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R E V I E W Open Access
Effect of fenugreek (Trigonella foenum-graecum L.)
intake on glycemia: a meta-analysis of clinical trials
Nithya Neelakantan
1*
, Madanagopal Narayanan
2
, Russell J de Souza
3,4
and Rob M van Dam
1,2,5
Abstract
Background and aim: Fenugreek is a herb that is widely used in cooking and as a traditional medicine for
diabetes in Asia. It has been shown to acutely lower postprandial glucose levels, but the long-term effect on
glycemia remains uncertain. We systematically reviewed clinical trials of the effect of fenugreek intake on markers of
glucose homeostasis.
Methods: PubMed, SCOPUS, the Cochrane Trials Registry, Web of Science, and BIOSIS were searched up to 29 Nov
2013 for trials of at least 1 week duration comparing intake of fenugreek seeds with a control intervention. Data on
change in fasting blood glucose, 2 hour postload glucose, and HbA1c were pooled using random-effects models.
Results: A total of 10 trials were identified. Fenugreek significantly changed fasting blood glucose by -0.96 mmol/l
(95% CI: -1.52, -0.40; I
2
= 80%; 10 trials), 2 hour postload glucose by -2.19 mmol/l (95% CI: -3.19, -1.19; I
2
=71%;7 trials)
and HbA1c by -0.85% (95% CI: -1.49%, -0.22%; I
2
= 0%; 3 trials) as compared with control interventions. The considerable
heterogeneity in study results was partly explained by diabetes status and dose: significant effects on fasting and 2 hr
glucose were only found for studies that administered medium or high doses of fenugreek in persons with diabetes.
Most of the trials were of low methodological quality.
Conclusions: Results from clinical trials support beneficial effects of fenugreek seeds on glycemic control in persons
with diabetes. However, trials with higher methodology quality using a well characterized fenugreek preparation of
sufficient dose are needed to provide more conclusive evidence.
Keywords: Fenugreek, Trigonella, Nutrition, Glycemia, Diabetes management, Clinical trials, Systematic review,
Meta-analysis
Introduction
The prevalence of diabetes mellitus is increasing world-
wide with approximately half of all persons with diabetes
living in Asia [1]. The herb fenugreek (Trigonella foenum-
graecum L., Fabaceae family) is used both in cooking and
for the treatment of diabetes in many parts of the world,
especially in China, Egypt, India and Middle Eastern
countries [2-4]. In low-income countries, individuals with
diabetes often do not have access to appropriate medica-
tions due to a lack of financial resources [5]. Active com-
pounds of fenugreek included soluble fiber [6-8], saponins
[9,10], trigonelle [11], diosgenin [12], and 4-hydroxyisoleucine
[13,14]. Hypoglycemic activities have mainly been attrib-
uted to dietary fiber [6,7] and saponin [9]. Fenugreek is a
widely used herbal medicine for diabetes, but its efficacy
for glycemic control remains unclear.
Animal studies have shown that fenugreek seed ex-
tracts have the potential to slow enzymatic digestion of
carbohydrates, reduce gastrointestinal absorption of glu-
cose, and thus reduce post-prandial glucose levels [8]. In
addition, fenugreek stimulated glucose uptake in periph-
eral tissues [15] and had insulinotropic properties in iso-
lated rat pancreatic cells [16]. In humans, fenugreek seeds
acutely reduced postprandial glucose and insulin levels
[17-20]. In addition, several longer-term clinical trials
showed reductions in fasting and post-prandial glucose
levels and glycated haemoglobin (HbA1c) [9,21-23], but
some trials did not show benefit [24,25]. Systematic re-
views that have evaluated the effect of various alternative
therapies for diabetes included only a few clinical trials of
fenugreek [26-29]. We therefore conducted a systematic
* Correspondence: nidhineel@gmail.com
1
Saw Swee Hock School of Public Health, National University of Singapore
and National University Health System, Singapore, Singapore
Full list of author information is available at the end of the article
© 2014 Neelakantan et al.; licensee BioMed Central Ltd. This is an open access article distributed under the terms of the
Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use,
distribution, and reproduction in any medium, provided the original work is properly cited.
Neelakantan et al. Nutrition Journal 2014, 13:7
http://www.nutritionj.com/content/13/1/7
review and meta-analysis of the effects of fenugreek on
glucose homeostasis based on a comprehensive literature
search leading to the identification of a reasonably large
number of trials with an evaluation of potential explana-
tions for differences in study results.
Methods
Data sources and searches
To identify articles on the effect of fenugreek on glucose
homeostasis we searched MEDLINE (PubMed), SCOPUS,
Web of Science, BIOSIS, and Cochrane Trials Registry
from inception through Nov 29, 2013 using key search
terms related to fenugreek (“fenugreek”,“trigonella”), an
experimental study design (“trial”,“clinical trial”,“inter-
vention”,“therapy”), to identify potentially relevant arti-
cles. The search strategy utilized both index terms and
free text to search for synonyms of trigonella, fenugreek
and diabetes/healthy subjects, and was limited to human
studies. Grey literature such as conference proceedings,
abstracts, dissertations and technical reports was identi-
fied using the same key terms through the electronic
search engines Google Scholar, SCIRUS, CINAHL, and
ProQuest. No language restriction was applied.
