrease the hepatic lipogenesis and plasma
triacylglycerol concentrations , as they exhibit non gel-forming
properties. Inulin-type fructans extracted from chicory roots regulate
appetite and lipid/glucose metabolism, namely, by promoting glucagon-like peptide-1 (GLP-1) production in the colon  (Figure
|Preliminary evidence in animals indicates that administration of
inulin extracted from chicory root favorably modifies serum lipid
levels and body weight due to their content of fructo-oligosaccharides
(FOS) . The FOS from the chicory root contain fructose polymer
with β (2-1) glycosidic linkages, unlike FOS from agave inulin containing principally β (2-1) linkages, but also some β (2-6), highly
ramified, and with terminal or internal glucose  with a probable
higher hypolipidemic effect.
|Material and Methods
|An open clinical trial was carried out by non-probability
consecutive sampling in 30 dyslipidemic, overweight and obese subjects of both genders between 30 and 70 years old. Pregnant or
lactating women as well as participants taking any drug with an effect
on the metabolic profile or insulin were excluded from the study. Study
subjects were classified as dyslipidemic according to the adult
treatment panel III (ATP III) guidelines and the cut-off values
considered to determine dyslipidemia were: [HDL-c (men <40 mg/dl;
women <50 mg/dl); hypertriglyceridemia (≥ 150 mg/dl),
hypercholesterolemia (≥ 200 mg/dl), LDL cholesterol (≥ 100 mg/dl)],
overweight or grade I-II obesity by body mass index (BMI) [calculated
as body weight (kg)/height (m2)] and according to the World Health
Organization classification as: (18.5-24.9 (normal), 25.0-29.9
(overweight), 30.0-39.9 obesity grade I and II). Blood pressure was
determined according to the Joint National Committee categories for
systolic blood pressure: Normal blood pressure values for systolic
blood pressure: (SBP) <120 and diastolic blood pressure (DBP) <80
mmHg, for normal-high blood pressure (prehypertension): SBP ≥ 120
to ≤ 139 and DBP ≥ 80 to ≤ 89 mmHg, and for hypertension: SBP ≥
140 y DBP de ≥ 90 mmHg [13,14]. To determine IR we used the
triglyceride/glucose index (TyG) [(Ln TG (mg/dl) × FG (mg/dl))/2] as a surrogate measure that has high sensitivity and specificity to
recognize IR , and HOMA-IR (glucose x insulin)/22.5.
|Due to the known adverse gastrointestinal events (abdominal pain,
diarrhea, bloating, flatulence and rumbling) by pre-biotics , the
gradual administration of these fibers increases their safety and
tolerance. For this reason, the pharmacological administration of agave
inulin powder was dissolved in any beverage or food (standard diet)
and divided in two parts. The first part consisted of a gradual threeweek
forced-titration of 5 g per day of agave inulin powder during the
first week, 10 g for the second week and 15 g for the third week. The
second part involved the administration of 15 g per day of agave inulin
powder during 60 days. Inulin was obtained by certified process from
the Tequila industry “Foundation Jalisco Produce” and the agave
process was provided by the company “El Triufo de Milpillas SPR de
R.L”. All volunteers maintained a stable body weight during 3 months
before the study with an isocaloric diet containing approximately 250
g/d of carbohydrates 3 days before the test and study subjects were
required to avoid exercise at least 72 h before the study; none of
participants received changes in nutritional habits and all patients were
monitored for the presence of adverse events throughout the study.
|The study protocol was reviewed and approved by the local ethics
committee of the University of Guadalajara, and written informed
consent was obtained from all volunteers. Subjects were selected from
the metropolitan area of Guadalajara, Jalisco, Mexico living in the
same residential area and of similar socioeconomic status. The study
was performed at 8:00 A.M. after a 10-12 hour overnight fast. For all
participants, a clinical history was performed using the following
determinations: height and weight were recorded with the subjects
wearing light clothing without shoes (TANITA TBF 300A® scale,
Arlington Heights, Il). The waist circumference was measured at its
smallest point with a relaxed abdomen and hip measurement was taken from the widest point. For both measurements we used a flexible
tape measure,the waist/hip ratio (WHR) was calculated as waist
measurement divided by hip measurement, systolic blood pressure
systolic (SBP), diastolic blood pressure (DBP) and heart rate (HR),
were recorded simultaneously using a fully automated device
(OMRON HEM-781INT), followed by laboratory tests in blood
samples to determine serum glucose using the glucose-oxidase
technique (Boehringer Mannheim GmbH, Mannheim, Germany),
with an intra- and interassay coefficient of variation of <3%. For
determination of HbA1c levels, ion-exchange high-performance liquid
chromatography was carried out (Bio-Rad Laboratories, Hercules, CA)
with an intraassay coefficient of variation of 2.8% and 3.5% and inter
assay coefficient of variation of <3.0%. Creatinine and lipid profile
(TC, HDL-c, TG) were measured enzymatically (Ortho-Clinical
Diagnostics, Johnson & Johnson Company, Rochester, NY, USA) with
an intra- and interassay coefficient of variation of <2%, LDL
cholesterol (LDL-c) was estimated by the Friedewald formula (LDLc=
TC-HDL-c-TG/5) and VLDL cholesterol (VLDL-c) with the TG/5
equation. Insulin concentrations were measured using the
microparticle enzyme immunoassay method (Abbott Diagnostics
Division, Japan Co. Ltd.) with an intra- andinterassay coefficient of
variation of 3.3 and 3.8%, respectively.
|Sample size was calculated by mean of a formula for clinical trials
 with a statistical confidence of 95%, statistical power of 80%, SD
for TC of 30.5 mg/dl , and an expected difference of at least one SD
of TC into the group, obtaining a total of 15 patients that included 20%
of expected loss. Data are expressed as mean ± standard deviation (SD)
for quantitative variables and frequencies for qualitative variables. The
inference analysis was performed with Chi-squared test. Intra-group
differences were tested with the Wilcoxon signed-rank test. Data were
analyzed with SPSS-20.0 software (SPSS Inc. Chicago, IL) and a pvalue
≤ 0.05 was considered statistically significant.
|The selection and screening of patients with the opportunity to meet
the inclusion criteria was conducted, thirty patients were recruited for
this study as shown in Figure 2, of which 73.3% (n=22) were female
and 26.7% (n=8) were male and the average age was 55.3 ± 8.4 years.
Statistical analyses revealed no significant differences with
anthropometric parameters and clinical measurements (Table 1).
However, we did find statistical differences for the following
parameters: fasting glucose (83.1 ± 13.4 vs. 76.5 ± 12.6 mg/dl;
p=0.006), triglycerides and glucose (TyG) index (3.9 ± 0.1 vs. 3.8 ± 0.2;
p=0.021), sodium (139.3 ± 3.0 vs. 140.4 ± 2.1 meqL; p=0.043) and urea
(31.4 ± 8.6 vs. 26.3 ± 5.4 mg/dl; p=0.001). In addition, a trend for
increased insulin concentrations (10.6 ± 4.5 vs. 13.1 ± 7.0 uUmmoL;
p=0.057) (Table 2) was also found.
|By analyzing differences between the basal and final results, a
significant decrease in glucose levels was confirmed in 21/30 (70%) of
all cases with an average reduction of -12.2 mg/dl (-41.0 to 1.0 mg/dl)
and a percent difference of -13.7 (-40.6 /-1.4) p=0.006. On the other
hand, in 19 cases (63.3%), the glycosylated hemoglobin was reduced by -0.4% (-0.9 to -0.1%). In addition, the TyG index was reduced
significantly-0.16 (-0.34 to -0.01) with a percent difference of -4.14
(-8.36 to -0.27) p=0.021.