The results (titles, abstracts and citations) of elec-
tronic searches were downloaded into EndNote software
(EndNote X5, 2011, Thomson Reuters, Philadelphia) and
initial screening for eligibility was performed by two inde-
pendent reviewers (Nithya Neelakantan, Madanagopal
Narayanan). When assessment of eligibility based on the
title and abstract was insufficient, the full text of the arti-
cles was obtained. The second screening of those full text
articles was then independently performed by at least two
reviewers (Nithya Neelakantan, Madanagopal Narayanan,
Rob M van Dam). Disagreements were resolved by con-
sensus. The kappa for the inter-reviewer reliability was
0.78. Study authors were contacted to verify results and
methodological quality of retrieved articles where neces-
sary. We used the Preferred Reporting Items for System-
atic Reviews and Meta-Analysis (PRISMA) statement to
report our findings [30].
Study selection
We included clinical trials that compared single herb
preparations of fenugreek in any dose or form with a
control intervention that was either placebo or no treat-
ment and evaluated effects on markers of glycemia [fast-
ing blood glucose, 2 hr postload glucose, glycosylated
hemoglobin (% HbA1c) and/or fasting serum insulin
levels]. We excluded trials that used combination prepa-
rations of fenugreek with other herbs, non-human stud-
ies, observational studies, literature reviews/editorials/
letters/case reports, and articles not reporting the out-
comes of interest. We also excluded trials with interven-
tions that lasted less than 7 days. The number of articles
that did not meet the eligibility criteria and the reasons
for their exclusion are shown in Figure 1.
Data extraction and quality assessment
Details of trial design, study setting, population, ran-
domization, blinding, sample size, duration of follow-up,
participant characteristics, interventions, total daily dose
and outcome characteristics were independently extracted
by two reviewers (Nithya Neelakantan, Madanagopal
Narayanan), using a standardized data extraction form.
Differences in data extraction were resolved by a third re-
viewer (Rob M van Dam). The quality assessment was
conducted using the CONSORT statement for herbal trials
[31] by two reviewers (Nithya Neelakantan, Madanagopal
Narayanan), with disagreements resolved by consensus.
From each trial, data on mean and SD for all outcomes
of interest were extracted. If trials reported fasting blood
glucose and 2 hr postload glucose (glucose concentra-
tions 2 hours after the start of the oral glucose tolerance
test) in units of mg/dL, this was converted to the stan-
dardized international unit [32] of mmol/L by multiplying
the glucose values in mg/dL by 0.0555; for fasting serum
insulin, we divided the serum insulin values reported in
pmol/L by 6.945 and reported the results in mU/L.
Parallel trials generally reported the baseline mean and
standard deviation and follow-up mean and standard de-
viation, but not the standard deviation (SD) of change
for the intervention and control groups. For parallel tri-
als, the net changes in each outcome measure were cal-
culated as the change in the intervention group minus
the change in the control group. For crossover trials, net
changes in the outcome measures were calculated as the
value of the outcome measure at the end of the inter-
vention period minus the value of the outcome measure
at the end of control period. We estimated the SD of the
change on the basis of reported p values for differences
in means, if available [33]. We used the p-values cutoff if
it was only reported that a p-value was below a thresh-
old (e.g., 0.05 if p < 0.05 was reported) leading to conser-
vative estimates [34,35]. If p-values were not reported,
we imputed SD of the change by using a pooled correl-
ation coefficient between baseline and final measure-
ments from a meta-analysis of correlation coefficients
from those trials reporting sufficient data. We derived
correlation coefficients for individual trials according a
standard formula [33] and we then imputed these corre-
lations into the meta-analysis as transformed z scores
(±SEs) to estimate the pooled correlation coefficient
[36]. For HbA1c and fasting serum insulin measures, due
to small number of trials, we estimated the SDs of the
change assuming a conservative 0.5 correlation and per-
formed a sensitivity analysis assuming alternative values of
0.25 or 0.75. To investigate the effect of imputed within-
person correlation coefficients, we performed sensitivity
Neelakantan et al. Nutrition Journal 2014, 13:7 Page 2 of 11
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analyses with a range of correlation coefficients (0.25, 0.50
and 0.75) [37], the pooled estimates did not change
substantially.
Meta-analysis
The meta-analysis was performed according to the
methods described by Curtin et al. [38]. In the combined
design meta-analysis, the pooled estimate of treatment
effect combining parallel and crossover trial results was
the weighted sum of the separate treatment effects esti-
mated, respectively, from parallel and crossover trials
divided by the sum of the associated weights. We antici-
pated large differences in the fenugreek drug preparation
format, active components/chemical composition, ad-
ministration of supplements, and dosages as well as
variation in the study population and study design.
Therefore, we a priori decided to use a random effects
model for this meta-analysis. Hence, for each outcome
measure, weighted mean differences and corresponding
95% confidence intervals (CI) were calculated by using
DerSimonian and Laird random-effects models. We also
conducted separate meta-analyses for parallel and cross-
over trials for the primary outcome measures, fasting
blood glucose, and 2 hr post prandial glucose.
Heterogeneity in study results was tested by using the
Cochran Qstatistic (and associated p value), and was
quantified by the I
2
statistic. The I
2
provides an estimate
of the percentage of variation in study results that is ex-
plained by between-study heterogeneity rather than sam-
pling error [39]. Potential sources of heterogeneity were
investigated using a priori defined stratified analyses by
study design (parallel or crossover), daily dose of fenu-
greek extract (<5 g, 5–10 g or >10 g), study duration
(<30 days or > =30 days), randomization (yes or no),
blinding (yes or no), baseline BMI (<25 or > =25 kg/m
2
),
study precision (SE of the effect estimate above or below
the median), geographical region (India vs. other coun-
tries) and age (above or below the median mean age of
all studies).
Meta-regression analyses were used to assess the signifi-
cance of differences in the effects of fenugreek between
strata. p-values for the overall F-test for a common mean
161 Potentially relevant articles screened
38 Duplicates
199 Potentially relevant articles identified
32 full text articles assessed for eligibility
129 Excluded
75 Review, editorial or protocol
38 Did not study fenugreek as an
independent exposure or blood glucose
parameters as outcome measures
12 Cross-sectional study, survey
2 Patents (1 human study, 1 animal)
2 Non human studies (animal/cell line)
23 Excluded
10 Acute studies (<7 days)
6 Combination preparation of fenugreek
with other herbs
4 Inappropriate /no control group
2 Unrelated study outcomes
1 Short review
9 articles reporting 10 trials included in meta-
analysis
- 4 Parallel trials
- 6 Crossover trials
Figure 1 Selection of trials for meta-analysis. (Search was conducted to identify articles up to 29 Nov 2013).
Neelakantan et al. Nutrition Journal 2014, 13:7 Page 3 of 11
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amongst three or more groups were obtained using one
way ANOVA. Publication bias was investigated by visual
inspection of funnel plots and by the Egger regression test
and the Begg adjusted correlation test [40]. The robust-
ness of the findings of the meta-analysis to different as-
sumptions were examined in a sensitivity analysis using
both fixed and random effects models, in which the meta-
analysis estimates were computed omitting one trial at a
time to assess the influence of each individual trial [41].
All tests were two-sided and p <0.05 was considered sta-
tistically significant. The data were analyzed by using Stata
version 11 (StataCorp, College Station, Texas).
Results
Search results
We identified 161 potentially relevant articles and screened
the abstracts for eligibility. The flow of trial selection is re-
ported in Figure 1. We evaluated 32 full text articles in de-
tail. Nine articles reporting 10 trials met the inclusion
criteria for the meta-analysis. Of these 10 trials, one trial
[42] reported results separately for participants with mild
and severe type 2 diabetes, and thus 11 data points are
presented in Table 1. Five of these had a parallel design
and six had a crossover design.
Trial characteristics
The mean age of participants in the trials ranged from
22.0 to 54.4 years (median: 43.1 y), and the median
percentage of males was 76%. Most trials included par-
ticipants with type 2 diabetes treated with diet or oral
anti-diabetic medication (Table 1). One trial was con-
ducted in persons with type 1 diabetes and two trials in-
cluded overweight or non-overweight participants without
diabetes. The sample size ranged from 5 to 15 participants
for crossover trials and from 25 to 69 participants for par-
allel trials. The sample size for all trials combined was
278. The daily dose of fenugreek seed ranged from 1 g to
100 g (median: 25 g), and the study duration from 10 to
84 days (median: 30 days). Fenugreek supplements were
administered as powdered fenugreek seeds, debitterized
powdered fenugreek seeds, or hydro-alcoholic seed extract
either in form of capsules or as an ingredient of unleav-
ened bread. These were provided in equal doses 2 to 3
times per day. All 10 trials [7,9,17,22,23,25,42-44] (11 data
points) reported fasting blood glucose, 7 trials [7,9,17,22,
23,42,44] (8 data points) reported 2 hr glucose, 5 trials
[22,23,25,43,44] reported fasting serum insulin and 3 trials
[9,17,23] reported HbA1c. With regard to study quality,
one trial [42] did not report whether groups were random-
ized, none of the trials reported details on the method of
randomization or allocation concealment, and most trials
[7,17,22,42,44] did not report the blinding status. Only
four trials reported the percentage of drop-outs [17,23,25,43].
Of which three studies [23,25,43] have reported low
percentage drop-out ranging between 0 to 5% and one
study [17] has reported 25% drop-out. These subjects
were not included in the statistical analyses that were
conducted for the primary studies. Most trials provided
information on the concentration of components of the
used fenugreek preparations. Reported components in-
cluded diosgenine, saponins, trigonelline (1.4%) and 4-
hydroxyisoleucine (1.5%) for the hydro-alcoholic extract
[25,43]; alkaloids, carpaine, erythricine, trigonelline, mele-
tin, and saponins for powdered fenugreek seeds [22,44];
and lipids (0.1%), protein (28.3%), starch (6.5%), total
fiber (51.7% [gum 19.2%]) for debitterized fenugreek
seeds [22,44].
Effect on glucose homeostasis
Fasting blood glucose
All 10 trials (11 data points) were included in the meta-
analysis of fasting blood glucose. The individual trial
results and the pooled estimates by trial designs are
shown in Figure 2. Based on the overall pooled estimate,
fenugreek significantly reduced blood glucose levels as
compared with control treatments (pooled mean differ-
ence = -0.96 mmol/l; 95% CI: -1.52, -0.40; p = 0.001).
There was large heterogeneity in study results (I
2
= 80%;
p < 0.001). There were no significant differences in the
effects of fenugreek on fasting glucose by study design,
study duration, geographical region, mean age and mean
BMI of the study population (Table 2). However, the ef-
fect of fenugreek on fasting blood glucose differed sig-
nificantly by diabetes status with substantial effects in
persons with type 1 diabetes and type 2 diabetes, but not
in persons without diabetes. There was a large variation
in the dose of fenugreek used ranging from 1 g per day
to 100 g per day of fenugreek seeds. The effect size dif-
fered significantly by the dose of fenugreek used suggest-
ing no effects for the studies using low doses (<5 g/day)
and greater effects with higher doses of fenugreek. Ef-
fects of fenugreek on fasting glucose also differed by
preparation method of the fenugreek supplement. Stud-
ies using debitterized fenugreek powdered showed the
greatest reduction in glucose levels, but these were
mostly the same trials that administered the highest dose
of fenugreek. Similarly, the trials using a hydro-alcoholic
extract were the same trials that used the lowest dose.