|Similarly, in 37% of all cases, TC serum concentration was reduced
-35.5 mg/dl (-105 to -1 mg/dl) without a significant decrease and a
percent difference of -14.3 (-36.0 to -0.4). In reference to LDL-c, in
23% of all cases, there was a reduction of 33.0 mg/dl (-97.0 a -3.0
mg/dl) with a percent difference of -21.6 (-55.3 to -1.8) and for TG,
53% of all cases showed a reduction of -55.6 mg/dl (-150.0 to -7.0
mg/dl) and a percent difference of -26.5 (-50.0 to -5.0) (Figure 3). We
must point out that in 19/30 patients (63%) we found increased HDL-c
levels by 9.0 mg/dl (1.0-20.0 mg/dl) with a percent difference of 19.0
(2.0-37.0), p=0.690. We did not observe significant differences in
weight 1.6 kg (-7.7 a -0.1 kg) with a percent difference of -2.1 (-8 a
-0.1) p=0.130, after an 8-week administration of 15 g of agave inulin
|Finally, by analyzing the percentages of our study group regarding
the diagnostic models for this study (hypertriglyceridemia,
hypercholesterolemia, combined dyslipidemia, overweight, obesity
grade I- II and prehypertension) before and after the intervention, we
found that 16.7% (p=0.025) of patients showed normal blood lipid
levels, reversing the diagnosis of hypercholesterolemia by 6.7%
(p=0.042), 13.3% showed hypertriglyceridemia (p=0.003), and 6.6%
had a combined dyslipidemia (p=0.043). Furthermore, 23.3% (p=0.008) of pre-hypertensive patients normalized their blood pressure
levels (Table 3). It is noteworthy that the analysis in terms of the
percentage difference refers only to the patients who had a reduction in
lipid levels; also, the benefit was greater in those with combined
|In relation to adverse reactions, only two patients reported slight
gastrointestinal problems (diarrhea and abdominal distention) that
could be associated with a low fiber consumption diet, but in general
all fiber supplementation was well tolerated by all patients and no
patients failed to complete the study due to adverse reactions.
|The controversy over the effect of using derivatives inulin fructans
has remained dormant for at least one decade. Functions of inulin
fructans have been linked to changes that enhance the metabolic status
of patients including weight loss, reduced blood lipid levels and serum
glucose and even a possible reduced cardiovascular risk. In this study,
the addition of agave inulin was aimed to evaluate the metabolic
profile and risk factors in dyslipidemic patients with an overweight and
|A reduction in fasting glucose levels was found at the end of the
intervention and is consistent with previous studies that have sustained
that the supplementation with agave fructans induces a higher
concentration of GLP-1 and its precursor, proglucagon mRNA in the
different colonic segments which are able to promote the production of
satietogenic/incretin peptides in the lower part of the gut, with
promising effects on glucose metabolism. On the otherhand, the main
function of peptides GLP-1 and GIP is the stimulation of post-prandial
secretion of insulin by pancreatic β-cells, mechanism that could
explain the association of fructans with the slight increase of insulin
levels in our patients .
|The aim of our study was to substantiate the effect of agave fructans
on the serum lipid profile and weight loss in overweight and obese
patients with dyslipidemia, based on previous reports with other
fructans which demonstrated increased satiety by regulating the
secretion of gastrointestinal hormones like glucagon-like peptide-1 and
glucagon-like peptide-2 and decreasing the level of ghrelin, and thus,
an active participation in reducing serum lipids. This reduction has
been attributed to a decrease in the gene expression of hepatic enzymes
responsible for de novo synthesis of lipids, increased muscle
lipoprotein lipase (LPL) enzyme activity; as well as by the increased
population of Bifidobacteria and the production of short chain fatty
acid (SCFA); butyrate which stimulates the differentiation of crypt cells
in enteroendocrine L cells, increasing the production of fatty acid
synthase, LPL, SCFA .
|Several works have studied the effects of prebiotics, however, results
are controversial; in some studies there was no reported effect on the
serum reduction of TC, TG and LDL cholesterol, nonetheless in others
of them a significant reduction was found: 12.7% for TC and two
studies reported a 16.4% reduction for TG and 16.2% for LDL-c. In a
study with inulin, a significant reduction in TG, TC, LDL-c and VLDLc
serum levels was observed following a 4-week ingestion of 7 g of
inulin powder previously dissolved in juice, milk or water .