Heterogeneity in effects on fasting glucose was partly ex-
plained by fenugreek dose (I
2residual
= 69%; adjusted R
2
=
47%), fenugreek preparation method (I
2residual
= 38%; ad-
justed R
2
= 83%), and diabetes status of the study popu-
lation (I
2residual
= 55%; adjusted R
2
= 61%).
The funnel plot for effects of fenugreek on fasting
blood glucose by study precision appeared to be asym-
metrical (Additional file 1: Figure S1, Begg test, p = 0.10)
and the Egger test was significant (p = 0.03) suggesting
potential publication bias. However, these tests are based
Neelakantan et al. Nutrition Journal 2014, 13:7 Page 4 of 11
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Table 1 Characteristics of the 10 trials (11 data points) included in the meta-analysis of the effects of fenugreek seeds on glycemia
Lead author, year and country Population,
medication
Design Age, y Male (%) Sample
size, N
Duration,
days
Fenugreek,
preparation
Daily
dose, g
Control Outcomes Study quality
RCT Blinding Dropout
Bordia et al., 1997 [42], India Mild T2DM, NR PL NR NR 40 30 Capsule, PS 5 Placebo FBG, 2 hr glucose NR NR NR
Bordia et al., 1997 [42], India Severe T2DM, NR PL NR NR 40 30 Capsule, PS 5 Placebo FBG, 2 hr glucose NR NR NR
Chevassus et al., 2010 [43], France Overweight, NR PL 38.0 100 40 42 Capsule, H 1.176 Placebo FBG, FSI Yes DB 5%
Gupta et al., 2001 [23], India T2DM, SU, BI PL 51.0 76 25 56 Capsule, H 1 Placebo FBG, 2 hr glucose,
HbA1c, FSI
Yes DB 4%
Lu et al., 2008 [9], China T2DM, SU PL 54.4 55 69 84 Capsule, PS 6.3 Placebo FBG, 2 hr glucose,
HbA1c
Yes DB NR
Alamdari et al., 2009 [17], Iran T2DM, Diet, OAD CO 43.1 100 12 56 PS 8 Unspecified FBG, 2 hr glucose,
HbA1c
Yes NR 25%
Chevassus et al., 2009 [25], France Healthy, NR CO 22.0 100 12 14 Capsule, H 1.176 Placebo FBG, FSI Yes DB 0%
Raghuram et al., 1994 [7], India T2DM, BI CO 46.6 NR 10 15 Chapati
a
, PS 25 Chapati FBG, 1 hr glucose,
HbA1c
Yes NR NR
Sharma et al., 1990 [44], India T1DM, Insulin therapy CO 22.7 70 10 10 Chapati
a
, DPS 100 Chapati FBG, 2 hr glucose, FSI Yes NR NR
Sharma et al., 1990 [22], India T2DM, BI/metformin CO 46.0 67 15 10 Chapati
a
, DPS 100 Chapati FBG, 2 hr glucose, FSI Yes NR NR
Sharma et al., 1990 [22], India T2DM, NR CO 42.0 NR 5 20 Chapati
a
, DPS 100 Chapati FBG, 2 hr glucose Yes NR NR
Abbreviations:NR not reported, T1DM type 1 diabetes mellitus, T2DM type 2 diabetes mellitus, SU sulfonylurea, BI biguanides, OAD oral antidiabetic drug, PL parallel, CO crossover trials, Daily dose, gfenugreek total
daily dose in grams, PS powdered fenugreek seeds, HHydro-alcoholic extract of fenugreek seeds, DPS Debitterized fenugreek seed powder, FBG fasting blood glucose, HbA1c % glycosylated hemoglobin, FSI fasting
serum insulin, RCT randomized control trial, DB double blinded,
a
Fenugreek incorporated into chapati (unleavened bread).
Neelakantan et al. Nutrition Journal 2014, 13:7 Page 5 of 11
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on detecting an association between study precision
(lower SE of effect estimates) and effect size. Less precise
studies also tended to use a greater dose of fenugreek
(r = 0.51 between dose and SE of the effect estimates)
and we could therefore not distinguish between poten-
tial publication bias and the dose of fenugreek used.
2 hr glucose
Seven trials (8 data points) reported effects of fenugreek
on 2 hr glucose values. Forest plots of 2 hr glucose ef-
fects in individual trials and the pooled analyses are
shown in Figure 3. Meta-analysis of the trials yielded a
pooled estimate for the effect of fenugreek on 2 hr glu-
cose of -2.19 mmol/l (95% CI: -3.19, -1.19, p <0.001).
There was large heterogeneity in study results (I
2
= 71%;
p = 0.001). Stratified analyses of effects of fenugreek on 2
hr glucose according to study characteristics are pre-
sented in Table 2. As observed for fasting glucose, a
higher dose was associated with greater effects on 2 hr
glucose concentrations. We also observed stronger ef-
fects for trials with study duration less than 30 days than
for trials with a longer duration and for trials that ad-
ministered debitterized fenugreek seed powder than for
trials using other fenugreek preparations. However, the
trials of short duration that used debitterized fenugreek
powder were the same three trials that administered a
substantially higher dose of fenugreek than the other tri-
als. Heterogeneity in effects of fenugreek on 2 hr glucose
was partly explained by fenugreek dose (I
2residual
= 42%;
adjusted R
2
= 72%) and fenugreek preparation method
(I
2residual
= 50%; adjusted R
2
= 61%). The funnel plot for 2
hr glucose data appeared to be asymmetrical (Additional
file 1: Figure S2, Begg test, p = 0.05) and the Egger test
(p = 0.03) also provided evidence for publication bias.
Again, less precise studies also tended to use a greater
dose of fenugreek (r = 0.54 between dose and SE of the
effect estimates) and we could not distinguish between
potential publication bias and the dose of fenugreek
used.
Other outcome measures (HbA1c and fasting serum insulin)
Three trials (2 parallel and 1 crossover trial) reported
the effects of fenugreek on HbA1c. Fenugreek signifi-
cantly reduced HbA1c values as compared with control
treatment (pooled mean difference -0.85%; 95% CI:
-1.49%, -0.22%, p = 0.009) (Additional file 1: Figure S3)
NOTE: Weights are from random effects analysis
.
.
Overall (I-squared = 80.1%, p = 0.000)
Parallel
Crossover
Sharma et al.(1990),T2DM-I
Subtotal (I-squared = 77.2%, p = 0.001)
Chevassus et al.(2009),Healthy
Gupta et al.(2001),T2DM
Sharma et al.(1990),T1DM
Lu et al.(2008),T2DM
Alamdari et al.(2009),T2DM
Study
ID
Bordia et al.(1997),Severe T2DM
Chevassus et al.(2010),Overweight
Subtotal (I-squared = 85.8%, p = 0.000)
Sharma et al.(1990),T2DM-II
Bordia et al.(1997),Mild T2DM
Raghuram et al.(1994),T2DM
-0.96 (-1.52, -0.40)
-2.32 (-4.44, -0.20)
-1.20 (-2.03, -0.38)
-0.20 (-0.38, -0.02)
-0.22 (-2.08, 1.64)
-4.20 (-6.73, -1.67)
-1.77 (-2.47, -1.07)
-0.84 (-1.58, -0.10)
ES (95% CI)
-0.82 (-2.10, 0.46)
0.38 (-0.08, 0.84)
-0.78 (-1.92, 0.37)
-2.27 (-3.88, -0.66)
-1.53 (-3.08, 0.02)
-0.54 (-1.52, 0.44)
100.00
4.79
52.68
15.03
5.66
3.71
12.29
12.01
%
Weight
8.47
13.86
47.32
6.75
7.05
10.39
-0.96 (-1.52, -0.40)
-2.32 (-4.44, -0.20)
-1.20 (-2.03, -0.38)
-0.20 (-0.38, -0.02)
-0.22 (-2.08, 1.64)
-4.20 (-6.73, -1.67)
-1.77 (-2.47, -1.07)
-0.84 (-1.58, -0.10)
ES (95% CI)
-0.82 (-2.10, 0.46)
0.38 (-0.08, 0.84)
-0.78 (-1.92, 0.37)
-2.27 (-3.88, -0.66)
-1.53 (-3.08, 0.02)
-0.54 (-1.52, 0.44)
100.00
4.79
52.68
15.03
5.66
3.71
12.29
12.01
%
Weight
8.47
13.86
47.32
6.75
7.05
10.39
favors fenu
g
reek favors control
0-7 -5 -3 -1 0 1 3
Figure 2 Forest plot of the effect of fenugreek on fasting blood glucose. The effects in individual trials are depicted as open squares with
95% confidence intervals (CIs). Pooled estimates with 95% CIs are depicted as open diamonds.
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Table 2 Stratified meta-analyses of the effects of fenugreek on fasting blood glucose and 2 hour postload glucose
according to trial and participant characteristics
Characteristics Fasting blood glucose 2 hr-postload glucose
n Pooled estimate I
2
(95% CI) P
hetr
P
EM
n Pooled estimate I
2
(95% CI) P
hetr
P
EM
Overall 11 −0.96 (−1.52, −0.40) 80 (65, 89) <0.001 8 −2.19 (−3.19, −1.19) 71 (40, 86) 0.001
Study design
Parallel 5 −0.78 (−1.93, 0.37) 86 (69, 94) <0.001 0.48 4 −1.71 (−2.73, −0.70) 59 (0, 86) 0.07 0.33
Crossover 6 −1.20 (−2.03, −0.38) 77 (49, 90) 0.01 4 −3.32 (−5.90, −0.75) 82 (54, 93) 0.001
Region
India 7 −1.43 (−2.26, −0.60) 48 (0, 78) 0.07 0.21 6 −2.60 (−4.06, −1.13) 73 (39, 88) 0.002 0.50
Others 4 −0.55 (−1.25, 0.16) 89 (75, 95) <0.001 2 −1.59 (−3.08, −0.10) 74 (0, 94)
Study precision
a
Below median 5 −0.54 (−1.15, 0.07) 86 (69, 94) <0.001 0.10 4 −1.55 (−2.52, −0.57) 67 (2, 89) 0.03 0.11
Above median 6 −1.68 (−2.62, −0.74) 43 (0, 77) 0.12 4 −3.42 (−5.56, −1.28) 67 (4, 89) 0.03
Study population
b
Healthy 2 0.05 (−0.51, 0.61) 82 (23, 96) 0.02 −− − −
T1DM 1 −4.20 (−6.73, −1.67) −−0.01 1 −3.20 (−6.92, 0.52) −−0.79
T2DM 8 −1.21 (−1.69, −0.73) 26 (0, 67) 0.22 7 −2.14 (−3.19, −1.09) 74 (45, 88) 0.001
Randomization
Yes 9 −0.94 (−1.56, −0.32) 83 (69, 91) <0.001 0.83 6 −2.54 (−3.87, −1.21) 73 (37, 88) 0.003 0.49
Unknown 2 −1.11 (−2.10, −0.12) 0 (0, 100) 0.49 2 −1.58 (−3.61, 0.45) 81 (17, 95) 0.02
Blinding status
Double-blinded 4 −0.44 (−1.22, 0.34) 88 (72, 95) <0.001 0.15 2 −1.95 (−3.02, −0.88) 16 (0, 55) 0.28 0.74
Unknown 7 −1.37 (−2.08, −0.67) 47 (0, 78) 0.08 6 −2.43 (−3.82, −1.04) 78 (50, 90) 0.000