|Patients in our study group did not show a significant difference in
weight and satiety was not evaluated, so possibly a greater and specific
diet control was necessary. However, our interest in not controlling the
diet and therefore achieve weight loss, was avoid attributing changes in
serum lipids to weight loss. We must also point out that other reports
with significant modifications in serum lipids have evaluated patients
with severe dyslipidemia more so than with patients with mild to
|However, the significant percentage reduction we observed in our
study, 14.3% for TC, 26.5% for TG and 21.6% for LDL-c, considering
this last variable as the most atherogenic and of clinical importance,
could be partly attributed to observations by Delzenne ,
considering that if the intrahepatic lipolysis mechanism is not
activated with fiber consumption as the activity of the enzyme
carnitinepalmitoyltransferase is not altered, an increase in lipid
catabolism by the extrahepatic pathway with agave inulin consumption
|Several indirect methods have been incorporated that allow IR
estimation. Recently, a new surrogate formula was proposed for
estimating IR from triglycerides (TG) and fasting glucose (FG),
referred to as the triglyceride/glucose (TyG) index based on the
product of the natural logarithm between TG and FG divided by 2,
whose formula is TyG=[(Ln TG (mg/dl) × FG (mg/dl))/2], this
formula was validated against the HOMA-IR index and the
euglycemic-hyperinsulinemic clamp . Furthermore, by evaluating
IR, the HOMA-IR index and the TyG index in our study population,
we found differences between baseline and final values for the TyG
index. These differences could be related to lipoprotein metabolic
alterations commonly present in overweight and obese individuals and
thus increase lipid serum levels which interfere with muscle glucose
metabolism and are in accordance with the hypothesis that the
elevation of triglycerides reduces insulin sensitivity. The TyG index
measures the triglycerides/glucose  product and by decreasing
triglycerides with the intervention of inulin, we could interpret that
agave fructans improve or enhance IR.
|Several studies [21-24] have shown modifications starting at three
weeks of consuming products with added probiotics, prebiotics and
phytosterols, therefore the intervention period for this study was
considered adequate. Longer intervention periods are required to
observe changes in colonic fermentation and its effects on weight
reduction and cardiovascular risk. As a weakness of our study, a larger
sample is required to confirm the dose-effect relationship where a
slight tendency to improve TC, TG and LDL-c, with slight increase in
HDL-C, and a comparison with the placebo control group was shown.
|Moreover, it has been suggested that adding fiber to the diet
increases the risk of diarrhea, and thus a decrease in the concentration
of electrolytes. However, in patients included in this study we did not
observe reduction of these electrolytes by the end of the study. On the
contrary, sodium was increased significantly, there is no precise
explanation behind this effect, but previous publications describe the
large intestine is the best absorption site to various molecules ,
which could be modified by changes in the gut microbiota.
|This research is considered pioneer in the study of the effects by
agave inulin blue variety on the lipid profile of overweight and obese
dyslipidemic patients. Agave tequilana Weber blue variety, produced in
our country and characterized by its FOS content, originally proposed
as functional food ingredients capable of improving parameters of the
metabolic syndrome, blood glucose concentration and lipid
metabolism, more recently, it has been hypothesized that agave inulin
may have an impact on body weight, possibly by modulation of
gastrointestinal hormones , although requires further research we
believe that it can contribute to improve the health of many patients
due to its low cost and inclusive, favor the development of the agave
|The use of inulin-type Agave tequilana Weber blue variety in a dose
regimen of 15 mg for 60 days in subjects with dyslipidemia diagnosed as overweight and obese significantly reduced fasting glucose as well as
the TyG index In addition, this agave inulin was effective in reducing
the percentage difference of TC, TG and LDL-c blood levels without a
significant change in body weight.
|The authors declare no competing interests with any of the
mentioned pharmaceutical companies. Financial support was provided
by the Instituto de Terapéutica Experimental y Clínica (INTEC),
Departamento de Fisiología, Centro Universitario de Ciencias de la
Salud, Universidad de Guadalajara, Guadalajara, Jalisco, México.
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