Daily dose (grams)
b
<5 3 0.02 (−0.46, 0.50) 63 (0, 89) 0.07 1 −1.34 (−2.83, 0.14) −−
5-10 4 −1.27 (−1.80, −0.74) 21 (0, 88) 0.28 0.01 4 −1.55 (−2.52, −0.57) 67 (2, 89) 0.04 0.02
>10 4 −2.07 (−3.58, −0.55) 68 (9, 89) 0.02 3 −4.42 (−5.96, −2.89) 8 (0, 35) 0.58
Preparation
b
Powdered seed 5 −1.12 (−1.63, −0.61) 29 (0, 72) 0.23 4 −1.55 (−2.52, −0.57) 67 (2, 89) 0.03
Hydro-alcoholic extract 3 0.02 (−0.46, 0.50) 63 (0, 89) 0.07 0.002 1 −1.34 (−2.83, 0.14) −−0.05
Debitterized seed powder 3 −2.68 (−3.82, −1.54) 0 (0, 90) 0.42 3 −4.42 (−5.96, −2.89) 0 (0, 90) 0.58
Study duration (days)
<30 5 −1.48 (−2.64, −0.32) 80 (52, 91) 0.001 0.39 3 −4.42 (−5.96, −2.89) 8 (0, 35) 0.58 0.02
> = 30 6 −0.78 (−1.68, 0.11) 83 (65, 92) <0.001 5 −1.49 (−2.28, −0.70) 55 (0, 84) 0.06
Mean Age (years)
<43.1 4 −0.73 (−1.61, 0.16) 86 (67, 94) <0.001 2 −4.14 (−5.80, −2.47) 0 (0, 100) 0.58
> = 43.1 5 −1.11 (−1.76, −0.47) 45 (0, 80) 0.12 0.60 4 −1.90 (−3.19, −0.61) 67 (4, 89) 0.03 0.21
Mean BMI (kg/m
2
)
<25 3 −1.62 (−3.21, −0.02) 93 (82, 97) <0.001 0.29 2 −2.52 (−3.75, −1.30) 0 (0, 100) 0.71 0.17
> = 25 3 −0.19 (−1.14, 0.76) 74 (12, 92) 0.02 2 −1.01 (−1.72, −0.30) 0 (0, 100) 0.62
Abbreviations:BMI body mass index, CI confidence interval, P
hetr
p value for heterogeneity, P
EM
p value for effect modification.
a
The cutoffs are based on the median of standard error of the effect size for fasting blood glucose and 2hr glucose respectively; For mean age and study
duration, the cutoffs are based on the median values of 11 data points.
b
P
EM
-value for the overall F-test for a common mean amongst the three groups (i.e., study population, and fenugreek drug preparation format), the overall
p-value for daily dose was obtained by modeling this as a continuous variable in meta-regression analysi s.
Neelakantan et al. Nutrition Journal 2014, 13:7 Page 7 of 11
http://www.nutritionj.com/content/13/1/7
without significant heterogeneity in study results (I
2
=
0%; p = 0.78).
Five trials reported fasting serum insulin concentra-
tions. However, fasting insulin may have been affected
by exogenous insulin use in persons with type 1 diabetes
and fasting insulin values had a strongly skewed distri-
bution in persons with type 2 diabetes. Therefore, we
only included two trials [25,43] in persons without dia-
betes in our meta-analysis of the effects of fenugreek on
fasting insulin. The pooled effect of fenugreek on fasting
serum insulin was not statistically significant (pooled
mean difference= -1.42 mU/L; 95% CI: -3.04, 0.19 mU/L;
p = 0.08) (Additional file 1: Figure S4). Heterogeneity for
effects on fasting insulin was substantial, but not statisti-
cally significant (I
2
= 62%; p = 0.10). Subgroup analyses
were not performed for HbA1c and fasting serum insu-
lin because of the limited number of trials for these
outcomes.
Sensitivity analyses
We conducted a sensitivity analysis excluding the trial
that did not report randomization status. This exclusion
had little effect on the pooled effect on fasting blood
glucose (-0.94; 95% CI: -1.56, -0.32) or 2 hr glucose
(-2.54; 95% CI: -3.87, -1.21). We also conducted sensitiv-
ity analyses for the effects of fenugreek on fasting blood
glucose and 2 hr glucose concentrations omitting one
study at a time. None of the individual trials dramatically
influenced pooled effect estimates, which ranged from
-0.78 mmol/l (95% CI: -1.31, -0.25) to -1.20 (95% CI:
-1.85 to -0.56) for fasting blood glucose and from -1.79
mmol/l (95% CI: -2.69, -0.90) to -2.52 (95% CI: -3.64 to
-1.39) for 2 hr glucose. We also conducted sensitivity
analyses with simultaneous exclusion of trials conducted
by the same researchers. The three trials reported by
Sharma et al. [22,44] had a much larger dose of fenu-
greek than the other trials and also the lowest precision.
In a sensitivity analysis that excluded these trials, the
pooled effect on fasting blood glucose (-0.62 mmol/l,
95% CI: -1.14, -0.10) and 2 h glucose (-1.49 mmol/l, 95%
CI: -2.28, -0.70) remained statistically significant. We
also conducted a sensitivity analysis after excluding the
Chevassus trials ([25,43]) that were the only trials in per-
sons without diabetes, used a low dose, and had the lar-
gest precision. After exclusion of these studies, the
pooled effect estimate for fasting glucose was larger
(-1.35 mmol/L; 95% CI: -1.92, -0.74).
Adverse effects
Chevassus et al. reported 2 cases of specific urine smell
and 1 case of abdominal pain in one trial [25] and 4
cases of mild gastrointestinal symptoms, and 1 case of
NOTE: Weights are from random effects analysis
.
.
Overall (I-squared = 70.9%, p = 0.001)
Lu et al.(2008),T2DM
ID
Alamdari et al.(2009),T2DM
Crossover
Subtotal (I-squared = 58.5%, p = 0.065)
Study
Sharma et al.(1990),T2DM-I
Sharma et al.(1990),T1DM
Subtotal (I-squared = 82.1%, p = 0.001)
Gupta et al.(2001),T2DM
Bordia et al.(1997),Severe T2DM
Bordia et al.(1997),Mild T2DM
Parallel
Sharma et al.(1990),T2DM-II
-2.19 (-3.19, -1.19)
-2.44 (-3.74, -1.14)
ES (95% CI)
-0.91 (-1.72, -0.10)
-1.71 (-2.73, -0.70)
-6.10 (-10.12, -2.08)
-3.20 (-6.92, 0.52)
-3.32 (-5.90, -0.75)
-1.34 (-2.83, 0.14)
-0.61 (-1.67, 0.46)
-2.68 (-4.12, -1.24)
-4.37 (-6.23, -2.51)
100.00
15.13
Weight
17.93
60.01
%
4.77
5.35
39.99
14.06
16.54
14.29
11.95
-2.19 (-3.19, -1.19)
-2.44 (-3.74, -1.14)
ES (95% CI)
-0.91 (-1.72, -0.10)
-1.71 (-2.73, -0.70)
-6.10 (-10.12, -2.08)
-3.20 (-6.92, 0.52)
-3.32 (-5.90, -0.75)
-1.34 (-2.83, 0.14)
-0.61 (-1.67, 0.46)
-2.68 (-4.12, -1.24)
-4.37 (-6.23, -2.51)
100.00
15.13
Weight
17.93
60.01
%
4.77
5.35
39.99
14.06
16.54
14.29
11.95
favors fenu
g
reek favors control
0-11 -9 -7 -5 -3 -1 0 1 3
Figure 3 Forest plot of the effect of fenugreek on 2 hour postload glucose. The effects in individual trials are depicted as open squares
with 95% confidence intervals (CIs). Pooled estimates with 95% CIs are depicted as open diamonds.
Neelakantan et al. Nutrition Journal 2014, 13:7 Page 8 of 11
http://www.nutritionj.com/content/13/1/7
specific urine and sweat smell in both the treatment
group and the control group in their other trial [43]. Of
the 12 participants in the treatment group in the study
by Gupta et al. [23], 5 developed dyspepsia and mild ab-
dominal distention for the first few days of therapy. This
subsided on continuation of the therapy. No renal or
hepatic side effects were reported and there were no
withdrawals due to the side effects. Lu et al. [9] reported
that 2 out of 46 participants of the treated group suf-
fered from stomach discomfort and nausea, and one
from diarrhea during the treatment period. These symp-
toms disappeared after 2 day drug withdrawal without
special treatment. No adverse reaction was found after
the treatment resumed and all participants finished the
trial.
Discussion
In our meta-analysis of 10 clinical trials, intake of fenu-
greek seeds resulted in a significant reduction in fasting
blood glucose, 2 hr glucose, and HbA1c. However, we
observed substantial heterogeneity in study results. Dif-
ferences in the diabetes status of participants and the
large variation in dose of fenugreek seed extract used
and type of preparation appeared to be contributors to
variation in study results. No major harmful side effects
of fenugreek were reported in all included studies.
We only found a significant reduction in glucose pa-
rameters for trials that administered medium to high
doses (≥5 g) of fenugreek seed powder and not for trials
that administered low doses (< 2 g) of hydro-alcoholic
extracts. Medium to high doses (range: 5–25 g) of fenu-
greek seed powder also lowered postprandial glucose
levels in acute studies [6,18,19,21,45,46]. Lower doses, as
used in three of the trials in our meta-analyses, were not
evaluated in acute studies of fenugreek.
The mechanisms by which fenugreek may lower blood
glucose levels have not been well established in humans.
Acute hypoglycemic effects of fenugreek seeds and its
extract have been evaluated in individuals with and with-
out diabetes [18,22,44]. Whole fenugreek raw seeds,
extracted seed powder, cooked seeds (25 g) and gum iso-
late of seeds (5 g) decreased postprandial glucose levels,
whereas degummed seeds (25 g) showed little effect
[18]. These findings suggest that acute effects of fenu-
greek seeds are mainly due to the gum fraction, but do
not exclude a longer term effect of other fenugreek com-
ponents on glycemia. Animal studies also indicate that
the soluble fiber fraction of fenugreek seeds reduces the
rate of enzymatic digestion and the absorption of glu-
cose from the gastrointestinal tract [8]. However, data
from other studies suggest an effect of other fenugreek
components on glucose homeostasis. In diabetic rats, tri-
gonelline ingestion increased insulin sensitivity and re-
duced blood glucose levels [47]. In addition, a novel
amino acid derivative extracted from fenugreek seeds, 4-
hydroxyisoleucine, stimulated glucose-dependent insulin
release in isolated rat and human pancreatic islet cells
[14]. In a trial of acute effects in healthy volunteers, tri-
gonelline reduced the early glucose response during an
OGTT [48].
The only previous meta-analysis of the effects of fenu-
greek on glycemia included only two clinical trials as
compared with 10 in the current meta-analysis [26].
Strengths of our study included the comprehensive lit-
erature search leading to the identification of a reason-
ably large number of trials and a detailed analysis of
potential sources of heterogeneity in study results. Our
study also has several limitations that need to be consid-
ered in the interpretation of the results. First, the quality
of the included trials was generally poor. None of the tri-
als reported the methods of randomization or allocation
concealment, and only a few trials provided information
on blinding status and drop-out rates. In addition, with
some exceptions [9] it was unclear whether other dia-
betes medication remained constant during the trial.
Most of the included crossover trials did not test the
carryover effect or report a washout period. However,
we did not find a difference in results between parallel
and cross-over trials suggesting that carryover effects did
not substantially affect the results. Second, tests for pub-
lication bias suggested that such bias may have been
present. Tests for publication bias are based on detecting
differences in effect sizes by study precision with a
greater effect size for less precise (‘smaller’) studies sug-
gesting the presence of publication bias. In our meta-
analysis less precise studies were also more likely to use
larger doses of fenugreek. Differences in dose are thus a
possible alternative explanation for the observed ‘small
study effect’, but we were unable to distinguish between
the effects of dose and publication bias on effect sizes.
Finally, we only found a significant effect on glycemia
for powdered fenugreek seeds and our findings do not
apply to other forms of fenugreek and may differ for
other strains as a result of natural variation in active
ingredients.
Our systematic review and meta-analysis suggest that
fenugreek seeds may contribute to better glycemic con-
trol in persons with diabetes mellitus with a similar
magnitude of effect as intensive lifestyle [49] or other
pharmaceutical treatment added to standard treatment
[50]. Fenugreek is widely available at low cost and gener-
ally accepted in resource poor countries such as India
and China where a large proportion of persons with dia-
betes in the world reside. Therefore, fenugreek may be a
promising complementary option for the clinical man-
agement of diabetes. The previously reported lipid low-
ering effect of fenugreek may be an additional benefit
[19,44,51]. However, given the limited quality of the
Neelakantan et al. Nutrition Journal 2014, 13:7 Page 9 of 11
http://www.nutritionj.com/content/13/1/7
included trials and potential for publication bias, a larger
double blind randomized trial should be conducted ac-
cording to rigorous standards for herbal interventions
[31] with an appropriate randomization procedure, an
adequate method of allocation concealment and trans-
parent reporting of these methods. The fenugreek herbal
product must be standardized and tested for the com-
position and can be administered in the form of capsules
with a recommended dose of at least 5 g per day. In
order to provide more conclusive evidence on the bene-
fit of fenugreek for glucose homeostasis, a trial in at least
100 (50 subjects in each of the study arms) persons with
diabetes is warranted. The duration should preferably be
at least three months to be able to evaluate effects on
HbA1c levels and given the longer duration a parallel
trial appears most appropriate.
Additional file
Additional file 1: Figure S1. Funnel plot for effect of fenugreek on
fasting blood glucose. The solid line represents the pooled effect
estimate expressed as the weighted mean difference and the dashed
lines represent pseudo-95% confidence limits. Figure S2. Funnel plot for
effect of fenugreek on 2 hour postload glucose. The solid line represents
the pooled effect estimate expressed as the weighted mean difference
and the dashed lines represent pseudo-95% confidence limits. Figure S3.
Forest plot of the effect of fenugreek on HbA1c. The effects in individual
trials are depicted as open squares with 95% confidence intervals (CIs).
The pooled estimate with 95% CI is depicted as an open diamond.
Figure S4. Forest plot of the effect of fenugreek on fasting serum insulin.
The effects in individual trials are depicted as open squares with 95%
confidence intervals (CIs). Pooled estimate with 95% CI is depicted as an
open diamond.
Competing interest
The authors declare that they have no competing interest.
Authors’contributions
NN, MN and RMvD contributed to the conception and design of the study.
NN and MN conducted the literature search and data extraction. NN
performed the statistical analyses. NN and MN drafted the manuscript. RMvD
supervised the study. NN, RJD and RMvD contributed to the interpretation of
data and critically revised the manuscript for important intellectual content.
All authors gave final approval. NN and RMvD are the guarantors of this
work and, as such, had full access to all the data in the study and take
responsibility for the integrity of the data and the accuracy of the data
analysis.
Acknowledgements
This work was supported by Saw Swee Hock School of Public Health,
National University of Singapore.
Funding
Saw Swee Hock School of Public Health, National University of Singapore.
Author details
1
Saw Swee Hock School of Public Health, National University of Singapore
and National University Health System, Singapore, Singapore.
2
Department of
Medicine, Yong Loo Lin School of Medicine, National University of Singapore
and National University Health System, Singapore, Singapore.
3
Department of
Clinical Epidemiology & Biostatistics, McMaster University, Hamilton, ON,
Canada.
4
Clinical Nutrition and Risk Factor Modification Center, St. Michael’s
Hospital, Toronto, ON, Canada.
5
Department of Nutrition, Harvard School of
Public Health, Harvard University, Boston, MA, USA.
Received: 23 July 2013 Accepted: 16 January 2014
Published: 18 January 2014
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doi:10.1186/1475-2891-13-7
Cite this article as: Neelakantan et al.:Effect of fenugreek (Trigonella
foenum-graecum L.) intake on glycemia: a meta-analysis of clinical trials.
Nutrition Journal 2014 13:7.
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